>>> I'D LIKE TO CALL THE RAC BACK INTO SESSION. TO START, WHY DON'T WE ALL HAVE THE RAC MEMBERS INTRODUCE THEMSELVES. DANIELLE? LET ME START WITH THE FIRST INTRODUCTION OF THIS PERSON ON YOUR LEFT IS OUR AD HOC MEMBER. >> I'M VIJAY. >> WE HAVE A MORE FORMAL INTRODUCTION FOR YOU. ASSISTANT PROFESSOR OF MEDICAL CENTER HARVARD MEDICAL SCHOOL MASS GENERAL. RECEIVED HIS MEDICAL AND PH.D. IN CELLULAR AND MOLECULAR SCHOOL OF MEDICINE IN NEW YORK. POST GRADUATE MEDICAL TRAINING INCLUDED INTERNSHIP AT MASS GENERAL HOSPITAL HARVARD MEDICAL SCHOOL AND COMPLETED CLINICAL AND RESEARCH FELLOWSHIP AT MASS GENERAL. RESEARCH INTERESTS INCLUDE TREATMENT OF CROHN'S DISEASE AND ULCERATIVE COLITIS AND UNDERSTANDING INFLAMMATORY BOWEL DISEASE AND FOCUSES ON UNDERSTANDING CELL SIGNALING AND LYMPHOCYTES, TUMOR AND NORMAL EPITHELIAL CELLS OF THE GI TRACT. WELCOME AND THANK YOU FOR JOINING US. >> CHRISTINA ARANGIO FROM WAKE FOREST -- I'M DAVID AR NELLIES FROM WAKE FOREST UNIVERSITY. >> CANCER CENTER IN NEW YORK. >> UNIVERSITY OF ALABAMA AT BIRMINGHAM. >> TEMPLE UNIVERSITY IN PHILADELPHIA. >> FORM FOST, UNIVERSITY OF WISCONSIN MADISON. >> REBECCA DRESSER, WASHINGTON UNIVERSITY IN ST. LOUIS. >> ANGELA ON PATIENT ADVOCATE FROM GEORGIA UNIVERSITY. >> NEW FOLK MEDICAL CENTER IN SOUTHERN CALIFORNIA. >> DONALD KOHN UCLA. >> [ INDISCERNIBLE ] >> [ INDISCERNIBLE ] >> DON WILLIAM UNIVERSITY, DAYTON OHIO. >> A SO, SO NORTHWESTERN UNIVERSITY CHICAGO. >> WILL CURRY MASS GENERAL HOSPITAL. >> MARSHAL STROME, MOUNT SINAI HEALTH CARE SYSTEM, NEW YORK. >> DENISE, FDA. >> CHRISTINA BORE, OFFICE OF HUMAN RESEARCH PROTECTIONS. >> DO WE HAVE ANYONE JOINING US ON THE PHONE? >> JOSEPH PILEWSKI UNIVERSITY OF PITTSBURGH. OUR FIRST ORDER OF BUSINESS IS THE GENE TRANSFER SAFETY ADVISORY BOARD REPORT AND I WILL GIVE THAT IN THE FOURTH-QUARTER OF 2013, 29 PROTOCOL SUBMISSIONS. DISEASE INDICATIONS FOR THOSE NOT SELECTED FOR REVIEW INCLUDED 14 FOR CANCER, FOUR FOR MUSCLE DISORDERS, TWO FOR EYE DISORDERS AND ONE FOR HIV AND ONE FOR WOUND HEALING, AND SICKLE CELL DECEASE AND ALS. AND ONE USED A RETROVIRAL VECTOR SIX LENGTH R.ULENTEDY VIRUSES, FOUR AV AND TWO POXVIRUS AND 7 PLASMIDS AND ONE ATTENUATED SALMONELLA. TWO RNA TRANSFER AND ONE WAS ATTENUATED MEASLES VIRUS. WE RECEIVED SERIOUS ADVERSE EVENT REPORTS, 46 OF THEM WERE REVIEWED FROM 19 DIFFERENT PROTOCOLS INCLUDING INITIAL AND FOLLOW-UP REPORTS. NO EVENTS MIRRORED BEING DISCUSSED TODAY. INTERIMS OF NEW PROTOCOLS OPENING IN THE 40 QUARTER, WE RECEIVED THREE NOTIFICATIONS -- FOURTH-QUARTER, OF PROTOCOLS OPENED WITHIN THE LAST SIX MONTHS. ALL OF THOSE WERE PUBLICLY REVIEWED PROTOCOLS AND I'LL BRIEFLY DESCRIBE WHAT THEY WERE. SO THE FIRST ONE WAS ENTITLED TREATMENT OF SUBJECTS WITH ADA, SCID AFTER ADDITIONAL OF NORMAL EFS-ADA LENTE VIRAL VECTOR. RESPONSE FROM THE RAC, A STOPPING RULE HAS BEEN ADDED IN THE EVENTS OF A CLONAL EXPANSION AND THE OTHER RELATED WHETHER PATIENTS WITH THIS RELATIVELY RARE LOW-GRADE MALIGNANCY SEEN IN ADA PATIENTS SHOULD BE EXCLUDED. THE COMMENTS WERE, ALTHOUGH DETECTING MUTAGENESIS COULD BE COMPLICATED IN INDIVIDUALS WITH THIS FIBROSARCOMA, THESE CHILDREN WILL NOT BE EXCLUDED IF THEY ARE NOT CURRENTLY RECEIVING TREATMENT OR IF THE DFSP IS NOT EXPECTED TO BE LIFE LIMITING WITHIN 5 YEARS OF GENE TRANSFER. IT IS RARE IN THE GENERAL POPULATION AND MORE COMMON IN THOSE WITH ADASCID. NINE HAD DOCUMENTS NODULAR DFS. AND INCLUDING SOME WHO RECEIVED GENE THERAPY. DFSS A SLOW-GROWING TUMOR METAFT SIDES IN ABOUT 1% OF PATIENTS. THE SECOND PROTOCOL THAT OPENED WAS A PHASE I RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF A MULTIANTIGEN DNA VACCINE PRIME DELIVERED BY IN VIVO ELECT PRO OPERATION. RVSV BOOSTER VACCINE AND HIV INFECTED PATIENTS WHO BEGAN ANTI-RETROVIRAL THERAPY DURING ACUTE EARLY INFECTION OBA PROTOCOL 1214 REVIEWED IN JUNE OF 2013. AND IN RESPONSE TO THE RAC REVIEW, INFORMED CONSENT WAS MODIFIED TO EXPAND POTENTIAL RISKS ASSOCIATED WITH STRUCTURED TREATMENT INTERRUPTION TO MAKE IT CLEAR THERE MAY BE ALTERNATIVE TRIALS AVAILABLE TO THEM. AND THEN THE THIRD NEWLY OPENED PROTOCOL WAS INFUSION OF ALLOGENEIC THIRD PARTY CD19-SPECIFIC T-CELLS IN PATIENTS WITH REFRACTARY CD19B LINEAGE MALIGNANCIES, OBA PROTOCOL 1236 REVIEWED IN SEPTEMBER OF 2013. AND THE RESPONSES WERE: [ READING ] THE OTHER RESPONSE TO OUR COMMENT WAS: [ READING ] ANY QUESTIONS? OKAY. THEN, WE'LL GO TO THE FIRST PROTOCOL TO BE REVIEWED THIS MORNING, AND THAT IS, PROTOCOL 13 10-1263 TITLED: A PHASE 2A RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, SEQUENTIAL DOSE ESCALATION STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AG014 ADMINISTERED ORALLY IN SUBJECTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS PI: WILLIAM SANDBORN, M.D., UNIVERSITY OF CALIFORNIA SAN DIEGO, PROFESSOR OF MEDICINE AND CHIEF OF THE DIRECTION OF GASTROISHOLOGY AND DIRECTOR OF THE UNIVERSITY OF CALIFORNIA AND SAN DIEGO HEALTH SYSTEMS IN LAHOYA, CALIFORNIA AND THE SPONSORS ARE ACTOGENIX. >> MY NAME IS BERNARD COOLEY. THE COMPANY LOCATED IN BELGIUM AND DR. SANDBORN IS HERE AND HE WILL ALSO PRESENT PART OF THE PROTOCOL. SO THANK YOU. GOOD MORNING, EVERYBODY. SO, WE HAVE SPLIT OUR PRESENTATION IN FIVE DIFFERENT PARTS. I WILL GO THROUGH THE INTRODUCTION JUST TO HIGHLIGHT WHAT THE PRODUCT IS AND THE RATIONAL BEHIND THE DEVELOPMENT. DR. SANDBORN WILL DISCUSS THE PHASE II A PROTOCOL AND THE ANSWERS GIVEN. I WILL DISCUSS SOME OF THE SAFETY LEARNINGS FROM THE PAST BECAUSE WE WENT WITH THIS SAME TYPE OF PLATFORM ALREADY IN UC AND OTHER DISEASES AND THAT WAS A SPECIFIC REQUEST FROM THE RAC TO DISCUSS THAT. DR. ROTTIERS WILL DISCUSS A PHASE I PROTOCOL WE WERE ASKED TO PRESENT. IT WILL NOT BE EXECUTED IN THE U.S. BUT IT WILL BE IN EUROPE AND I THINK IT IS IMPORTANT AS PART OF THE OVERALL PACKAGE TO UNDERSTAND WHAT WE WILL DO THERE. AND WE WILL ALSO DISCUSS PRECLINICAL AND PRODUCT CHARACTERISTICS ALSO IN RESPONSE TO THE QUESTIONS THAT WERE RAISED. SO, THE RATIONAL FOR DEVELOPING AG014 IS BASED ON MUCOSAL DELIVERY AND NEUTRALIZATION OF TNF ALPHA. IT IS EXPRESSED IN THE GUT IN IBD PATIENTS, ONE OF THE DRIVERS OF THE DISEASE AND OF COURSE THERE ARE COMPONENTS ON THE MARKET USED TO TREAT PATIENTS NOTABLY TREAT DIFFERENT PATIENTS AT THE MOMENT THAT ARE BEING USED IN CROHN'S AND/OR ALSOATIVE COLITIS. ULCERATIVE COLITIS. WE HAVE SHOWED THAT L LACKTIS ADMINISTERED TO PATIENTS IS PRESENT IN INFLAMED GUT TISSUE. IF WE MODIFY THE L LACTIS TO EXPRESS AND SECREASE TNF ALPHA, WE CAN FIND IT AT THE SITE OF THE INFLAMMATION WITHIN THE GUT WALL OF THE COLON AND WE ALSO SHOW THAT THERE IS NO SYSTEMIC EXPOSURE TO ANTITFF ALPHA AND NO EVIDENCE FOR IMMINO GENISITY AND OVER ALL IMPROVED SAFETY PRO PILE WHEN COMPARED TO SYSTEMICALLY ADMINISTERED ANTI-TNF ALPHA. THE SUMMARY OVERVIEW OF THE PRODUCT ITSELF, ACTIVE PRINCIPLE IS IT'S AN ANTI-TNF ALPHA. FAB, ALSO KNOWN ON THE MARKET AS -- THAT'S THE MONOCLONAL FAT LOCALLY SECRETED BY L LACTIS. IT IS A FOOD-GRADE LACTIC ACID BACTERIA USED IN TERMITATION OF CHEESE. WE HAVE MADE THIS L LACTIS RESISTANT TO BILE IN CONDITIONS IN THE GI TRACT SO IT SURVIVES PASSAGE THROUGH THE GI TRACT. WE FORMULATED THESE BACTERIA AS A FREEZE-DRIED POWDNER A CAPSULE DESIGNED TO RELEASE JUST BEFORE ENTERING THE COLON. WE HAVE SHOWN IN PHARMACODYNAMIC STUDIES WITH THE SURROGATE STRAIN THAT IT IS EFFICACIOUS IN DIFFERENT COLITIS MOUSE MODELS. HUMAN ANTI-TNF ALPHA IS NOT CROSS REACTIVE WITH MOUSE TNF ALPHA SO WE CREATED A STRAIN THAT SECRETES A MOUSE TNF ALPHA IN ORDER TO SHOW THE EFFECT IN THE COLITIS MODELS. PHARMACOKINETICS STUDIES IS A MODEL SHOWING EXPOSURE TO PROTEIN AS WELL AS BACTERIA AT THE SITES NOTABLY IN COLON. WE DID A REPEAT DOSE TOXICITY STUDY DEMONSTRATED NO TREATMENT RELATEED TOXICITY, 6 WEEKS IN A COLITIS MODEL. ADDITIONAL MODELS DEMONSTRATED NOWAK REAMIA OR SEPSIS OR SHEDDING OF THE EXPRESS OF CASSETTES. NO JEAN TRANSFER. IT'S NOT TRULY GENE-GENE THERAPY. THE INSERT REMAINS WITHIN THE BACTERIA. AND ONCE THE BACTERIAL YUM DICE IT -- DIES IT IS GONE. -- [ BACKGROUND NOISE ] --ANDSCOPIC SAMPLING METHOLOGY TOW CHARACTERIZE THE PK OF OUR SUBJECT IN EUROPE AND WE WILL GIVE YOU THE DETAILS OF THAT PROTOCOL AS PART OF THIS PRESENTATION. SECONDLY, THAT IS OF COURSE TOPIC OF DISCUSSION TODAY, A PHASE II A RANDOMIZED MULTI-CENTER DOUBLE-BLINDED PLACEBO-CONTROLLED STUDY, SEQUENTIAL DOSE ESCALATION WITH PRIMARY ENDPOINT SAFETY AND TOLERABILITY. WE WILL LOOK AT PK AND AS WELL AS IN THE NEXT EXPLORATORY MANNER, MEASURE EFFICACY BY ENDSCOPIC CLINICAL SYMPTOMS AND MICROSCOPY. AND THIS IN PATIENTS WITH MODERATE TO SEVERE ALSOATIVE COLITIS. WE HAVE R. HAD A PREIND MEETING WITH THE FDA ON JUNE 13. AS WELL AS THE PROTOCOL. WE DISCUSSED THE CLINICAL PROTOCOL SYNOPSIS AT THAT TIME. BUT SOME OF THE DESIGNS AND ACTIONS TAKEN WERE DRIVEN BY THE FEEDBACK FROM THE FDA. SO WITH THAT, I WILL LEAVE THE FLOOR TO BILL WHO WILL DISCUSS THE PHASE II PROTOCOL AS WELL AS THE QUESTIONS THAT WERE RAISED. >> GOOD MORNING. THANK YOU. SO THIS IS A CONVENTIONAL STRAIGHTFORWARD INDUCTION STUDY FOR ULCERATIVE COLITIS SO WE THINK OF TRIALS AS INDUCTION OF REMISSION AND RESPONSE OR MAINTENANCE OF REMISSION. INDUCTION TRIALS TEND TO BE 6-8 WEEKS IN DURATION. SO THIS IS AN ASCENDING DOSE ESCALATION STUDY. THREE COHORTS RANDOMIZATION 2-1 OF THE ACTIVE PLACEBO WITHIN EACH COHORT AND THE TRIAL DURATION IS 6 WEEKS. THERE IS ENDOSCOPY AT THE BEGINNING AS WELL AS AS AT THE END OF THE STUDY AND WE KNOW FROM OTHER ACTIVE AGENTS YOU CAN SEE CHANGES IN ENDOSCOPY AS WELL AS CLINICAL SYMPTOMS OVER A 6 WEEK PERIOD AND MOST OF THE PROOF DRUGS ARE 6-8 WEEK CLINICAL TRIAL DESIGN. YOU CAN SEE THE DOSING STRATEGIES ON THE FAR RIGHT AND THE STRATEGY IS TO DO A STAGGERED APPROACH SO IN EACH COHORT EVERY SINGLE SUBJECT OF THE FIRST SIX WILL BE DOSED FOR SEVEN DAYS CONSECUTIVELY BEFORE THE NEXT SUBJECT CAN BE DOSED. NOT MORE THAN ONE SUBJECT STARTS ON A GIVEN DAY SO THAT IF ANYTHING UNEXPECTED WERE TO HAPPEN AND YOU WILL HEAR MORE ABOUT PREVIOUS EXPERIENCE WITH THIS DELIVERY MECHANISM, BUT YOU'RE NOT HAVING TOO MANY PATIENTS STAGGERED OR COMING ON ALL AT ONCE. SOME OF THE QUESTIONS THAT CAME UP INCLUSION AND EXCLUSION CRITERIA SO THIS IS ADULTS ONLY 18 YEARS OR MORE. THE MAYO CLINIC STORE IS A COMPOSITE INSTRUMENT THAT MEASURES STOOL FREQUENCY, RECTAL BLOODING, ENDOSCOPY FINDINGS AND A PHYSICIAN GLOBAL ASSESSMENT THAT RANGEES FROM ZERO-12 AND THE LABELED PRODUCTS FOR MODERATE DISEASE ANTI-TNF BIOLOGICS RECRUITED SUBJECTS WITH MAYO SCORES OF 6-12. SO THAT TRACKS WITH WHAT WE ARE DOING. THE MAYO SCORE IN THAT RANGE INTERFERES WITH QUALITY OF LIFE FOR SURE FOR THE PATIENTS AND AGAIN THE PATIENTS THAT WILL BE RECRUITED LOOK VERY MUCH LIKE THE PATIENTS THAT WERE RECRUITED FOR ALL THE PIVOTAL STUDIES OF THE THREE APPROVED ANTITNF BIOLOGICS FOR ULCERATIVE COLITIS. WE SHOULD ACKNOWLEDGE THAT SURGERY IS A TREATMENT FOR ULCERATIVE COLITIS. I THINK IT IS PROBABLY NOT QUITE RIGHT TO CHARACTERIZE IT AS A CURE. THE AVERAGE PATIENT WILL HAVE SIX STOOLS DURING THE DAY AND ONE AT NIGHT AND OF COURSE HALF OF THE PATIENTS ARE ABOVE AVERAGE. THERE IS A SUBSTANTIAL RATE OF FEMALE INFERTILITY IN WOMEN OF CHILD BEARING AGE AND A LOT OF COMPLICATIONS THAT CAN COME FROM THE SURGERY. IF YOU REALLY NEED SURGERY, IT IS THE POUCHES ARE A GOOD ALTERNATIVE TO -- BUT THEY COME WITH A LOT OF BAGGAGE. SO, HAVING MEDICAL THERAPY ALTERNATIVES, I THINK BOTH PHYSICIANS AND PATIENTS ARE REALLY LOOKING FOR THAT. FROM A STOPPING RULE, PERSPECTIVE, OF COURSE WE ARE MONITORING FOR CLINICAL SEPS SIS. I MUST SAY IN THE REAL WORLD IN CLINICAL PRACTICE, PATIENTS ARE TAKING PROBIOTICS ALL THE TIME. AND SEPS SIS FROM THE PROBIOTICS ESSENTIALLY DOESN'T OCCUR IN THE SETTING OF SYSTEMIC ANTI-TNF IF WE HAVE A BLOOD CULTURE YOU CAN TRACK BACK TO THE PRODUCT BY PCR, WE CAN STOP THE STUDY AND IF YOU HAVE BACTEREMIA THAT IS LIKELY RELATED BUT WASN'T NAILED BY THE PCRF WE SAW THAT WITH THREE CONSECUTIVE BLOOD CULTURES WE WOULD STOP. FROM A CONCOMITANT MEDICATION PERSPECTIVE, WHAT IS DONE WITH THE SYSTEMIC ANTI-TNF BIOLOGICS IS TO ALLOW VARIOUS, ESSENTIAL TOW ALLOW STANDARD OF CARE THERAPY IN THE BACKGROUND SO THAT CAN INCLUDE FIVE AMINO PRODUCTS. WE WILL ALLOW THAT AS WELL. STEROID DOSES WE ARE CAPPING AT 20 MILLIGRAMS PER DAY OR LESS OF PREDNISONE AND THEN WE WANT THAT TO BE STABLE SO THE PATIENTS WOULD BE ON FOR FOUR WEEKS WITH THE STABLE DOSE OF AT LEAST TWO WEEKS PRIOR TO SCREENING AND THEN FOR THE RELATIVELY SHORT SIX WEEK INDUCTION STUDY WE WOULD FIX THE STEROID DOSE OF WHATEVER THEY CAME IN ON TO AVOID CONFOUNDING EFFECTS AND THIS IS VERY STANDARD METHODOLOGY THAT HAS BEEN USED IN THE TRIALS AND THE OTHER DRUGS THAT ARE AVAILABLE CURRENTLY. AND THERE IS ALSO -- A STEROID WITH THE HIGH FIRST PASS HEPATIC METABOLISM AND MMX IS A POLYMER DELIVERY SYSTEM THAT DELIVERS TO THE COLON. SO ORAL IS A TOPICAL STEROID FOR THE COLON WITH LITTLE SYSTEMIC EFFECTS. THAT WOULD BE AN APPROVED PRODUCT NOW SO THAT WOULD BE PERMITTED AS WELL. WE WILL NOT ALLOW PATIENTS TO RECEIVE SYSTEMIC ANTITNF THERAPY SO WE ARE LOOKING AT THIS AS A STAND ALONE TOPICAL ANTITNF THERAPY TO THE GUT LUMEN AND GUT WALL ALONG THE LINES OF WHAT DR. COULEE EXPLAINED JUST A FEW MINUTES AGO. CERTAINLY WE WOULDN'T ALLOW PATIENTS TO GET THIS PEG LATED VERSION OF. [ INDISCERNIBLE ] IN THE TRIAL. THE OUTCOME -- THERE WAS A QUESTION OF WHETHER THERE IS A CLINICAL TRIAL EVALUATING SEMSIA FOR IBD THAT WOULD BE DUE IN 2013 THERE IS NO TRIAL GOING ON IN ULCERATIVE COLITIS. A FEW YEARS AGO AN ABSTRACT HAD BEEN TREATED OFF LABEL FOR ULCERATIVE COLITIS IN A CLINICAL OBSERVATION SETTING BUT THEIR NO CLINICAL TRIALS RUNNING WITH ULCERATIVE COLITIS. IT'S APPROVED IN THE U.S. FOR CROHN'S DISEASE AND SO THAT IS REALLY WHERE THE USE IS. SO, EXCEPT FOR THE FACT THAT THE BLAZE MAB CONSTRUCT IS THE SAME FOR HE014 AND FOR SEMSIA, IT IS OTHERWISE A COMPLETELY DIFFERENT PRODUCT PROFILE, THE FORMULATION, DRUG SUBSTANCE, ORAL ADMINISTRATION, THE DOSING FREQUENCY, THE FACT THAT WE ARE DELIVERING IT LOCALLY, WE'LL HAVE A DIFFERENT PK PROFILE AND EVERYTHING IS COMPLETELY DIFFERENT FROM PEG LATED SYSTEMIC SEPSIA. SMART OTHER THINGS THAT CAME UP IN THE REVIEW, WE PLAN TO ADAPT THE PROTOCOL TO INCLUDE SERUM PREGNANCY TESTING, ONLY THIS IS AN EARLY AND VERY SHORT SIX-WEEK TRIAL. SO WE DIDN'T FEEL THAT PSYCHOLOGIC SUPPORT AND LONG TERM FOLLOW-UP WOULD BE USEFUL. IT'S NOT TYPICAL OF EARLY-PHASE TRIALS IN THIS THERAPEUTIC AREA. AGAIN, EVALUATION OF HOME ENVIRONMENT FOR AN EARLY PHASE STUDY, WE DIDN'T THINK IT WOULD BE VERY USEFUL. WE WILL BE COLLECTING BLOOD, COLON, BIOPSY AND FECAL SAMPLES, AND WE PLAN A BROAD RANGE OF BIOMARKER ANALYSIS. THE INFORMED CONSENT WILL BE DISCUSSED EXTENSIVELY AND WILL BE SHARING ALL OF THAT WITH THE RAC OVER TIME. AND WITH THAT, I'LL STOP AND HAND IT BACK TO BERNARD WHO WILL DISCUSS IN DETAIL SOME OF THE PAST HISTORY WITH THE DELIVERY SYSTEM FOR SAFETY. >> THANK YOU, BILL. SO, AS WE DID A UC TRIAL, SO A TRIAL IN ULCERATIVE COLITIS IN THE PAST IN EUROPE, BUT WHICH WAS DISCUSSED AT THE RAC, WE DECIDED AFTERWARDS NOT TO DO IT IN THE U.S. BECAUSE THE FDA REQUESTED US FOR TO DO SOME FUNDAMENTAL PROTOCOL CHANGES AND BY THAT TIME IT ALREADY HAD STARTED IN EUROPE. THE RAC ASKED US TO GIVE THE SAFETY FEEDBACK OR INFORMATION COMING OUT OF THAT TRIAL BECAUSE IT'S OF COURSE RELEVANT TO WHAT WE ARE DISCUSSING TODAY. AND ALSO WHAT I WILL GIVE IS THE SAFETY SUMMARY OF AG013, A DIFFERENT PRODUCT DEVELOPED AND CANCER PATIENTS RECEIVED TRIPLE CHEMOTHERAPY. IT WAS DISCUSSED AT THE RAC A COUPLE OF YEARS AGO AND THE STUDY WAS CONDUCTED IN THE U.S. SO THAT KIND OF SAFETY INFORMATION IS AVAILABLE, OF COURSE TO THE RAC. COMING BACK TO AG011, WHICH WAS AGAIN SAME PLATFORM, NOT SECRETING ANTI-TNF BUT ANTIFLAMTORY CYTOKINE INTERLEUKIN 10, TESTED IN A PROTOCOL QUITE SIMILAR TO WHAT WE ARE DISCUSSING TODAY WITH THE EXCEPTION THAT WE DIDN'T HAVE A STAGGERED APPROACH THEN AND SECONDLY, WE COMBINED IT WITH RECTAL ADMINISTRATION SO IT WAS ORAL, PILLS AND RECTAL EN MA ADMINISTRATION OF THAT SAME BACTERIA. OVER ALL, THE PRODUCT WAS GENERALLY SAFE AND WELL TOLERATED. THE MOST FREQUENTLY REPORTED EVENT WAS COLITIS. THERE WERE ASSAYS REPORTED IN THREE PATIENTS UNDER ACTIVE AND TWO PATIENTS THAT WERE PLACEBO TREATED. THE SAEs WERE ALL RELATED TO WORSENING OF COLITIS IN THE PLACEBO OF THE TWO ONE WORSENING OF COLITIS AND SECONDARY ANEMIA AND ONE WAS A THROMBOSOMESEMIA. NO CHANGING IN THE LAB RESULTS. NO SYSTEMIC EXPOSURE TO HUMAN IL10 AND NO HUMAN GEISITY. SO HUMAN IL10 WAS DISTRESSED AT THAT TIME. FOR 13, GENERALLY, SAFE AND WELL TOLERATED. PROFILE SIMILAR TO PLACEBO. HERE YOU HAVE A LIST OF THE MOST FREQUENTLY REPORTED EVENTS IN THE PHASE I B. FOUR SUBJECTS EXPERIENCED SAEs NOT ATTRIBUTED TO PHASE 1B AND I THAT ARE MENTIONED HERE. THERE WAS NO SEPSIS. NO CLINICALLY RELEVANT CHANGES IN LAB RESULTS AND NO SYSTEMIC EXPOSURE TO BACTERIA OR -- SO HUMAN FACTOR 1 WAS THE PROTEIN EXPRESSED FOR THIS SPECIFIC PRODUCT. FOR YOUR INFORMATION IT IS A MUCOSAL REPAIR FACTOR THAT RESTORES THE MUCOSAL INTEGRITY IN THIS ORAL PATIENT POPULATION. SO COMING BACK TO THE WORSENING OF CLUESIT, THAT WAS A SIGNAL THAT WAS CLEAR -- COLITIS WITHIN THE PATIENT POPULATION. RECEIVING L LACTIS. SO THERE WAS A TREND TOWARDS INCREASED NUMBER OF AEs LABELED AS WORSENING OF COLITIS IN THE ACTIVE VERSUS PLACEBO. WHEN WE ANALYZED DATA FURTHER, WE FOUND OUT THAT 50% OF THESE AEs WERE CLASSIFIED AS UNLIKELY OR NOT RELATED TO STUDY MEDICATION IN THE FIRST PLACE. AND THERE WAS NO DOSE DEPENDENCY. SO THE PATIENTS RECEIVED THREE DOSE LEVELS. COMBINED WITH RECTAL ADMINISTRATION AND THE WORSENING OF COLITIS WAS NOT DOSE DEPENDENT. ALSO, OF THOSE PATIENTS THAT COULD BE ANALYZED AND THOSE DATA ARE IN THE INFORMATION PACKAGE, THAT COULD BE ANALYZED OR COULD BE EVALUATED WHEN THEY KIND OF STEPPED OUT OF THE STUDY BECAUSE OF WORSENING OF COLITIS AND IT WAS REPORTED, WE SAW THAT THERE WAS NO INCREASE IN THE ENDSCOPIC COLITIS SCORES OR NO INCREASE IN HISTOLOGICAL COLITIS SCORES. STOW COULDN'T BE SUBSTANTIATED BY OBJECTIVE MEASURES OF WORSENING OF COLITIS. SO IT WAS A PATIENT-REPORTED AE OR EVENT. AND SO IN THE BACKUP SLIDES, YOU SEE THE DETAILS ON THE PATIENTS. WE ARE AWARE OF THIS AND WE WILL KEEP THIS AS ONE OF THE END 90s WE WILL BE MEASURED. WE HAVE THE STAGGERED APPROACH AND THE DSNB IN BETWEEN, SO WE WILL BE BLINDED BUT THAT IS SOMETHING THAT NEEDS TO BE FOLLOWED UP. A LAST WORD, WORSENING OF COLITIS, THIS IS IMPORTANT ALSO TO KNOW THAT THE PRODUCT DIDN'T WORK. SO AG011 DIDN'T WORK. AND THE REASON FOR THAT WAS A PHARMACOKINETIC REASON WHICH HAS BEEN SOLVED. SO THERE WAS ACTUALLY HEARTY EXPOSURE TO THE PROCT DID. THESE PATIENTS WERE RECRUITED IN ACTIVE PHASE OF DISEASE, THE REASON THEY CAME TO THE PHYSICIAN AND THEY ARE HAVING ACTIVE COLITIS UNDER STANDARD CARE. UNDER STANDARD TREATMENT. THAT MEANS THAT THEY WERE IN THE PHASE OF WORSENING OF COLITIS ANYWAY AND IF THE PRODUCT DOESN'T WORK, OF COURSE YOU SEE THIS HAPPENING. THE NUMBERS WERE LOW. NOW THE LOW NUMBER OF PLACEBO PATIENTS IT WAS 2-1 RANDOMIZATION AND THAT PLAYED A ROLE, I THINK. SO, I THINK THAT COVERS THIS SPECIFIC TOPIC. SO PETER WILL DISCUSS PHASE I HEALTHY VOLUNTEER STUDY PACKING -- TAKING PLACE IN EUROPE APRIL AND MAY SO WE WILL DO THAT STUDY BEFORE WE START THE PHASE 2A IN THE U.S. OKAY. SO I WILL BRIEFLY DESCRIBE THE DESIGN OF THE STUDY I ALREADY MENTIONED IT WAS PERFORMED IN EUROPE AND PERFORMED BEFORE THE PHASE 2A STUDY. SO IT WILL BE A SINGLE CENTER OPEN LABEL STUDY. IT WILL BE CONDUCTED IN 16 HEALTHY SUBJECTS AND WE HAVE TO MAIN OBJECTIVES. THE FIRST IS SAFETY. IT WILL NOT BE A CLASSICAL DOSE ESCALATION STUDY. WE WILL DEMONSTRATE SAFETY USING HIGHEST DOSE SELECTED FOR THE PHASE 2A STUDY. AND A SECOND OBJECTIVE IS PHARMACOKINETICS OF AG14 SO WE WILL DEMONSTRATE THE PRESENCE OF BACTERIA AND THE PROTEIN SECRETED END BLOTS IN STOOL AS WELL AS RELATED TO THE LATTER ONE IS WE WOULD ASSESS ENDSCOPIC SAMPLING METHODOLOGY TO SAMPLE BIOPSIES IN THE CONTENT AND DIFFERENT PARTS OF THE COLON IN ORDER TO ASSESS THE PK PROFILE IN THE ENTIRE COLON. SO IT WILL BE A STUDY, SO THE FIRST TIER WE WILL ASSESS SAFETY AND PKAG14 ONLY ADMINISTERED ONCE. SO FOUR CAPSULES IN THE MORNING ONLY ONCE. SO THIS IS A TOTAL DOSE OF 4 TIMES 10 TO THE 11th AND WE WILL COLLECT BLOT AS WELL AS FECES STUDY FROM INP DOSE UP TO 4-5 DOSE POST DOSING AND ASSESS THE BACTERIA PROTEIN END BLOT AS A SAFETY ASSESSMENT AND FECES FOR PK PROFILING AND THE SECOND WE WILL USE THE SAME SUBJECTS AND DOSE THE PATIENTS ONLY AGAIN FOR FOUR DAYS AND SO THE INP DOSING WILL BE FOUR CAPSULES TWICE DAILY AND SO FOUR IN THE MORNING AND FOUR IN THE EVENING AND THIS WILL TREAT AND WILL END UP WITH A TOTAL DOSE OF 8 TIMES 10 TO THE 11 WHICH CORRESPONDS TO THE HIGH DOSE THAT WE WILL APPLY IN THE PHASE II A STUDY. AND THEN ON THE FOURTH DAY AN ADDITIONAL DOSING OF FOUR CAPSULES AND THEN DEPENDING ON THE OUTCOME OF THE PK STUDY THE FIRST WILL DETERMINE THE OPTIMAL TIMING FOR PERFORMING ENDOSCOPE WHICH WILL -- RESIDING IN THE COLON. SO THE NEXT SLIDE IS MORE LABELED TO SOME OF THE QUESTIONS THAT WERE RAISED DURING THE PACKAGE OF AG14 SO I LISTED SOME COMMENTS RELATED TO THE QUESTIONS. WE ONLY HAVE DEMONSTRATED -- WITH THE SURROGATE STRAIN AND NOT AG14 COLITIS MODEL AND THE REASON IS QUITE SIMPLE. NO HUMANIZED COLITIS AVAILABLE TO DO AN ASSESSMENT IN COLITIS. THE SECOND IS RELATED TO THE FACT THAT WE PERFORMED NONGLP STUDIES IN THE COLITIS MODEL AND THE QUESTION WAS, IS THE FDA AND EMA AWARE OF THAT? AND THE ANSWER IS, YES, WE ARE. -- TO CONTACT THE TOX STUDIES USING A SURROGATE IN THE MOUSE COLITIS ACKNOWLEDGED BY THE FDA AND ALSO WE CANNOT PERFORM THAT IN THE STRICTLY GLP CONDITIONS AND ALSO ACKNOWLEDGED BY THE EMA AND THE FDA. SO, DURING WHEN WE SUBMITTED THE DATA, THE PACKAGE FOR THE RAC REVIEW, THERE WAS STILL SOME DATA MISSING WITH RESPECT TO THE SAFETY PHARMACOLOGY AND SO THOSE DATA ARE AVAILABLE AND THOSE ARE RELATED TO TWO STUDIES. THE FIRST WAS WE WANT TO ASSESS THE RISK FOR POTENTIAL OF THE THEORETICAL POSSIBILITY THAT THE TRANSFERS FROM THE BACTERIA TO THE HOST CELLS AND THOSE DATA CONFIRMS THIS IS NOT THE CASE AND STOW THAT WE HAVE NO EVIDENCE OF SHEDDING OF THE EXPRESSION CASSETTE AFTER ORAL ADMINISTRATION IN ANIMALS. THERE IS NO RISK FOR ACCUMULATION OF THE EXPRESSION IN THOSE TISSUES PREDISPOSED FOR THE ADMINISTRATION. AND THE SECOND STUDY WAS RELATED TO THE FACT THAT WE ASSESSED THE RISK FOR POTENTIAL SYSTEMIC INFECTION, THE WORST CASE SCENARIO AND THE BLOOD STREAM DURING TREATMENT AND SO WE MIMIC THAT AND WE DEMONSTRATED THAT AFTER IV ADMINISTRATION AND CLITIC MICE, THERE IS NO EVIDENCE WHATSOEVER FOR SEPSIS AND CONFIRM THE BACTERIA CANNOT SURVIVE IN THE SYSTEM IN THE PERIPHERY. THERE WAS ONE QUESTION RELATED TO THE FACT HOW SURE ARE WE THAT IT IS SECRETED AND IS CORRECTLY ASSEMBLED AND COMFORT THEM THAT THIS IS THE CASE BECAUSE WE HAVE SHOWN SECRETED DISPLACED FULLY BIOLOGICAL ACTIVITY AND SHOULD COMPARE IT WITH SEMSIA (?) [ INDISCERNIBLE ] NEUTRALIZATION CAPACITY AND REQUIRES BINDING OF TNF AND BINDING REQUIRES ASSEMBLY OF THE CHAIN. SO WE ARE CONFIDENT THAT THE FACT THAT IT IS SECRETED BY LACKTIS IS CORRECTLY ASSEMBLED AND THE LAST COMMENT WAS RELATED TO THE FACT, WHAT IS THE MODE OF ACTION? HOW IS THE INTESTINE DELIVERED ANTIBODY AT CONTROLLING ON NEUTRALIZING TNF, MAINLY EXPRESSED IN THE LAMINA? AND THE ANSWER COMES FROM STUDIES WE PERFORMED WITH A SURROGATE IN COLITIS MODELS AND THAT WE HAVE EVIDENCE THAT THE BACTERIA GOT TRAPPED AND INFLAMED TISSUE. SO WHAT YOU SEE HERE IS ELECTRONIC MICROSCOPIC VISUALIZATION OF INFLAMED GUT FROM COLITIS MICE. WHAT YOU SEE ARE THEAND ROW SITES. THESE ARE LAMINA PROPPIAY SO YOU SEE THAT HERE AS THE LUMEN PART. AND SO YOU SEE THAT MARKED HERE WITH THE ARROW THAT ARE EMBEDDED IN THE LAMINA PROPPIA. AND YOU ONLY SEE THAT IN THOSE REGIONS WHERE YOU HAVE ERODED ZONES AND DISTURBED BARRIER. SO MEANING THAT INDICATING THAT THE BACTERIA CAN TRANSFER TO THE LUNG PROPPIA. AND WE KNOW THAT THESE ARE VIABLE BASED ON HISTORIES. AND ON TOP OF THAT, WE COULD DEMONSTRATE THAT THOSE BACTERIA ARE ACTIVELY DELIVERING THE PROTEIN AND THIS IS DEMONSTRATED IN THIS FIGURE HERE, HISTOCHEMISTRY STAINING OF ANTI-TNF AND YOU NOTICE IT IS EXPRESSED WITHIN THE LAMINA PROPPIA ASSOCIATED WITH THE SURFACE OF THE LAMINA PROPPIA CELLS, MOST LIKELY TNF MACROPHAGES OR ACTIVATED T-CELLS SO WE DELIVERED THE ANTI-TNF ON THE SITE WE NEED TO HAVE PENETRATION OF THE TNF. SO THIS IS HOW WE BELIEVE AND WHY WE BELIEVE THAT THIS WORKS REALLY EFFICIENT AND THAT YOU DON'T NEED HIGH AMOUNTS OF ANTI-TNF. THIS SLIDE I WILL HAND OVER TO MY COLLEAGUE. >> IN RESPONSE TO THE QUESTION, WHAT CONTAINMENT PLAN WE HAVE IN PLACE, WE WOULD LIKE TO ELABORATE THE FOLLOWING: THAT ALL SPILLAGE WE HAVE INDICATED THAT ALL SPILLAGE OF THE PRODUCT CAN EASILY DECONTAMINATED WITH DETERNAL ENT. SOAP OR BLEACH. BACTERIA ARE SUSCEPTIBLE TO BOTH OF THESE AGENTS AND THIS PHYSICAL CONTAINMENT ACTUALLY WORKS ON TOP AND INDEPENDENT OF THE INHERENT ENVIRONMENTAL CONTAINMENT SYSTEM WHICH WE HAVE BUILT IN WHICH AS BY DEFINITION TRAVELS ALONG WITH THE MODIFIED STRAIN AND REASSURES THAT THE STRAIN CANNOT CONTAMINATE THE ENVIRONMENT. I THINK THIS CONCLUDES OUR PRESENTATION AND WE ARE HAPPY TO TAKE ANY QUESTIONS THAT REMAIN AFTER THIS PROPOSAL. >> OKAY. THANK YOU VERY MUCH. WE'LL GO TO THE RAC REVIEWERS. MICHELLE? >> FIRST OF ALL, ISLAND LIKE TO THANK THE TEAM FOR A VERY WELL-EXPLAINED PROTOCOL. I UNDERSTAND THE CONSTRUCTION OF WORKING WITH THIS AGENT AND NOT HAVING ANIMAL MODEL. YOU TRIED TO ADDRESS MANY, MANY POSSIBLE SCENARIOS. THE QUESTION ABOUT GLP WAS CLEARLY DISCUSSED WITH THE FDA, WHICH GAVE ME A MUCH BETTER FEELING ABOUT THIS AND YOU HAVE QA CONTROL OF SOME OF THE ANIMAL STUDIES AND HOPEFULLY EVERYTHING WILL BE DOCUMENTED AND REVIEWED. SOME OF THE DISCREPANCIES THAT I FOUND IN ANIMAL STUDIES WERE WELL ADDRESSED. I UNDERSTAND THAT EACH STUDY WAS DONE WITH A DIFFERENT MIND-SET TO TRY TO ACHIEVE A DIFFERENT RESULT. FOR ME, IT WAS VERY DIFFICULT TO GO FROM ONE TO THE OTHER IN TERMS OF DOSING. BUT, I UNDERSTAND THAT THAT IS THE CONSTRUCTION OR THE LIMITATION OF THE ANIMAL MODEL THAT YOU HAD TO WORK WITH. I'M SORRY. I'M JUST GOING THROUGH JUST TO MAKE SURE THAT I'M NOT MISSING ANYTHING. SO, THE SECOND QUESTION WAS, YOU SHOWED THAT THERE WAS NO BACTERIA IN THE SYSTEM CIRCULATION OF THE PEEKS BUT THERE WAS NO DATA SHOWN TO PROVE THAT. YOU DID SAY IN YOUR REPLY THAT IN FACT YOU DIDN'T NOTICE ANY PRESENCE OF IT. BUT IN SUPPORT OF THIS RESULT, YOU SHOWED THE WAY OF TREATED AND UNTREATED PIG LET, I BELIEVE IT WAS, AND THAT STILL IS A LITTLE BIT UNCLEAR TO ME. SO WERE YOU EXPECTING TO SEE A HUGE DISCREPANCY? OR WHAT WAS THE CONTROL OF SUCH AN EXPERIMENT IF YOU HAD A LOT OF BACTERIAL EFFECT IN THE TREATED ANIMALS, WOULD YOU EXPECT TO SEE A DRAMATIC DECREASE OR INCREASE? >> NO. NOT AT ALL. FIRST WE DIDN'T EXPECT ANY SYSTEMIC EXPOSURE. THAT IS WHY IF IT'S NOT THERE, YOU CAN NOT PRESENT DATA OF COURSE. THAT'S ONE THING. AND SO WE DID THAT EXERCISE JUST IN CASE TO SHOOT ANY TOXICITY YOU COULD MEASURE BY THE WEIGHT. SO IT IS MORE GLP-LIKE METHODOLOGY THAT WE FOLLOWED. BUT WE DIDN'T EXPECT ANYTHING TO CHANGE. >> I JUST HAD A HARD TIME. >> SO ALSO THE REASON WHY WE HAVE TAKEN IT UP IN THE FIRST RAC DOCUMENT. >> OKAY. AND THE FOLLOWING QUESTION WAS ABOUT THE IMINOLOGY CALL STUDIES AND POTENTIAL CYTOKINES THAT YOU COULD SEE BEING ACTIVATED YOU HAVE A CENTRAL LAB AND I DON'T FINISH IT IS LOCATED IN THE STATES OR IN EUROPE, BUT HOPEFULLY IT WILL CONDUCT IN COMPLIANCE AND WITH CONTROLS AND EVERYTHING. SO I'M OKAY WITH THAT ANSWER. THE CRITERIA FOR DISCONTINUATION, I WAS SINCE I'M NOT TOO FAMILIAR WITH THIS DISEASE AND THE TREATMENT, I WAS CONFUSED BY THE SEPSIS VERSUS BACTEREMIA AND THE THREE TIMES VERSUS ONE TIME AND THE PCR VERSUS THE CULTURES. BUT I THINK YOU ADDRESSED THAT AND I UNDERSTAND IT NOW. THE SERUM PREGNANCY TEST, JUST DESTROYED MY EYES. I DON'T KNOW WHY YOU DID HOME. >> SOME CASES AND NOT IN OTHERS. I ASSUME YOU'RE CORRECTING IN DOING ALL SERUM. THAT'S FINE. THE ISSUE OF MODERATE TO SEVERE ACTIVE UC LEVEL IN THE PATIENTS THAT YOU RECRUIT MADE ME WORRY THAT THERE COULD BE BIAS IN HOW THE PATIENTS OR VOLUNTEERS WERE DISTRIBUTED WITHIN THE GROUP. BUT YOU SEEM TO HAVE RANDOMIZATION EVEN WITH THE SLOW NUMBER OF PATIENTS THAT WOULD ACCOUNT FOR THIS. DOSE SELECTION -- SO NOW, DID I UNDERSTAND CORRECTLY THAT YOU DO HAVE A DOSE PICKED? IS THAT RIGHT? >> SO WE PRESENTED THREE DOSES SO TWO TIMES 10 TO THE 11th AND 4 TIMES 10 TO THE EVENth AND THEN 8 TIMES 10 TO THE EVENst THIS WILL BE ADAPTED IN CASE WE SEE SOMETHING IN THE PHASE I STUDY. BUT THE PHASE I STUDY WILL ALSO FURTHER JUSTIFY THE DOSES WE HAVE SELECTED IN THE PHASE II A. >> IN CASE OF OVERDOSE, YOU SAID THAT -- AND YOU PRESENTED SOME SCENARIO. YOU DESIGNED SOMETHING VERY SENSITIVE AND MY QUESTION WAS, THINS IS A CRUCIAL TYPE OF ASSAY, HAVE YOU VALIDATED THE ELIZA? YOU SEEM TO HAVE A GOOD IDEA OF RANGE OF THE DETECTION IN TERMS OF LEVEL OF SENSITIVITY. I'M OKAY WITH THAT. TO BE HONEST. MY BIGGEST TROUBLE WITH THIS IS STILL DO WE KNOW THIS IS GOING TO WORK? DO WE REALLY KNOW THAT YOU ARE DETECTING IN VITRO NEUTRALIZATION ASSAY IS REALLY A FUNCTIONAL FAD? I UNDERSTAND THAT YOU CAN BLOCK THE TNF ACTIVITY ON THESE CELLS BUT THAT IS THE ONLY WAY THAT YOU'RE DEMONSTRATING THIS IS REALLY A PHYSICAL FUNCTIONING FAB FRAGMENT AND I KNOW ANOTHER REVIEWURE RAISED THE SAME ISSUE. THAT'S I DIDN'T SUGGESTED DOING IMMUNOPRECIPITATION EXPERIMENTS TO PROOF THIS IS INDEED CORRECTLY FOLDED MOLECULE IS WHAT I WAS SUGGESTING AND YOU SAID THERE IS QUANTITY LIMITATIONS THAT PREVENT YOU FROM DOING -- THE PART I DIDN'T UNDERSTAND IS WHY WOULD GROUND NEGATIVE BACTERIA NOT DO IT BUT GROUND POSITIVE DO IT? I'M A LITTLE CONFUSED. >> THE REFERENCE TO THE GROUND NEGATIVE IS THE GROUND POSITIVE AND MOST EXPERIENCE HAS BEEN SET UP WITH GROUND NEGATIVE BACTERIA AND MOVING FROM ONE TO ANOTHER EVERY MONOCLONAL IS DIFFERENT IN THE WAY TO EXPRESS. SO, THERE HAVE BEEN A REPORT THAT A LOT OF DIFFICULTIES TO EXPRESS MONOCLONAL ANTIBODIES AND E.COLI. THIS ORGANISM IS FUNDAMENTALLY DIFFERENT AND ONLY HAS ONE MEMBRANE VERSUS TWO IN THE GROUND NEGATIVE. SO, AND WE ARE ONLY TALKING ABOUT THIS FAB FRAGMENT FOR THE MOMENT SO WE ARE REALLY CONFIDENT THAT THE LACKTIS CAN ASSEMBLE FUNCTIONING ASSEMBLE BOTH HEAVY AND LIGHT CHAIN FRAGMENTS AND IT IS DIFFERENT FROM E.COLI IN MANY ASPECTS NOTABLY THE SINGLE MEMBRANE AND ALSO THE EXPRESSION LEVEL. SO E.COLI BRINGS MUCH MORE OR STRONGER EXPRESSION OF THE RECOMBINANT PROTEIN NOT ALWAYS ANY GOOD OF CORRECT FOLDING. SO, WE ASSUME THE CONCENTRATION RANGE WHERE WE WORK REALLY FAVORS ASSEMBLY OF SECRETED PROTEINS NOT ONLY THE FAB BUT ALSO THE OTHER PROTEINS THAT WE HAVE BEEN STUDYING. COMING BACK TO THE FUNCTIONALITY, THE FUNCTIONALITY IS NOT ONLY SHOWN IN THE LG9 CELLS WHERE WE HAVE PRESENTED THAT DATASET BECAUSE THERE WE HAVE A CLEAR COMPARATOR. WE ALSO SEE PERFECT BINDING ON IMMOBILIZED SURFACE IN THE ELIZA WHERE WE ALSO NEED FUNCTIONALITY AND THERE WE CAN'T COMPARE TOSOMESSIA BECAUSE THEY ARE SERVING US REFERENCE PROTEIN TO MEASURE CONCENTRATION. SO THAT IS WHY WE DENT THINK -- THERE ARE TWO INDIVIDUAL TECHNIQUES THAT SHOW CLEAR BINDING, SO ELIZA, ANY FUNCTIONALITY BECAUSE TNF IS IMMOBILIZED ON THE SURFACE AND ALSO TOXICSITY ASSAY YOU NEED FUNCTIONALITY. >> ONE QUESTION I HAVE REGARDING THE NANOBODY PAPER THAT WAS RECENTLY PUBLISHED IN "NATURE," IN THAT PARTICULAR ONE THAT YOU PROVIDED IN SUPPORT OF THIS, THIS WAS THE ACTUAL MOUSE CHANGE STRUCTURE COMPARED TO THE HUMAN. YOU TALKED ABOUT THE ANTIBODY BEING FROM A CAMMA LID SEQUENCE. IS THIS ALSO FOR THE AG014? >> NO THIS IS A COMPLETE HUMAN. EXACT THE THE SAME SEQUENCE. HUMAN ANTIBODY. THAT'S A DUAL CHAIN ANTIBODY. >> OKAY. >> AND THE CAMMA LID IS A SINGLE CHAIN SINGLE DOMAIN. >> I THOUGHT MAYBE I MISSED THANK YOU. SO THIS IS ADEQUATE. I MEAN, AS FAR AS YOU CAN TELL, IT IS FUNCTIONAL AND WE I WISH THE YOU BEST FOR THE TRIAL. AND JUST TO FINISH UP ON MY -- THERE WAS A MINOR COMMENT AND YOU ADDRESSED IT ABOUT THE CFU. SO THAT WAS FINE WITH ME AND I THINK I'M DONE WITH MY REVIEW. SO THANK YOU VERY MUCH. >> THANK YOU. SO THEY ANSWERED ALL YOUR QUIS? THANK YOU. NEXT DR. STROME? >> [ OFF MIC ] VERY WELL DONE PRESENTATION. ONE OF THE FIRST THINGS I ASKED WAS WHY NO PHASE I TRIAL AND YOU EXPLAINED THAT BUT ONE THING THAT WOULD HAVE BEEN NICE FROM MY PERSPECTIVE IS, THAT WE WOULD HAVE HAD THAT PHASE I DATA BEFORE WE WERE LOOKING AT THE PHASE II DATA. AND SO, WHAT WAS YOUR RATIONAL FOR SAYING, OKAY, WE ARE GOING TO DO A PHASE I TRIAL AND NOW PRESENTING YOU WITH INFORMATION THAT WE WOULD LIKE TO HAVE YOU ACCEPT ON A PHASE II A TRIAL BEFORE WE HAVE THE CHANCE TO LOOK AT THE PHASE I DATA? >> I THINK IT IS A COMBINATION OF TIMING ON ONE HAND AND THE RAC DEADLINES. AND OUR DEVELOPMENT TIME LINES SO THAT IS ONE THING. AND SECONDLY, ACTUALLY, THE PHASE II A WAS THERE BEFORE THE PHASE I. WE FELT THAT AT THAT POINT IN TIME WITH THE BIG DATA IN PLACE, IN TERMS OF PHARMACOKINETICS AND THE PHARMACODYNAMIC DATA COLITIS MODEL, THOSE TWO COMBINED, JUSTIFIED THE NEXT STEP BEING THE PHASE II A AS WE HAVE PRESENTED IT. IT WAS ONLY AFTERWARDS THAT WE DECIDED AND THE PREIND MEETING WITH THE FDA AND WE STARTED TO REALIZE THAT OKAY, MAYBE WE NEED MORE CENTERY ABOUT BEHAVIOR OF THE BACTERIA AND THE SECRETION OF PROTEIN FROM A PHARMACOKINETIC POINT OF VIEW IN HEALTHY VOLUNTEERS. AND NOTABLY USING ENDOS COPE TOW MEASURE IT. BECAUSE WE INITIALLY WE THOUGHT LET'S RELY ON WHAT WE MEASURE AS A PHARMACOKINETIC ENDPOINT. BUT IN THE THINKING PROCESS AS WE MOVED ALONG, WE DECIDED OKAY, LET'S GO FOR ENDOSCOPY AND TRY TO VALIDATE IN HEALTHY VOLUNTEERS. SO, THE TIMING REFLECTS THE WAY THE DEVELOPMENT PLAN EVOLVED OVER TIME. SO WE COULD HAVE POSTPONED THE RAC BUT BY THAT TIME, I MEAN THE PHASE I CAME ACTUALLY AFTERWARDS. >> I THINK YOU CAN UNDERSTAND THAT IT IS JUST EASIER WITHOUT QUESTION TO HAVE SOME OF THAT DATA AND HAVE THE OPPORTUNITY TOW LOOK AT IT BEFORE YOU MAKE FINAL RECOMMENDATIONS ABOUT A MORE ADVANCED TRIAL. AND THEN, YOU KNOW, IN THE OBJECTIVE STATEMENT, YOU HAD, YOU TRIED TO ANSWER IT. IT WAS MORE SEMANTICS, I THINK THAT YOUR FINAL GOAL SEEMED TO SUGGEST THAT YOU ARE LOOKING TO INDUCE REMISSION WHEN REMISSION WAS DIFFICULT TO CATEGORIZE RELATIVE TO PLACEBO. AND I THOUGHT IT WOULD BE BETTER STATED TO SAY THAT THE OBJECTIVE WOULD BE TO OBTAIN AND MAINTAIN A CLINICAL RESPONSE. NOW, YOU SAID IT WOULD BE BETTER TO HAVE A BIOPSY RESPONSE. BUT FOR THE PATIENT, AND I'M PATIENT-ORIENTED. IF I'M STILL GOING 10 TIMES A DAY AND MY BIOPSY LOOKS A LITTLE BETTER, I'M NOT SO SURE THAT I'M GOING TO KNOW THE DIFFERENCE. >> I AGREE WITH YOU FOR SURE ULTIMATELY THE PATIENT NEEDS TO FEEL BETTER. FOR THE EARLY PHASE TRIALS, THERE IS AN IMPORTANT SORT OF PROOF OF CONCEPT PIECE TO IT AND THAT CERTAINLY IS WHERE THIS IS AT. AND WHAT THE EVOLUTION OF THESE TRIALS HAS GONE FROM THE ENDOSCOPY BEING READ BY THE LOCAL ENDOSCOPIST OR LOCAL INVESTIGATOR TO VIDEOTAPING THE TRIALS AND THEN HAVING THE ENDOS COPY AND HAVING IT CENTRALLY READ. AND WHAT WE HAVE LEARNED IS THAT YOU CAN GO FOR INTRAOBSERVER VARIABILITY FROM ABOUT 60%. YOU CAN DRIVE IT UP TO 80-90% AGREEMENT BY USING EXPERIENCED TEAM OF CENTRAL REVIEWERS. SO, PATIENTS REPORTED STOOL FREQUENCY AND RECTAL BLOODING, THERE IS A NATURAL AMOUNT OF NOISE THAT COMES WITH THOSE. WHAT IS THE STOOL? IS IT RECTAL DRY HEAVE OR IS IT AN ACTUAL STOOL BEING PASSED? AND JUST NOISE GETS LOST IN THE CLINICAL MEASURES. WITH CENTRALLY READ ENDOSCOPE, YOUIC TIGHTEN THAT UP. SO WE THINK ENDOSCOPE IS THE LEAST NOISY WAY OF GETTING A CLINICAL READ OUT. YOU CAN DO IT IN A COUPLE OF WAYS. WE ARE STARTING WITH PATIENTS WITH SORT OF MODERATE TO SEVERE ENDSCOPIC FINDINGS AND YOU CAN LOOK IN A DICHOTOMOUS WAY HOW MANY PATIENTS HAVE COMPLETE NORMALIZATION OR DOWNGRADE FROM MODERATE TO SEVERE TO MILD FINDINGS, AND YOU CAN ALSO LOOK AT THE ENDOSCOPY SHIFT SCORES. SO THE DISTRIBUTION WITHIN A TREATMENT GROUP FROM ENDSCOPIC SCORE OF TWO OR THREE TO ZERO-3, AND THAT IS ACTUALLY QUITE A SENSITIVE WAY OF LOOKING AT A CLINICAL EFFECT AND WE KNOW FROM PHASE III TRIALS THAT THERE IS QUITE A TIGHT CORRELATION BETWEEN CHANGES IN CENTRALLY READ ENDOSCOPY AND ULTIMATELY IF YOU HAVE ENOUGH PATIENTS, CHANGES IN THE CLINICAL FINDINGS. SO I THINK I WOULD ARGUE IF WE WERE TALKING ABOUT SIR ISIS, YOU DON'T ASK THE PATIENT HOW YOU FEEL. YOU LOOK AT THE SKIN IN A SENSE THE ENDOSCOPY IS A PHYSICAL EXAMINATION OF THE DISEASE. AND SO IN ONE SENSE YOU COULD ARGUE THAT IT IS THE MOST ROBUST MEASURE BUT EVENTUALLY YOU WANT THE PATIENT TO FEEL BETTER. BUT I THINK WHETHER YOU LOOK AT THE ENDOSCOPY AS THE DISEASE OR LOOK TAT AS A ROBUST SURROGATE OF THE DECEASED, IT'S TIGHT LOW CORRELATED WITH THE THINGS YOU CARE ABOUT. >> YOU ANSWERED THE QUESTION ABOUT THE APPROACH IN TERMS OF HOW YOU'RE GOING TO STAGGER THE DELIVERY SYSTEM. AND ALSO YOU ANSWERED MY QUESTION RELATIVE TO THE TRIAL COMPLETED IN DECEMBER AND I ACCEPT THAT ANSWER. ONE OF THE THINGS I WAS CONCERNED ABOUT AND YOU ATTEMPTED TO ANSWER IT WAS, THAT IF THE ENTIRE COLON IS INVOLVED, WHICH OBVIOUSLY ISN'T THE CASE IN THE HUMAN SUBJECTS THAT ARE NORMATIVE SUBJECTS, THIS CLEARLY IS MORE OF AN INFLAMMATORY RESPONSE IN THOSE PEOPLE. 30% OR 40% THAT HAVE THE TOTAL COLON INVOLVED. IF THEY HAVE ADVANCED DISEASE, ONE MIGHT QUESTION WHETHER THE PRODUCT WOULD POTENTIALLY LEAD TO MORE INFLAMMATION AND/OR MORE OF AN ALLERGIC-TYPE RESPONSE. YOU HAVE GOT SUCH A HUGE AREA FOR EXPOSURE AS OPPOSED TO RELATIVELY LIMITED EXPOSURE. WHAT DOES THAT MEAN RELATIVE TO THE POTENTIAL FOR MORE PROBLEMATIC RESPONSES TO THE PRODUCT? MAYBE IT DOESN'T BUT AS I WAS LOOKING AT IT, I THOUGHT IT MIGHT. >> OF COURSE WE CAN ONLY RELY ON THE TOXICITY LAID OUT OR THE REPEAT TOXICITY STUDIES WE DID. REPEAT DOSE TOXICITY STUDIES WE DID IN THE COLITIS MODEL FOR THAT REASON. SO THE TOX STUDIES WERE NOT DONE IN HEALTHY ANIMALS. SO NO EVIDENCE FOR THAT. BUT HOW CAN YOU EXTRAPOLATE TO THE HUMAN SITUATION? AGAIN, WE ARE AWARE THAT POSSIBILITY MAY OCCUR AND SO HENCE THE DESIGN OF THE STUDY. I DON'T THINK THAT BASED ON THE DATA WE ACCUMULATED THE PREVIOUS STUDY THAT WORSENING OF COLITIS IS DEMONSTRABLE. THERE WAS A TREND BUT THERE ARE MANY, MANY FACTORS THAT PLAY A ROLE THERE. AND THEN ALSO THE USE OF PROBIOTICS WITH PATIENTS THAT YOU SEE IN IBD IN GENERAL AND I DON'T THINK THERE IS EVIDENCE THAT THEY HARM. I'M NOT SURE THERE IS EVIDENCE THEY WORK BUT AT LEAST THEY DO NOT DO ANY HARM. >> THAT IS CLEARLY ONE OF THE THINGS THAT IF YOU HAVE TO BE LOOKING FOR IS THAT RISK THAT YOU MENTIONED. THAT'S STILL REMAINING SOMEWHAT OF CONCERN TO ME. ONE OF THE OTHER THINGS WAS, AND YOU SAID IT WAS A REASONABLE IDEA. IS THAT WHY NOT START WITH RECTAL ADMINISTRATION? YOU DON'T HAVE TO ATEACH SOMETHING TO KEEP THE BILE FROM MAKING THE PRODUCT AVAILABLE EARLIER IN THE GUT. 60% OF THE PATIENTS HAVE LEFT SIDED DISEASE AND IT WOULD JUST SEEM THAT IT WOULD BE CLEANER PRODUCT THAT YOU COULD GET THE ANSWERS THAT YOU WANT AND DISEASE THAT IS MORE LIMITED AND POTENTIALLY DECREASE THE CHANCE FOR AT VERSE EVENT. MY PERSPECTIVE. >> I WANT TO BACK UP JUST ONE SECOND TO THE PREVIOUS COMMENT THAT YOU MADE. SO IF WE THINK ABOUT THE POTENTIAL FOR WORSENING COLITIS OR IF YOU WILL, A LOCAL ADVERSE EVENT, WE WANT TO THINK OF THIS IN TWO PIECES. ONE IS THE DELIVERY ORGANISM AND THE OTHER IS THE SECRETED PROTEIN. SO FROM A SECRETED PROTEIN STANDPOINT, WE HAVE ENORMOUS EXPERIENCE WITH GIVING A WIDE RANGE OF DOSES WITH ANALOGOUS MOLECULE. WE STUDIED IN CLINICAL TRIALS OF THE 20 MILLIGRAMS PER KILOGRAM. AND WE HAVE NOT SEEN DOSE DEPENDENT TOXICITY. SO THERE IS A FAIR AMOUNT OF INTERPATIENT VARIABILITY WITH SYSTEMIC ADMINISTRATION. SO SOME OF THE PATIENTS GET ASTRONOMICALLY HIGH CONCENTRATIONS OF ANTITNF SYSTEMICALLY AND WE DON'T SEE EXPOSURE SAFETY RELATIONSHIPS WITH PK. SO I THINK IT'S UNLIKELY THAT VARIATIONS BETWEEN SUBJECTS AND HOW MUCH THEY GET LOCALLY IS GOING TO HAVE ANY MEANINGFUL IMPACT ON TOXICITY. SO THEN ITS AND BACK TO THE ORGANISM AND THIS IS A FOOD ORGANISM WHERE THERE IS A LOT OF EXPERIENCE INCLUDING IN PATIENTS WITH IBN THEIR DIET. AND SO I WILL BE SURPRISED IF WE SEE WORSENING FROM THE FOOD DELIVERY ORGANISM. BUT OBVIOUSLY WE NEED TO MONITOR CAREFULLY. AND AS DR. COOLEY SAID, WHAT WE SEE IN CLINICAL TRIALS IS THAT THESE PATIENTS MODERATE TO SEVERE DISEASE, YOU WILL SEE 10-15% OF THE PATIENTS IN INDUCTION STUDY WORSE EPING FROM BASELINE ON PLACEBO. WHAT YOU'RE LOOKING FOR WITH AN EFFECTIVE DRUG IS ACTUALLY TO HAVE LESS OF. THAT SO LESS PATIENTS HAVE WORSENING OF COLITIS AS AN SA. AND THAT IS THE MERE IMAGE OF SEEING EFFICACY. SO IN THE PREVIOUS COMPOUND, WHERE THIS VEHICLE WAS USED TO DELIVER INTERLEUKIN 10, THAT TREATMENT STRATEGY WASN'T EFFECTIVE AND SO, YOU CAN SEE WORSENING OF COLITIS IN BOTH GROUPS AND THE SEVERE END OF THAT WAS WORSENING AS SAE, 7.5% ON THE DRUG AND 10% ON PLACEBO. SO, I THINK THAT STUFF FITS WELL. IN TERMS EVER RECTAL VERSUS ORAL, THE WAY I THINK OF THIS CONCEPTUALLY IS THIS, WHETHER YOU GIVE IT ORALLY OR RECTALLY, THIS IS TOPICAL INTRALUMINAL THERAPY. SO YOU'RE BASICALLY RETARDING THE RELEASE UNTIL YOU HIT THE TERMINALIL YUM, JUST PROXIMAL TO THE COLON AND THEN DUMPING THIS AT THE TOP OF THE COLON VERSUS INSERTING IT FROM BELOW WITH MA THAT WILL MEAN, WE HAVE DELAYED RELEASE DELIVERY SYSTEMS IDENTICAL TO THIS BASICALLY. IT'S STILL TOPICAL EITHER WAY YOU GIVE IT. SO I GUESS FROM A SAFETY PERSPECTIVE, IT'S NOT OBVIOUS TO ME THAT IT WOULD MAKE MUCH DIFFERENCE. AND USUALLY WHEN WE THINK OF ORAL DRUG, WE ARE THINKING OF SYSTEMIC AVAILABILITY SO IT WOULD BE DIFFERENT FROM RECTAL OR TOPICAL DELIVERY. IN THIS CASE, IT IS TOPICAL. ORAL TOPICAL OR RECOLLECT CALL TOPICAL BUT IT IS KIND OF THE SAME THING. >> STILL, AND I UNDERSTAND EXACTLY WHAT YOU'RE SAYING. BUT THERE IS ALWAYS THE UNKNOWN IN A FIRST TRIAL. WE CAN SAY NOTHING WILL HAPPEN THROUGH THE SMALL INTESTINE OR WHATEVER. BUT IF YOU GIVE IT RECTALLY, YOU OBVIATE ANY OF THOSE CONSIDERATIONS? THEY MAY NOT HAVE SUCH TO OBVIATE. SO, WHAT DO I KNOW? I MEAN, WHEN YOU CLEAN NOSES FOR A LIVING, I SUPPOSE IT'S NOT DIFFERENT THAN CLEANING OUT COLONS BUT WHEN YOU LOOK AT IT, IT WOULD SEEM THAT IT WOULD BE SAFER FOR THE FIRST NUMBER OF PATIENTS TO DO IT RECTALLY. AND THEN YOU DON'T NEED WHATEVER YOU ADD TO PREVENT FROM HAVING TO NOT RESOLVE THE -- AND LET THE BACTERIA BE PRESENT IN THE COLON. I LOOK TAT AND I THINK THAT WOULD BE A CLEANER WAY TO DO IT AND I UNDERSTAND ALSO WE ARE TALKING ABOUT CLEAN WAYS TO DO THINGS THAT YOU MIGHT HAVE PATIENTS THAT MEET THE SCORE CRITERIA THAT YOU DON'T HAVE TO GIVE SOMETHING LIKE A STEROID. IN ALL YOUR TRIALS YOU EXPLAINED MOST OF THEM HAVE STEROIDS AND WHAT NOT. IT'S JUST ALWAYS CLEANER IF YOU JUST USE YOUR PRODUCT ALONE. AND NOT HAVE THINGS CONFOUNDED. TWO WEEKS OF A STABLE STEROID WHERE THEY MAY HAVE BEEN INCREASING THE DOSE UP TO THAT POINT IN TIME, AND AND YOU HAVEN'T HAD A PROTRACTED ENOUGH PERIOD OF TIME TO SEE THAT INCREASES DOSE OF STEROID IS ACTUALLY HAVING AN AFFECT. AGAIN, IT'S JUST ANOTHER THING THAT TENDS, FROM MY PERSPECTIVE TO MAKE IT LESS CLEAN. SO IF YOU DIDN'T NEED THE STEROID BUT YOU HAD THE STAGE AND YOU HAD THE RECTAL DISEASE, THEN THE WHOLE THING T MAY BE HARD TO FIND PATIENTS LIKE THAT FOR ENTRY CRITERIA. I DON'T KNOW. BUT AGAIN, IT SEEMS LIKE IT WOULD BE CLEANER AND POTENTIALLY BETTER STUDY. I'M NOT -- AND I UNDERSTAND WHAT YOU'RE SAYING. I'M LOOKING AT IT FROM THAT PERSPECTIVE. >> IT'S A HELPFUL PERSPECTIVE: WE SOMETIMES GET -- IN OUR OWN FIELDS. THE ONE THING I WOULD SAY ABOUT THE CONCOMITANT MEDICATION IS, THAT I THINK IRBs AND ETHICS COMMITTEES AS THEY ARE LOOKING AT THE ETHICS OF PLACEBO CONTROL, AT FLEET OUR AREA, THE INVESTIGATORS, PATIENTS AND ETHICS COMMITTEES HAVE ACCEPTED THAT ALLOWING BACKGROUND STANDARD OF CARE MEDICINE WOULD THEN PLACEBO CONTROL WAS AN ACCEPTABLE STRATEGY FOR TREATMENT. IN THE FEW INSTANCES A SPONSOR HAS TRIED TO WITHDRAW ALL COP COMINANT MEDICATIONS, LIKE WHAT MIGHT BE DONE IN ASTHMA TRIAL, AND HAVE DRUG VERSUS PLACEBO WITH NO COM COMINANT MEDICATIONS, THAT IS ESSENTIAL EP NOT BEEN ACCEPTED BY THE INVESTIGATORS AND IT'S NOT BEEN ACCEPTED BY THE ETHICS COMMITTEE. SO IN THIS THEY WERE PUTIC AREA, OUR EXPERIENCE SO FAR IS THAT THE ETHICS COMMITTEE WON'T ACCEPT NOT HAVING STANDARD OF CARE THERAPY IN THE BACKGROUND. SO, WE ARE PROBABLY SORT OF STUCK WITH THAT. >> ONE OF THE THINGS I MIGHT SUGGEST IS THAT TWO WEEKS MIGHT BE A LITTLE BIT SHORT. IN THE TIME COURSE TO FIND OUT IF THE STEROIDS ARE GOING TO BE EFFICACIOUS. YOU MIGHT WANT TO TAKE THAT OUT TO A LITTLE LONGER TO A MONTH OR SOMETHING LIKE THAT. >> AND JUST FOR CLAIROL CLARITY, WE ARE REQUIRING THE PATIENTS BE ON STEROIDS FOR A MINIMUM OF 4 WEEKS OR A MONTH AND THEN HAVE A STABLE DOSE FOR TWO WEEKS. >> RIGHT. SO MY SUGGESTION MIGHT BE YOU TAKE THAT STABLE DOSE OUT JUST A LITTLE BIT LONGER. YOU ANSWERED MY QUESTION ABOUT THE DNF BEING PRODUCED BY MICROPHAGES AND LYMPHOCYTES AND IN THE LAMINA AND I THINK THAT WAS WELL COVERED. WE TALKED ABOUT THE TRANSRECTAL ADMINISTRATION AND THEN, I HAD A LITTLE CONSIDERATION OF ENTRY CRITERIA BECAUSE IT'S ALWAYS HARD WHEN ONE LOOKS AT STAGING, NOT STAGING, BUT CATEGORIZATION. AND YOU TRY TO PUT THINGS INTO NICE PACKAGES. BUT, WHAT YOU SAID WAS, WHICH WAS CONCERNING TO ME. YOU SAID WE HAD TO GET TO THE NUMBER 6. FOR IMEXCLUSION THAT WAS MODERATE DISEASE AND THEN YOU WENT AHEAD AND CATEGORIZED THAT JUST A LITTLE DIFFERENTLY. AND YOU SAID, THAT AT LEAST A RATING OF ONE IS REQUIRED FOR BLEEDING. THAT MEANS JUST A LITTLE BLOOD STREAKING IN THE STOOL. AND THE NUMBER OF STOOLS ABOVE NORMAL ARE 1-2 FOR INCLUSION. THESE SEEM LIKE THE THINGS THAT MOST AFFECT THE PATIENTS F I'M BLEEDING, GOSH, I COULD HAVE A HEMORRHOID AND GET THAT. IF I TOOK A LITTLE TOO MUCH FIBER ONE, I COULD HAVE THREE STOOLS A DAY. SO THEN I HAVE A LITTLE BIT OF BLEEDING AND A LITTLE BIT OF ACCESS NUMBER OF STOOLS, THEN ALL I NEED IS A BIOPSY OF TWO, WHICH ISN'T TOO TERRIBLE AND A GLOBAL SCORE OF TWO, AND I'M INCLUDED. AND THAT DOESN'T SEEM LIKE TOO ADVANCED DISEASE. IF YOU LOOK AT THE SCORE IT'S ADVANCE BUT IF YOU LOOK AT THE PATIENT IT ISN'T TOO ADVANCED. I WOULD LIKE TO SEE A LITTLE MORE IN TERMS OF THE CRITERIA FOR INCLUSION, MAYBE A RATING OF TWO ON EACH OF THOSE THINGS WHICH ARE CRITICAL FOR A PATIENT. IF I WERE A PATIENT AND MY BIOPSY LOOKED BAD, AND GLOBAL SCORE, WHATEVER THAT INCLUDES, YOU KNOW, AND ALL I HAD WAS A LITTLE BLOOD IN MY STOOL AND 2-3 STOOLS A DAY, I MIGHT NOT BE SO WILLING IF I WERE PROPERLY INFORMED. >> SO JUST FOR CLARITY, THE BIOPSIES ARE NOT PART OF THAT MAYO SCORE. IT'S THE VISUAL ENDOSCOPY THAT WILL BE THE TOTAL LOOK OF ENDOSCOPY AT THE SIGMOID AND RECTAL AND DESCENDING COLON. IT'S CENTRALLY READ WHICH AND THE CENTRAL READER IS BLINDED AND HAS NO IDEA WHETHER THE PATIENT IS IN SCREENING OR FOLLOW-UP AND THEY HAVE NO INCENTIVE TO RECRUIT THE PATIENT. SO IT IS REALLY A REPRODUCIBLE OBJECTIVE MEASURE. AND THERE IS SOME PATIENT TO PATIENT VARIATION. SO YOU CAN HAVE -- ALTHOUGH RECTAL BLEEDING IS A REPORT OF ULCERATIVE COLITIS. SOME PATIENTS MIGHT HAVE 10 STOOLS A DAY AND HAVE BLINDED CENTRAL EN DOZCOPEY AND FEEL TERRIBLE BUT THEY HAVE LITTLE RECTAL BLOODING. SO THE MOST DISEASE VISIT A SPECTRUM OF CLINICAL PRESENTATION AND THE SCORING SYSTEM IS DESIGNED TO ALLOW PATIENTS WITH SIGNIFICANT SYMPTOMS WHO HAVE SOME PATIENT TO PATIENT VARIATION IN THE CLINICAL PRESENTATION COMING INTO THE TRIAL. I THINK WHAT I WOULD SAY IS THAT THESE ARE EXACTLY ENTRY CRITERIA THAT WERE USED FOR SYSTEMIC ADMINISTRATION OF REM CADE AND HUMIRA AND SYMPHONY FOR ULCERATIVE COLITIS AND MANY OTHER DRUGS THAT HAVE CONSIDERABLY MORE WORRISOME TOXICSITY PROFILES THAN THIS. IF YOU TRACK THE -- AND WITH THE RANGE EVER SIX-12, THE MEDIAN SCORES, TYPICALLY ARE 9 IN THE CLINICAL TRIAL LIKE THIS, AND IF YOU LOOK AT SF36 SCORES AS A GENERIC MEASURE OF QUALITY OF LIFE, TRA THAT TO OTHER DISEASES, PATIENTS THESE ENTRY CRITERIA HAVE A QUALITY OF LIFE THAT TRACKS TO DIALYSIS DEPENDENT RENAL FAILURE TO STAGE 3 OR 4 CONGESTIVE HEART FAILURE. THEY ARE POOR QUALITY OF LIFE. SO, I CAN SEE HOW WHEN YOU TRY TO ADD UP THE MATH THE WAY THAT YOU DID, IF YOU'RE NOT USED TO SEEING THE PATIENTS, I CAN SEE HOW YOU CAME TO THE QUESTIONS THAT YOU CAME, BUT I THINK WE KNOW FROM A LOT OF CLINICAL TRIAL EXPERIENCE IS, THAT THESE ENTRY CRITERIA LEAD TO A DEBILITATED SET GROUP OF PATIENTS. >> THE THING IS, IT IS STILL THERE. AND WILL IT IS VARIED. AND IF THE MEDIAN SCORE IS 9, AND THIS IS THE FIRST IN HUMAN TRIAL, WHY NOT SAY IT? WE ARE GOING TO HAVE A MEDIAN SCORE OF 9 FOR OUR ENTRY CRITERIA? AND YOU WON'T RUN THE RISK OF HAVING A PATIENT THAT HAS RELATIVELY LIMITED SYMPTOMS BUT AN ENDOSCOPY SCREENING THAT PUTS THEM INTO THE ACCEPTABLE CATEGORY. >> THE ONLY THING I WOULD BE WORRIED ABOUT IS IF YOU SKEW TOO FAR TO THE, WHAT I WOULD SAY AS THE TRAIN WRECK PATIENT, SOMETIMES IT GETS DIFFICULT, THE DECISION WILL BE MADE ULTIMATELY ON THOSE DATA ABOUT WHETHER TO TAKE IT INTO PHASE 2B AND PHASE III CLINICAL TRIALS. AND IF YOU PUSH TOO FAR TO A COMPLETELY SEVERE REFRACTARY PATIENT POPULATION IN A SMALL PHASE TA TRIAL, IT'S HARD TO SEE AN EFFECT AND IN A BROADER PERSPECTIVE YOU MIGHT WRONGLY CONCLUDE THERE IS NO BENEFICIAL EFFECT AND STOP DEVELOPMENT OF SOMETHING THAT WOULD HAVE BEEN EFFECTIVE IF YOU HAD A BIT MORE DIVERSE PATIENT POPULATION. WE ARE NOT TALKING ABOUT MILD PATIENTS HERE. SO I SEE YOUR POINT. TWO SIDES TO IT. >> I UNDERSTAND. BUT ENTRY CRITERIA FOR A TRIAL FIRST IN HUMAN TRIAL FOR ME IS JUST A LITTLE BIT DIFFERENT. AND WE DON'T HAVE THE PRELIMINARY DATA YET. SO. SO THAT'S STILL REMAINS PROBLEMATIC FOR ME. AND THEN WHEN YOU TAKE IT FORWARD FROM MY LAST QUESTION BECAUSE I DON'T WANT TO MONOPOLIZE THIS, THE ENTRY CRITERIA, 18 IS STILL TEENY. THE REALITY IS WHEN YOU GET TO 21, MAYBE IT'S A LITTLE DIFFERENT. AND I THOUGHT THAT THE BASIC PRODUCT HAS YET TO BE APPROVED FOR THE TEENAGED POPULATION. SO, I'D LIKE TO SEE THIS A LITTLE TITER AS I SAID, IN THE ENTRY CRITERIA RELATIVE TO WHAT WE JUST TALKED ABOUT AND THE GRADING SYSTEM AND NOT HAVE TEENAGERS INVOLVED IN THE INITIAL STUDY. THAT'S PRETTY MUCH FOR ME. AND I KNOW IT HAS BEEN TOUGH BUT I THINK THE PRESENTATION WAS VERY WELL DONE. THANK YOU. >> THANK YOU. >> THANK YOU. SO, WOULD YOU SAY THEY RESPONDED SATISFACTLY TO YOUR COMMENTS? WE CAN DISCUSS IT. >> BEFORE I EVEN KNOW THE WAY I AM, I'D LIKE TO SEE IT IN A LITTLE OLDER POPULATION. NOT INCLUDING TEENS. AND I'D LIKE TO SEE THE CRITERIA FOR ENTRY BE SOLIDIFIED A LITTLE BIT MORE. I JUST DON'T LIKE THE BOTTOM WHERE YOU HAVE THE BLOOD STREAKING IN THE STOOL AND MAYBE THREE STOOLS A DAY AND I KNOW THE NUMBER OF PATIENTS WOULD BE SMALL BUT THIS IS STILL A PHASE I TRIAL, OR A FIZZ R. FIRST IN HUMAN TRIAL AND I JUST FROM MY PERSPECTIVE, I THINK YOU HAVE TO LIKE THE PATIENTS THAT ARE A LITTLE MORE ON THE SEVERE END FOR ME. >> WHAT IS THE PROPOSED TOTAL END FOR THE STUDDIE? >> 60. >> [ OFF MIC ] >> ONE OF THE THINGS I WANTED TO COMMENTED ON, YOU READ THE POINTS TO CONSIDER AND ACTUALLY WHEN YOU DID YOUR INITIAL WRITE UP, YOU HAD TAKEN CARE TO RAISE THE QUESTIONS THAT HAVE BEEN ASKED AS CORE ETHICAL QUESTIONS. SOMEONE TO SAY BEFORE I SAY ANYTHING ELSE, THANK YOU FOR READING THAT DOCUMENT. I DID HAVE SIMILAR QUESTIONS. AND I THINK YOU ANSWERED SOME OF OR, ONE I THINK WAS STILL STRUGGLING ON ONE, THE PATIENT SELECTION AND THE AGE OF THE PATIENT. THIS IS A DISEASE THAT TYPICALLY OCCURS IN YOUNG TEENS UP TO 25 WAS YOUR AGE RANGE AND IT'S A DEVASTATING DISEASE BECAUSE IT HAS SO MUCH TO DO WITH THE LACK OF BODILY INTEGRITY AND CONTROL AND LINKED WITH DEVELOPING SEXUALITY. THIS IS REALLY A HEAVILY FRAUGHT DISEASE FOR TEENS TWO. THINGS I THOUGHT ABOUT. ONE IS NOT STARTING ATTAIN. IT'S A SMALL END. YOU DON'T NEED THOSE PEOPLE IN A YOUNGER END OF THE DISEASE. I WOULD FEEL MORE COMFORTABLE IF YOU WENT WITH A 21 AS YOUR CUT-OFF DATE AND HAD SOME TIME TO AJUST COME TO TERMS WITH IT AND REACH SOME MATURITY AND AROUND WHAT THIS DISEASE MIGHT MEAN FOR THEM. THAT IS JUST FIRST OFF. >> I THINK WE CAN EASILY AGREE TO THAT. NO PROBLEM. LET'S JUST SAY 21. >> GREAT. THANK YOU. THAT WAS EASY. I WISH IT WAS ALL THIS WAY. THE SECOND IS A PROBLEM THAT COMES UP ON VERY MANY PHASE I CLINICAL TRIALS, WHICH IS THE TESTING ENTITIES WANT TO HAVE IT OR WANT TO BE SUCCESSFUL. IT'S A GOOD IDEA AND IT'S SCIENTIFICALLY FASCINATING AND YOU WANT TO WORK. IT'S HARD TORE GET IT TO WORK IN SICKER PATIENTS. IT'S NOT UNIQUE TO YOUR TRIAL. IT'S TRUE FOR EVERY PHASE I FIRST USE IN HUMANS TRIAL. FOR SPINAL CORD INJURY WE WERE ARGUE BEING HOW AFFLICTED THE SPINAL CORD AND YOUR PATIENT WILL BE. YOU'LL GET BETTER RESULTS IN HEALTHIER PEOPLE. SO, THERE IS ALWAYS ATTENTION IN PLANNING ABOUT HOW SEVERE THE DISEASE HAS TO BE. NOW IN GENE THERAPY, WE TYPICALLY THINK ABOUT DOING THESE IN PEOPLE THAT HAVE NO OTHER CHOICE. THESE INTERVENTIONS IN PEOPLE WITH THE GLIOBLASTOMAS AND PEOPLE WITH NO OTHER CHOICE. WHEN WE ISSUE THERAPY IN PATIENTS WITH MILD TO MODERATE DISEASE, I KNOW THEY ARE SICK BUT YOU COULD GET A HIGH MAYO SCORE WITH A LITTLE -- GET TO 6 WITH A LITTLE RECTAL BLOODING AND FREQUENT SCHOOLS. DON'T NEED TO HAVE SOME OF THE OTHER ENDOSCOPIC EFFECTS. YOU COULD FEEL TAPER ABOUT IT AND GOAT A HIGHER SCORE. SO SINCE IT'S A SOFT TARGET SCORE, THE PHYSICIAN MIGHT BE SWAYED BY SOMEONE WHO FEELS BADLY ABOUT THEIR SITUATION. SO, THESE ARE PATIENTS IN COULD BE TREATED POTENTIALLY WITH OTHER INTERVENTIONS. AND SO IT ALWAYS RAISES QUESTIONS FOR ME ABOUT ENTERING PATIENTS IN EARLY PHASE GENETIC THERAPY TRIALS. I SEE THE PROBLEM. YOU'LL GET A BETTER RESULT AND YOU WANT TO GET A GOOD RESULT SO THEY CAN BE EXTRAPOLATED AND HELP MORE PEOPLE. >> SO ONE POINT OF CLARIFICATION, THERE IS A DOOR REQUIRE -- DUAL REQUIREMENT. 6-12 AND CENTRALLY READ BLINDED ASSESSMENT OF ENDOSCOPIC SEVERITY MODERATE TO SEVERE. SO NO WAY TO GAIN THAT. I UNDERSTAND THAT EXCEPT YOU REPORT THAT YOU JUST DID IN YOUR PRESENTATION, YOU NOTICE THERE WAS SAEs IN PLACEBO TRIALS WITH AND IN BOTH PLACEBO ARMS AND TREATED ARMS. AND THEY DIDN'T HAVE GOOD BIOLOGICAL FINDINGS BUT PATIENTS CLEARLY MUST HAVE REPORTED THEY WERE SEVERELY EFFECTED. THAT'S WHY THEY COUNTED. SO IF THE PATIENT SAYS I'M MISERABLE AND WORSE, I NEED TO DROP OUT, YOU WOULDN'T COME BACK TO THEM AS A PHYSICIAN AND AS AN INVESTIGATOR SAY, I'M SORRY BUT OUR MEASURES AND OUR NUMBERS SHOW YOU'RE FINE. I WOULD SAY I GUESS YOUR LIGHT SIS WORSENING. I HOPE YOU WOULD SAY THAT. COLITIS IS WORSENING. >> THE DECISION TO EXIT THE TRIAL FOR SAEs, THAT'S A SEPARATE ISSUE FROM EFFICACY. BUT THEY ARE OFTEN LINKED IN SOME WAY. BUT THE REASON WE MOVED TO CENTRAL READING, WE LEARNED OVER TIME THAT INVESTIGATORS CAN UPCODE AND YOU CAN GET PATIENTS INTO THE TRIALS AND ALL THE USE OF CENTRALLY READ ENDOSCOPY TAKEN OFF OVER THE LAST COUPLE OF YEARS. THERE WAS JUST A TRIAL RECENTLY REPORTED WITH THE SAME ENTRY CRITERIA WHERE THE PLACEBO RATE WAS ZERO. SO THE CENTRALLY READ ENDOSCOPY DRIVES UP THE CLINICAL SCORES AND WEEDS OUT ANY INVESTIGATORS GAMING THE SYSTEM. WHAT I'M WORRIED ABOUT IS RAISING THE BAR SO HIGH HERE. THESE SAME ENTRY CRITERIA HAVE BEEN USED FOR CLINICAL TRIALS FOR ANTICD3 ANTIBODIES, ANTITNF TO, GIVE A VARIETY OF THINGS. SYSTEMIC AND IMMUNE SUPPRESSIVES WITH CONSIDERABLE POTENTIAL FOR TOXICITY. THIS -- . >> I'M NOT ARGUING ALL THE OTHER KIDS JUMP OFF THE ROOF TOO. IF IDENTIFIES THAT COMMITTEE, I WOULD HAVE RAISED THE SAME THING. I'M WONDERING SINCE YOU SAY IN YOUR DESCRIPTION, THE MODERATE DISEASE SPONTANEOUSLY SOMETIMES GOES INTO REMISSION OR DISAPPEARS, I'M WORRIED ABOUT TRUSTING OTHER PEOPLE WHO MIGHT BE SPONTANEOUSLY GETTING BETTER ON THEIR OWN ANYWAY. ESPECIALLY IF THEY HAVE THE STRONG AND HAVING ALL THIS ATTENTION AND SAYING NO IT'S A GENE THERAPY. BECAUSE THIS IS A DEEPLY PSYCHOLOGICAL AFFECTED DISEASE, IT IS SO INTENSELY INTERTWINED WITH PSYCHOLOGICAL REALITIES OF THEIR SITUATION, OF BEING A TEEN. I JUST REALLY TRUST THAT OTHER PEOPLE DO IT AND THAT MAY BE A GOOD ENOUGH ARGUMENT FOR HAVING A SIMILAR CONSTRUCTED GROUP. BUT YOU SEE THE PROBLEM? IF IN YOUR OWN EDUCATIONAL MATERIAL, YOU EXPLAIN THEY CAN SOMETIMES SPONTANEOUSLY GET BETTER. >> IN RETROSPECT, THAT WAS WHAT WE KNOW TODAY, IT IS PROBABLY A SLIGHTLY POOR CHOICE OF WORDING BECAUSE WE ARE REALIZING THAT IF YOU SELECT PATIENTS MODERATE TO SEVERE ENDOSCOPY FINDINGS, THE CHANCES THEY WILL SPONTANEOUSLY REMIT IS PROBABLY ZERO TO 5%. IT IS REALLY LOW. >> THEN MAYBE YOU SHOULDN'T SAY THAT. >> THAT'S A FAIR POINT. >> AND YOU ANSWERED WELL ABOUT THE FLY A FEW WEEKS THAT IS EFFECTIVE. AND ON THE -- YOU HAD NOT WANTED TO HAVE PSYCHOLOGICAL SUPPORT BECAUSE YOU SAID IT WAS ONLY A SHORT PERIOD OF TIME DOING AN INTERVENTION. I WONDERED HOW PROVE THAT WAS. >> I'M NOT SURE WHAT -- MAYBE YOU COULD HELP ME UNDERSTAND A LITTLE BIT MORE. IN THIS THERAPEUTIC AREA, THERE IS ALWAYS AN ELEMENT OF PSYCHOLOGIC SUPPORT WITH THE PHYSICIANS CARING FOR THE PATIENTS WE ARE ATTEMPTING TO MONITOR THEIR PSYCHOLOGIC WELL-BEING THROUGHOUT THE COURSE OF TREATMENT AND CERTAINLY IN THE CONTEXT OF CLINICAL TRIALS. I AM NOT AWARE OF A PARTICULAR CODIFIED STRATEGY FOR THAT BEYOND THE BROAD CARE. DID YOU HAVE SOMETHING IN MIND SO WE SHOULD CONSIDER? >> NO, I WAS WONDERING -- BECAUSE THE DISEASE, PSYCHE LOCK CALL COMPONENTS NOTED IN YOUR EXPLANATION TO US. WONDERED WHY THAT WASN'T BUILT INTO THE TRIAL. BUT YOUR ANSWER WAS A SHORT DURATION WAS ONLY TWO WEEKS STARTING A WHOLE NEW THERAPY RELATIONSHIP SHOULD BE PRUDENT IN ANY CASE. THAT SEEMED TO BE -- >> ENING REALITY WE PROBABLY COULD HAVE FORMULATED A BETTER RESPONSE TO YOUR QUESTION, REALLY THE INFLAMMATORY BOWEL DISEASE CENTERS WHERE MOST OF THE PATIENTS WOULD BE RECRUITED AND ARE VERY MUCH TUNED INTO THE CARE OF THE WHOLE PATIENT AND RECOGNIZING THE PSYCHOSOCIAL BURDEN. WE HAVE A LOW THRESHOLD TO REFER TO PSYCHOLOGY AND PSYCHIATRY AND WE ARE ATTEMPTING TO MONITOR AND MANAGE THE EMOTIONAL FALL OUT OF THE DISEASE FOR SURE. >> AND THEN YOU HAD A GOOD ANSWER TO MY OTHER QUESTIONS ABOUT LIFELONG -- HOW LONG YOU WERE GOING TO FOLLOW IT, 40 WEEKS. THAT'S PROBABLY NOT A REASONABLE SOLUTION. ONCE THIS INTERVENTION IS MADE T ALTERS THE COURSE OF THE DISEASE BUT THEN YOUR INTERVENTION OF 40 WEEKS SEEMED REASONABLE TO ME. I THOUGHT YOU DID A GOOD JOB. ONE QUESTION ON THE PUBLIC HEALTH ISSUE. YOUR ANSWER WAS, ESSENTIALLY THAT YOU ENGINEERED THE BACTERIA SO IT CAN SURVIVE IN THE WILD. >> YOU HOOKED A SUICIDAL SYSTEM TO IT AND IN THE BACKUP PLAN FOR WHEN THAT FAILED ADDS IT -- I MUST SAY IT INEVITABLY WILL FAIL IN SOME CASES, IS THAT IF THERE WAS THEIR IS A SPILLAGE OR FECES, THERE WOULD BE OR SOMEONE WOULD COME AND CLEAN IT UP WITH BLEACH. BUT SINCE THIS IS BEING ADMINISTERED AT HOME, HOW WOULD THAT EVER BE MONITORED? >> FIRST -- >> IT'S NOT LIKE YOU HAVE THE PATIENTS IN HOUSE IN A SETTING WHERE SOMEONE REALLY IS DOING A GOOD JOB WITH THE BLEACH IF THERE IS VOMIT OR SPILLAGE OF SOME SORT. >> IF THERE IS AN ACCIDENTAL SPILLAGE, LET ME FIRST COME BACK TO THE INITIAL PART OF YOUR QUESTION. WE ARE VERY CONFIDENT THAT THE INHERENT SUICIDAL SYSTEM WILL HOLD IN ANY CIRCUMSTANCE BECAUSE FOR THIS, THE ONLY THING WHICH WE HAVE TO MODIFY IS TAKE OUT AN ESSENTIAL GENE IN DNA METABOLISM SO NO WAY TO GENE CAN BE REACQUIRED. WE HAVE SHOWN THAT. AND ABSENCE OF GENE MAKES THE BACTER YUM BECOMES CRITICALLY DEPENDENT ON A COMPONENT, WHICH IS NOT PRESENT IN THE ENVIRONMENT. AND IF IT DOES HAVE THAT COMPONENT, IT WILL SWITCH ON A SYSTEM TO CLEAVE ITS OWN GENOME AND THIS IS VERY ANCIENT SYSTEM PRESENT IN EVERY LIVING CELL, TO AVOID ACCUMULATION OF MUTATIONS. IF YOU GET DEVOID OF NUCLEOTIDES, YOU MIGHT WANT TO BUILD IN WRONG NUCLEOTIDES AT WRONG POSITIONS AND SO THIS IS A VERY ANCIENT SYSTEM, WHICH SHOWS BY DEFINITION, IT'S ROBUSTNESS. SO THE ONLY THING TO IMAGINE TO HAPPEN IS THERE IS AN ACCIDENTAL SPILLAGE AND WHERE YOU HAVE FOR A VERY SHORT TIME, YOU HAVE A RELATIVELY HIGHER CONCENTRATION AND THAT PATIENT CAN SEE AND CAN USE ANY HOUSEKEEPING DETERNAL ENT OR HOUSEKEEPING CLEAN TORE GET RID OF IT. >> I I APPRECIATE THAT. AND IN MANY CANCER IMMINO THERAPY TREATMENTS, THE PATIENT IS STRONGLY URGED TO GO HOME AND CARRY A BOLTS OF BLEACH AROUND AND HAVE A BOLT OF BLEACH HELP THEY URINATE FOR BLADDER CANCER, THAT IS THE TREATMENT PROTOCOL. I WONDERED THAT MORE ROBUSTLY STATED IN THE INFORMED CONSENT. AND SO THAT SEEMED LIKE ANOTHER EASY CHANGE TO MAKE. >> YES, WE AGREE TO THAT. >> THOSE WERE MY QUESTIONS. >> THANK YOU. >> SINCE WILL BE 21 YEARS AND NOT 18-YEAR-OLDS, I'M CONVINCED THEY WILL TAKE THE ADVICE ABOUT THE BLEACH. >> THANK YOU FOR THE OPPORTUNITY TO REVIEW THIS EXCELLENT PROTOCOL. IT WAS REALLY WELL WRITTEN AND I THINK THANK YOU FOR ALL YOUR ANSWERS. I'LL GO THROUGH MY POINTS. I THINK I LEARNED A LOT OF YOUR VIEW OF THE CLINICAL TRIALS. I'M IN THE SAME BUSINESSLIKE BILL, RECRUITING PATIENTS AND SO MY OPENING SENTENCE IS THAT THESE ARE REALLY DIFFICULT DECISIONS. WE USUALLY USE 18 AS AN AGE BECAUSE AN 18-YEAR-OLD COLLECTING A VERY SERIOUS ISSUE THAN A 21-YEAR-OLD. SO WE OFTEN NEGLECTED OUR PEDIATRIC PATIENTS SUFFERING THE MOST. THEY ARE ALWAYS THE LAST TO GET THE DRUG AND NOT THE FIRST. AT THE SAME TIME ACCIDENT ULCERATIVE COLITIS IS A DIFFERENT AND NEGLECTED DISEASE COMPARED TO CROHN'S. CROHN'S A LOT OF TREATMENT. ANTI-TNFs DO WELL. BUT THERE IS A LOT MORE TNFs IN ULCERATIVE COLITIS. A LOT OF THE MAJOR CENTERS GIVE VERY HIGH DOSES OF REM CADE AND THAT IS ONE WAY TO OVERCOME. SO THERE ARE A LOT OF NUANCES AND WE DON'T QUITE UNDERSTAND WHY CROHN'S IS SO MUCH MORE SENSITIVE RATHER THAN ULCERATIVE COLITIS. SO HAVING SAID THAT, I THINK THE DESIGN IS OKAY BY ME. I DON'T SEE ANY ALARMS OF SYMPTOMS OR ALARM ISSUES. AND NIH FUNDED TRIALS HAVE BEEN SIMILAR. I DON'T THINK IT IS VERY DIFFERENT AND AS BILL POINTED OUT, VICE SIS GENETICALLY VERY SIMILAR DISEASE EFFECTING DIFFERENT TISSUES, PLACEBO RATES IN PSORIASIS IS ZERO COMPARED TO OUR DISEASES WHERE THEY RUN 20-30%. I ALSO STRUGGLE WITH THE FACT THAT THEY DID NOT USE ANY RECTAL FORMULATION. I BROUGHT THAT UP. IF YOU WANT TO USE A MAYO SCORE, YOU CAN NOT USE RECTAL FORMULATION BECAUSE THAT PART WILL BE HEALED AND WON'T BE AS ACCURATE. BUT I'M NOT NECESSARILY CONVINCED THAT IS A GOOD IDEA. ALSO NOT VERY CONVINCED THAT LATE TO MODERATE MAY HAVE BEEN A FIRST BETTER STUDY RATHER THAN GOING TO THE VERY SEVERE PATIENT. A COUPLE OF 90s CAME UP IN THE DISCUSSION IS, I THINK - A COUPLE OF POINTS THAT CAME UP -- I DON'T THINK IT WAS SPECIFIED CLEARLY TO ME. OTHER POINTS WAS SIX MILLIGRAMS OF MMX IS NOT AVAILABLE IN THE UNITED STATES. I DON'T KNOW HOW THE INVESTIGATORS PLAN TO GET THIS DRUG. BUT WHAT IS AVAILABLE IS NINE MILLIGRAMS SO THAT WILL CHANGE THE PREDNISONE DOSE. SO I THINK WE NEED A CLARIFICATION ON THAT. AND THEN I'M STRUGGLING WITH WITH THE FACT WHETHER THIS IS PHEASMIS MAB. THE PRIMARY SEQUENCE IS SIMILAR AND I CAN DEFER THIS TO AN FDA COLLEAGUE. THIS SAY DIFFERENCE BETWEEN NECKS YUM AND PHYLLO SEC, TWO COMMONLY USED PPIs. THEY ARE PRETTY MUCH -- IT'S A VERY SIMILAR IN MANY WAYS YET DISTINCT. SO SHOULD THIS BE -- THE ONLY REASON WHY I'M STRUGGLING WITH THIS IS IT IT EFFECTS HOW OTHERS PERCEIVE THIS INTERIMS OF PATIENT RECRUITMENT. THIS WILL BE ONE WAY TO STELL AS JUST ANOTHER SYMPTOMSIA GIVING THROUGH BACTERIA RAN TAKING INJECTIONS. NEXT COMMENT I HAVE IS THAT IN THE 011 TRIAL, LACK TOW BACILLUS FOUND IN THE MUCOSAL BIOPSIES? AND THE SECOND WAS, WHEN WE GIVE CLINICALLY PATIENTS A LOT OF PROBIOTICS, THE FIRST THING THEY COM EXPLAIN DIARRHEA. DID YOU SEE ANY LACTOSE INTOLERANCE OR DIERA IN THE STUDIES THAT IN TERMS OF LACTOSE INTOLERANCE THEY WERE NOT EXCLUDED BECAUSE IT HAS NOTHING TO DO WITH LACTOSE. THESE ARE LACK TICK ACID BACTERIA. THEY MAY USE LACTOSE AS A SOURCE OF ENERGY BUT NOT IN OUR CASE BECAUSE THEY ARE DEVOID OF THE GENE THAT USES LACTOSE AS A CARBOHYDRATE SOURCE. SO, THAT IS NOT AN ISSUE. DIARRHEA, NO. NO INCREASE IN DIARRHEA RELATED TO ACTIVE VERSUS PLACEBO. ADDRESSING SOME OF THE OTHER QUESTIONS AND I WILL ALSO BACK TO BILL, ULCERATIVE COLITIS, I'M NOT SURE IF IT'S THE RIGHT THING TO DO, BECAUSE IT'S PLACEBO-CONTROLLED TRIAL, DOUBLE-BLIND. IT MEANS THAT WE ARE GOING POTENTIAL TOW STOP PATIENTS THAT ARE NOT RESPONDING TO TREATMENT BECAUSE THEY ARE TAKING PLACEBO AND WE WILL STOP. I MEAN, THAT WILL BE FROM A CLINICAL LOGISTICAL POINT OF VIEW AN ISSUE. BECAUSE WE WILL HAVE TO REPLACE THEM ALL THE TIME. I MEAN, THAT IS SOMETHING THAT ONE NEEDS TO CONSIDER. SO, I MEAN, I THINK THE RULES WE HAVE IN PLACE RELATED TO SERIOUS ISSUES, SUCH AS SEPTEMBERSEMIA OR CLINICAL BACTEREMIA BUT A WORSENING OF COLITIS SHOULD BE -- OBVIOUSLY FROM A CLINICAL TRIAL, LOGISTIC POINT OF VIEW -- >> NEEDS TO BE HOSPITALIZED FOR DEHYDRATION AND PROBABLY SHOULD STOP AT THAT TIME. >> DAY IN IN SICK. IF THEY GET SICKER FROM BASELINE, THEN THAT IS PROBABLY OKAY. THE SYSTEM IN OTHER TRIALS, WE COULD THINK THROUGH THAT AND PROPOSE WHAT OFTEN HAPPENS IS YOU -- THERE IS A PARTIAL MAYO SCORE WHICH IS RECTAL BLOODING, STOOL FREQUENCY AND PHYSICIAN GLOBAL ASSESSMENT AND WE COULD SET A THRESHOLD OF AN INCREASE FROM BASELINE IN THE PARTIAL MAYO SCORE AND THEN YOU CONFIRM IT WITH SORT OF EARLY ENDOSCOPY AND THE PATIENT WOULD EXIT IF THERE WERE SOME -- THAT HAS BEEN DONE BEFORE. >> IT IS A WELL RAISED POINT. THAT'S WHY WE PROPOSED A DISCLAIMER IN THE BROCHURE THAT OF COURSE WE DO NOT WANT TO NOURISH THIS CONFUSION IN THIS SENSE. >> BUT YOU DON'T THINK WE SHOULD GIVE A NEW NAME TO IT? >> THE PRODUCT NAME IS AG014. THE TWO GENETIC SEQUENCES ENCODE FOR -- SO THE SECRETED PROTEIN IS FRIZZ MAB. WE NEED TO FIND A NEW NAME FOR THAT BECAUSE IT'S NOT SYMPTOMSIA. IT'S SPECULATED. SO CERTAINLY -- [ INDISCERNIBLE ] [ MULTIPLE SPEAKERS ] >> AND GLYCOSYLATION AND OTHER THINGS. SO, IN THE TERTIARY STRUCTURES, I'M CONFIDENT I DON'T KNOW OFFHAND IT MUST BE DIFFERENT. >> THE LEVELS OF SECRETION ARE NOT HIGH ENOUGH TO DECIPHER THE TERTIARY STRUCTURE OF THE PROTEIN. WE CAN ONLY SERVE IF FUNCTIONALLY, DIFFERENT ASSAYS WE HAVE USED. IT'S IDENTICAL TO SEMSIA. >> AT CERTAIN LEVELS IT'S PROBABLY AN FDA NOMENCLATURE ISSUE. IT'S BIOSIMILAR IN FLEX MAB. IT'S THE SAME DISCUSSION. REMEMBER -- [ INDISCERNIBLE ] DOES ALSO PRODUCED BY E.COLI. SO IT IS ALSO A BACTERIAL PRODUCT WHICH WILL BE -- IT DOESN'T HAVE THE MAMMALIAN GLYCOSYLATION. I THINK OUR INTENTION IS TO REFER TO BY THE 014 TEST PRODUCT NAME. >> OKAY. ONE OF THE THINGS IS THAT THE T-CELL TRANSFER MODEL DATA PRESENTED TODAY? I THOUGHT IT WASN'T COMPLETED. DO WE HAVE THE DATA? >> WE USED THAT MODEL FOR THE DURATION OF THE TOXICITY. SO THESE DATA WE HAVE AND WE HAVE PARTS TO SHARE WITH YOU. AND ALSO CURRENTLY DOSE FINDING STUDIES. WE DON'T HAVE DATA FOR THE MOMENT. >> AND THE LAST COUPLE OF POINTS WAS I THINK I FEEL CONFIDENT THAT BASED ON MY CLINICAL EXPERIENCE IS THAT I'M NOT EXPECTING SYSTEMIC SEPTICEMIA WITH THIS BUT I DO EXPECT MICROBIAL CHANGES IN THE GUT LUMINAL ENVIRONMENT AND I PROPOSED THAT WE SHOULD DO A BASIC 16S SEQUENCE BEFORE THE TREATMENT AND AFTER. I THINK WE LEARN SOMETHING MORE ABOUT SAFETY PROFILE. I'M GLAD YOU AGREED. AND THEN MY LAST COMMENT BECAUSE THIS IS GENE THERAPY AND ALL THE CONCERNS RAISED, IF YOU LOOK AT ALL OUR TRIALS, SOME OF THE MAJOR DON'T NOT RECRUIT MUCH WHERE THE MOST SOPHISTICATED TRAINED EXPERIMENTAL GASTROENTEROLOGISTS UNDERSTAND A LOT OF THIS STUFF. OFTEN THEY COME FROM COMMUNITY CENTERS. IS THIS SOMETHING WE ALL AGREE THEY SHOULD BE RESTRICTED TO REAL ACADEMIC CENTERS? IS THAT SOMETHING YOU WORRY ABOUT? >> I THINK WHAT WE HAVE FOUND IS THE HETEROGENEITY HAS SUBSTANTIALLY GONE AWAY WITH CENTRAL ENDSCOPIC SCORING FOR ENTRY CRITERIA. THIS IS SO MANY SELECTION BIASES THAT COME INTO PATIENTS WITH MEDICALLENTS AND DEPENDING ON THE MARKET AND REGION EVEN PATIENT ACCESS, FOR INSTANCE WHERE I PRACTICE IN SOUTHERN CALIFORNIA, 40% OF THE ENTIRE POPULATION IS AT KEISER AND KEISER DOESN'T REFER OUT. SO THERE IS JUST A LOT OF PRACTICAL THINGS THAT I THINK MAKE THAT TOUGH. AND I GUESS I'M JUST CONTINUING TO BE IMPRESSED OVER THE LAST COUPLE OF YEARS HOW MUCH TITER THE CHIP CALL TRIAL POPULATIONS ARE GETTING WITH CENTRALLY READ ENDOSCOPY, EVEN IF YOU LOOK AT HISTORICALLY THERE WERE PROBLEMS WITH HETEROGENEITY OF PATIENTS RECRUITED IN EASTERN EUROPE, THAT HAS REALLY GONE AWAY WITH HAVING AN OBJECTIVE CENTRALLY READ MEASURE OF DISEASE ACTIVITIES TO COME INTO THE TRIAL. >> I THINK IT'S A POINT VERY WELL TAKEN. I MEAN, THE FACT THAT WE ARE CLASSIFIED AS GENE THERAPY WITHOUT ACTUALLY BEING GENE THERAPY IS HURTING US. AND I FULLY AGREE BUT WE NEED TO FOLLOW THE GUIDELINES AND AS YOU KNOW, THIS PRODUCT ALSO NEEDS TO BE APPROVED NOT ONLY BY IRB, BUT ALSO THE INSTITUTIONAL BIOSAFETY COMMUNITY. AND OF COURSE THESE PRACTICES YOU ARE REFERRING TO NOT NECESSARILY HAVE THAT. SO THAT IS OR COULD BE A POTENTIAL HURDLE IN RECRUITMENT OF PATIENCE AND WE FULLY AGREE WITH THAT. >> THAT'S ALL FOR MY COMMENTS. >> THANK YOU VERY MUCH FOR YOUR PERSPECTIVE. ANY OTHER QUESTIONS FROM OTHER RAC MEMBERS? >> I JUST HAD A QUESTION FOR INFORMATION ABOUT THE POSSIBLE IMMUNOGENICITY OF PRODUCT DELIVERED THROUGH THIS ROUTE. SO YOU SAID THE ANTIBODIES IS A HUMAN ANTIBODY OR HUMANIZED? AND IS THE FAB HUMOR NOT? SO ARE THERE EVER, WHEN IT'S GIVEN SYSTEMICALLY, ANY IMMUNE RESPONSES AND IF IT DOESN'T OCCUR, IS THERE A POSSIBILITY THAT BEING EXPRESS THE IN THE GUT AND INFLAMMATORY CONTEXT THAT MAY BE DIFFERENT? >> FOR SURE, THE SYSTEMICALLY ADMINISTERED PEG LATED PRODUCT DOES HAVE SOME IN IMMUNOGENISITY AND YOU CAN SEE THAT AND THE ANTIBODIES CAN BE NEUTRALIZING AND EFFECT THE PK. SO YOU DEFINITELY CAN SEE IT WITH THE SYSTEMIC PRODUCT AND WE PLAN TO LOOK FOR IT. >> AND WE HAVE PLENTY OF EXAMPLES DEMIS THAT ITING THAT A LOT IS DELIVERING IN THE GI TRACT AND WE HAVE PROVEN THAT NOT ONLY HEALTHY ANIMALS BUT ALSO IN ANIMALS WITH FULL-GROWN COLITIS SO YOU DELIVER THE ANTIBODY IN A SOUP OF CYTOKINES. WE HAVE AN EXAMPLE WITH THE ANTIBODIES SO IF YOU INJECT IN IV, WITHIN 3-5 DAYS, YOU HAVE IMMUNORESPONSE AND IF YOU DELIVER IT IN LIGHTIC CONDITIONS, AND NONE OF THE ANIMALS WE COULD FIND IMMUNOGENICITY. IT IS FEATURE OF THE GI TRACT AND MORE PRONE TO INDUCE TOWARDS RATHER THAN IMMUNIZATION OR IMMUNITY. SO WE ACCOUNTED FOR THAT AND NOW USE A HUMAN ANTIBODY FRAGMENT. BUT IN WE USE AN IMMUNOGENIC ANTIGEN EVEN IN THIS CASE, IT WILL NOT RESULT IN IMMUNOGENNISTIC. >> SO YOU'RE GOING TO MONITOR THAT IN PATIENT. >> YES. >> I JUST HAVE A SHORT COMMENT TO ADDRESS YOUR ISSUE ABOUT IS THIS REALLY PHEASMAB. IS THERE SUCH A THING AS CALLING IT PHEASMAB-LIKE OR LIKE PHEASMAB? I CAN'T PRONOUNCE IT. >> I WAS GOING TO SUGGEST MAYBE SOMETHING LIKE THE ACTIVE COMPONENT. SOME TERMINOLOGY TO SAY IT'S NOT IDENTICAL. BUT BIOSIMILAR. >> THAT IS AN OPTION, YES. >> I HAVE A QUESTION ABOUT IN THE DISCUSSION YOU INDICATED YOU COULD LOOK AT EARLY ENDOS COPY AND A SIGN OF WORSENING AS A POSSIBLE WITHDRAWAL FROM STUDY. WHAT IS THE TURN AROUND TIME FOR CENTRAL READING IF IT'S DONE AT A CENTER? >> IT'S ABOUT 48 HOURS OR SO. THE EQUIPMENT THAT IS USED COMPRESSES VIDEOS, UP LOADED OVER THE INTERNET TO CENTRAL READING SITE AND THEN THAT IS STAFFED IN A WAY THAT CAN BE TURNED AROUND IN 48 HOURS. SO IT'S REASONABLY QUICK. >> ANY OTHER RAC MEMBER QUESTIONS? >> WHEN YOU ASKED ME IF I HAD ANYTHING ELSE THAT WASN'T CONSIDER, FOR ME, AND I KNOW THERE IS A DIFFERENCE OF OPINION AND A FIRST IN HUMAN STUDY. MY PREFERENCE WOULD BE TO SEE RECTAL ADMINISTRATION FIRST. I'D LIKE TO SEE THE STEROID DOSE STABILIZE FOR A MONTH BEFORE ENTRY. I'D LIKE TO SEE THE STAGE INCREASED ABOUT SIX FOR ENTRY, MAYBE 7, MAYBE 8. AND PERSONALLY AND I'M NOT SURE THAT EVERYONE WILL AGREE WITH IT, GIVEN FIRST IN HUMAN TRIAL BEFORE I COULD VOTEIOS THIS STUDY, I'D LIKE TO SEE THE PHASE I DATA. >> AND JUST TO CLARIFY, I THINK SOMEONE SAID THE CUT OFF IS 6 OR HIGHER SCORE. THE PROTOCOL SAYS 5. >> IT WILL BE 6. >> I HAD A SPECIFIC QUESTION AND YOU MIGHT HAVE ALREADY ADDRESSED IT WITH PARTICULAR REGARD TO AG011. WITH THE IL10 EXPRESSION. SO I UNDERSTAND IT IS THE SAME BACTERIA AND SAME EXPRESSION BUT THE THERAPY QUOTE/UNQUOTE DID NOT WORK. DID YOU HAVE EVIDENCE OF ACTIVITY OF INTENDED MECHANISTIC ACTIVITY? >> SO IT'S NOT EXACTLY THE SAME BACTERIA. YES. IT IS LACK CAUCUS LACT US. BASED ON THAT INITIAL STUDY, WE FOUND OUT THE BACTERIA DIDN'T SURVIVE BY THE TIME THEY WERE EXCRETED. IT TURNED OUT THERE WERE HIGHLY SUSCEPTIBLE TO BIOSALTS. WE KNEW THAT LACTOCAUCUS TO HIGH LEVELS ARE SUSCEPTIBLE. THAT'S THE REASON WE USED THESE. SO WE WEREN'T EXPECTING THAT EVEN LOWER LEVELS OF BIOSALT CONCENTRATIONS IN THE COLON, WHICH ARE HIGHER IN PATIENTS WITH THE MORE RAPID TRANSIT, THAT THERE WERE ALSO DETRIMENTAL TO THE LACT CAUCUS. SO WE HAD TO CHANGE THE GENETIC BOARD TO MAKE THEM RESISTANT. SO WHAT WE ARE USING TODAY HAVE DIFFERENT BACKGROUND THAN THE ONES USED INITIALLY. SO THEY ARE RESISTANT TO BIOSALTS. SO WE ANTICIPATE TO HAVE AN EFFECT BASED ON THE ANIMAL DATA. NOTABLY BASED ON THE PK DATA. PICKS ARE USED FOR PK BECAUSE THEY HAVE A CUT WHICH IS VERY SIMILAR TO HUMAN SITUATIONS FROM A TRANSIT POINT OF VIEW AND ALSO FROM A BIOSALT COMPOSITION POINT OF VIEW. FOR EXAMPLE, BIOSALTS ARE LESS TOXIC IF I MAY CALL IT THAT TO LACTOCAUCUS THAN THE ONES FROM OM IN THIS VORCE. AND A PIG IS AN OMNIVORE. IF WE COMPARE THE OLD ONES COMPARED TO THE NEW ONES, SURVIVAL TIME WAS LESS THAN AN HOUR. IT WAS ALL GONE. WHILE HERE WE HAVE FIND LIVING BACTERIA UP TO 30 HOURS AFTER CAPSULE ADMINISTRATION. SO THERE IS SAY FUNDAMENTAL DIFFERENT THERE. INTERESTINGLY ENOUGH, REFERRING TO YOUR QUESTION THAT YOU PICK UP ANY KIND OF BIOLOGICAL ACTIVITY IN THAT OLD TRIAL? WE DIDN'T. SO THERE WAS NO EFFECT ON MUCOSAL HEALING AND ALSO WE TOOK A NUMBER OF BIOPSIES FOR A NUMBER OF DIFFERENT DOWNSTREAM BIOMARKERS FOR IL10 RECEPTOR ACTIVATION AND DIDN'T FIND MUCH. SO THAT TRIAL WAS SUB OPTIMAL. I MEAN NO EXPOSURE. >> AND I COULD INFER THAT THIS WAS NOT -A THAT AGENT WAS NOT EXEMPT IN PIGS? >> AFTERWARDS. WE USED IT AS CONTROL. ALL THE PK IN THOSE DAYS WAS IN RODENTS AND WE HAD GOOD SURVIVAL AND WHEN THE DATA CAME OUT, OF COURSE THAT WAS A BIG SURPRISE. SO WE STARTED LOOKING FOR A DIFFERENT ANIMAL MODEL. WE TESTED THE SAME IN THE PIG AND NO SURVIVAL. HOWEVER, WHEN WE CO-ADMINISTERED WITH QUEST RAN, WHICH IS A RESIN THAT BINDS BIOSALTS AND NEUTRALIZES THEM, WE WERE ABLE TO BOOST VIABILITY BACK TO 100%. WE KNEW WHAT THE CULPRIT WAS. >> THANK YOU. >> OTHER RAC MAB QUESTIONS? ANY QUESTIONS FROM MEMBERS OF THE PUBLIC? SEEING NONE, WE'LL TAKE A SHORT BREAK TO DISCUSS OUR RECOMMENDATIONS. >>> WE'LL GO BACK INTO SESSION AND I WILL READ THE DRAFT LETTER OF RECOMMENDATION AND THEN WE CAN COMMENT DISCUSS IT AND VOTE ON IT. SO BASED ON THE DISCUSSIONS WE HAVE SEVERAL RECOMMENDATIONS TO THE INVESTIGATORS. UNDER THE HEADING OF CLINICAL, OUR FIRST ONE IS THAT THIS IS A PHASE II A STUDY THAT WILL BE CONDUCTED AFTER A PHASE I STUDY IN HEALTHY VOLUNTEERS. THE PREVIOUS STUDY USING L BACILLUS IN ULCERATIVE COLITIS PATIENTS IS LIMITED UTILITY IN ASSESSING SAFETY BECAUSE IT DID NOT SURVIVE. CONSIDER CONCEPT STUDY USING RECTAL ADMINISTRATION TO ESTABLISH THIS BACTERIA SECRETING THE ACTIVE COMPONENT CAN HEAL MUCOSA BEFORE MYSELFING -- MOVING TO A PHASE II A STUDY AND THEN PROTOCOL REVIEWED SUBJECTS WITH THE MARROW CLINIC SCORED GREATER. THIS COULD INCLUDE PATIENTS 1-2 STOOLS OF A DAY WITH MODERATE DISEASE. CONSIDER WHETHER THIS FIRST IN HUMAN TRIAL SHOULD BE LIMITED TO PATIENTS WITH MORE SYMPTOMATIC DISEASE, A SCORE OF 7 OR HIGHER, ASS THE DISEASE IS LIKELY SIGNIFICANTLY IMPACTS THEIR QUALITY OF LIFE. THE THIRD COMMENT IS WHILE THIS DISEASE EFFECTS TEENS AND YOUNG ADULTS, IN THIS FIRST IN HUMAN STUDY, CONSIDER WHETHER YOU CAN ENROLL A MORE MATURE POPULATION REQUIRING THE LOWER LIMITS AGE FOR ENROLLMENT TO BE 21 YEARS. THE FOURTH CLINICAL COMMENT IS, THE PROTOCOL WILL LIMIT ENTRY TO PATIENTS WHO ARE ON STEROID DOSE THAT DOESN'T EXCEED 20 MILLIGRAMS PER DAY. PROVIDED THE PATIENT IS ON STEROIDS FOR 4 WEEKS PRIOR TO SCREENING AND THE DOSE MUST BE STABLE FOR TWO WEEKS. MAYBE PRUDE TONIGHT REQUIRE STABLE DOSE OF STEROIDS FOR 4 WEEKS. THE EARLY WITHDRAW CRITERIA SHOULD INCLUDE STOPPING RULE THAT SETS A THRESHOLD TO RECOGNIZE THERE WILL BE SOME FLUXATION IN COLITIS SYMPTOMS OVER THE COURSE OF THE TRIAL. BUT WITHDRAW SHOTS HAVE ADVERSE EVENT DURING THE TRIAL USING CLINICAL AND/OR ENDOSCOPY CRITERIA. ETHICAL LEGAL SOCIAL RECOMMENDATIONS, THERE WAS A QUESTION REGARDING THE PRODUCT OF THIS BACTERIA IS FLIES MUST BE. IT'S NOT PEG LATED AND THERE MAY BE OTHER DIFFERENCES. KNOW FORMED CONSENT STATES TO MAKE AG014 THE DNA HAS BEEN ENGINEERED IN THE LABORATORY TO SECREASE FRIZZIMABLE. CONSIDER WHETHER A MORE ACTIVE STATEMENT. AND IN THE LAST RECOMMENDATION THE INFORMED CONSENT SHOULD CLEARLY ARTICULATE THAT BLEACH BE USED TO CLEAN UP OF SPILLAGE OF BODY FLUIDS THAT CONTAIN THE VECTOR. THOSE ARE OUR COMMENTS. ANY RESPONSES FROM THE INVESTIGATORS TO THESE POINTS? >> THANK YOU VERY MUCH. I THINK IN TERMS OF THE INCLUSION CRITERIA FOR CLINICAL TRIAL ITSELF, OF COURSE THIS WE NEED TO CONSIDER AND WE WILL NEED TO BALANCE THIS ALSO AGAINST THE POSSIBILITY OF PRECLUDING PATIENTS. NOTABLY A STABLE DOSE OF STEROIDS OVER FOUR WEEKS IN ACTIVE COLITIS PATIENT CAN BE A CHALLENGE. THIS IS SOMETHING WE KNOW FOR SURE. TWO WEEKS IS ALREADY SHARP OF COURSE WE NEED TO DISCUSS THIS INTERNALLY. DOING TRANSRECTAL ADMINISTRATION FIRST AGAIN WE HAVE DIFFICULTIES TO UNDERSTAND THE RATIONAL FROM A SAFETY POINT OF VIEW AS WE THINK THAT IT IS AS -- DIFFS THE SAME EXPOSURE AS AN ORAL ADMINISTERED CAPSULE IN DISTAL COLITIS VERSUS PEN COLITIS. WE RUN THE RISK OF NOT SPEAKING UP EFFICACY SIGNAL BECAUSE YOUR RECTAL ADMINISTRATION WILL ONLY GO UP TO THE LECTURE IF YOU'RE VERY LUCKY. THAT'S MOST OPTIMAL ADMINISTRATION CONDITIONS. HOWEVER IF YOU HAVE DISEASE BEYOND THAT T WILL CONTRIBUTE TO THE SYMPTOMS SO, WE MAY NOT PICK UP EFFICACY SIGNAL BY JUST USING RECTAL ADMINISTRATION. SO THIS IS SOMETHING WE NEED TO CONSIDER AND IF THIS IS STANDING OUT, WE NEED TO CONSIDER OR DOING THIS STUDY AS SUCH IN U.S. WE FULLY CONCUR WITH THE STATEMENTS RELATED TO THE CHANGE OF THE INFORMED CONSENT FORM SO RELATED TO THE CONSTRUCT AS WELL AS THE USE OF BLEACH AND ALSO 21-YEAR-OLD LIMITATION IS OF COURSE SOMETHING THAT WE ARE HAPPY TO TAKE ON. FINALLY, THE SEVERITY OF THE DISEASE. LET ME PUT THIS IN PERSPECTIVE AGAIN. WE ARE TRYING TO FIND A WAY TO TREAT PATIENTS TO, BRING ACTUALLY A BIOLOGICAL UP TO FIRST LINE OR MAYBE SECOND LINE TO BRING THIS TO HELP PATIENTS GETTING RID OF THE STEROIDS THAT THEY GET FIRST. THAT'S THE NORMAL STANDARD WAY OF TREATING PATIENTS THAT COME IN AS FIRST WITH COLITIS. UNLESS THEY NEED TO BE HOSPITALIZED AND EVEN THEN THEY WILL GET IV STEROIDS. WHAT WE TRY TO DO IS FIND A WAY TO BRING BENEFITS OF NTTF TO THIS PATIENT POPULATION. BY INCREASING HURDLES IN TERMS OF SEVERITY OF DISEASE. WE MAY RUN THE RISK OF NOT SEEING THE SIGNAL WE WANT TO SEE IN THIS STUDY. HAND SIGNALS, WE WILL NEVER GET TO THE PATIENT WE REALLY INTEND TO TREAT. SO I'M A BIT CONFUSED ALSO BECAUSE THE MODERATE TO SEVERE IN ANY KIND OF CLINICAL TRIAL, WITH A BIOLOGICAL THESE DAYS, IS BASED ON THE CRITERIA THAT WE USE. QUI EVAPORATE MADE NEW CRITERIA FOR MODERATE TO SEVERE. -- WE HAVEN'T MADE NEW CRITERIA. THESE ARE CRITERIA USED FOR ANY BIOLOGIC FOR ANY TREATMENTS. MAYBE SOME OF THE NEW ORAL ADMINISTERED MODULATORS, THEY ALL GO THROUGH THE SAME CRITERIA. I'M NOT SURE. I MEAN, WE HAVE SOME ISSUES WITHERATION THE BAR FOR THIS DRUG, WHILE YOU DON'T RAISE IT FOR DRUGS THAT ARE FAR MORE TOXIC AND ARE THE ONES THAT ARE USED IN STANDARD PRACTICE. >> ANY OTHER RAC MEMBERS WANT TO RESPOND? THEN WE WILL VOTE ON OUR RECOMMENDATIONS STARTING WITH DR. ORNELLES. >> YES. >> APPROVED. >> KOCH YES. >> FOST, YES. >> DRESSER, YES. >> HARD SON, ABSTAIN. >> YES. >> KOHN, YES. >> YES. >> YES. >> WOOLLY YES. >> YES. >> CURRY, ABSTAINED STAIN. CURRY ABSTAIN. ... >> YES. >> WHAT ARE THE REASONS FOR THE ABSTENTIONS IF YOU MIND SAYING? >> MINE SPECIFICALLY REALITIES TO THE TRANSVECTAL VERSUS ORAL ADMINISTRATION. I DON'T FEEL STRONGLY AT ALL THAT IT NEEDS TO BE TRIED TRANSRECTALY FIRST. >> I'M STILL JUST NOT COMFORTABLE WITH THE ARGUMENT ABOUT THE INCLUSION CRITERIA. I HEAR THE ARGUMENT FOR BOTH SIDES AND I'M NOT SURE I FEEL COMFORTABLE WITH EITHER. >> WHICH COMPONENT? >> ABOUT THE SCORE, CHANGING IT FROM 5-6 AND WANTING TO CONSTRAIN THE STUDY TO THE SICKER POPULATION. I'M JUST NOT SURE THAT I UNDERSTAND WELL ENOUGH WHY WE WANT TO RECOMMEND THAT. >> WOULD YOU JUST READ THE SECTION AGAIN ABOUT THE TRANSRECTAL? HOW STRONGLY WAS THAT WORDED? MAYBE A MISHEARD IT BUT I THOUGHT IT WAS PERMISSIVE. >> THIS IS A PHASE II A STUD THEY WILL BE CONDUCTED AFTER PHASE I STUDY IN HEALTHY VOLUNTEERS. PREVIOUS STUDY USING LACKTIS EXPRESSING IL10 IN ULCERATIVE COLITIS PATIENTS IN UTILITY SAFETY BECAUSE THE BACTERIA DO NOT SURVIVE THE TRANSIT TO THE COLON. CONSIDER PERFORMING A SMALL INITIAL PROOF OF CONCEPT STUDY USING RECTAL ADMINISTRATION TO ESTABLISH THE BACTERIA SECRETING THESE COMPONENTS CAN HEAL THE MUCOSA PRIOR TO MOVING TO A PHASE II A STUDY. IT SAYS, CONSIDER. WHICH SEEMS TO ME A MILD RECOMMENDATION. AND IT IS COMPATIBLE WITH THEM CONSIDERING IT AND REJECTING IT. SO, THAT'S WHY I DIDN'T THINK IT WAS -- I MEAN, I SHARE -- I DON'T THINK WE SHOULD SET LIMITS ON THE ADMINISTRATION ISSUE, AND THAT SEEMS TO ME TO ALLOW THEM TO DO IT WHICHEVER WAY THEY WANT. >> I AGREE WITH THAT. IT DOES DOCUMENT IT, THOUGH. AND COULD IMPACT OTHER REGULATORY BODIES. >> SO WE HAVE ON RECORD THE BASIS FOR YOUR ABSTENTION IS THAT. OKAY. SO THANK YOU. THAT CONCLUDES THIS DISCUSSION. THANK YOU AGAIN AND BEST OF LUCK FOR YOU AND YOUR PATIENTS. WE WILL TURN TO OUR NEXT PROTOCOL: TRANSFER PROTOCOL #1310-1266: A PHASE 1, OPEN-LABEL CLINICAL TRIAL EVALUATING THE SAFETY, TOLERABILITY AND IMMUNOGENICITY OF INTRADERMALLY ADMINISTERED ID-LV305 IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC CANCER EXPRESSING NY-ESO-1 PI: NEETA SOMAIAH, M.D., UNIVERSITY OF TEXAS, MD ANDERSON CANCER AN ASSISTANT PROFESSOR OF THE DEPARTMENT OF SARCOMA MEDICAL ONCOLOGY IN THE DIVISION OF CANCER MEDICINE AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER IN HOUSTON, TEXAS. THE SPONSOR IS IMMUNE DESIGN CORPORATION. AND OUR PRESENTERS WILL BE THE CHIEF SCIENTIFIC OFFICER OF IMMUNE DESIGN CORPORATION AND RICHARD KENNY, CHIEF MEDICAL OFFICER OF THE IMMUNE DESIGN CORPORATION. WELCOME AND TAKE YOUR TIME TO GET READY. >> GOOD MORNING. MY NAME IS RICHARD KENNY, THE CHEF MEDICAL OFFICER FOR IMMUNE DESIGN AND WE WANTED TO THANK YOU FOR GIVING US AN OPPORTUNITY TO COME AND PRESENT THE CANCER VACCINE CANDIDATE. 305. I WILL BE GIVING A LITTLE BIT OF AN INTRO. DR. R. OUR CHIEF SCIENTIFIC OFFICER IS HERE AND WILL BE GOING THROUGH MOST OF THE PRECLINICAL STUDIES AND SOME OF THE CMC. OUR PROFESSOR AT MD ANDERSON IS AN EXPERT IN SARCOMA ANCOLOGY. THE PI FOR THE CLINICAL STUDY AND SHE'LL BE DETAILING SOME OF THAT. WE WILL BE GOING THROUGH A LITTLE BIT OF THE RATIONAL. TAKING OVER TO TALK ABOUT THE FEATURES OF THE VECTOR THAT HAS BEEN MODIFIED SUBSTANTIALLY. WE'LL TALK ABOUT THE CMC AND THEN GO INTO THE CLINICAL STUDY DESIGN AND SHOW YOU THE DETAILS OF THAT. JUST TO START OUT WE WANTED TO SHOW WHY WE ARE DOING WHAT WE ARE DOING. DR. MEL MAN DID A NICE SUMMARY A COUPLE OF YEARS AGO THAT TALKED ABOUT THE 3 TYPES OF APPROACHES YOU CAN TAKE TO WORK ON TUMOR IMMUNOTHERAPY. IF YOU LOOK AT THE DENDRITIC CELLS, YOU CAN TRY TO DRIVE THE SYSTEM. IF YOU WORK ON THE T-CELL RESPONSE, THE MOST CURRENT CLINICAL TRIALS ARE WORKING ON THE AXE TOYS TRY TO FIGHT THE IMMUNOSUPPRESSION. WE FOCUS ON THE DENDRITIC CELLS AND TRY TO MAKE THEM THE ENGINE THAT DRIVES THE SYSTEM TO ACCELERATE THE PRODUCTION OF THE CYTOTOXIC T-CELLS. CANCER IMMUNOTHERAPY OF COURSE HAS SUFFERED OVER THE LAST DECADE OR MORE. MOSTLY DUE TO THE INEFFICIENT GENERATION OF CTLs. THERE IS CERTAINLY BEEN CLINICAL PROOF OF CONCEPT THAT HAS BEEN DEMONSTRATED MOSTLY WITH EX-VEVO GENERATED DENDRITIC CELL APPROACHES. THE PROBLEM WITH THAT IS THAT THESE CELLS REALLY HAVE A HARD TIME MIGRATING TO THE SITE OF THE TUMOR. THEY ARE GIVEN BACK TO THE BLOOD. AND THE PROCEDURE ITSELF WAS VERY DIFFICULT TO STANDARDIZE AS KNOW AND IT CAN BE VERY COSTLY. WE ARE MAKING THIS VACCINE CANDIDATE AS A FIRST IN CLASS APPROACH TO IMPROVE THE GENERATION OF CTLs. WE HAVE A SELECTIVE TARGETING OF TUMOR ANTIGENS TO THE DEN CRITIC CELLS WITH A VECTOR APPROACH WHICH IS INTERESTING. WE'LL GO THROUGH THAT. WE HAVE DONE A LOT OF PRECLINICAL WORK IN VARIOUS MOUSE MODELS THAT HAS SHOWN WE GENERATE VERY ROBUST CTL RESPONSE AND GET TUMOR CONTROL. I THINK IN A WAY THAT IS WELL DEMONSTRATED. WE ARE USING A VALIDATED TUMOR ASSOCIATED ANTIGEN. YNES1 SELECTIVELY EXPRESSED IN TUMORS AND HIGHLY IMMUNOGENIC WHEN IT IS PRESENT. IT IS A MAJOR TARGET FOR CD8 POSITIVE T-CELLS AND TOW IS GIVES ITS RATIONAL BEHIND WHAT WE ARE DOING. WE WILL BE FOCUSING IN THE CLINICAL TRIAL ON THE IMMUNOLOGICAL RESPONSE TO LOOK FOR EARLY PROOF OF CONCEPT. AND SO NOW I WANT TO TURN THE PRESENTATION OVER TO YAWN TO TALK ABOUT THE FEATURES. >> THANK YOU VERY MUCH FOR THE INTRODUCTION. AND LET ME EXPLAIN TO YOU WHY WE CHOSE LENTE VIRUS VECTOR AS THE CANDIDATE FOR OUR CANCER VACCINE APPROACH. NOW, YOU KNOW OF COURSE THAT THE DENDRITIC CELL IS THE MAIN ENGINE OF DRIVING GENERATION OF T-CELLS AND WE WANT TO TARGET SPECIFICALLY DENDRITIC CELLS IN VIVO. WHAT DO WE NEED FOR IT? WE NEED THE VECTOR AND WE HAVE TO BE ABLE TO TRANSDUCE THE CELLS AND EXPRESS RECOMBINANT PROTEINS. IT COMES FROM A ENVELOPE PROTEIN OF A VIRUS THAT NATURALLY INFECTS DENDRITIC CELLS. ALPHA VIRUS TRANSMITTED BY MOSQUITOES THAT HAS BY VIRTUE OF A GLYCOSYLATION OF ENVELOPE PROTEIN, DENDRITIC CELLS. SO THIS ENVELOPE PROTEIN IS WHAT WE USED TO TYPE OUR LENTE VIRUS VECTOR AND IT IS MODIFIED AND I'LL WALK YOU THROUGH THE DETAILS IN A MINUTE. WE TARGET A VERY IMPORTANT RECEPTOR CELL THAT ALL OF YOU KNOW. IT'S THE DC SPECIFIC INTRACELLULAR ADHESION MOLECULE NONINTERGRIN. IT'S A BINDING RECEPTOR THAT IS PRESENT ON CERTAIN DC SUBSETS FOUND IN THE SKIN MUCOSAL OF THE LIMP NOSED. AND THE PATHOGENS THEN START TO GET ACTIVATED AND MY GREAT THE LYMPH NODE AND ACTIVATE T-CELLS. SO, BY VIRTUE OF USING A MODIFIED SYNTHESIS VIRUS ENVELOPE DEVOID OF THE NATURAL VIRUS, WE ALSO ATTENUATE THE VECT TORAND I WANT TO EXPLAIN THAT AS WELL. NOW YOU MAY KNOW THAT DENDRITIC CELLS HAVE RESTRICTION FACTORS THAT MAKES THEM RESISTANT TO INFECTIONS WITH LENTE VIRUSES. WE INCLUDED A PROTEIN FROM ANOTHER LENTE VIRUS CALLED UKX TO ENABLE EFFICIENT TRANSDUCTION. WE ARE AWARE THIS WILL BE ONE OF THE FIRST TIMES WE ARE TAKING A LENTE VIRUS VECTOR INTO HUMANS IN VIVO. SO FAR, THERE HAS BEEN A LARGE BODY OF DATA GENERATED WITH LENTE VIRUSES IN EX-VEVO SETTINGS. DCs AND OTHER CELLS SEEM TO BE VERY SAFE, HOWEVER, WE KNOW THAT WE HAVE TO GO ONE STEP BEYOND THIS TO BE ABLE TO PROOF THAT THE SAFETY ACCEPTABLE FOR IN VIVO EXPERIMENTATION. NOW THE BACKBONE OF THE INVESTOR IS A STATE-OF-THE-ART APPLICATION IN THE GENERATION. LENTE VECTOR DERIVED FROM HIV LAB STRAIN CALLED NL4. EXPENSIVELY MODIFIED. I'LL SHOW WHAT YOU WE DID TO IT T HAS SEVERAL ENHANCED SAFETY FEATURE TO REDUCE THE VERY LOW RISK OF RECOMMENDATIONS OF THESE VECTORS AND HAS A NOVEL FEATURE. IT SETS IT APART FROM ALL OTHER LENTE VECTORS USED IN HUMANS. THIS IS A NATURE PAPER SHOWING THE VIRUS IS WELL UNDERSTOOD AND STUDIED AND HAS BEEN CRYSTALIZED. THE STRUCTURE OF THE PROTEIN IS KNOWN TO EXTRACELLULAR LOOPS THERE. AND THIS CARTOON SHOWS INTRODUCING MUTATIONS IN THE E2. SUBOCCUPANT OF THE PROTEIN TO INCREASE BINDING TO A SIGN AND B REMOVE A SO-CALLED SULFATE BINDING SITE T IS FOUND IN THE MANY CELLS IN THE BODY AND OUR RE-- ARE RESPONSIBLE IN PART OF THE VIRUS WHICH WE DON'T WANT. THE WE WANT THE VIRUS TO TARGET DENDRITIC CELLS. I TELL YOU THAT IT IS A BINDING RECEPTOR SO IN ORDER TO MAKE THE VECTOR LOOK LIKE THE VIRUS, WITH RESPECT TO -- WE REINTRODUCE THEORY. >> R. GLYCOSYLATION THAT ONLY INSECT CELLS NORMALLY DO. SO WE ARE GROWING THE VECTOR IN THE PRESENCE OF THE INHIBITOR AND THAT RESULTS IN A HIGH GLYCOSYLATION OF THE PROTEIN WHICH THEN EFFECTIVELY LOOKS LIKE AS IF IT CAME OUT OF AN INSECT CELL WITH THE DIFFERENCE BEING THE MUTATIONS I JUST EXPLAINED. MUTATION ARE MOST OF THEM ARE AVAILABLE PUBLICLY SO THE PHENOTYPIC CHANGES CABLE LINKED TO THE MODIFICATIONS AND A LOT IS KNOWN ABOUT THE GLYCOSYLATION AS WELL. SO HOW DOES THE DC FRANCE DEDUCTION NOW WORK AND WHAT EVIDENCE DO WE HAVE THAT IT IS SPECIFIC? WE BASE MOST OF OUR EXPERIMENTS ON MONOCYTE DERIVED DISEASE. AND THIS CARTOON SHOWS THIS IS A FLOW EXPERIMENT THE VECTOR IN THIS CASE AND WE CALL OUR VECTOR PLATFORM VP02. SO IN THE FOLLOWING WHEN I REFER TO VP02, THIS IS THE GENERIC VECTOR PLATFORM EXPRESSING PROTEIN AS YOU CAN SEE HERE. WHENEVER SOMETHING LIGHTS UP ON THE RIGHT-HAND SIDE OF THE BOX, THAT MEANS GFP EXPRESSION AND YOU SEE THAT WHEN YOU TAKE THESE HUMAN MONOCYTE DERIVED DENDRITIC CELLS AND TRANSFECT THEM WITH THE VECTOR, YOU GET NICE TRANSDUCTION IN A DOSE-DEPENDENT FASHION INHIBITED BY REVERSE TRANSCRIPTORS. WHEN YOU ADD AN ANTIBODY, YOU ABROGATE THE TRANSDUCTION. SO THE TROPISM IS DEPENDENT ON DC SIGN. THANS DUNGS IS DEPENDENT ON VPX, ACCESSORY PROTEIN DERIVED IN A SEEMIAN LENTE VIRUS THAT INTERACTS SAM HD1, OVER EXPRESSED DENDRITIC CELLS AND PREVENTS THESE CELLS FROM BEING INFECTED WITH VIRUSES. AND THE PROTEIN IN THIS PACKAGE INTO OUR PARTICLES AS THIS WESTERN BLOT SHOWS, THESE ARE AGAIN DCs AND EXPERIMENTATION TRANSDUCED WITH VECTORS WHICH ARE HERE FOR EXAMPLE MADE IN THE PRESENCE OR ABSENCE OF THE INHIBITORS AND ONLY IF YOU HAVE THE GLYCOSYLATION AND THE VP PRESENT, DO YOU GET TRANSDUCTION AND AGAIN DOSE DEPENDENT AND CAN BE INHIBITED BY REVERSE TRANSCRIPTION. WHAT DID WE DO TO MAKE THIS VECTOR SAFER THAN THE EXISTING PLATFORMS? TO BEGIN WITH, OUR VECTOR IS A INDUSTRY STANDARD LENGTHY VECTOR BACKBONE BASED ON A 5 PLASMID SYSTEM WHICH IS TRANSFECTED INTO 293 CELLS. THE GENE HAS ANOTHER CONTROL OF A PROMOTOR AND THE TRANSGENE IN OUR CASE IS THE TUMOR ANTIGEN. IT IS A GENOME STANDARD IN THE INDUSTRY WHICH MEANS THAT AT THE 3 PRIME REGION HAVE YOU MULTIPLE DELETES LESIONS THAT RACKETED ACTIVATE ELEMENTS. SO IF THIS VECTOR SHOULD INTEGRATE, YOU PREVENT ACTIVATION OF DOWNSTREAM SIMILAR GENES FROM THE PROMOTOR. SO WE EXTENDED THE DELETIONS HERE TO MAKE IT EVEN SAFER AND WE ALSO DELETED A POLYPURINE TRITE WHICH LEADS TO FORMATION OF SINGLE LTR EPISOMES IN THE NUCLEUS AS OPPOSED TO DOUBLE LTRDNA WHICH CAN INTERGREAT. THIS IS DEPICTING THE PLASMID THAT CARRIES THE METRICS QUALITY IN THE CAPSID IN THE REVERSE TRANSCRIPTASE AND THE INTERGRAZE. WE PREVENT THE PROBLEM IN THE FIELD RECOMBINATION DUE TO SIMILARITIES OF THE SEQUENCES HERE. WE REMOVE THIS ELEMENT HERE WHICH COULD RECOMBINE WITH THIS ELEMENT. AND INTRODUCE A MUTATION OF THE VIRUS. THIS IS INTERESTING AND IS WELL-KNOWN AND WELL DESCRIBED AND IT HAS AN ACTIVE CENTER AND THERE ARE A COUPLE OF IMPORTANT AMINO ACIDS IN ACTIVATING THIS ONE IN POSITION 64 ABOLISHES THE INTEGRATION CAPACITY OF THE INTERGRAZE AND THEN THE VECTOR HAS PROTEINS AND ONE IS STANDARD NEEDING THAT FOR ENHANCEMENT. AND FINALLY, OUR ENVELOPE. NOW I SPOKE ABOUT INTEGRATION DEFICIENCY AND WE ARE SEEING THIS DATA NOW. THIS IS COMPLEX SO I'LL TRY TO EXPLAIN IT IN DETAIL. WE STUDY INTEGRATION AND WE ASKED THE QUESTION IF WE TRANSDUCE CELLS. THESE ARE NOW TWO 93 CELLS THAT EXPRESS DC SIGN AND TRANSDUCE THE VECTOR AGAIN EXPRESSING GFP AND HOW DO WE MEASURE INTEGRATION EVENTS? YOU WANT PCR AND VECTOR SEQUENCES AND ALLOWS YOU TO DETERMINE THE INTEGRATION EVENTS IN THE GENOME AND IF YOU COMPARE THESE TWO OR PARCELS HERE, YOU SEE THAT THE VECTOR LEADS TO A 300-700 REDUCTION OF INTEGRATING EVENTS AS MEASURED BY PCR. THE NEXT QUESTION IS HOW MANY OF THESE EVENTS WOULD LEAD TO RECOMBINANTLY EXPRESSED PROTEINS? WE MEASURE IN THIS CASE BY INTRODUCING A NEOMICE IN RESISTANT GENE AND YOU SEE AGAIN WE KNOCK DOWN INTEGRATION BY UP TO THREE LOGS AND THIS IS A TIME CROSS EXPERIMENT WHERE WE ASK THE QUESTION IF YOU NOW LOOK AT THE CELLS OVER TIME AND THE LOSS OF THIS PROTEIN EXTENSION FUNCTION, YOU SEE AFTER 30 DAYS, THE CELLS TRANSDUCE WITH A VECTOR WHAT INITIALLY EXPRESSING GFP AND THE LEVEL EXPRESSION GOES DOWN TO ALMOST THE LEVEL OF CONTROL HERE AND HERE IN NUMERICAL CALCULATIONS. SO I THINK WE CAN SHOW YOU PRETTY CONSISTENTINGLY THAT WE REDUCE INTEGRATION CAPACITY OF THIS VECTOR BY UP TO 3 LOTS. SO IT'S NOT ZERO BUT IT IS VERY SUBSTANTIALLY IMPAIRED IN THE INTEGRATION CAPACITY. AND WE THINK IT MAKES IT SAFE FOR EWES IN HUMANS. THIS AGAIN IS A CONTRASTING NEW DEVELOPMENTS. BOTH USE SPLIT GENOMES. BOTH HAVE 3 PRIMES. WE EXTENTED THOSE AND WE HAVE A SPECIFIC TROPISM CELL INTEGRATION DEFICIENT AND THIS IS WHY WE THINK THAT WE HAVE A VERY LOW RISK OF GENOTOXICITY WHEN WE USE THIS IN VIVO. THIS IS ALL INTERESTING BUT DOES THE VECTOR DO SOMETHING? SO, WE EXPLORED VARIOUS MOUSE MODELS WITH OUR VECTOR SYSTEM AND MOUSE CAN BE TRANSDUCED AND THEY DO MAKE STRONG IMMUNE RESPONSES. SO I'LL WALK YOU THROUGH MORE RELEVANT TO THIS MEETING, THE TUMOR AND FIELD AND THIS IS AN EXPERIMENT WHERE WE TOOK, A VERY AGGRESSIVE TUMOR MEDICALEL -- MODEL AND TOOK A CD26 CANCER CELL LINE FROM THE MOUSE. IMPLANTED IN THE FLANK AND THE TUMORS GROW OUT VERY FAST AND EVENTUALLY ANIMALS HAVE TO BE SACRIFICED OTHERWISE THEY WOULD DIE FROM THE TUMOR. AND THE SINGLE INJECTION OF THE VECTOR EXPRESSING ONE EPITOPE, A NEW EPITOPE IN THIS TUMOR, DAY 5 AFTER TUMOR CHALLENGE CONFERS SOLID PROTECTION. AND 6% OF THE ANIMALS SURVIVE WHERE THE OTHERS DRY AROUND DAY 30 AND THIS CORRELATES IN A DOSE DEPENDENT FASHION WITH CD8 T-CELLS SPECIFICALLY BY TETRAMER STAINING. THIS IS AN EVEN MORE STRINGENT EXPERIMENT AND VERY RELEVANT TO OUR CLINICAL PROGRAM. WHAT WE DID HERE IS WE TOOK THE SAME TUMOR CELL LINE, CD26 AND MADE IT RECOMBINANT FOR EXPRESSION OF TUMOR ANTIGENS WE WILL EVALUATE IN PATIENTS. SO THIS IS A MOUSE TUMOR CELL EXPRESSION EXPRESSING A HUMAN TUMOR ANTIGEN. AND THE CHALLENGE IS AS FOLLOWS. YOU INJECT THE MICE WITH A LARGE DOSE OF THESE CELLS SYSTEMICALLY, 1.5 TIMES 10 TO THE 5 AND VERY QUICKLY THE TUMOR WILL CEDE THE LUNGS OF THE MOUSE. THEY ARE STAINED WITH PINK AND THAT'S WHY THEY ARE BLACK. THAT'S WHAT THE LUNGS LOOK LIKE FOR 14 DAYS. SO THEY SUCCUMB VERY QUICK 3 THIS MASSIVE METASTASIS IN THE LUNGS. THIS IS A SINGLE TREATMENT ON DAY 3 AFTER CHALLENGE WITH A HIGH DOSE OF VECTOR 5-9 EQUIVALENCE AT 5-8 AND YOU SEE THAT YOU REDUCE THE NUMBER OF METASTASIS VERY SIGNIFICANTLY AND CORRELATES VERY, VERY NICELY WITH A STRONG CD8 RESPONSE UP TO 5 OR 6% OF THE CD8 CELLS SPECIFIC FOR THE TUMOR ANTIGEN AND ALSO FUNCTIONAL. AND THESE ARE REALLY STRINGENT THERAPEUTIC EXPERIMENTS THAT CONVINCE US THAT THE VECTOR HAS A HIGH KLANS OF WORKING AND PEOPLE IN THIS MODEL AS WELL. NOW THE QUESTION OF COURSE IS WHAT DO WE KNOW ABOUT TROPISM AND SAFETY AND FORMAL STUDIES? WE DID BY DISTRIBUTION STUDIES IN MICE, WE DID THEM TWICE NOW. THIS IS DIFFERENT THAN THE ONE WE SUBMITTED TO YOU. WE SUBMITTED A GRAPH USING RESEARCH MATERIAL AND THIS IS A EXPERIMENT USING MATERIAL PRODUCED UNDER GMP-LIKE CONDITIONS USING THE SAME PROCESS USED FOR THE MATERIAL. THE EXPERIMENT IS AS FOLLOWS. TAKE MICE AND INJECT AT THE TAIL BASE WITH A TUMOR AND HAVE 5 TIMES TO THE 8 GENOME THEY GET IMMUNIZATIONS EVERY TWO WEEKS. ONE MORE THAN THE PATIENTS GET AND THEN LOOK AT THE ANIMALS AND SACRIFICE THEM AT THE TIME POINTS AND YOU TAKE A BIOPSY FROM THE TAIL BASE FROM THE DRAINING LYMPHNODES AND YOU CAN SEE THAT IN BOTH EXPERIMENTS, THERE IS A VERY NICE AND VERY REPRODUCIBLE DECLINE OF DETECT ABILITY OF SIGNAL IN THE SKIN T DOESN'T GO TO ZERO HERE SO WE DON'T HAVE CLEARANCE IN THIS EXPERIMENT. WHEY IT IN THE PRIOR EXPERIMENT. YOU SEE THAT THE ONLY OTHER WAY TO DETECT SIGNAL IS IN THE DRAINING LIMP NOTE. AGAIN, WITH IN THIS CASE CLEAR ON DAY 49. THE SIGNAL ARE IN OTHER ORGANS BUT LIMITED TO DAY ONE OF THE OBSERVATION AND THEY SHOW UP VERY FEW MICE. EACH IS ONE MOUSE AND ONLY ONE INSTANCE WHERE THE SIGNAL IS STRONGER OF QUANTIFICATION. AND WE BELIEVE THIS BASICALLY REPRESENTS DENDRITIC CELLS WHICH MIGRATE TO THE LYMPHNODES WHICH THEY ARE SUPPOSED TO DO. YOU DETECT THEM FOR EXAMPLE IN THE SPLEEN HERE ON DAY ONE. SO WE THINK THIS IS PRETTY CONVINCING EVIDENCE WE HAVE CLEARANCE SO WE HAVE A FORMAL EXPERIMENT WHERE WE TOOK PRIMARY HUMAN CELLS AS OUTLINED IN THE LEFT-HAND SIDE HERE AND TRANSDUCED WITH A VECTOR AND THEN AGAIN, DID TWO DIFFERENT READ OUTS INVESTIGATING THE TRANSDUCTION. ONE IS WITH ACUTE PCR AND WITH FLUORESCENCE TO LOOK FOR GFP EXPRESSION. YOU CAN SEE IN THE HUMAN CELLS, THE ONLY CLEAR SIGNAL WE GET IS IN THE DENDRITIC CELLS. EVERYTHING SHADED GRAY IS BELOW 1% COMPARED TO THE POSITIVE CONTROL, WHICH ARE CELLS EXPRESSING COMINANT DESIGN. ONE EXCEPTION. WE HAD A SMALL SIGNAL IN T-CELLS WHICH WE REGARD AS BACKGROUND SIGNAL. ONE QUESTION OF ONE OF THE REGULARS. 293 T-CELLS ARE KNOWN TO BE PERMISSIVE FOR TRANSDUCTION EXPERIMENTS AND THIS HAS BEEN OBSERVED IN OTHER LENTE VIRUSES EXPERIMENTS AS WELL. THERE IS A BACKGROUND TRANSDUCTION WITHOUT IN THIS CASE, THE SPECIFIC RECEPTOR BEING PRESENT. WHEN WE DO THIS ON THE PROTEIN LEVEL, THE ONLY CELLS THAT LIGHT UP ARE HUMAN DENDRITIC CELLS. WE DID EXPERIMENTS IN MONKEY CELLS AND MOUSE CELLS AS WELL IF YOU'RE INTERESTED LOOKING AT THEM, THE RESULT IS THE SAME. NO OFF TARGET ACTIVITY OF THE VECTOR. SO THAT LEADS ME TO SOME OTHER MORE FORMAL EXPERIMENTS WE DID A GOP TOX STUDY TO SUPPORT OUR PHASE I TRIAL. THE SETUP AGAIN FOR VACCINATIONS INVOLVE EVERY TWO WEEKS AT TWO DIFFERENT DOSE LEVELS DETERMINED BY THE GENOME COUNTS 5 TIMES 10 TO THE EIGHTH AND 5 TIMES 10 TO THE 7. EVALUATION ONE DAY POSITIVE VACCINATION AND THEN A RECOVERY PERIOD AND NO SERIOUS EVENTS OBSERVED IN MICE APART FROM SOME LOCAL INFLAMMATION. WHICH IS TO BE EXPECTED. AND IT WAS DEFINED AS THE MAXIMUM DOSE ADMINISTERED IN THIS CASE WAS 5 TIMES 10 TO THE 8 AND THIS IS BY WEIGHT. SO, WE WERE ALLOWED THIS CALCULATE THIS BY WEIGHT. PLUS CLINICAL DOSISMING AT. I WILL SAY A FEW WORDS TO THE MANUFACTURING PROCESS. THERE IS NOT A REAL INDUSTRY STANDARD AROUND MANUFACTURING LENTE VIRUS BUT MANY COMPANIES DO MANUFACTURE THEM SO THERE IS SOME EXPERIENCE AND KNOWLEDGE AROUND THIS AND ALSO NOWADAYS DO IT AS WELL. ALL BASED ON TRANSFECTION MAINLY OF 29 THREE SELLS WITH 5 PLASMIDS. WE DO MULTIPLE SEQUENTIAL HARVESTS FOLLOWED BY FILTRATION AND TREATMENT. WE DO TWO STEPS AND FILTRATIONS AND WE FREEZE DOWN THE BULK LATER CONCENTRATIONS TO MAKE THE PRODUCT AND WE DO A FILTRATION FOLLOWED BY DILUTION AND THEN FINISH. WE HAVE A PRETTY EXTENSIVE QC PLACED IN PROTOCOL. ALL OF THIS IS FAIRLY STANDARD FOR ELECTRICITY VIRUSES. OBVIOUSLY LINKED TO THE CELL LINE YOU'RE USING AND YOU HAVE TO DETECT T ANTIGEN FOR EXAMPLE AND SO ON. I JUST WANT TO HIGHLIGHT A COUPLE OF ASSAYS SPECIFIC IN OUR CASE, THAT IS IDENTITY AS A FOR THE ENVELOPE WE ARE USING AND IT IS AN 8Y ASSAY WE HAVE TO MEASURE AND THE SA2 MEASURE OR EXCLUDE THE PRESENCE OF REPLICATION COMPETENT PARTICLES. NOW THIS WAS QUITE AN ADVENTURE TO COME UP WITH THIS BECAUSE OBVIOUSLY WE HAVE A LOT OF FACTORS HERE WHICH ARE DIFFERENT FROM THE STANDARD. WE TRIED TO HAVE THIS CELL LIONEL MAKE IT TRANSGENIC FOR EXPRESSING DC SIGN AND TRIED TO MAKE REPORTER VIRUSES BASED ON FOR EXAMPLE, HIV PROTOTYPE AND ENVELOPE AND OTHER THINGS AND NONE OF THESE COMBINATIONS REALLY LED TO A ASSAY THAT WAS ROBUST ENOUGH AND SENSITIVE ENOUGH. YOU HAVE TO RUN THE ASSAY WITH THE ADDITION OF [ INDISCERNIBLE ] ALSO THE FDA AND WE SET OUT FOR ASSAY WHICH IS NOW BASED ON F CELLS RECOMBINANTLY EXPRESSING DR SIGN AND AS A POSITIVE CONTROL USING THE VIRUS 4070, A STRAIN AND THE ASSAY IS A STANDARD PRODUCT ENHANCED REVERSE TRANSCRIPTASE ASSAY THAT DETECTS 95% PROBABILITY IN HARVEST. WITH THIS I'M HAPPY TO HAND OVER TO RICK AGAIN TO INTRODUCE OUR CLINICAL PROGRAM. >> JUST AS AN OVERVIEW, WE AGAIN ARE USING THE VECTOR PARTICLES TO TRANSDUCE DENDRITIC CELLS AND THEY ATTACH TO THE DENDRITIC CELL THROUGH THE DC RECEPTOR AND THE CELL IS THE MACHINE THAT PUTS THE PEPTIDES FROM NYES1 ON TO THE MHC CLASS ONE TO STIMULATE THE CD8 T-CELL RESPONSE. THEN THEY HAVE THE JOB OF GOING TO THE TUMOR AND INDUCING A TUMOR DEATH RESPONSE THAT IS ANTIGEN-SPECIFIC AND NYES1 PEPTIDE HAS TO BE PRESENT ON THE SURFACE OF THE TUMOR CELLS FOR THIS SYSTEM TO WORK TO GET TUMOR CELL DEATH. WE IN THE PHASE I STUDY, WANT TO ESTABLISH A STUDY OF THE ESCALATING DOSES. USING THIS VECTOR THAT IS REPLICATION INCOMPETENT AND INTEGRATION EFFICIENT TO TRY TO SHOW THAT IN A WAY THAT WE CAN USE INTERTHERMAL INJECTION BECAUSE THAT IS WHERE THE DENDRITIC CELLS LIVE. WE WILL SHOW PROOF OF CONCEPT LOOKING AT PERIPHERAL BLOOD AND WHEN WE CAN, USE BOPS TOW LOOK FOR CD8 T-CELLS AND THE REDUCTION OF THE T-REGTORY T-CELLS. WE WILL BE LOOKING AT SEVERAL DIFFERENT TUMOR -- TUMOR TYPES AND WHY IT WAS SELECTED BECAUSE IT IS FAIRLY BROADLY EXPRESSED AMONG LOTS OF DIFFERENT TYPES OF TUMORS. WE THE PROTEIN WAS IDENTIFIED IN PATIENTS WITH SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS. ITS FUNCTION IS STILL UNKNOWN. DID IS ONLY EXPRESSED IN TUMORS AND IN CERTAIN CELLS IN THE TESTIS. THE SER TOLLIES CELLS PROTECTED FROM THE IMMUNE SYSTEM SO USUALLY NO ANTIBODY RESPONSE OR CELL LARRY SPONSE IN ADULTS. THE PROTEIN ITSELF WHEN IT IS EXPRESSED IN A WAY THAT THE IMMUNE SYSTEM CAN SEE, IT IS HIGHLY IMMUNOGENIC AND YOU CAN SEE THIS IN A SUBSET OF CANCER PATIENTS. THERE ARE TUMOR TYPES THAT ARE POSSIBLE SELECTIONS. WE TRIED TO SELECT A FEW REPRESENTATIVE THAT HAVE HIGHER EXPRESSIONS. YOU CAN DO THIS BY IMMUNOHISTOCHEMISTRY OR PC R AND THIS IS A SURVEY OF THE LITERATURE TO SHOW DIFFERENT LEVELS OF EXPRESSION. A GENE EXPRESSED IN DIFFERENT PARTS OF THE TUMOR AND DIFFICULT TO SHOW THAT SOMEBODY IS EXPRESSING BUT IT WILL BE USEFUL TO USE THIS AS A FIRST STEP. WHAT I'D LIKE TO DO IS LET DR. SA MAIA TELL YOU ABOUT THE DETAILS OF THE STUDY JUST AS AN OVERVIEW. WE WILL BE DOING A STANDARD 3 PLUS 3 DESIGN SET UP BY THE AACR TO SHOW SAFETY IN SMALL COHORTS AND THEN TRY TO GET AN EXPANSION OF THE EXPERIENCE AND SAFETY AND IMMUNOGENICITY IN SEVERAL DIFFERENT TUMOR TYPES AND LOOKING AT A COHORT WITH A LOW DOSE OF THE VECTOR. YOU ENROLL THREE SUBJECTS AND YOU OBSERVE THEM FOR A PERIOD AND THEN WE WILL LET A COMMITTEE REVIEW THE OBSERVATIONS BEFORE WE PROCEED TO COHORT TWO. THESE ARE DONE IN ONE LOG INCREMENTS AS DIFFERENT DOSES IN A DOSE ESCALATION STRATEGY AND THEN WE HAVE A LONG OBSERVATION PERIOD TO SEE IF THERE IS ANY CLINICAL RESPONSE. ONCE THE SAFETY SEESTABLISHED IN THE DOSE ESCALATION FASHION, WE WANTED TO EXPAND THE COHORT EXPERIENCE A LITTLE BIT TO GET A LITTLE BIT BETTER UNDERSTANDING OF THE IMMUNOGENICITY. ACTIONERNITA COULD YOU COME HELP OUT WITH THE DETAILS? >> I'M AN ASSISTANT PROFESSOR AT MD ANDERSON AND I WAS GOING TO GO OVER A FEW DETAILS OF THIS TRIAL. SO THE PRIMARY OBJECTIVE OF THIS PHASE I STUDY IS -- [ INDISCERNIBLE ] THE OBJECTIVES INCLUDE EVALUATION OF CELLULAR IMMUNOGENISITY WITH COLLECTIONS PRE AND POST THERAPY AND THEN THE CLINICAL RESPONSES BY RESIST AND IMMUNE RELATED RESPONSE CRITERIA AND ALSO TIME TO PROGRESSION. AND IN PATIENTS WHERE WE HAVE THE AVAILABLE AND CONSENT, WE MIGHT HAVE PRE AND POST TUMOR BIOPSIES SPECIMENS WE WILL LOOK FOR IMMUNOLOGICAL MARKERS. SO PATIENTS WHO MEET THE ELIGIBILITY CRITERIA AND GIVE INFORMED CONSENT WILL BE SCREENED FOR THE PRESENCE OF THIS IN THEIR TREATMENT SPECIMEN BY RTPC R AND IF THEY ARE POSITIVE, THEY WILL START ENROLLMENT IN THE TRADITIONAL 3 PLUS 3 DESIGN ENROLLING IN GROUP ONE WHERE PATIENTS WILL GET FIVE FOR EIGHT VIRAL PARTICLES AND 8 DIVIDED DOSEOS DAY ZERO, 21 AND 42. AND NOW IF ZERO OUT OF 3 OR LESS THAN TWO OUT OF 6 PATIENTS, THIS COHORT SHOWS SIGNS OF ANY TOXICITIES, THEN WE WILL ENROLL IN GROUP TWO WHERE SIMILARLY WE WILL START WITH 3 PATIENTS THAT WE'LL INJECT PARTICLES INTRADERM ALLEY. IF WE ESTABLISH SAFETY IN THIS COHORT WE WILL GO TO GROUP 3 WHERE WOO TREAT UP TO 6 PATIENTS AND ONCE ALL OF THESE PATIENTS -- THIS WILL COMPLETE THE EXPANSION COHORT OR EXPANSION PHASE OF THE TRIAL. AND THEN WE WILL HAVE ANALYSIS AT DAY 63 AND IF WE ESTABLISH SAFETY, THAT IS WHEN WE EXPAND THESE COHORTS. THE MTD OR MAXIMUM FEASIBLE DOSE, THAT COHORT WILL BE EXPANDED TO 12 PATIENTS AND THE LOWER WILL BE EXPANDED TO 8 EACH AND THIS IS TO COLLECT ADDITIONAL DATA ABOUT SAFETY AND IMMUNOGENICITY OF THIS VIRAL VECTOR VACCINE. NOW ALL PATIENTS WILL HAVE STAGING EVERY 8 WEEKS TO LOOK FOR PROGRESSION WHICH WILL BE DEFINED BY IMMUNE RELATED RESPONSE CRITERIA REQUIRING A 4 WEEK SCAN. AND THE VIRAL PERSISTENCE WILL BE DETECTED IN BLOOD SAMPLES THAT WILL BE COLLECTED AT 4, 6, 12 MONTHS AND THEN EVERY YEAR UP TO TWO YEARS AND EVEN BEYOND IF WE DETECT ANY PERSISTENCE IN THESE SAMPLES. THE KEY INCLUSION CRITERIA WE WANT PATIENTS WITH LOCALLY ADVANCED METASTATIC CANCER WITH EITHER BREAST CANCER OR LUNG CANCER, MELANOMA, OR OVARIAN CANCER OR SOFT TISSUE SARCOMA THAT IS DO HAVE TUMORS IN WHOM THE TUMORS EXPRESS BY RTPCR. WE REQUIRE PATIENTS HAVE RECEIVED PRIOR TREATMENT AND FOR THOSE WITH BREAST AND LUNG CANCER, TWO LINES OF THERAPY. WE EXPECT THAT PATIENTS WITH BREAST AND LUNG CANCER WILL PROBABLY HAVE MULTIPLE LINES OF THERAPY BEFORE THEY GO TO THIS TRIAL BUT FOR SOMEONE WITH SARCOMA, FOR EXAMPLE, THEY WILL HAVE FEWER LINES OF THERAPY BECAUSE THEY ARE LIMITED STANDARD AND CLINICAL TRIAL OPTIONS AVAILABLE FOR THEM. PERFORMANCE STATUS SHOULD BE ZERO OR ONE AND THIS IS TO LIMIT EXSPORURE TO PATIENTS WHO MIGHT NOT BE ABLE TO SAFELY MAKE IT THROUGH THE 9 WEEKS OF THERAPY. EXCLUESB COLLUSION CRITERIA INCLUDE NO INVESTIGATIONAL THERAPY 3 WEEKS PRIOR TO THE DOSING PRIOR ADMINISTRATION OF EITHER-OR ANY TARGETING THERAPEUTIC AND PATIENTS WHO REQUIRE CONCURRENT IMMUNOSUPPRESSIVE THERAPY. DOSE LIMITING TOXICITY WILL BE DEFINED AS ANY ORGAN SPECIFIC GRADE III OR HIGHER. TOXICITY IS DEFINITELY, PROBABLY OR POSSIBLY RELATED TO THIS AGENT AND THE SEVERITY WILL BE DESCRIBED BASED ON THE NCI VERSION 4.03. NOW THE CLINICAL ENDPOINTS WILL BE LOOKING AT SAFETY, WHICH WE WILL DESCRIBE THE NATURE AND FREQUENCY AND SEVERITY OF THE TOXICITY WE WILL COLLECT BASED ON THE CLINICAL HISTORY AND EXAM AND LABORATORY PARAMETERS. THE IMMUNOGENICITY WILL DESCRIBE THE GINGS FROM THE BASELINE AND ANTIBODY AND OTHER CELLULAR IMMUNOLOGICAL PARAMETERS INCLUDING CD4 POSITIVE AND CD8 POSITIVE T-CELLS AND THEN TUMOR RESPONSE WILL BE BASICALLY RESPONSE BASED ON RESIST AND IMMUNE-RELATED RESPONSE CRITERIA CR, APPROXIMATE. R OR STABLE DISEASE AND THEN TIME TOW PROGRESSION. WE HOPE THIS DATA WILL BE ABLE TO GET DATA ENOUGH TO GET THIS PRODUCT FURTHER AND I'LL TURN IT OVER TO DR. KENNY AGAIN FOR CLOSING REMARKS. >> ONE SLIDE IN CONCLUSION. WE ARE USING THIS THIRD-GENERATION VECTOR THAT IS MODIFIED WITH A SURFACE PROTEIN THAT MAKES IT DC SPECIFIC. DENDRITIC CELLS ARE A NICE TARGET BECAUSE THEY ARE THE ENGINE THAT DRIVES THE IMMUNE RESPONSE IN A FASHION WE THINK CAN HELP CURE THESE TUMORS. WE MADE MULTIPLE ENHANCEMENTS TO IMPROVE SAFETY IN VIVO. WE THINK THIS VECTOR IS SHOWN TO BE REPLICATION INCOMPETENT AND INTEGRATION DEFICIENT. THE TECHNOLOGY ITSELF IS BEING USED SAFELY IN 21 CLINICAL TRIALS NOW AND HAS SHOWN CLINICAL EFFICACY IN MULTIPLE DISEASES AS INTEGRATING VECTORS. WE ARE TRYING TO USE THIS AS A NONINTEGRATING VECTOR WITH DIRECT INJECTION INTO THE SKIN. EUR CLINICAL DESIGN IS MEANT TO EXPOSE FEW PATIENTS AT VARIOUS DOSES TO SHOW DOSE THAT CAN BE USED SAFELY. AND WITH THAT, I WILL THANK YOU AGAIN AND OPEN IT UP FOR QUESTIONS. >> THANK YOU FOR THAT PRESENTATION. SO WE'LL HEAR FROM OUR INDIVIDUAL RAC REVIEWERS ONE AT A TIME AND GO THROUGH THEIR REVIEWERS AND YOUR RESPONSES. >> THANK YOU. I'LL GO THROUGH THE COMMENTS AS OUR ROUTINE. MY FIRST QUESTION IS IF THE STUDY IN MACAQUES DIDN'T TURN OUT SO WELL, WHAT DOES THAT IMPLY FOR SUCCESS IN HUMANS? AND YOUR ANSWER WAS NOTHING AND THAT SEEMS APPROPRIATE TO ME AND NOTHING FURTHER NEED BE SAID ABOUT THAT. SECOND HAD TO DO WITH THE MONITORING PLAN AND TO WHAT DEGREE THE MONITORING IS DONE BY INDIVIDUALS OR GROUPS THAT ARE INDEPENDENT FROM IMMUNE DESIGN. I THINK THERE ARE TWO ISSUES HERE. ONE IS AUDITING WHICH I THINK IS TECHNICAL KIND OF PROCEDURE DO MAKE SURE THAT THE PROCEDURES ARE BEING FOLLOWED AND THE FORMS ARE BEING FILLED OUT CORRECTLY. AND THAT SEEMS APPROPRIATE. THE SECOND IS MONITORING FOR ADVERSE EFFECTS AND WHILE FORMAL DATA MONITORING COMMITTEES ARE NOT COMMON IN PHASE I TRIALS, SOME DATA MONITORING PLAN IS NECESSARY AND HERE, YOU SEEM TO BE STATING THAT THE DATA MONITORING WILL BE DONE AND I QUOTE HERE, INCLUDE THE SPONSOR, INVESTIGATORS AND INDEPENDENT MEDICAL EXPERTS AND THAT SEEMS TO ME ATYPICAL. USUALLY DATA MONITORING IS DONE BY A GROUP THAT IS INDEPENDENT OF THE SPONSOR. SO, IT DOES SEEM TO BE AN ATYPICAL FORMAT FOR DATA MONITORING AND MAYBE I SHOULD STOP THERE AND ASK IF YOUR RESPONSE ABOUT THAT. >> SURE. THIS IS A VIEW USED QUITE OFTEN IN THE PAST THAT IN A PHASE I STUDY WHERE YOU'RE WORKING TO BRING PRECLINICAL PRODUCTS IN THE CLINIC, THE GUIDANCES ARE PRETTY CLEAR THAT YOU CAN AND OFTEN MORE APPROPRIATELY BECAUSE THE PEOPLE ARE INVOLVED AND UNDERSTAND ALL THE BACKGROUND DETAILS, USE A COMPANY GROUP THAT TOGETHER WITH THE PRINCIPAL INVESTIGATORS THAT ARE INVOLVED IN THE CLINICAL TRIAL, AND ADDING INDEPENDENT OUTSIDE PHYSICIAN TO HELP WITH THE INTERPRETATION OF ANY SAFETY SIGNALS. THAT IS ESTABLISHED WHERE AT EACH DOSE ESCALATION LEVEL WE HAVE A MONITORING REVIEW ANY TIME THERE IS A SUSPECTED SUE SAR, ADVERSE REACTION THAT MIGHT BE SIGNIFICANT. WE ASK COMMITTEE TO MEET TO TALK. THE GUIDANCE IS -- IS AN EXPECTATION OF A FULLY INDEPENDENT DATA SAFETY MONITORING BOARD IN PHASE II AND 3 AND WE CERTAINLY WOULD DO THAT. WE WILL HAVE A DATA MONITORING PLAN THAT IS SUBMITTED TO ALLOW FOR A FORMAL SOP-TYPE APPROACH TO THIS MONITORING. BUT, IN MY EXPERIENCE, THIS IS FAIRLY TYPICAL AS AN APPROACH. >> OKAY. I'M NOT -- I DON'T SEE ANY REASON -- PHASE I STUDY CAN'T HAVE -- IF YOU AGREE THAT A PHASE II AND 3 STUDY SHOULD HAVE INDEPENDENT MONITORING, I DON'T SEE ANY REASON WHY PHASE I STUDY -- >> CERTAINLY AT THE CAN. THEY CAN BE SET UP AS AN EXTERNAL COMMITTEE. THAT LEVEL OF REVIEW IS SOMETHING THAT FDA IN THEIR GUIDANCE HASN'T ASKED FOR IN PHASE I. IN A LARGE SETTING WHERE YOU HAVE A NUMBER OF PATIENTS, THERE IS AN EFFORT TO TRY TO -- IT'S A FUZZY LINE SOMETIMES IN TERMS OF HOW INDEPENDENT IT IS NECESSARY AND HOW MUCH BACKGROUND INFORMATION IS HELPFUL. AND SO THIS IS THE BALANCE THAT HAS BEEN TAKEN INTO GUIDANCE. >> THEIR ISSUE IS PUBLICATION POLICY AND YOUR POLICY STATES THAT IMMUNE DESIGN WILL MAKE ALL DECISION BUSY PUBLICATIONS AND REVIEW APPROVAL MANUSCRIPTS. IN AN AREA WHICH CRIMINAL MISCONDUCT BY PHARMACEUTICAL COMPANIES NOW SO COMMON AS TO BE ALMOST THE RULE RATHER THAN THE EXCEPTION. VIRTUALLY ALMOST EVERY MAJOR PHARMACEUTICAL COMPANY HAS BEEN SUBJECT TO CRIMINAL PENTS WHICH EXCEED 10 BILLION DOLLARS OVER THE PAST DECADE. I DON'T KNOW IF GENE THERAPY COMPANIES ARE ANY SIMILAR TO THESE COMPANIES AND I HAVE NO REASON TO THINK YOUR COMPANY WOULD DO SUCH THINGS BUT IT HAS BECOME SUCH UBIQUITOUS THAT IT SEEMS TO ME TO HAVE A PUBLICATION POLICY THAT PROHIBITS OR ALLOWS FOR A VETO OVER PUBLICATIONS WHICH THE INVESTIGATORS WHO ARE MIGHT WANT TO DO IN ADDITION TO WHAT THE COMPANY WANTS TO PUBLISH, IT SEEMS TO ME A PROBLEMATIC POLICY. I MENTIONED OR SUBMITTED A REFERENCE TO THE GSK POLICY ON PUBLICATIONS WHICH JUST AS AN EXAMPLE OF WHAT SEEMS TO ME, A ROBUST POLICY THAT GREATLY REDUCES THE RISK THAT UNWELCOME INFORMATION WILL FILE GET PUBLISHED OR THAT INFORMATION WILL GET DISTORTED IN PUBLICATIONS. PROHIBITION ON GHOSTWRITING AND SO ON. AND ALL THAT HAVE BECOME UBIQUITOUS IN PHARMA-SPONSORED TRIALS. I DON'T SEE WHY ALL COMPANIES SHOULDN'T HAVE GUIDELINES ABOUT HAVING A VETO POLICY THAT SEEMS TO ME MIGHT PROHIBIT A INVESTIGATOR FROM PUBLISHING SOMETHING WHICH THE COMPANY DIDN'T WANT PUBLISHED. AFTER AN APPROPRIATE DELAY. >> I DON'T BELIEVE WE HAVE A STRICT VETO POLICY. I'M NOT SURE WHERE THE STATEMENT CAME FROM. IN OUR CONTRACTS, THERE IS DELAY YOU MIGHT EXPECT FOR REVIEW OF INTELLECTUAL PROPERTY. INVESTIGATORS ARE FREE TO PUBLISH. THE PRIMARY PUBLICATION OF COURSE THAT COMES ANY TRIAL IS USUALLY SOMETHING THAT THE COMPANY IS VERY INVOLVED WITH IN WORKING WITH THE PIs TO GET THE DATA TOGETHER. SWEPT PUBLICATIONS ARE TYPICALLY MUCH SIMPLER TO FASHION DEPENDING ON WHAT THE INTEREST IS AND WE HAVE SIMILAR POLICIES AS MOST OTHER COMPANIES. I USED TO WORK AT GSK, I AND WE ARE NOW A COMPANY OF 28 PEOPLE RIGHT NOW SO NOT AS WELL ESTABLISHED. BUT IT IS SOMETHING THAT WE EXPECT TO MAKE INDUSTRY STANDARDS. >> I'M QUOTING FROM YOUR OWN APPIDATION SAYS IMMUNE DESIGN WILL MAKE ALL DECISION BUSY PUBLICATIONS AND THEN ELSEWHERE IT SAYS, AND I QUOTE, IMMUNE DESIGN INCLUSION ATTEMPTS TO REVIEW AND APPROVE, END QUOTE, MANUSCRIPTS BEFORE SUBMISSION. SO THAT SOUNDS TO ME LIKE VETO POWER. I DON'T SEE ANY REASON WHY YOU CAN'T PHOTO COPY GSK'S POLICY. I DON'T THINK IT IS PROPRIETARY. I'M SURE THEY WILL BE DELIGHTED TO HAVE IT COPIED. I DON'T THINK YOU HAVE TO DEVELOP YOUR OWN POLICY F THERE IS PARTS ABOUT IT THAT SEEM INAPPROPRIATE, YOU COULD MODIFY IT. BUT IT SEEMS TO ME THE DESIRABLE MODEL. >> THANK YOU. >> THE NEXT ISSUE HAD TO DO WITH REOCCURRING ISSUE AT THE RACK WHICH IS ABOUT THE STATEMENT OF BENEFITS. AND YOUR CONSENT FORM THINGS LIKE WE DO NOT EXPECT YOU WILL RECEIVE ANY BENEFIT OR UNLIKELY TO RECEIVE OR EXCUSE ME. THOSE ARE MY SUGGESTIONS. YOUR CONSENT FORM AS IS, SAYS THINGS LIKE YOU MAY OR MAY NOT HAVE BENEFIT. DESPITE THE OPTIMISM YOU HAVE FOR THIS WHICH WE ALL HAVE AND YOU WOULDN'T BE DOING THIS UNLESS YOU THOUGHT IT WAS GOING TO WORK, BUT THAT IS TRUE OF ALL PHASE I TRIAL AND EVERY INDUSTRY THAT THERE IS. 95% OF THEM FAIL AT DRUG TRIALS AND MORE THAN 99% FAIL IN GENE THERAPY TRIALS. SO DESPITE THE TREMENDOUS OPTIMISM AND EXPANSE AND TROUBLE YOU GO TO, SADLY MOST OF THESE THINGS DON'T GET TO CLINICAL USE. SO, THE NOTION THE PATIENT IMPLYING SAYING YOU MAY OR MAY NOT RECEIVE ANY BENEFIT, IT SOUNDS LIKE A 50 FIRST I CHANCE. THE PROSPECT OF BENEFIT IN A PHASE I TRIAL IS EXTREMELY REMOTE AND UNLIKELY AND IT'S NOT THE PURPOSE OF A PHASE I TRIAL. AND SO THERE IS TEMPLATE LANGUAGE THAT NIH HAS DEVELOPED AND RELEVANT SENTENCE THAT WE RECOMMENDED IN OTHER TRIALS IS QUOTE, NO DIRECT CLINICAL BENEFIT IS EXPECTED AS A RESULT OF PARTICIPATION IN THE STUDY. ALTHOUGH KNOWLEDGE MAY BE GAINED T MAY BENEFIT OTHERS. AND YOU HAD SUGGESTED YOU RATHER DELETE ANYTHING ABOUT BENEFIT RATHER THAN SAY THAT BUT THAT DOESN'T SEEM TO ME THE RIGHT APPROACH SINCE IT IS HIGHLY LIKE THATLY THAT SUBJECTS WILL NOT EXPERIENCE ANY OF THE THEY SHOULD KNOW THAT THAT IS ACT LET THE PRIMARILY PROBABILITY AT LEAST BASED ON A COUPLE OF DECADES OF GENE THERAPY RESEARCH. I'LL PAUSE AND LET YOU RESPOND TO THAT. >> CONSENTS ARE TOUGH. AND IT IS PROBABLY NOT APPROPRIATE TO TRY TO, IN A CONSENT, ESTIMATE THE POTENTIAL FOR BENEFIT. WHETHER IT IS 1% OR 50%. I JUST DON'T THINK THAT THAT IS KNOWN. AND CERTAINLY IT ISN'T SOMETHING YOU CAN EXPRESS IN CONSENT. WE WOULDN'T BE DOING THE STUD FE WE DIDN'T EXPECTED SOME SORT OF BENEFIT. AND SO, THAT IS WHERE I PUSHED BACK A LITTLE BIT ON THAT TYPE OF A STATEMENT WHERE THERE IS NO EXPECTATION OF BENEFIT, THAT ACTUALLY IS A ISSUE THAT INSURANCE COMPANIES HAVE MADE AS WELL. AND SO I THINK THAT THE JURY IS OUT IN TERMS OF HOW TO BEST DO THAT. WHAT WE LIKE TO DO IS TO TAKE ANOTHER LOOK AT THE NIH LANGUAGE AND ADJUST THE CONSENT STORM WE WILL WORK TO MAKE THAT IN LINE WITH NORMAL APPROACH. >> THE JURY IS IN. AT LEAST NIH CONVENED A JURY. I THINK A VERY WELL BALANCED PANEL OF SCIENTISTS AND SO ON AND CAME UP WITH A RECOMMENDATION. AND IN FACT MOST PHASE I STUDIES WE HAVE SEEN IN MY TIME ON THE RAC HAVE INCORPORATED -- IT DOESN'T SAY THERE WILL BE NO BENEFIT T JUST SAYS THAT NO DIRECT CLINICAL BENEFIT IS EXPECTED. IT SEEMS TO BE CORRECT WHEN OVER 95% OF SIMILAR STUDIES DID NOT PRODUCE ANY BENEFIT. THE NEXT COMMENT WAS ABOUT THE SAME THING WHICH IS YOUR COMMENT ON THE CONSENT FORM WAS AS WITH ANY INVESTIGATIVE VACCINE IT MAY NOT BE EFFECTIVE. IT MAY NOT BE EFFECTIVE SUGGESTS THAT WE ARE SORT OF EXPECTING IT TO BE EFFECTIVE BUT IT MAY NOT HAPPEN. AND THAT, AS I SAID, YOU WOULDN'T BE DOING IT UNLESS YOU HOPED FOR THAT. THAT IS TRUE OF 1000 OTHER PHASE I STUDIES THAT HAVE BEEN DONE. SO IT SEEMS TO ME, IT CREATES A INAPPROPRIATE OPTIMISM AT THIS STAGE ABOUT THE EFFECTIVENESS. AND THE LAST ISSUE IS ABOUT FUTURE USE OF SAMPLES FOR RESEARCH PURPOSES AND YOU HAD A SHORT AND SIMPLE OPT IN OR OPT OUT FOR THAT AND I SUGGESTED EXPANDING THAT TO THREE OPTIONS, ONE, I DON'T WANT ANY OF MY SAMPLES USED OUTSIDE OF THIS STUDY, B, I WANT TO BE RECONTACTED IF YOU WANT TO USE THEM AGAIN, OR C, YOU CAN USE THEM FOR ANYTHING WITHOUT CONTACTING ME AND YOU WERE AGREEABLE TO THAT. SO THAT IS RESOLVED. >> THANK YOU. Y. >> SO TO SUMMARIZE, HAVE YOU CONCERNS WITH THE DSMB PUBLICATION -- [ INDISCERNIBLE ] >> [ OFF MIC ] -- DEVELOP A RESPONSE THAT IS APPROPRIATE AND IN LINE WITH EXPECTATIONS. >> WITH REGARD TO THE DATA MONITORING, I WILL CONCEDE ON THAT. BUT WHAT YOU'RE DOING IS CONSISTENT WITH FDA GUIDELINES AND I THINK IT IS ACCEPTABLE FOR YOU OBVIOUSLY TO DO THAT. SO I'LL SAY THAT IS A SATISFACTORY RESPONSE. ON THE PUBLICATION, ISSUE, I HEARD YOU SAY THAT YOU DON'T INTEND TO SUPPRESS PUBLICATIONS BUT THE PROTOCOL AND THE APPLICATION AS WRITTEN DOES SEEM TO ME TO GIVE YOU THAT AND IT SEEMS TO ME THERE ARE ALTERNATIVE GUIDELINES. AND I THINK IN THE RESPONSE I -- I DON'T MEAN TO INTERRUPT, BUT WE SUGGESTED WE WOULD CHANGE THAT IN THE AMENDMENT. SO I HOPE WE WILL BE IN LINE. >> IF IT SELL CHANGED TO BE SIMILAR TO THE GSK GUIDELINES, THEN THAT WOULD BE HIGHLY WELCOMED. ON THE CONSENT LANGUAGE, I THINK THAT THE LANGUAGE THAT HI SUGGESTED IS WIDELY ACCEPTED BY NIH GUIDELINES AND THE MAJORITY OF THE OTHER PHASE I, INCLUDING CANCER GENE THERAPY STUDIES SO IT SEEMS TO ME IT HAS BECOME STANDARD WITH VERY LITTLE EXCEPTION. THE ONE EXCEPTION BEING SOME CANCER AND SOME GENES THAT ARE TREATING FOR CANCERS THAT ARE MUCH FURTHERED ALONG AND HAD MUCH GREATER SUCCESS IN WHICH THE INVESTIGATOR CAN MORE ACCURATELY SAY FROM IS A REASONABLE PROSPECTED OF BENEFIT. BUT FOR OUR FIRST OR FOR SOMETHING AT THE EARLY PHASES SUCH AS YOUR IDEA, IT SEEMS TO ME, IT IS THAT THAT SORT OF OPTIMISM IS NOT WARRANTED. I GUESS I DIDN'T HEAR THAT YOU ARE YET READY TO EMBRACE THAT LANGUAGE. >> I USED TO SIT ON THE NIH IR. AND DISAGREED WITH IF THEN BUT I WILL CONCEDE AND WE CAN USE THE NIH STANDARD LANGUAGE. >> THAT WOULD BE SOLVE THAT PROBLEM. >> OKAY. >> THANK YOU. THANK YOU. >> FIRST, I WANT TO THANK YOU FOR A VERY CLEAR PRESENTATION AND A VERY INTERESTING PROTOCOL. I THINK MANY OF US APPRECIATE HOW DIFFICULT IT HAS BEEN TO GENERATE GOOD CTLs ESPECIALLY TO CANCER SEEN IN VIVO AND DENDRITIC CELLS ARE LIKELY TO BE A COMPONENT. SO IT'S A VERY INTERESTING DEVELOPMENT THAT YOU HAVE DEVELOPED A LENTE VIRUS VECTOR ASSIGNED SPECIFICALLY GOING TO DENDRITIC CELLS. I STILL HAVE SOME CONCERNS ABOUT THE PROTOCOL, ALTHOUGH MY FIRST COMMENT IS ACTUALLY ABOUT THE DATA SAFETY OR DATA MONITORING COMMUNITY BECAUSE IT WAS UNCLEAR TO ME WHEN I FIRST READ THE PROTOCOL, IT SEEMED CLEAR THAT THE SUMMER WOULD INVOLVE THE INVESTIGATORS AND THE SPONSOR BUT IT WASN'T QUITE CLEAR SO YOU CLARIFIED THAT AND THEN YOU GO ON TO SAY LIKE YOU SAID BEFORE, DID IS NOT FDA MANDATED THAT YOU HAVE A DATA SAFETY MONITORING BOARD AND WHILE I APPRECIATE THAT, I STILL WOULD THINK THAT IT WOULD BE IN YOUR BEST INTEREST, YOU MIGHT WANT TO CONSIDER TO HAVE A LITTLE BIT MORE INDEPENDENCE RATHER THAN ONE INDEPENDENT EXPERT THAT LOOKS AT THE DATA. THERE IS A BALANCE IN HERE WHERE YOU COULD HAVE SOMEBODY LOOKING AT THIS INDEPENDENT AND THEN KIND OF ADVISORY RATHER THAN HAVING ALL THESE PEOPLE MEET WHERE SOME OF THE PEOPLE ARE SPONSORS AND INVESTIGATORS THAT HAVE A VESTED INTEREST AND MAYBE BIASED ALTHOUGH I KNOW THAT ALL OF US HOPE THAT WE ARE NOT GOING TO BE BIASED. IT HAPPENS YOU'RE BIAS WHEN YOU HAVE A SELF INTEREST. IT SEEMS IT WOULD BE IN YOUR BEST INTEREST TO DO THAT. I ACCEPT IT'S NOT MANDATED. YOU DON'T HAVE TO DO IT. BUT MAYBE YOU WOULD THINK MORE ABOUT THIS. I DON'T KNOW IF HAVE YOU ANY COMMENTS. >> SIMPLY THAT I HAVE USED THIS APPROACH MANY TIMES AT GSK AND OTHER PLACES AND IT IS THE 0 DIFFICULT TO PUT THE TYPES OF ADVERSE EVENTS THAT MIGHT BE EXPERIENCED IN THE CONTEXT WITH ALL THE PRECLINICAL DATA WHEN YOU ARE COMING AT THE SITUATION AS A NOVEL INVESTIGATOR. >> BUT YOU COULD HAVE A COMPROMISE SOLUTION WHERE YOU HAD SOMEBODY LOOKING AT FROM THE OUTSIDE AND THEN CONSULTING WITH THE SPONSORS AND THE INVESTIGATORS. >> THAT SOMEBODY IS ON THE COMMITTEE AND I DO THINK IT IS VERY IMPORTANT TO ADD THAT PERSON. IT'S A DICHOTOMY. YOU EITHER HAVE A FULLY INDEPENDENT COMMITTEE OR YOU DON'T. AND IN THIS CASE, THE GUIDANCE CLEARLY SAYS THAT YOU DON'T NEED IT. THERE IS NO EXPECTATION. AND IN DOING IT BOTH WAYS, I FOUND THAT IT ACTUALLY WORKS BETTER TO HAVE THE GROUP OF PEOPLE INVOLVED IN THE STUDY IN A OBVIOUSLY POTENTIALLY BIASED SETTING. ANY TIME YOU HAVE A NONINDEPENDENT COMMITTEE, THERE IS A POTENTIAL FOR BIAS. THERE -- THIS IS A SMALL NUMBER OF PATIENTS AND THEY ARE WE THINK UNLIKELY TO HAVE SERIOUS ADVERSE EVENTS AND SO, I THINK THE RISK IS VERY SMALL HERE OF A SIGNIFICANT CONCERN. SO THAT IS OUR PREFERRED APPROACH. >> SO MY SECOND QUESTION HAD TO DO WITH THE POTENTIAL PERSISTENCE OF THE VECTOR AND WITH INTEGRATION. ALTHOUGH I APPRECIATE THAT YOU, IF IT TARGETS TO DENDRITIC CELLS, HAVE YOU ANIMAL DATA SUGGESTING AND IF DOESN'T INTEGRATE, YOU THINK AT LEAST INTEGRATION IS VERY LOW COMING NATION OF THOSE TWO THINGS, WOULD PROBABLY LEAD TO THAT VECTOR IS NOT GOING TO PERSIST FOR VERY LONG. BUT, I STILL WANT TO MAKE SURE THAT YOU ARE LOOKING FOR THAT BECAUSE AS YOU SAID IN THE PRESENTATION, INTEGRATION DEFICIENT DOESN'T MEAN SERUM INTEGRATE. WITH HIGH TITER VIRUS ADMINISTRATION, YOU STILL HAVE SOME INTEGRATION AND EVEN INTEGRATION DEFICIENT VIRUS WE KNOW THAT EVEN NONINTEGRATING VIRUSES CAN INTEGRATE ONCE IN A WHILE. SO, I JUST WANTED TO MAKE SURE THAT THERE WERE GOING TO LOOK FOR THAT BY PCR. AND I ASSUME YOU'RE GOING TO DO THAT ON TOTAL SET OF PERIPHERAL MONONUCLEAR CELLS NOT JUST LOOKING AT DENDRITIC CELLS. AND THE MOST USEFUL SOURCE OF THAT IS THE PROTOCOL WRITTEN SO WE LOOK FOR THE POTENTIAL FOR INTEGRATION AT 4, 6 AND 12 MONTHS REPEATED AT TWO YEARS F ANY OF THOSE ARE POSITIVE, IT KEEPS GETTING REPEATED ANNUALLY. THE EXPECTATION IS THAT THERE IS NOINTEDIGRATION THAT ANY DENDRITIC CELL THAT GETS TRANSDUCED DIES AND IS CLEARED BUT IT'S A VERY SERIOUS OR SIGNIFICANT CONCERN. >> AND SINCE THIS IS THE SIMPLE LIMP OF THE NEW ENTITY AND THE FIRST TIME IT IS GOING IN HUMAN, YOU HOPE IT WILL STICK TO THE DENDRITIC CELLS. >> AND YOU CAN COME UP WITH UNANTICIPATED PROBLEMS. >> SO THEN I HAD A BUNCH OF QUESTIONS ABOUT THE INFORMED CONSENT AND THEY ARE VERY SIMILAR TO DR. FOST. I DON'T THINK I NEED TO GO INTO ALL OF THEM. SO, YOU SAID THAT ONE OF THE THINGS THAT WASN'T TOUCHED UPON SPECIFICALLY WAS THE STUDY VACCINE IS ASSIGNED TO PROVIDE YOUR BODY'S IMMUNE SYSTEM, CONTROLLER AND ELIMINATED TUMOR CELLS AND THERE YOU HAD PUT IT IN THE DOCUMENT, ESPECIALLY SEEMED TO IMPLY THERE WAS A HIGH LIKELIHOOD THAT PATIENTS HAD BENEFIT. SO I THINK WHAT YOU DID WAS MOVED IT TO SOME OTHER PLACE TO MAKE IT SOUND LESS THAT HAD TO DO WITH BENEFIT. I THINK THAT'S HOW YOU RESPONDED. I THINK THAT SEEMS OKAY. AND THEN YOU SAID THE VACCINE VECTOR HAS BEEN MODIFIED TO REMOVE GENERIC FRAGMENTS SO IT IS NOT ABLE TO REPRODUCE SO BECOMING INCORPORATED INTO YOUR DNA AND CAUSE HARM TO YOUR BODY'S IMMUNE SYSTEM. SO I THOUGHT THAT SENTENCE SHOULD BE MODIFIED SINCE THE RISKS ARE NOT KNOWN SINCE THIS IS FIRST IN HUMAN AND NOT KNOWN -- SO, I ASKED YOU TO CHANGE IT TO TO SOMETHING LESS LIKELY AND I THINK YOU MADE APPROPRIATE MODIFICATIONS TO REFLECT THAT UNKNOWNS AND THAT IT IS LESS LIKELY BUT YOU DON'T -- COULD BE STILL SOME RISK. AND THEN THERE WAS A TYPO YOU CHANGED. AND YOU ALSO SAID THERE WAS ANOTHER THING ABOUT INTEGRATION. THE VECTOR WAS MODIFIED TO MAKE THIS POSSIBILITY EXTREMELY UNLIKELY AND I DIDN'T LIKE -- SO MAYBE UNLIKELY WOULD BE OKAY BUT NOT EXTREMELY. SO YOU CHANGED THAT. AND THEN YOU SAID THAT INCLUDING GENES MAY CAUSE -- [ INDISCERNIBLE ] SO I THOUGHT FOR CLARITY AND ALSO FOR FACTUALITY, THIS SHOULD BE CHANGED TO MATERIAL IN PRODUCTS SINCE THE VECTOR, IF YOU -- YOU'RE TESTING FOR RECOMENANCE SO YOU DON'T HAVE ANY RECOMENANCE. WHAT YOU DELIVER IS NOT AS VECTOR SEQUENCES WHICH ARE SEQUENCES AND THE SYMPT. B SEQUENCES (?) -- SIB SEQUENCES AND THEN THE LENTE VIRUS PROTEIN. SO YOU CHANGED IT TO THE VECTOR MATERIALLY IN PRODUCT MAKE IT MORE ACCURATE. AND YOU DID THAT. AND THEN SOME REDUNDANT STATEMENT ABOUT SIDE EFFECT THAT YOU CHANGED. AND THEN THE LAST THING IS THAT YOU SAY YOU MAY ALSO WITHDRAW FROM PARTICIPATING FROM THIS STUDY. AND I COMMENTED ON THE PATIENTS CANNOT TRULY WITHDRAW FROM THIS SINCE YOU DON'T KNOW IF THE VECTOR WILL PERSIST. CAN'T TRULY WITHDRAW FROM THE REAL SENSE OF THE WORD. SO THIS SHOULD BE EXPLAINED BETTER SO THE PATIENTS UNDERSTAND IT IS A VACCINE AND STILL WILL BE IMPORTANT FOR THEM TO BE MONITORED FOR POTENTIALLY PERSISTENCE AND INTEGRATIONS DURING THE FOLLOW-UP PERIOD AND MAY BE IN THEIR BEST INTEREST IF THEY WANT TO WITHDRAW FROM THIS FOLLOW-UP. I THINK YOU SAID THAT YOU COMPLETELY. [ READING ] I DON'T WANT KNOW IF YOU PROPOSED TO PUT THAT INTO THE INFORMED CONSENT. >> WHICH ONE? >> THAT YOU WILL -- THE PI WILL EXPLAIN THE IMPORTANCE OF FOLLOW-UP IN THE CONTEXT TO MONITOR POTENTIAL ADVERSE EVENTS AND ASSESS THE POSSIBILITY OF VECTOR PERSISTENCE. CAN YOU PUT THAT IN YOUR INFORMED CONSENT? >> I THINK IT IS F IT'S NOT STRONG ENOUGH, WE CAN MAKE TO LOOK IT STRONGER. I DIDN'T QUITE KNOW HOW TO ANSWER YOUR QUESTION BECAUSE THE ABILITY FOR THE SUBJECTED TO WITHDRAW FROM THE FORMAL TRIAL IS -- >> BUT I THINK MAYBE CLARIFY. >> I THINK IT WASN'T DONE -- YOU SAID YOU HAVE THE RIGHT TO WITHDRAW BUT YOU DIDN'T -- >> CERTAINLY WHEN YOU INJECT SOMEBODY WITH SOMETHING THAT COULD BE LONG TERM. YOU'RE RIGHT. THEY END UP HAVING THE POTENTIAL FOR A LONG TERM INTERACTION WITH THIS PRODUCT. BUT THAT IS SEPARATE FROM THEIR ABILITY TO WITHDRAW FROM THE TRIAL AND SO WE CAN -- WE CAN STRENGTHEN THE LANGUAGE TO MAKE THAT CLEARER. >> DO YOU HAVE ANY REMAINING CONCERNS THEN? >> NO. I HAVE THE SAME REMAINING CONCERNS ABOUT THE LANGUAGE OF THE INFORMED CONSENT THAT DR. FOST HAD BUT APART FROM THAT, NO. >> DR. WILLARD? >> THANK YOU FOR YOUR PRESENTATION. A LOT OF MY QUESTIONS ARE ABOUT THE VECTOR. I'M GOING TO START WITH THE VIRUS GLYCOPROTEIN. I HAD ASKED TO LIST THE MUTATIONS MADE, HOW EACH IS THOUGHT TO ENHANCE BINDING AND HOW DOES THE GLYCOSYLATION ENHANCE BINDING, COULD THERE A BE A POINT AT WHICH EXTRA GLYCOSYLATION IMPEDES BINDING, I WAS THINKING WHERE YOU MAY HAVE SO MUCH GUY CLASSALATION AND HOW DO THESE PREVENT BINDING TO OTHER POTENTIAL RECEPTORS. SO YOU PROVIDED THE TABLE WITH THE MUTATIONS AND THE FIRST TWO SHOW REDUCED SULPHATE BINDING AND THEN THE THIRD MUTATION INCREASED DENDRITIC CELL TARGETING. NOW IT SAYS REDUCED OR INCREASED. WHERE THESE STATISTICALLY SIGNIFICANT REDUCTIONS OR INCREASES IN THE AFFINITY OR BINDING IN THOSE PUBLISHED STUDIES? WHAT WAS THE FOLD CHANGE? BECAUSE FOR EXAMPLE, HEPARIN SULPHATE IS VERY UBIQUITOUS. SO YOU HAVE TO HAVE A REALLY SIGNIFICANT REDUCTION TO SEE AN AAFFECT IN VIVO. >> THIS IS A GOOD QUESTION. AND TO TELL YOU THE TRUTH, I DON'T KNOW. FROM RECALLING THE PAPERS, SOME OF THEM WERE SIGNIFICANT BUT I COULDN'T TELL YOU WHETHER THE AFFINITIES WERE MEASURED IN FACT. >> BUT YOU'RE SAYING THEY WERE STATISTICALLY SIGNIFICANT REDUCTION OR INCREASES. >> AND WE KNOW, REVERSE EXPERIMENT, WHEN WE USE OUR VECTOR IN THE ABSENCE OF THE GLYCOSYLATION, WE DIDN'T SHOW THE DATA, BUT THE TRANSDUCTION DROPS BY MORE THAN 90%. >> I WAS TALKING ABOUT ASIDE FROM THAT GLYCOSYLATION, THE FIRST MUTATIONS. THE POINTED MUTATIONS. SO I WAS JUST TALKING ABOUT THOSE AT FIRST. AND THEN I ASKED ABOUT MECHANISMS. SO, YOU HAVE REDUCED OR INCREASED, IS THERE ANYTHING KNOWN ABOUT THE BIOCHEMICAL MECHANISM OF THESE MUTATIONS AND HOW THEY ARE INTERACTING? >> NOT TO MY KNOWLEDGE. AS YOU WELL KNOW, THE HEPARIN SULPHATE BINDING WAS DISCOVERED MAINLY IN CELL CULTURE SO IT'S SOMETHING THE VIRUS DEVELOPS DURING CELL CULTURE PASSAGE AND MANY OF THE STRAINS YOU USE ARE SUBCULTURE DERIVED AND THOSE STRAINS ARE THE HIGH AFFINITY TO HEPARIN SULPHATE TEND TO BE VERY PATHOGENIC IN MICE THAN WILDTYPE STRAINS. SO PART OF THE ENTIRE HEPARIN SULPHATE STORIES COMES FROM IN VITRO SYSTEMS IN WHICH THE VIRUS WAS BASICALLY MADE TO INCREASE HEPARIN SULPHATE BINDING. >> NOW, THEN THE LAST MODIFICATION WAS THE HIDE MANOSE. IN YOUR ANSWER, YOU SAID YOU BELIEVED THAT THIS VIRUS WITH THE HIGH MANOSE WILL BIND THE MANOSE RECEPTOR ON DENDRITIC CELLS. THAT'S WHAT YOU'RE THINKING? >> SO IT IS A C TAB ELECT IN THAT IS CLASSIFIED AS A MANOSE BINDING RECEPTOR. HAVING SAID THAT, WE ANTICIPATE THAT OTHER MANOSE BINDING LECTINS ON ADJUVANT PRESENTING CELLS MAY TAKE UP VECTOR AS WELL. WE DON'T HAVE DIRECT EVIDENCE FOR IT AS OF YET BUT DEFINITELY JUST BASED ON LOGICAL THINKING WE CANNOT EXCLUDE IT. >> SO THAT MAY BE COMPLETELY SEPARATE MECHANISM? >> IT IS NOT NECESSARILY SEPARATE MECHANISM. YOU -- AS YOU KNOW, THESE LECTIN BINDING RECEPTORS AND A HUGE CLASS AND THEY ARE RELATED AND THEY DIFFER A LITTLE BIT IN THE EXACT BRANCHES THAT ARE RECOGNIZED ON THOSE STRUCTURES FOR EXAMPLE. BUT, THE BASELINE OF IT IS THAT ALL THESE RECEPTORS WERE DEVELOPED DURING HUMAN EVOLUTION TO DETECT FOREIGN ANTIGENIC MATERIAL COMING FROM PARASITES MAINLY, FUNGI, SOME VIRUSES FROM INSECTS. THIS IS WHAT THEY ARE MADE FOR. NOW, THE MAJORITY OF MACROPHAGES HAVE MENOSE RECOGNIZING RECEPTORS. SO WE MAY END UP HAVING THE OCCASIONAL MACROPHAGE TAKE UP THE VECTOR THROUGH THE MENOSE BINDING RECEPTOR AND THEN PRESENT THE PROTEIN AS WELL. >> I WAS GOING TO ASK ABOUT POTENTIALLY OTHER CELLS. SO THAT ANSWERED THAT QUESTION. LET'S JUST TRY TO PICTURE WHAT IS GOING ON IN MY MIND. SO THE ENVELOPE PROSTEIN BINDING TO THE DC SIGN AND THEN BECAUSE OF THE HIGH MANOSE, IT'S BINDING BETTER AND POSSIBLY TO OTHER ELECT INS? >> RIGHT. >> AND POSSIBLE TOW OTHERS? >> YES. >> RIGHT. OKAY. NOW MY NEXT QUESTION. AND THEN YES, THERE WAS JUST YOU SAID NO EVIDENCE THAT EXTRA GLYCOSYLATION WOULD IMPEDE -- >> WE HAVEN'T DONE ANY FORMAL GLYCOCHEMISTRY WHERE WE STARTED TO TRIM DOWN THE MENOSE. THIS IS JUST THE EXPERIMENTS WE SHOWED BY ADDING THE MENOSE TIME 1 INHIBITOR. YOU GET THE HIGH MENOSE STRUCTURE BUT HAVEN'T BEEN TAKING IT FURTHER. THAT'S NOT TRUE. WE USED OTHER INHIBITORS AND DIDN'T SHOW THIS DATA EITHER. SO WE CANNOT ONLY SHOW IT WITH -- WE USED COVENANT SINCE (?) IN THE PRODUCTION PROCESS BECAUSE IT IS A SMALL MOLECULE APPROVED IN A -- FOR THERAPY OF A RARE GLYCODISTROPHIC DISORDER. SO IT IS A SAFE MOLECULE. WE HAVE DATA USING OTHER INHIBITORS THAT REPRODUCE THESE FINDINGS. >> OKAY. AND THEN MY NEXT QUESTION WAS ABOUT DOSE BUT IT'S REAL BEHOW YOU CHARACTERIZE THE STUFF. SO I WAS READING THROUGH THE DOCUMENTS AND BASICALLY THERE ARE TWO WAYS TO CHARACTERIZE A VICE. ONE IS TO LOOK AT THE GENOMES THE NUMBER OF VIRAL GENOMES THAT ARE THERE AND THAT TELLS YOU HOW MANY TOTAL PARTICLES THAT ARE THERE AND THEN THE OTHER IS TO SEE HOW MANY IN FICIENCY PARTIALS ARE THERE USUALLY REFERRED TO AS A TRANSDUCTION ASSAY. I THINK BOTH ARE IMPORTANT. AND IN YOUR ANSWER, YOU MENTIONED THAT YOU WERE HAVING DIFFICULTY WITH THE TRANSDUCTION ASSAY. IT SOUNDS LIKE YOU'RE DOING IT BY PCR TRANSFUSIONING AND THEN DOING A PCR AND YOU HAD A NARROW RANGE AND YOU WERE WORRIED THE DATA MIGHT BE SKEWED. >> RIGHT. WE ARE ALSO TRYING TO SET UP A ASSAY-BASED ON FLORESCENT DETECTION. THAT ALL OF THAT IS IN THE WORKS. BUT COMING UP WITH A ASSAY THAT HAS THE RIGHT LINEAR RANGE AND IS ROBUST TAKES A WHILE. WHAT WE ARE PRESENTING IS WHAT WE HAVE NOW. >> YOU DID PRY SOME DATA BECAUSE HIV VIRUS AND VECTORS THAT ARE DRIVING HIV ARE NOTORIOUS FOR HAVING HIGH AMOUNTS OF DEFECTIVE PARTICLES AND SOMETHING COULD GO WRONG WITH PRODUCTION. YOU MIGHT HAVE A LOT OF DEAD VIRUSES THERE AND THEN YOU'RE GOING TO DO THIS STUDY AND WON'T LEARN MUCH ABOUT SAFETY. SO MY QUESTION IS, ARE YOU GOING TO AT LEAST USE THE TEST THAT YOU HAVE? FOR THIS STUDY? AND HAVE THAT DATA? EVEN THOUGH YOU'RE CONCERNED ABOUT THE ASSAY? >> NO, IT'S BEING USED. NOT AS A RELEASE ASSAY. THAT IS THE GENOME ASSAY BUT IT IS BEING USED AS CHARACTERIZATION ASSAY AND WE DO IT ON THE TOXIC MATERIAL AS WELL IT'S BEING RUN? AND THEN YOU'RE TRYING TO MOVE AWAY FROM DOING THE PCR AND DOING SOME KIND OF FLUORESCENCE. YOU'RE GOING TO STAIN FOR THE ANTIGEN? IS THAT WHAT YOU'RE THINKING. >> WE ARE IN THE PROCESS OF DOING THAT STAINING FOR THE ANTIGEN. BUT IT REQUIRES VERY GOOD STANDARDS AND SO ON AND SO FORTH. BUT THAT IS IN THE WORKS. >> RIGHT. I THINK IT IS IMPORTANT TO HAVE BOTH TESTS IN THAT IT SHOULD BE RECOMMENDED TO BE PART OF THE RELEASE DATA THAT YOU KNOW HOW MANY TOTAL PARTICLES WERE THERE AND HOW MANY WERE CAPABLE OF INFECTING THE CELL. SO I DO THINK THAT WILL BE IMPORTANT TO HAVE BOTH FOR QUALITY CONTROL. I'M JUST SCROLLING DOWN TO MY NEXT QUESTION. THIS WAS ABOUT DENDRITIC CELLS AND THE LIFE EXPECTANCY. AND YOU DO SAY IT VARIES DEPENDING ON ANATOMICAL LOCATION BUT IT SOUNDS LIKE NORMALLY IT WOULD BE LESS THAN TWO MONTHS. >> YES, SO THERE ARE, AS YOU MAY KNOW, NOT THAT MANY DATA OUT THERE THAT YOU KNOW, IN A CREDIBLE EXPERIMENTAL FASHION, ADDRESS THE QUESTION OF HOW LONG DENDRITIC CELLS PERSIST IN HUMANS TO BEGIN WITH. EX-VEVO, THAT IS EASY AND THEN IT IS ALWAYS A FEW WEEKS. THE QUESTION IS, HOW LONG DO THEY PERSIST IN VIVO? THERE IS VERY LITTLE OUT THERE. THE BEST WE COULD FINE IS ONE EXPERIMENT WE DESCRIBED WHERE HUMAN DISEASE WERE TRANSDUCED AND THEN GIVEN INTO IMMUNOINCOMPETENT MICE AND LIFESPAN WAS FOLLOWED AND THAT IS WHAT WAS AFTER THREE WEEKS. I THINK THE PEOPLE YOU TALK TO, THEY SAY IT IS IN A FEW WEEKS, MAYBE A COUPLE OF MONTHS BUT THAT'S ABOUT IT. >> AND YOU SAID THERE IS NO EVIDENCE THEY GO QUIESENT AND THEN COULD BE REACTIVATED LITTER AND -- LATER. AND THEN THIS IS ASSUMING THAT YOU DON'T HAVE ANYTHING THAT ALTERS THE CELTZM CELL TO LOSE THE ABILITY TO NATURALLY FINESSE. MOVING TO THE NEXT QUESTION ABOUT THE INTEGRATION DEFICIENCY. SO I WAS READING THE 2-3 LOG REDUCTION AND THEN I'M LOOKING AT THE DOSES AND TRYING TO IN MY MIND FIGURE OUT HOW MANY THEORETICAL INTEGRATIONS A PERSON COULD GET AND THEN YOU PROVIDED DATA ON DEFECTIVE PARTICLES. SO IT BOILS DOWN TO IN YOUR ANSWER YOU SAY THAT ON THE PERSON GETTING THE LOWEST DOSE THEY COULD HAVE 10,000 AND THEN ON THE HIGHEST, A MILLION. WHICH IS STILL A SIGNIFICANT NUMBER OF INTEGRATIONS. AND THEN THAT FEEDS INTO SOME OF MY COMMENTS ON THE CONFORM AND I SUGGESTED A INHIBITOR. YOU POINTED TO A STUDY THAT HAD NO EFFECT BUT THEN IT MAY BE DUE TO NONINTEGRATED FORMS? >> LET ME JUST TOUCH UPON THE CALCULATIONS. IT WAS CORRECT THE WAY YOU PRESENTED THEM WITH THE EXCEPTION YOU DIDN'T KNOW THAT THE RATIO. THE INTEGRATION DATA I PRESENTED WERE ALL DERIVED FROM EXPERIMENTS WERE MADE WITH CELL LINES. SO EITHER 293 SELLS OR -- WE HAVE NOT YET -- WE ARE CONSIDERING TO ASK THE QUESTION, DO WE GET INTEGRATION IN DENDRITIC CELLS IN PRIMARY CELLS? WE HAVEN'T DONE THAT YET. SO, I DON'T KNOW WHAT THE OUTCOME WILL BE BUT THAT IS SOMETHING THAT NEEDS TO BE FACTORED INTO THE -- BECAUSE NONDIVIDING CELLS, YOU MAY HAVE A DIFFERENT RATE OF INTEGRATION. SORRY, WHAT WAS THE OTHER? >> THE STUDY. YOU POINTED TO A STUD THEY LOOKED AT THE INTEGRATION INHIBITOR AND THERE WAS NO DIFFERENT VIRUS WITH OR WITHOUT AN INHIBITOR. NO DIFFERENCE BUT THEN IN YOUR WRITE UP, YOU SAID THAT WAS DUE TO NONINTEGRATED FORMS. >> NO, NO, NO. SO FIRST OF ALL, I FOUND YOUR QUESTION VERY GOOD. I REALLY LIKED IT THE IDEA ADDING THE INTERGRACE TO MAKE IT SAFER. SO WE DUG INTO THE LITERATURE AND CAME UP WITH JUST ONE PAPER THAT DESCRIBED IT IN SUPPLEMENTARY INFORMATION HAVING DONE THE EXPERIMENT USING EXACTLY THE INTERGRACE ACTIVATING MUTATION WE HAVE AND ADDING A STRAND, DISPLACEMENT INHIBITOR TO IT. AND WHAT THEY SAY IS WHEN YOU LOOK AT THE FIGURE INITIALLY, THERE IS NO DIFFERENCE IN WHETHER YOU'RE USING INTEGRATING OR NONINTEGRATING AND THAT IS DUE TO THE EP SOMAL STATE OF THE DNA FROM THE NONINTEGRATING. OVER TIME, AT DAY 14, THE SIGNALS DROP. BOTH FROM THE NONINTEGRATING VECTOR AS WELL AS FROM THE NONINTEGRATING VECTOR PLUS THE INTEGRATING INHIBITOR. SO NO DIFFERENCE. SO YOU LOSE THE -- MAYBE IT WAS A LITTLE BIT CONFUSINGLY EXPLAINED. SO YOU LOSE THE NONINTEGRATING FORMS AND THEN AT THE END OF THE DAY, YOU DROP DOWN TO THIS LEVELS AND THERE IS NO DIFFERENCE BETWEEN. >> AT THE END OF THE DAY, YOU'RE LOOKING AT THE INTEGRATED FORMS? >> RIGHT. >> SO BASED ON THIS ONE EXPERIMENT, IT SEEMS TO BELIEVE FAIRLY WELL DONE, I DON'T THINK THERE IS ENOUGH EXPERIMENTAL INDICATION THAT THIS WOULD WORK IN VIVO. >> I WANTED TO MAKE SURE THEY WERE LOOKING AT INTEGRATED FORMS BY DAY 14. THE NONINTEGRATED ONES HAVE BEEN REDUCED AND SO THAT AT THE END OF THE DAY, LIKE YOU SAID, THEY ARE LOOKING AT WHAT WAS INTEGRATED. >> THEY ARE LOOKING AT, DIDN'T MEASURE INTEGRATION, THEY LOOKED AT GFP POSITIVE CELLS AND OBVIOUSLY LOOKING AT THE FIGURE HERE IT HAS DROPPED TO BELOW 1%. SO THE QUESTION IS, THEY DON'T GIVE A MOCK CONTROL HERE. THIS IS PROBABLY SIMILAR TO WHAT WHY SEE. >> IT WOULD HAVE BEEN INTERESTING TO SEE THE DATA LIKE YOUR PCR HAD THE ALLOREPEATS TO LOOK AT HOW MANY INTEGRATED VERSUS NONINTEGRATED BUT THEY DIDN'T DO THAT. >> NO. >> SO IT STILL IS MAYBE IF THAT WERE LOOKED AT, MAYBE IT DOES DECREASE ACTUAL INTEGRATIONS AND MAYBE SOMETHING TO THINK ABOUT FOR THE FUTURE TO ACTUALLY DO THAT STUDY. JUST TO DOT PCR ASSAY THAT REALLY LOOKS AT INTEGRATIONS WITH OR WITHOUT THE INHIBITOR. >> IT IS AN INTERESTING QUESTION AND WE WILL CONTEMPLATE THINGS LIKE THIS. BUT ONE MAY HAVE TO COME UP WITH A MORE THOROUGH AND PHYSIOLOGICALLY MORE RELEVANT DESIGN. >> RIGHT. MY NEXT QUESTION IS ABOUT THE SELF INACTIVATION AND I THINK WHEN I WAS READING IT, LANGUAGE YOU WERE USING WAS, PREVENTS TRANSCRIPTION. AND THEN I REFERRED TO THIS PAPER AND YOU REFERENCED THAT ALSO. BUT I THINK THE BOTTOM LINE IS, EVEN WITHOUT TAD, THERE IS A VERY LOW-LEVEL OF TRANSCRIPTIONAL ACTIVITY THEY CAN BE DETECTED WITH A VERY SENSITIVE ASSAY. AND THAT WAS MY ONLY POINT. I THINK IT DOES SIGNIFICANTLY REDUCE THE CHANCES OF TRANSCRIPTION FROM THE LTR AND SO I ALWAYS PREFER LANGUAGE RATHER THAN SAY IT PREVENTS IT, HAVE PEOPLE THINK THIS IS COMPLETELY 100% SELF UPACTIVATED. I AGREE, IT IS REALLY SIGNIFICANTLY REDUCES IT. >> IT WAS A VERY GOOD QUESTION AGAIN. WE APPRECIATE YOUR QUESTIONS AND JUST ADDING TO THAT, THE DELETION IN THE OLDER VERSION OF A VECTOR, LITERATURE FROM THE LATE 90s. IT HAD DELETIONS SMALLER THAN IN OUR VECTOR. SO WE BASICALLY EXTENDED THE DELETIONS AND BESIDES THAT, ASSUMED WE WOULD HAVE AN EVEN LOWER LEVEL. SO FIRST OF ALL, I DON'T KNOW IF WE CAN GET U3 REPAIRED WITH OUR VECTOR AND SECONDLY, WE WOULD THEY WANTED OUR BACKGROUND LEVEL OF TRANSCRIPTION WOULD BE SIGNIFICANTLY LOWER THAN WHAT THEY DESCRIBED HERE. >> I DO THINK THAT IS VERY POSITIVE YOU EXTINCTIONED THE DELETION. SO MY NEXT COUPLE OF QUESTIONS WERE ON THESE POTENTIAL OFF TARGET EFFECTS AND IN ONE OF YOUR RESPONSES TO APPENDIX M, YOU HAD DONE AN EXPERIMENT SHOWING SELECT ACTIVITY TOWARDS DENDRITIC CELLS IN A LETOGINOUS POPULATION OF CELLS DERIVED FROM PPMC. I WAS WONDERING COULD THERE BE STEM CELLS IN THERE? WHAT IS THE PROBABILITY THEY STEM CELLS COULD BE INFECTED? IN YOUR ANSWER YOU SAY CD34 POSITIVE CELLS DO NOT EXPRESS DC SIGN. SO THUS YOU'RE NOT EXPECTING THOSE TO BE TRANSDUCED BUT WHAT ABOUT THE MANOSE RECEPTOR? AND OTHER ELECT INS. >> VERY GOOD QUESTION. COMING BACK TO THE STEM CELLS, WE DON'T EXPECT IT BUT WE HAVEN'T TEST TODAY OBVIOUSLY. WE HAVE -- WE HAVEN'T TESTED IT. WE HAVE LIMITED EVIDENCE WE CAN TRANSDUCE DENDRITIC CELLS THAT ARE DC SIGN NEGATIVE AND MADE THROUGH DIFFERENT MATURATION ROUTES THAN THE ONES I SHOWED YOU. SO WE HAVE GENERATED CELLS THAT ARE SUPPOSED TO BE LANGERHANS CELLS BY WAY OF PROTOCOL. AND THEY ARE EXPRESSED A LOT OF THE CELL MARKERS BUT THEY ARE NOT -- THIS IS TOO MUCH DETAIL MAYBE BUT THESE CELLS WE CAN TRANSDUCE AT A LOW-LEVEL AS WELL. SO THIS IS HOW WE MADE THE POINT. WE ARE VERY SPECIFIC FOR DC SIGN BUT BECAUSE OF THE GLYCOSYLATION, THERE IS A CHANCE THAT OTHER DENDRITIC CELLS OR APCs TAKE UP THE MANOSE BINDING ELECT INS AS WELL. >> HOW ABOUT STEM CELLS? IS THERE MAYBE VERY LOW CHANCE THOSE COULD BE? >> I GUESS ONE WOULD HAVE TO DO THE EXPERIMENT. >> THAT WOULD BE A CONCERN GOING IN VIVO THEN POTENTIALLY STEM CELLS BEING TRANSDUCED. >> IT IS A CONCERN. I AGREE. >> AND THEN, MY NEXT QUESTION WAS ABOUT THE 293 T-CELLS WHICH YOU ADDRESSED IN YOUR PRESENTATION THAT THOSE SEEM TO HAVE A HIGHER INFECTIVITY RELATIVE TO THE OTHER NEGATIVE CELL LINES BUT IT WAS PRETTY LOW AND I THINK YOU PROVIDED A REASONABLE EXPLANATIONS FOR WHY THAT MAY HAVE OCCURRED. THE N QUESTION WAS JUST THE STEPS TO DERIVE THE CONSTRUCT AND YOU BASICALLY DESCRIBED WHERE IT WAS OBTAINED AND WHAT BASIC TYPES OF TECHNIQUES THAT YOU USED AND IN THE END THEY WERE SEQUENCED WITH THE 4X COVERAGE AND THAT WAS A VERY SATISFACTORY ANSWER. THE NEXT QUESTION WAS ON MATERIAL USED TO PREPARE THE MATERIAL, AND I HAD JUST ASKED I THINK IN YOUR INITIAL RESPONSE TO APPENDIX M, YOU MADE REFERENCES IN OTHER PARTS TO THE 293 CELLS BUT YOU SAY THAT YOU PURCHASED THEM AND MODIFIED THEM AT THE MODIFICATIONS WERE CONSIDERED A TRADE SECRET. AND SO, THAT IS KIND OF AN UNKNOWN. WHENEVER I'M LOOKING AT VIRAL VECTOR PRODUCTION I'M ALWAYS CONCERNED ABOUT THE TYPE OF CELLS YOU'RE PRODUCING IT IN. COULD THERE BE ANYTHING IN THERE TO INTERACT WITH THE VECTOR, POTENTIALLY RECOMBINATION? MY QUESTION IS, DID YOU MAKE GENETIC MODIFICATIONS IN. >> NO. IT'S 293 CELLS AND THE STRAIN WAS DERIVED AT APARENTEDLY SUPPORTS THE TRANSDUCTION INFECTION PRODUCTION THAT'S IT. >> MAYBE A CLONE THAT WAS BETTER TRANSDUCED OR SOMETHING? BUT YOU'RE NOT ADDING ANY -- >> NO, NO, NO. THEY ARE NOT CHANGED AT ALL. >> THEN MY NEXT CONCERN WAS, IN YOUR WRITE UP, THE IDLB305 IS A VIRUS-LIKE PARTICLE THAT SEN ENGINEERED FROM A SPECIAL TYPE OF VARIANCE CALLED AULENTEDY VIRUS. MY CONCERN THERE IS THAT THAT -- CALLED A LENTE VIRUS. TO CALL IT A PARTICLE WAS INCORRECT AND THEN YOU CORRECTED THAT. >> WEECT WHYED THE LANGUAGE. YOU'RE RIGHT. WE CORRECTED THE LANGUAGE. >> BUT IN YOUR NEW MODIFIED LANGUAGE, I STILL HAVE A LITTLE ISSUE WITH THE FIRST SENTENCE BECAUSE IT SAYS, IDL305 IS WHAT IS KNOWN AS A VIRAL VACCINE VECTOR THAT WAS DERIVED FROM MODIFIED GENETIC ELEMENTS FROM A LAB ADAPTED STRAIN OF OF THE HUMAN IMMUNODEFICIENCY VIRUS, HIV. WHEN I READ THAT SENTENCE, I'M AN HIV RESEARCHER AND HIV VECTOR RESEARCHER. I HAD TO FOPPERY READ THATNESS AND SAY WHAT ARE THEY REALLY SAYING? THIS IS IN THE CONSENT FORM. SO I'M CONCERNED AND THE BIOLOGIST MIGHT WANT TO WEIGH IN. IF I'M STRUGGLING WITH IT AS AN HIV RESEARCHER, HOW IS A LAYPERSON GOING TO UNDERSTAND WHAT THIS IS? AND THIS POINT GETS INTO THE TERMINOLOGY OF VIRAL VECTORS. SO WHEN I SEE VECTOR, I IMMEDIATELY THINK OF THE NUCLEIC ACID WHEREAS WHEN I SEE, VIRUS, I KNOW I HAVE A PARTICLE THERE. AND ACTUALLY, THE TERM WAS COINED VECTOR VIRUS AND WE ALWAYS DESCRIBED THINGS IN TERMS OF VECTOR VIRUS OR VECTOR. SO WE ALWAYS KNEW IF WE HAD NUCLEIC ACID OR AN ACTUAL VIRUS PARTICLES. IT TELLS SOMEONE LIKE ME WHAT I ACTUALLY HAVE. SO IN YOUR NEW LANGUAGE, WHEN IT SAYS, VECTOR, I'M THINKING IT'S NUCLEIC ACID BUT IT'S REALLY NOT. IT'S THE PARTICLE. AND THEN, WHEN IT SAYS, DERIVED FROM MODIFIED GENETIC ELEMENTS FROM A LAB ADAPTED STRAIN. THAT -- THAT'S A LITTLE CONFUSING. AND THEN WHEN YOU SAY LAB ADAPTED STRAIN, IT ALMOST IMPLIES THAT'S SAFER AND THERE ARE MANY LAB ADAPTIVE STRAINS THAT GOING ON TO CAUSE AIDS AND LAB WORKERS HAVE BEEN INFECTED CERTAINLIY WITH HTLB3B AND POSSIBLY THE NL4-3 YOU USED AND THOSE PEOPLE HAVE GONE ON TO DEVELOP AIDS. SO, ESPECIALLY SINCE THIS IS IN THE CONSENT FORM, TO ME, THE LANGUAGE THAT WOULD BE MUCH SIMPLER IS THAT IDLB305 IS WHAT IS KNOWN AS A VECTOR VIRUS AND IS DERIVED FROM HIV. IT IS DERIVED FROM HIV. AND THAT IS MUCH SIMPLER. YOU GO ON THEN TO SAY HOW IT HAS BEEN MODIFIED AND MADE SAFER, WHICH IS GREAT. BUT I THINK PEOPLE NEED TO KNOW, THIS IS DERIVED FROM HIV. AND I THINK THE PROBLEM IS THAT HIV IS STILL A SCARY VIRUS TO A LOT OF PEOPLE AND THERE IS A STIGMA ATTACHED TO IT. SO I THINK WHEN YOU'RE WRITING UP A CONSENT FORM LIKE THIS, YOU DON'T WANT TO SCARE PEOPLE, BUT ON THE OTHER HAND YOU WANT THEM TO KNOW WHAT THEY ARE GETTING. THAT WOULD BE THE LANGUAGE I WOULD RECOMMEND BECAUSE I DO THINK IT IS A VECTOR VIRUS. IT'S A VIRUS. IT'S AN INFECTED VIRUS BUT IT'S STILL A VIRUS PARTICLE. >> I SEE YOUR POINT AND WE KNOW WHAT THIS IS ABOUT. THIS IS NOT HIV. THIS IS A VECTOR BUT WE DON'T WANT TO CONCEAL THE FACT THAT IT'S DERIVED FROM HIV. MY QUESTION TO IS, THIS IS NOT THE FIRST LENTE VECTOR BASED ON HIV. IS THIS THE LANGUAGE YOU RECOMMEND TO ALL PEOPLE? >> I ALWAYS RECOMMEND IT PERSONALLY. WHEN I'M REVIEWING ANY PROTOCOL. >> SO ARE THERE OTHER WAYS PHRASING THAT THAT OTHER PEOPLE USE WHICH ARE SCIENTIFICALLY CORRECT BUT AVOID ANY IDEA THAT THIS HAS SOMETHING TO DO WITH THE HIV VIRUS? THE HI VIRUS? >> AND I HAD THROWN OUT A FEW TERMS SO VECTOR VIRUS, REPLICATION DEFECTIVE VIRUS. REPLICATION DEFICIENT VIRUS. WHAT YOU'RE CREATING IS ALL OF THOSE THINGS. THOSE ARE THE TERMS THAT ARE ALWAYS USED IN MY WORLD FOR DESCRIBING AND MOST ACCURATELY. AS I READ A LOT OF PROTOCOLS NOT JUST YOURS, A LOT OF PEOPLE THROW THESE TERMS AROUND, VECTOR OR VIRUS AND THEY ARE NOT ALWAYS THINKING ABOUT HOW THAT COMES ACROSS IN THE DOCUMENT IN TERMS OF SOMEONE LIKE ME READING IT. AND ESPECIALLY NOW WITH THIS BEING IN THE CONSENT FORM, THAT FIRST SENTENCE IS STILL VERY CONFUSING. SO I'LL BE HAPPY TO HEAR OTHER SUGGESTIONS FROM THE PANEL. >> I PERSONALLY THINK YOU SHOULD TAKE OUT THIS MODIFIED LAB STRAIN. BECAUSE IF YOU READ THAT, THEN PEOPLE SOMETIMES KNOW ABOUT ATTENUATED VACCINES AND SOMEHOW SEEMS LIKE IT IS BE AN ATTENUATEED STRAIN BUT CERTAINLY IS NOT. PEOPLE HAVE BEEN INFECTED WITH IT AND I THINK AT LEAST MY LAB WORK, I SEE -- DISCERP DISCERN DISCERN -- [ INDISCERNIBLE ] TO DEVELOP AIDS. >> I THOUGHT THAT DR. WOOLLY SUGGESTED LANGUAGE WAS REASONABLY BALANCED. HONEST BUT NOT SCARY AND HAD APPROPRIATE REASSURANCES. AND IT SEEMED OKAY TO ME. >> IT GOES ON TO SAY, UNLIKE HIV, VERY EXTENSIVE MODIFICATIONS WERE MADE. I'M SAYING KEEP ALL THAT LANGUAGE. IT'S JUST THE FIRST SENTENCE I HAD A PROBLEM WITH. SO. LET'S MOVE ON. >> IF I MAY. THIS IS SOMETHING THAT EVERYBODY STRUGGLES WITH TO PRECEPT AN UNBIASED -- TO THE PATIENT WHO WILL BE RECEIVING THIS. AND YOU'RE TRYING TO SHOW A FULL SENSE OF WHAT IS HAPPENING AND THE FULL SENSE IS THIS ISN'T HIV. THE PROBLEM IS, WHEN WHENEVER YOU SAY IT IS DERIVED FROM HIV, THAT IS KIND OF THE OBVIOUS CONCLUSION. THAT YOU'RE INJECTING ME WITH HIV. AND ALL WE ARE TRYING TO DO IS FIND A WAY THAT IS BETTER TO DO THAT. I THINK THAT WEEK TAKE OUT THE, LAB ADAPTIVE STRAIN. I WONDER IF YOU AGREE THAT BEING DERIVED FROM MODIFIED GENETIC ELEMENTS OF HIV WAS -- THE AMOUNT OF HIV GENOME IN THERE IS VERY SMALL. AND IS COMPLETELY INCONSISTENT WITH REPLICATION IN AN HIV-LIKE FASHION. SO TRYING TO EXPLAIN THAT IS TOUGH. >> WHEN YOU SAY DERIVED FROM MODIFIED GENETIC ELEMENTS. IT SOUNDS LIKE YOU TOOK THEM AND PIECED THEM TOGETHER AND -- >> WE DID. >> AS OOH POSED TO TAKING THE GENOME AND DEPENDS ON -- I GUESS IT GOES HOW IT WAS SYNTHESIZED ALSO. BUT FOR A LAYPERSON, THAT STILL IS VERY CONFUSING. >> BUT DERIVED FROM HIV IS SCARY. SO, I DON'T KNOW THAT THE BALANCE IS THERE. >> SO IF I CAN COMMENT. >> SO I DO TRIALS WITHULENTEDY VIRALS VECTORS AND OUR CONSENTS SAY IT IS DERIVED FROM HIV. MY OPINION IS PEOPLE NEED TO KNOW IT IS COMING FROM THAT. WE TRY TO MAKE IT NOT SO SCARY BY SAYING THERE IS LITTLE BITS OF IT THERE. ONE OF THE OTHER POINTS THERE WAS A REPORT WE HEARD AT THE LAST RAC MEETING FROM INVESTIGATORS USING A LENTE VIRAL VECTOR THAT TRIGGERED A FALSE-POSITIVE HIV TESTING IN THE PATIENT AND THROAT A LOT OF INVESTIGATIONS AND IT'S A FALSE-POSITIVE BUT THAT IS ANOTHER RATHER THAN TO INFORM THEM IT IS DIE ARRIVED FROM HIV YOU COULD HAVE A FALSE-POSITIVE HIV TEST. TELL YOUR DOCTOR YOU HAD GENE THERAPY STATEMENT. SO THAT IS AN OPINION. IT'S NOT A POLICY. >> THAT IS IN THE PROTOCOL, BY THE WAY. >> WE CAN CONCEDE THE POINT. AND I DON'T WANT TO PUSH IT. IT SIMPLY IS SHOWING THE DIFFICULTY IN EXPLAINING IT. >> I JUST WANT TO MAKE ONE FURTHER POINT ON THIS. IT'S NOT INTUITIVELY OBVIOUS TO A LAYPERSON THAT HIV IS THE VIRUS THAT CAUSES AIDS. BUT AS SOON AS THEY LOOK IT UP ON GOOGLE, THEY SEE THAT. THAT IS WHAT IS AT STAKE. YOU DON'T WANT THEM TO SIGN IT AND HEAR FROM THEIR MOTHER-IN-LAW THAT WHAT? THIS IS THE -- DON'T YOU KNOW THAT CAUSES AIDS? SO JUST ADDRESS IT HEAD ON AND BE HONEST AND FRANK AND EXPLAIN WHY YOU THINK IT IS PERFECTLY SAFE. >> WE INCLUDE IN THE CONSENT THE NOTION THAT YOU MIGHT BECOME HIV POSITIVE BY THE TEST THAT IS AVAILABLE. >> BUT YOU HAVE TO MAKE IT EXPLICIT. AND THEY'LL KNOW SOMETHING IS UP BECAUSE OF ALL THE ANXIETY AROUND SEXUAL PROTECTION AND BEING STERIL. SO THAT SHOULD CORRELATE TO SOME UNDERSTANDING OF WHY THIS IS SUCH AN ANXIETY PROVOKING MOMENT. >> ABSOLUTELY. >> SO, MY NEXT POINT FEEDS OFF OF THAT BECAUSE IT GOES TO THE LANGUAGE THAT SAYS, MAY CAUSE SOME HIV SCREENING TOASTS BECOME FALSELY POSITIVE. I HAVE AN ISSUE WITH THE WORD, FOLLOWSLY. IN THIS CASE, YOU'RE INJECTING PARTICLES. AND ALTHOUGH THE DEFECTIVE GENOME DOESN'T ENCODE CAPSID OR MATRIX T IS PRODUCED WITH THE CAPSID AND THE PRAY TRICKS AND YOU'RE IN VECTING IT AS A VACCINE AND THE PEOPLE RECEIVING IT WILL HAVE IMMUNE RESPONSE TO THOSE PROTEINS. SO, HIV SCREENING TESTS LOOK FOR ANTIBODY RESPONSE TO THOSE PROTEINS. AND MOST OF THE COMMERCIAL TESTS NOW HAVE THE P24 AND THE ENVELOPE G120. SO ON A SCREENING TEST T IS HIGHLY LIKELY THEY ARE GOING TO COME UP POSITIVE, THAT THEY WILL HAVE ANTIBODIES TO P24. SO THEY WILL SCREEN POSITIVE. AND THEN THEY IMMEDIATELY GO TO THE WESTERN BLOOD -- WESTERN BLOT. NOW YOUR LANGUAGE SAYS WESTERN BLOT WOULDN'T SHOW A POSITIVE RESULT. THAT IS TRUE. THERE IS AN IMPLICATION THAT THE RESULT IS NEGATIVE AND THAT'S NOT TRUE EITHER. ON A WESTERN BLOT, MOST LIKELY, THE PERSON WILL HAVE P24 ANTIBODIES AND P17. THOSE ARE THE TWO MOST ABUNDANT PROTEINS. SO THOSE BANDS WILL LIGHT UP ON THE WESTERN BLOT BUT YOU'RE GOING TO BE MISSING OTHER IMPORTANT ONES LIKE THE ENVELOPE PROTEIN. SO ON A WESTERN BLOT, READS LIKE THAT, IT IS LISTED AS INCONCLUSIVE. SO SOMEONE RECEIVING THIS VACCINE WILL GO IN FOR AN HIVEST AND SCREEN POSITIVE AND ON THE WESTERN BLOT THEY WILL BE UNDETERMINED. THAT WILL BE THE LANGUAGE THAT WILL COME BACK ON THEIR LAB TEST RESULTS. POSITIVE ELIZA AND INCONCLUSIVE. SO, I THINK THAT FOR THE CONSENT FORM, PEOPLE NEED TO KNOW THAT -- THAT'S WHY I DON'T THINK IT'S A FALSE-POSITIVE. IT MEANS SOMETHING WENT WRONG WITH THE TEST IT'S A REAL POSITIVE. THEY GOT INJECTED WITH CAPSID PROTEIN. THEY HAD IMMUNE RESPONSE TO IT. IT'S FALSELY POSITIVE FOR WILDTYPE HIV. BUT IT IS A REAL POSITIVE RESULT IT'S NOT JUST SOME AB RAPT CROSS CREATE ACTIVITY. >> COULD YOU JUST SAY IT IS FALSELY POSITIVE FOR HIV INVENTION? >> WELL, THEY WERE INFECTED WITH THE VIRUS THAT WAS DERIVED FROM HIV SO THAT IS A LITTLE -- BUT WHEN I WAS THINKING ABOUT LANGUAGE, I JUST THOUGHT FALSELY POSITIVE FOR WILDTYPE OR FOR THE FAUX -- AGAIN, IT IS -- >> TO SAY IT STRAIGHTFORWARD LIE, YOU MAY GET THIS VIRUS IN YOUR BLOODSTREAM OR IN YOUR BODY BUT YOU NEED TO TELL YOUR DOCTOR THAT YOU'RE ON A GENE THERAPY PROTOCOL AND IT IS NOT LIKELY THAT IT IS THE SAME VIRUS AS CAUSES THE BAD DISEASE, AIDS, THE FATAL DISEASE, AIDS. WHATEVER YOU CALL IT. >> THE FULL VIRUS. >> THAT LEADS TO THE DISEASE, AIDS. BUT THE TROUBLE IS, THAT OF COURSE IT COULD. >> SO THE LANGUAGE THAT I WOULD LIKE TO SEE IN THE CONSENT FORM IS, MAY CAUSE SOME HIV SCREENING TESTS TO BECOME POSITIVE AND WESTERN BLOT TO BECOME IN DETERMINANT, PARENTHESES, NOT POSITIVE. WE SAY IT'S NOT POSITIVE, THEY ARE GOING TO GO, IT'S NEGATIVE. BUT IT COULDN'T COME BACK LIKE THAT EITHER. IT WOULD COME BACK FROM THE LAB IN DETERMINANT. THAT'S WHAT THEY ARE GOING TO SEE IF THEY ASK THEIR DOCTOR FOR A REPORT, IT WILL SAY INCONCLUSIVE. >> ALTHOUGH, I THINK GOING INTO THE DETAIL OF WESTERN BLOT IN A CONSENT FORM IS WAY TOO MUCH. >> I THINK THEY HAD IT THERE. THEY HAD R. HAD IT AND I WAS PLAYING OFF WHAT THEY HAD. >> I DON'T THINK THEY SHOULD HAVE IT EITHER. >> AND IT'S A TERMINOLOGY THING THAT IS A CHALLENGE TO EXPLAIN IN A CONSENT FORM. I CAN'T SAY THAT IT IS TRULY POSITIVE FOR THE HIV INFECTION. THAT IS THE ONE THING I THINK IS A SLIPPERY SLOPE. >> THAT IS ABOVE THE LAYPERSON'S LEVEL OF UNDERSTANDING. BUT MAYBE IT MAY CAUSE SOME KOREANING TESTS TO BECOME POSITIVE -- SCREENING TESTS BUT LATER TESTS WOULD CONFIRM THE FULL HIV VIRUS IS NOT THERE. THAT'S LAY LANGUAGE A PERSON COULD UNDERSTAND MORE THAN WHAT IS HERE. SO I'D LIKE WHAT I JUST SAID. SO THAT KIND OF MAYBE IS A GOOD COMPROMISE. JUST ELIMINATE SOME OF THAT WESTERN BLOT STUFF. I THINK THE REMAINING ONES HAVE BEEN PRETTY WELL ANSWERED. SO NUMBER 11, THIS WENT TO THE INTEGRATION DEFICIENCY AND THEN YOU AGREED TO MODIFY THE LANGUAGE JUST TO SAY THAT IT REDUCES THE CHANCES OF THE VECTOR MAY BECOME INCORPORATED. I LIKE THAT. THE NEXT ONE INITIALLY RED, IT'S DESIGNED TO TRAVEL AND BIND TO SPECIFIC CELLS BUT I POINTED OUT IT IS ACTUALLY INFECTING THEM AND YOU AGREED TO SAY, IT IS DESIGNED TO BIND AND INFECT SPECIFIC CELLS. SO I LIKED THE NEW LANGUAGE ON MY COMMENT 12. 13 WAS JUST A TEXT OMISSION AND THAT WAS CORRECTED. 14. AGAIN, THAT WAS TOWARDS THE INTEGRATION ISSUE AND YOUR NEW LANGUAGE SAYS THAT THE VECTOR IS DESIGN TO REDUCE SUCH INTEGRATION AND THAT WAS THE LANGUAGE I WAS GOING FOR. S AND THEN QUESTION 15, IN YOUR FORM T SAID T IS NOT KNOWN IF IDLB305 CAN BE TRANSFERRED FROM ONE PERSON TO THE NEXT BY CLOSE CONTACT. IMTHINKING THAT SOMEONE IS VACCINATED AND THEIR CHILDREN AROUND YOUNG CHILDREN OR GRANDCHILDREN AROUND, WHAT HAPPENS IN THE WORST CASE SCENARIO THERE IS A HORIZONTAL TRANSMISSION AND THE CHILD HAS AN IMMUNE RESPONSE TO THE ANTIGEN? COULD THAT EFFECT THEIR DEVELOPMENT? I THINK YOUR ANSWER SAID THAT THE CELLS AFFECTED WERE A PROTECTED SITE FROM THE IMMUNE SYSTEM. SO WHAT I'M HEARING IN YOUR ANSWER IS, EVEN IF THERE WAS A HORIZONTAL TRANSMISSION AND THE CHILD HAD AN IMMUNE RESPONSE, IT WOULD NOT GET TO THOSE CELLS THAT WOULD DESTROY THEIR NORMAL TESTICULAR DEVELOPMENT? >> I DON'T KNOW THAT IT HAS BEEN STUDIED BUT MY UNDERSTANDING IS THAT CANCER PATIENTS HAVE T-CELLS AGAINST NYSE1 DO NOT BECOME STERIL. I EXPECT THAT. BECAUSE CELLS ARE AYEs LATED FROM THE IMMUNE SYSTEM AND THEY ARE THE ONLY ONES THAT MIGHT BE KILLED BY AN IMMUNE RESPONSE. SO YES, I THINK THAT IF THERE WAS SOME SORT OF INTRAVENUS HORIZONTAL TRANSMISSION, THEN THAT COULD OBVIATE THAT CONCERN. >> AND I'M NOT A MEDICAL DOCTOR SO I DON'T KNOW IF THERE WOULD BE A DIFFERENCE IN A CHILD WHO IS STILL DEVELOPING. >> AND IT IS A GREAT QUESTION. WE WOULD NOT RECOMMEND THIS FOR A PREGNANT WOMAN. >> RIGHT. I WAS JUST GOING FOR THE STATEMENT THAT YOU MADE THAT YOU DON'T FINISH IT COULD BE TRANSMITTED HORIZONTALLY. AND THAT LED ME TO THINK, WHAT IF A CHILD OR GRANDCHILD WERE AROUND THE HOME AND DID GET EXPOSED SOMEHOW? >> THERE ARE SEVERAL POINTS AND I DON'T WANT BELABOR THE TIME BUT THE FACT THAT THIS IS A NONREPLICATING VIRUS, IF YOU CAN EVEN DALA VIRUS, BECAUSE IT GOES AND INFECTS AND THEN DIES, IT IS A OR MAKES THE CONSEQUENCE OF A POTENTIAL HORIZONTAL TRANSMISSION MUCH LESS WORRISOME OR RISKIER. >> RIGHT. >> AND SO, LIKE I SAID, EVEN IF THERE IS SOME SORT OF INTRAVENOUS HORIZONTAL TRANSMISSION THAT MIGHT GO TO THE TESTTICULAR CELLS, THE CHANCES OF IT CAUSING A PROBLEM TO THAT ARE -- >> OBVIOUSLY THE CHANCES OF GETTING HIGH ENOUGH DOSE GENERATE AN IMMUNE RESPONSE WOULD BE PRETTY LOW. >> SO YOUR COMMENT DID STIMULATE SOME EXPERIMENTAL MOVEMENT AND WE DID A PRELIMINARY EXPERIMENT TO LOOK FOR SHEDDING, WHICH IS THE NORMAL APPROACH YOU LOOK FOR THESE THINGS. AND FOUND THAT AT 30 MINUTES, YOU CAN DETECT IF YOU SWAB THE SITE, SOME VIRUS. AND SO, IT IS SOMETHING THAT NEEDS TO BE PURSUED AND OF COURSE WILL YOU BE COVERING THE SITE AND RECOMMENDING PRECAUTIONS THAT YOU USE IN THE STANDARD TYPE OF A WAY, LIKE ANYBODY WITH HIV, FOR INSTANCE. WOULD USE THE SAME TYPES OF PRECAUTIONS. BUT I DON'T THINK IT IS A HIGH LEVEL OF CONCERN. AND THE FACT THAT IT IS A NONREPLICATING VIRUS REDUCES THAT LEVEL SUBSTANTIALLY. >> I AGREE. OKAY. THAT'S ALL OF MY COMMENTS. >> THANK YOU. ANY OTHER COMMENTS FROM THE RAC MEMBERS? I GUESS I WOULD MAKE ONE. WE DID EXPERIMENTS WITH NONINTEGRATING OR INTEGRATION DEFECTED LENTIES WITH A MARKER AND CLONED OUT A DOZEN OR SO OF THE INTERGRANTS, NOT INTEGRATED MEDIATED. SO NO DUPLICATION. SO IT'S PROBABLY JUST END CAPTURE INTO DOUBLE-STRANDED BREAKS. SO THAT WOULD BE WHY ADDING A INHIBITOR MAY NOT LOWER THE INTEGRATION RATE ANY FURTHER BECAUSE THEY ARE PROBABLY NOT DUE TO RESIDUAL CATALYTIC ACTIVITY OF THE INTEGRATION BUT PROBABLY JUST ANY DNA GETTING TO A CELL TO GET IN CORPORATED AT SOME LOW-LEVEL. >> MY UNDERSTANDING IS THESE FORM EPISOMES AS THEIR NORMAL PHYSIOLOGY. >> SO OTHER COMMENTS FROM RAC SO THEN WE'LL TAKE A SHORT BREAK >> OK I'LL READ BACK OUR RECOMMENDATION LETTER AND THEN WE'LL VOTE ON IT. SO THE FIRST RECOMMENDATION UNDER PRECLINICAL, CONSIDER A STUDY USING INTERGRACE IN HIN TORTO SEE IF ADDITION WOULD FURTHER REDUS RISK OF THE INTEGRATION OF THE VECTOR USING PCR ASSAY TO DETECT INTEGRATION MIGHT ANSWER THIS QUESTION. PRIOR TO MOVING FORWARD WITH STUDY, IT IS SOMETHING TO CONSIDER AS THE PRODUCT IS DEVELOPED T WOULD BE HELPFUL TO ESTABLISH IF THIS IS ABLE TO TRANSDUCE HEMATOPOIETIC STEM CELLS OTHER THAN DC SIGN. TWO CLINICAL POINTS. IMPORTANT TO THE RESULTS OF THE CLINICAL TRIALS ARE PUBLISHED, POSITIVE AND NEGATIVE RESULTS. THE POLICY ARTICULATED IN THE PROTOCOL IS NOT CLEAR WHETHER COMPANY WILL PREVENT CERTAIN PUBLICATIONS. CONSIDER EXPANDING UPON THIS POLICY DRAWING FROM OTHER ESTABLISHED TEMPLATES TO MORE CLEARLY AR TICK LACE YOUR INTENT TO ALLOW PUBLICATION ONCE PRIMARY RESULTS ARE PUBLISHED. IMPORTANT TO KNOW WITH THE RELEASE PRODUCT THAT YOU KNOW HOW MANY DEFECTIVE VIRAL PARTICLES HAVE YOU COMPARED TO HOW MANY VIRAL PARTICLES ARE CAPEAL OF INFECTING THE CELLS INFORMING SAFETY OF PARTICULAR DOSE. THEN THREE, ETHICAL LEGAL SOCIAL POINTS. THE FIRST ONE IS THIS IS A PHASE I TRIAL AND WHILE WE HOPE THE RESULTS OF YOUR PACKAGE WILL RESULT IN A CLINICAL BENEFIT, IT IS IMPORTANT THAT SUBJECTS UNDERSTAND THAT STATISTICALLY, LOOKING ACROSS ALL STUDIES DIRECT LIFT ABOUT -- BOST PHASE I TRIALS IS NOT COMMON. WE SUGGEST YOU REVIEW THE LANGUAGE FROM NIH GUIDANCE ON INFORMED CONSENT FOR GENE TRANSFER RESEARCH ON WAYS TO BENEFIT AS A MODEL FOR STATEMENT REGARDING BENEFIT. WE HAVE A LINK TO THAT. THE SECOND ONE THE IS INFORMED CONSENT SHOULD CLARIFY THAT WITHDRAWAL FROM THE STUDY IS WITHDRAW FROM THE STUDY FOLLOW-UP AND PROCEDURES BUT THE PRODUCT CANNOT BE WITHDRAWN BECAUSE IT HAS THE ABILITY TO PERSIST. AND THEN THE LAST POINT HERE IS THE INFORMED CONSENT -- TWO MORE POINTS. INFORMED CONSENT SHOULD SIMPLIFY STATEMENT REGARDING SOURCE OF IDLV305 AND MAKE IT CLEAR THIS VECTOR IS A VIRUS PARTICLE AND INFORM SUBJECTS THERE ARE GENES IN THIS VIRAL VECTOR DERIVED FROM HIV. I MIGHT CHANGE THAT FROM GENES TO SEQUENCES. NOT HIV GENES. AND THEN THE LAST POINT IS SUBJECT TO INFORMED, THEY MAY HAVE A FALSE-POSITIVE HIV TEST AS A RESULT OF DETECTION OF CERTAIN HIV SEQUENCES PRESENCE IN THIS VIRAL VECTOR AND POTENTIALLY IMMUNE RESPONSE TO THE HIV VIRAL PROTEINS IN THE VIRAL VECTOR PARTICLES. MIGHT BE MORE ACK TREAT SAY THAT THEY MAY -- A TOAST SCREEN FOR HIV VIRUS MAYBE POSITIVE BUT RESULTS REFLECTING VIRAL VECTOR IT DOESN'T REPRESENT HIV INFECTION. SO THOSE ARE OUR COMMENTS AND OUR RECOMMENDATION. ANY COMMENTS OR RESPONSES? >> WE ARE RIGHT NOW SEE FIGURE WE CAN TRANSDUCE HEMATOPOIETIC STEM CELLS. >> THANK YOU. ANY OTHER COMMENTS FROM THE RAC MEMBERS BEFORE WE VOTE ON THESE RECOMMENDATIONS? NO? THEN DR. AR NELLIES? >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> YES. >> DR., PILEWSKI, TO MAKE SURE YOU'RE NOT ON THE PHONE? THANK YOU. THEN THE MEETING IS ADJOURNED AND SEE YOU IN MARCH.