>> ONCE AGAIN, WE THANK YOU VERY MUCH FOR PRESENTING FOR US TODAY. I WANT TO READ FOR YOU THE DRAFT RECOMMENDATIONS AND ASK FOR COMMENTS FROM MEMBERS OF THE RAC. THIS IS FOR PROTOCOL 1153 FROM THE PRECLINICAL. IN YOUR PRECLINICAL MOUSE MODELS, THE CD34 HUMAN STEM CELLS FOR TRANSFUSED AND MATURE INTO MACROPHAGES AND DEMONSTRATED NORMAL SURFACE PHENOTYPES. SINCE THE TARGET CELL OF THIS INTERVENTION IS CD4T CELLS PERFORMING SIMILAR PHENOTYPES OF MATURE TRANSFUSED CD4T CELLS. CLINICAL. IN THE CLINICAL TRIAL PROTOCOL THE SECONDARY OBJECTIVE INCLUDES EVALUATING IMUNION RECONSTITUTION. THESE ANALYSIS WOULD INCLUDE MEASURING IMMUNE RESPONSES TO RECALL ANTIGENS OF THE CEF PEPTIDE POOL REPRESENTING CMB, BBE AND INFLUENZA VIRAL ANTIGENS. THERE'S NO REASON TO SUSPECT THE CLINICAL PARTICIPANTS WILL BE EXPOSED TO -- UNLESS THE VIRUS REACTIVATES POST TRANSPLANT. IMMUNIZATION WITH AN APARTMENT GEN SUCH AS -- SHOULD BE INCLUDED IN THIS ANALYSIS. ETHICAL AND LEGAL SOCIAL . THE INFORM CONSENT SHOULD INCLUDE THE RISKS OF AN INTERRUPTION IN THE ART RECOGNIZING THE MONITORING PROGRAMS DESIGNED TO MITIGATE THE RISK. NUMBER TWO, WHILE THERE'S A SEPARATE CONSENT OF THE DMT THE INFORMED CONCEPT FOR THIS TRIAL SHOULD ALSO MENTION THE RISK SUBTRANSPLANT. NUMBER THREE, THE CHANGES IN THE INFORMED CONSENT AND RESPONSE TO THE WRITTEN RAC MEMBER WILL USE IMPROVED CONCEPT BY THE LANGUAGE THIS COULD BE MISINTERRUPTED BY THE APPROACH OF THE THERAPY. NUMBER FOUR THE INFORMED CONCEPT HAS BEEN CLARIFIED TO STATE THE PATIENT WILL THOUGHT BE BILLED FOR THE EXPERIMENTAL PARTS IT SHOULD BE CLARIFIED LONG TERM APPROACH WILL NOT BE RECOGNIZED IMMEDIATELY OR COVERED. NUMBER FIVE THE INFORMED CONCEPT SHOULD STATE SIMPLY THAT CONCEPT TO THE INTES INTUNL MUCOSAL BIOPSIES ARE NOT REQUIRED FOR PARTICIPATION ON THIS PROTOCOL. SO THOSE ARE CURRENTLY THE DRAFT RECOMMENDATIONS. ANY COMMENTS FROM THE RAC, ADDITIONS OR MODIFICATIONS? COMMENTS FROM THE INVESTIGATORS? OKAY. SO DO I HAVE A MOTION FOR A VOTE? >> YES, YES, YES, CHATTERJEE YES, YES, MASS TRICHLOROETHYLENE YES, YES, FONG YES, YES, BADLEY YES, YES, YES. >> ANYBODY ON THE PHONE. >> BOOK MEYER YES AND MOLINO YES. >> THANK YOU DR. MITSUYASU. THAT'S GOING TO CONCLUDE THIS DISCUSSION. >> THANK YOU. IT'S MY PLEASURE. >> THANK YOU VERY MUCH FOR YOUR PARTICIPATION. >> YOU'RE VERY WELCOME. BYE-BYE. >> IT'S COME THAT TIME TO THANK ALL THE RAC MEMBERS THAT ARE ABOUT TO BE PAROLED. JACKIE. >> I DON'T THINK I COULD HAVE SAID THAT BETTER MYSELF. YES. SO IT'S EVERY JUNE THAT WE HAVE THE UNFORTUNATE OPPORTUNITY TO SAY GOOD-BYE TO THE MEMBERS WHO HAVE COMPLETED THEIR TERM ON THE RAC AND DR. AMY PATTERSON OUR ASSOCIATE DIRECTOR OF POLICY USUALLY IS HERE TO PROVIDE YOU SMALL TOKEN AND SHE IS UNFORTUNATELY UNABLE TO COME HERE BUT DOES WANT TO EXTEND HER THANKS TO YOU ON BEHALF OF THE OFFICE OF THE DIRECTOR. I'M GOING TO STAND IN FOR HER AND SAY A COUPLE WORDS. OVER THE PAST SEVERAL YEARS YOU'VE REALLY ADVISE THE US ON THE SCIENTIFIC AND SAFETY DIMENSIONS OF SAFETY AND COLLINAL APPLICATIONS IN COMMON DNA RESEARCH AND PROVIDED A CRITICALLY IMPORTANT SERVICE NOT ONLY TO THIS AGENCY BUT ALSO TO THE RESEARCH COMMUNITY AND THE PUBLIC AT LARGE. AND WITH YOUR INDIVIDUAL EXPERTISE, EACH OF YOU BRINGS A CRITICALLY IMPORTANT PERSPECTIVE TO THIS TASK THAT PROVIDES US WITH BROAD, THE RAC WITH ITS BROAD AND NATIONALLY RESPECTED POINTS OF VIEW. I WANT TO SAY THAT IT'S BEEN SUCH A PLEASURE AND PRIVILEGE FOR MYSELF AND I THINK I SPEAK FOR MY COLLEAGUES AT OBA TO GET THE OPPORTUNITY TO KNOW YOU OVER THE TERM OF YOUR SERVICE AND HOW MUCH WE LEARN FROM EACH OF YOU. AS YOU GO FORWARD AND CONTINUE TO SERVE SCIENCE AND THE PUBLIC WE HOPE THAT YOU WILL LOOK BACK ON YOUR TIME OF THE RAC AS AN EXPERIENCE THAT'S REWARDING AS YOU'VE BEEN ON THE FOREFRONT OF SOME FASCINATING DEVELOPMENTS. OF COURSE AS YOU KNOW, AT NIH GREAT WORK IS ALWAYS RECOGNIZED AND WE NOW JOIN THE GROUP OF RAC ALUMNI. LIKE ALL ALUMNI GROUPS DO NOT BE SURPRISED IN WE OFFER YOU THE OPPORTUNITY TO CONTINUE YOUR SERVICE. IN ACKNOWLEDGMENT OF YOUR SERVICE AS DR. PATTERSON ALWAYS SAYS WE GIVE YOU A PIECE OF PAPER FOR THOSE FOUR YEARS OF WORK. ACTUALLY WE'RE GOING TO DO SOMETHING A LITTLE DIFFERENTLY. IN LIGHT OF OUR NEW COPY REGULATIONS I'VE DECIDED THAT WE'LL ADD SOMETHING SO THAT YOU WILL BE ABLE TO BRING A COPY WITH YOU TO WHATEVER NEXT NIH MEETING YOU ARE CALLED TO. I WOULD LIKE TO START FIRST WITH PROFESSOR MASTROIANNI WHO IS A PROFESSOR AND HAS SERVED ON THE RAC NOW FOR THREE YEARS. I THINK OUR BIO ETHICISTS FOR TRIAL DESIGN ISSUES THAT MAY BE RISED. AND ANNA HAS EXCELLED AS THAT. AS GAB THERAPY HAS MOVED FORWARD AND WE'VE HAD SOME VERY NICE AND ENCOURAGING CLINICAL RESULTS THE COMMITTEE HAS MORE OFTEN BEEN ASKED TO REVIEW PROTOCOLS IN THE ROLE OF PEDIATRIC PATIENTS AND PROFESSOR MASTROIANNI HAS TAKEN A LEAD IN HELPING THIS COMMITTEE REALLY THOUGHTFULLY REVIEW THOSE ISSUES IN THE COMPETING INTERESTS AT HAND. SHE CAN BE VERY SOFT SPOKEN BUT WHEN THERE'S AN ISSUE TO DISCUSS, WE REALLY APPRECIATE HER WILLINGNESS TO CONTINUE THE DIALOGUE UNTIL THERE IS A REVOLUTION. WITH THAT I WOULD LIKE TO WELCOME YOU UP HERE. [APPLAUSE] >> THANK YOU SO MUCH. >> THANK YOU. WE'RE GOING TO DO EVERYONE IN THE ROOM AND THEN I WILL GO TO OUR MEMBERS ON THE PHONE. JOSEPH -- IS ASSOCIATE PROFESSOR OF BIOLOGY AT THE UNIVERSITY OF WHICH SERVED ON THE RAC FOR FIVE YEARS. IN ADDITION TO HIS SERVICE ON THE RAC JOE SERVED ON THE NATIONAL SCIENCE ADVISORY BOARD FOR BY OWE SECURITY. THIS JOINT MEMBER SHEEP AROSE OUT OF THE RAC'S COMMUNITY COLLABORATION ON SYNTHETIC BIOLOGY AND JOE WAS A KEY MEMBER OF THE GROUP THAT DEVELOPED THE PROPOSE REVISION OF THE SYNTHETIC -- WE DO HOPE TO FINALIZE VERY SHORTLY AND ACTUALLY PUBLIC. OF NOTE IT WAS IN 2009 THAT JOE TOOK A LEADING ROLE IN UPDATING THE GUIDELINES FOR RESEARCH WITH H5N1 AND I THINK THAT HELPED YOU PROPOSE FOR YOUR WORK. WE ARE ONLY AN E-MAIL AWAY AND WE HOPE TO KEEP THAT RELATIONSHIP. DO YOU KNOW TO COME UP. [APPLAUSE] IS -- UNIVERSITY OF CHAPEL HEALTH. SHE'S BEEN ON THE RAC FOR YEARS AND GENE TRANSFER ASSESSMENT BOARD. I REALIZE THE REPORTS MAY BE SOMEWHAT BRIEF SOMETIMES A LITTLE BIT DRY BUT I THINK TO REALLY PRESSURE THE WORK THAT THE GTSAB DID I ACTUALLY TOOK AND LOOKED AT THE 300 PLUS PAGE PACKAGE THAT JIM RECEIVED BY E-MAIL ABOUT A WEEK BEFORE A TELECONFERENCE CALL AND I THINK PROBABLY THE BIGGEST CHALLENGE IS FINING THE PASSWORD TO OPEN UP THAT PACKAGE. IN ALL SERIOUSNESS JIM HAS ALWAYS PROVIDED SAGE ADVICE AS WE REVIEW NEW SAFETY DATA AND HELP US IDENTIFY THOSE ISSUES THAT WARRANTED FURTHER DISCUSSION BY THE GTSAB OR TAKING THIS TO A FULL SAFETY CONFERENCE HE HAS HELPED US GUIDE THE DEVELOPMENT OF A NUMBER OF OUR CONFERENCE INCLUDING THE CONFERENCE ON THE DESIGN OF TRIALS OF GENETICALLY MODIFIED T CELL RECEPTORS AND CONTINUE TO HEAR UPDATES ON THOSE PROTOCOLS AND ONE OF THE CLINICIANS TO ADDRESS THE PROTO CALLS OF NUCLEOTIDES. THESE WERE IN DECEMBER ABOUT EMERGING RNA AND WE HOPE THAT NOW YOU'LL HAVE A LITTLE BIT MORE FREE TIME AND WE CAN GIVE YOU A COUPLE MORE HOURS A WEEK TO RELAX. [APPLAUSE] AND ON THE PHONE MIKE ARE YOU STILL ON THE PHONE? >> I'M HERE. >> GREAT. MIKE IS THE DEPUTY DIRECTOR. >> I HAVE MY DIPLOMA IN FRONT OF ME. >> HE IS A DEPUTY DIRECTOR OF THE PACIFIC SOUTHWEST CENTER FOR BIODEFENSE -- INFECTIOUS DISEASE AT THE UNIVERSITY OF CALIFORNIA IRVINE AND HE'S BEEN A MEMBER OF THE RAC FOR FOUR YEARS AND HAS BEEN A CRITICAL MEMBER OF OUR BIOSAFETY WORKING GROUP WITH HIS INSIGHTS IN EXPERTISE IN HIGH CONTAINMENT RESEARCH HE HAS HELPED GUIDE MANY OF THOSE DISCUSSIONS AND INCLUDING WITH A KEY MEMBER IN DEVELOPING THE BIOSAFETY AND -- BIOSECURITY FRAMEWORK WORKING WITH -- LOWER CONTAINMENT FACILITIES IN THAT WE THINK AND WE HOPE WILL REALLY FACILITATE THIS IMPORTANT RESEARCH THAT WILL PROTECT THE PUBLIC HEALTH. SO I WANT TO THANK YOU MICHAEL FOR ALL ON YOUR CONTRIBUTIONS TO THE RAC AND WE WILL MISS YOU BUT WE WILL KEEP YOUR E-MAIL. AND FINALLY -- >> I DO WANT TO INDICATE I WILL BE VERY INTERESTED IN CONTINUING WITH THE BIOSAFETY WORKING GROUP. >> GREAT. FINALLY WE HAVE TO SAY GOOD-BYE TO DR. ROYCEMAN WHO COULD NOT JOIN US TODAY. HE'S AT THE UNIVERSITY OF CHICAGO. I'M SORRY HE'S NOT ABLE TO JOIN US BECAUSE HE HAS BEEN SUCH A CRITICAL MEMBER IN HELPING US SORT THROUGH A NUMBER OF COMPLEX ISSUES. I NEED NOT SAY ANYTHING MORE ABOUT HIS, PERTISE IN VIROLOGY -- HE HAS HELPED OUR STAFF THROUGH A NUMBER OF VERY THORNY ISSUES. HE WAS QUITE RESPONSIVE AND REQUEST EVERY QUESTION WE HOPE TO CONTINUE TO BENEFIT FROM HIS WISDOM IN THE FUTURE. SO I WOULD LIKE TO OFFER SOME APPLAUSE FOR DR. ROYCEMAN. [APPLAUSE] THAT CONCLUDES OUR PRESENTATION OF CERTIFICATES. >> MOVING TO THE LAST AGENDA ITEM, WE WELCOME OUR VISITORS WHO COME TO TALK TO US ABOUT PROTOCOL NUMBER 1016 ENTITLED A PHASE TWO STUDY TO DETERMINE THE EFFICACY AND SAFETY OF AL ALLO GENIC CHONDROCYTES. I THANK YOU THE INVESTIGATORS AND SPONSORS FOR BEING HERE TODAY TO DISCUSS IT. PRESENTING TODAY WILL BE THE PI MICHAEL A.MONT FOR JOINT PRESERVATION AND REPLACEMENT ORTHOPEDICS HE DID HIS FELLOWSHIP TRAINING AT THE JOHNS HOPKINS MEDICAL INSTITUTIONS AND HE PRESENTLY IS AN ASSOCIATE PROFESSOR. HE'S CURRENTLY PUBLISHED OVER 400 ARTICLES AND BOOK CHAPTERS ON VARIOUS ASPECTS OF RECONSTRUCTION AND IS ON THE BOARD OF EDITORS OF MULTIPLE JOURNALS INCLUDING THE BONE EXPWROINT SURGERY. THE SPONSORS INCLUDING KWAN HEE LEE. HE IS CHIEF MEDICAL OFFICER OF TISSUE GENE. HE PREVIOUSLY SERVED AS PROFESSOR AND DIRECTOR OF THE CLINICAL RESEARCH CENTER AT THE HOSPITAL IN KOREA AND A GUEST RESEARCHER AT THE NATIONAL INSTITUTES OF HEALTH. IN ADDITION DR. LEE SERVED AS A MEMBER OF THE GENE THERAPY COMMITTEE FOR THE KOREAN FDA. ALSO HERE IS MARTIN LOTZ WHO IS A PROFESSOR IN THE DEPARTMENT OF MOLECULAR AND EXPERIMENTAL MEDICINE AT THE SCRIPTS RESEARCH INSTITUTE AT LA JOLLA, CALIFORNIA. HE'S AN ADD -- ADJUNCT PROFESSOR -- IN LA JOLLA CALIFORNIA. HIS RESEARCH INCLUDES ARTHRITIS PATHOGENESIS AND NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES. HIS OSTEOARTHRITIS FOCUSES ON THE MECHANISM OF JOIRNLT AGING. GEAN EXPRESSION ANALYSIS WILL DOCUMENT THE COMPLETE SPECTRUM OF GENES CHECK PRESS BY CHONDROCYTES IN NORMAL APRILING AND OSTEOARTHRITIC TISSUES. I WELCOME OUR VISITORS. DR.MONT. ARE YOU ON THE PHONE. >> YES. I WANT TO THANK DR. FONG AND DR. CORRIGAN-CURAY FOR COORDINATING THE TIME FOR PRESENTING THIS AND OBVIOUSLY THE REST OF THIS COMMITTEE FOR LISTENING TO THIS PRESENTATION. JUST TO SUMMARIZE WHAT I WILL BE TALKING ABOUT FOR THE NEXT FEW IMAGES AND OBVIOUSLY I CAN STOP AT ANY POINT FOR QUESTIONS. I'M GOING TO GIVE A LITTLE BACKGROUND ON THE PURPOSE OF THIS STUDY. THEN WE'LL TALK ABOUT SOME OF THE NON-CLINICAL DATA THAT WE HAVE PERFORMED, TISSUE GENE PERFORMED SINCE THE LAST MEETING HERE. WE'LL TALK ABOUT THE DESIGN OF THE STUDY. WE'LL GIVE THE STATUS UPDATE OF THE STUDY AND WE DID MAKE SOME STUDY ADJUSTMENTS SINCE THE LAST MEETING AND THEN WE'LL OPEN IT UP TO FURTHER QUESTIONS. SO I DON'T HAVE TO REITERATE TOO MUCH ON THIS SLIDE BUT WE ALL KNOW THE TERRIBLE PROBLEM WE HAVE WITH ARTHRITIS THAT IS PROBABLY UNDER EXAGGERATED FROM THIS SLIDE WHICH SAYS 27 MILLION ADULTS ARE AFFECTED BY OSTEOARTHRITIS. I DON'T KNOW ANY ADULTS NOT AFFECTED IF YOU LIVE LONG ENOUGH. I CERTAINLY HAVE TO SOME DEGREE ARTHRITIS MYSELF. SOMETIMES RISK OF KNEE ARTHRITIS IS ABOUT 45% AND AN INCREASE THAT GETS UP TO -- I THINK THESE ARE EXAGGERATED NUMBERS. THIS IS A NEW TECHNOLOGY THAT WAS DEVELOPED BY DR. LEE IN KOREA AND BROUGHT OVER HERE TO TISSUE GENE. IT'S AN ENGINEERED KNEE THERAPY ALLO GENETIC CELLS WITH NORMAL CELLS AND THESE TRANSFORMED CELL LINES THAT PRODUCE TGF-BETA. THAT MIXTURE IS TGC. THE CLINICAL WORK WITH ANIMAL CELL LINES AND WITH SOME STUDIES THAT WERE DONE IN KOREA. AND WE'VE DONE SOME STUDIES HERE. THE THEORY THERE IS YOU INJECT THESE CELLS THEY PRODUCE TGN BETA AND THEY CAN REGENERATE CARTILAGE FROM ARTHRITIC KNEE JOINTS. SO HERE IS THE HISTORY OF WHERE WE'VE COME BEFORE THIS COMMITTEE. WE'VE HAD A RAC REVIEW THAT MARCH 11 OF 2010, THERE WAS PRELIMINARY ANIMAL TESTING THAT WAS INITIATED, THE PROTOCOL WAS REVISED. THIS WAS RESUBMITTED. A PHASE ONE MEETING, THE RESULT OF PHASE ONE SUBMITTED IN 2010 WE FURTHER REVISED THE PROTOCOL YOU'RE GOING TO SEE AND WE INITIATED THE STUDY THAT I'M GOING TO DESCRIBE MAY 17TH, 2011. SO YOU'RE GOING TO SEE THE ORIGINAL 77 PATIENTS THAT WERE ENROLLED IN THIS STUDY. BEFORE I GET INTO THE STUDY WHERE WE'RE AT THERE, I'M GOING TO SHOW YOU A LITTLE BIT ABOUT SOME OF THE PRECLINICAL DATA. I HAVEN'T DONE THESE EXPERIMENTS BUT DR. LEE AND CREW ALSO WANT TO THANK OGDEN COPELAND WHO REPRESENTS TISSUE GENES AND HAS DONE A LOT OF THESE STUDIES SO THEY CAN CLARIFY SOME OF THE DETAILS HERE. THESE WERE SOME OF THE QUESTIONS THAT THIS COMMITTEE RAISED ABOUT SOME OF THE CLINICAL OR PRECLINICAL STUDIES CONCERNED IN TISSUE GENE C. THE FIRST ONE WAS WHAT'S HAPPENING TO THE TISSUE GENE C, DOES IT REALLY ADHERE TO THE CARTILAGE. SO FIRST STUDIES WERE DONE WITH RABBIT MODEL. MAKING CELLS IN STUDIES WITH DEFECTS IN RABBITS ABOUT THREE TO SIX MILLIMETERS. THEY LOADED THE CELLS WITH MEDIA AT DIFFERENT TIME POINTS AND THEY THEN BATHED IT WITH MEDIA AND TURNED IT OVER AND TRIED TO ASSESS HOW MANY CELLS WERE ADHERING TO THE CARTILAGE GREATER THAN 98% ADHERED TO THE CARTILAGE IN THE RABBIT MODEL. THEY DID A STUDY WITH HUMANS NOTING THE SURFACE FOR 60 TO 120 MINUTES AND FOUND 40 TO 60% OF THE LOADED CELLS STAYED ON THE CARTILAGE. WHEN THEY WERE BONE SURFACES THAT WERE EXPOSED THERE WAS LESS CELLS ADHERING TO THE BONE SURFACES. THE NEXT WAS THEY'RE USING INSTEAD OF USING DMM THEY'RE USING A NEW VEHICLE WHICH IS PROPRIETARY BUT IT INVOLVES GROWTH FACTORS IN DMS CELLS AND THEY WANTED TO SEE IF THIS NEW VEHICLE INTRODUCING THE TISSUE GENE C WAS AS EFFICACIOUS SO THEY DID THOSE EXPERIENCE WITH RABBITS AND THEY FOUND HAT THEY WERE, THEY WERE EQUALLY EFFICACIOUS. THERE WERE TOXICITY STUDIES AND I'LL GET TO AND THEY LOOKED WHETHER THIS WAS TRANSFORMING CELLS WITH TUMOR GENICITY AND THEY DID NOT FIND AT ANY DOSAGES OR AT THE HIGHEST DOSAGES THERE WAS SOME TUMOR GENIC EFFECT AND THERE WAS 3,000 TIMES PLEASE CORRECT ME IF I DON'T HAVE THIS EXACTLY RIGHT. THREE THOUSAND TIMES A DOSE THAT WAS USED IN ANY CLINICAL OR PRECLINICAL STATE OF MINIMAL TUMOR GENICITY. HERE'S THE FATE OF WHAT HAPPENED TO THESE TUMOR GENE CELLS AND THESE ARE EXPERIMENTS IN HUMANS AND RABBITS. YOU CAN SEE THE CELLS ADHERED TO HUMAN CARTILAGE OR RABBIT CARTILAGE. THEY FOLLOWED THIS OUT EIGHT WEEKS AND 12 WEEK WITH SOME RADIO LABORING EXPERIMENTS THEY FOUND THE TISSUE GENE IS STILL PRESENT. >> I HAVE A QUESTION. THIS IS MARTIN LOTZ. DO THESE CELLS ALSO ADHERE TO THE SYNOVIAL MEMBRANE AND DO YOU HAVE ANY STUDIES WHETHER IT LEAVES THE JOINTS AND LYMPHATICS OF BLOOD VESSELS WHETHER THEY ARE IN THE SYSTEM -- >> SO TWO WEEKS. DO THE CELLS ADHERE TO THE CELL, SYNOVIAL MEMBRANES. AND ANY SYSTEMIC EFFECTS,. >> COULD WE GET DR. LEE A MICROPHONE. >> AFTER THE INJECTION WE HAVE CHECKED THE SIGN OF HUMAN, ALSO THE AFFECTED AREA. ON THE SURFACE WE COULD NOT FIND OUT THE TISSUE BUT AS YOU WILL SEE THERE IS SOME KIND OF INFLAMMATORY CHANGE. WE BELIEVE THAT IS BECAUSE OF THE TGF TGF-BETA EFFECT AND SOME INFLAMMATORY HAS CHANGED. AFTER TWO OR THREE WEEKS LATER WE COULDN'T FIND THAT INFLAMMATORY SIGN WITHIN THE KNEE JOINT OF THE ANIMAL. SO WE BELIEVE THAT AND ALSO THE OTHER IMPORTANT POINT HERE IS IN HOUR SYSTEM TGF-BETA EXPRESSION IS FINISHED WITHIN TWO WEEKS SO WE BELIEVE THAT THAT IS A CAUSE OF TRANGENT BETA EFFECT BUT THAT DISAPPEARED AFTER THE TGF-BETA HAS BEEN ELIMINATED. THAT'S OUR UNDERSTANDING RIGHT NOW. >> WERE THERE ANY SYSTEMIC -- >> YES, WE CHECKED ALL THE TISSUES BUT I THINK AS WE HAVE DONE IN THE PHASE ONE AND PHASE TWO STUDYING THE HUMAN, WE ALSO CHECKED THE BETA LEVEL FROM ALL THE PATIENTS AND WE DIDN'T SEE THE KIND OF VALUATED BETA LEVEL -- ELEVATED BETA LEVEL IN THE SERUM. WE BELIEVE IT'S A CONFINED REGION AND WE BELIEVE IT'S PRESSED WITHIN THE KNEE JOINT DOES NOT PENETRATE INTO THE SERUM AND ELEVATE THE -- THAT'S THE OBSERVATION WE HAD. >> I UNDERSTAND THE COMMENTS ABOUT TGF-BETA PROTEIN LEVELS. THE QUESTION ALSO WAS TRYING TO UNDERSTAND WHETHER THE CELLS, WHETHER THE INDUCED CELLS OR CHONDROCYTES THAT'S INJECTED INTO THE JOINTS FOR CIRCULATION HAVE YOU PERFORMED ANY PRECLINICAL STUDIES FOR EXAMPLE TO DETERMINE WHETHER THEY LEAVE THE JOINT SPACE. >> ACTUALLY THERE IS THE PRECLINICAL ANIMAL STUDY WHICH HAS BEEN INFUSED IV AND WE DIDN'T FIND OUT ANY KIND OF REMNANT CELLS. FROM THAT OBSERVATION WE CONCLUDED THAT THE CELLS HAVE BEEN ELIMINATED FROM THE CIRCULATION. SO THAT CELL WE HAVE DONE IN THE DISTRIBUTION STUDY BEFORE. SO AT THIS TIME WE DON'T BELIEVE EVEN THOUGH THAT CAN PENETRATE INTO THE CIRCULATION BY SOME KIND OF TECHNICAL ERROR OR DURING THE INJECTION THEY MAY VACATE BUT WE THINK THAT KIND OF EVENT CANNOT CAUSE A DEVASTATING EVENT. SO AT THIS TIME WE BELIEVE THAT EVEN THOUGH THERE IS MAYBE SOME PENETRATION INTO THE CIRCULATION BUT FROM OUR BIO DISTRIBUTION STUDY WE THINK THAT THAT CELL HAS BEEN ELIMINATED FROM THINGS LIKE THAT. >> OKAY. SO AT THE BOTTOM OF THIS DOES DESCRIBE THERE'S A REVERSIBLE FLATION OF THE SYNOVIUM ON INOF INJECTION OF TISSUE GENE WHICH MIGHT BE EXPECTED FROM MUCH LITERATURE OF THE TGF-BETA EFFECT. WE DON'T HAVE ANY OTHER QUESTIONS ABOUT THE PRECLINICAL STUDIES, I WILL GO INTO THE CLINICAL STUDIES. >> THIS IS MARTIN LOTZ AGAIN ONE MORE QUESTION ABOUT THE PRECLINICAL STUDIES. PERHAPS RELATED TO YOUR TUMOR GENICITY STUDIES. HAVE YOU DONE TESTS TO PERFORM THE SAME DOSE OF CELLS SUBCUTANEOUSLY AND WHAT HAPPENED THEN? >> THIS IS OGDEN -- WE'VE DONE A NUMBER OF PRECLINICAL STUDIES AND WE CHECKED DOSES EQUIVALENT TO OUR CLINICAL DOSE AND EVEN HIGHER THAN OUR CLINICAL DOSE. AND WE'VE DONE AS DR. LEE MENTIONED THE BIODISTRIBUTION STUDY WE DID IV INJECTION AND BIODISTRIBUTION TESTING WOULD WE INJECTED INTERARTICULARLY. THOSE ARE HIGHER THAN WHAT WE ARE LOOKING AT CLINICALLY. >> MY QUESTION -- >> SUBCUTANEOUSLY, DID YOU INJECT. >> WE'VE DONE SUBCUTANEOUS INJECTIONS ALSO IN MICE. AND THEN ALSO IN THE TUMOR GENICITY STUDIES AND THEY DISAPPEAR THERE AS WELL. >> DID YOU EVER INJECT CELLS SUBCUTANEOUSLY. >> I'M SORRY I DIDN'T UNDERSTAND YOU. >> THE QUESTION IS IF YOU HAVE TESTED THE FATE OF YOUR PRODUCT WHEN IT'S INJECTED SUBCUTANEOUSLY. >> WE'VE DONE TESTING IN MICE WHERE SUBCUTANEOUS INJECTIONS AND A BOLUS IS FORMED INITIALLY AND THAT DISSIPATES OVER A FEW DAYS AND THEY'LL KNOW ADVERSE EFFECTS, NO TOXICITY SEEN FROM THOSE INJECTIONS SUBCUTANEOUSLY. >> YOU FOLLOWED THAT AND IF I UNDERSTAND THAT IT UNDERGOES CELL DEATH AND EVENTUALLY THE SMALL TUMOR FROM THE ORIGINALLY INJECTED CELLS DISAPPEARS. >> YES. >> THERE'S NO FIBROSIS, THERE'S NO PERSISTENT TUMOR OF INJECTED CELLS. >> THAT'S CORRECT. >> THE TUMOR MEANING SWELLING. >> WELL TUMOR IN THE KNEE. HE'S REFERRING TO THE SWELLING FROM THE INJECTION. >> OKAY. ALL RIGHT. SO NOW I WANTED TO JUST BRIEFLY DO, SHOW A SYNOPSIS OF THIS CLINICAL PROTOCOL THAT WE'VE BEEN DOING AND THEN SHOW YOU WHAT ARE THE RESULTS SO FAR. AND REMEMBER, I'M PI, THIS IS BLINDED STUDY SO I DON'T HAVE ACCESS TO, I HAVE ACCESS TO GENERAL DATA BUT I BELIEVE THIS IS ALL BLINDED AT THIS POINT. SO THE PLACEBO CONTROLLED RANDOMIZED TWO TO ONE RATIO OF HERE GETTING THE TISSUE GENE C VERSUS A CONTROL GROUP OF INJECTIONS. IT'S THREE CC'S OF SALINE THAT SHOULD MATCH THE TISSUE GENE C. THE PATIENTS ARE 18-70 YEARS OF AGE WITH GRADE THREE OSTEOARTHRITIS. AND THEM WE DID A SCREENING PRIOR TO DOSING, 24 HOURS LATER AND THEN MONTHS ONE RIGHT UP TO TWO YEARS. AND THESE PATIENTS ARE FOLLOWED, DO CONSENT TO BEING FOLLOWED 15 YEARS AFTER THE SURGERY. WE'RE LOOKING FOR VARIOUS ADVERSE EVENTS AND WE'RE DOING A LOT OF CLINICAL CHEMISTRY, HEMO LOGICAL EXAMS -- CESSED BY LISA AND OTHER TESTS OF THE VECTOR DNA WE'RE LOOKING AT DIFFERENT IMMUNE RESPONSES AND THE STAFFING CRITERIA WOULD BE ANY SERIOUS ADVERSE EVENTS, GRADE TWO EVENTS THAT ARE CONSIDERED SEVERE. SO THE EFFICACY CRITERIA ARE, WE'RE LOOKING AT KNEE SYMPTOMS, PAIN AND FUNCTIONALLY AND THEN A WHOLE NUMBER OF SECONDARY END POINTS LEADING TO THE SECONDARY END POINT MIGHT BE TOTAL REARTHROPLASTY AND EVALUATIVE METHODS INCLUDING MRI'S, THERE ARE FOUR MRI'S AT BASELINE THREE, SIX AND 12 MONTHS. THAT'S THE BIGGEST HARDSHIP FOR THE PATIENT TO GO AND GET FOUR MRI'S. ORIGINALLY WE'RE GOING TO DO PROBABLY TWICE THAT NUMBER OF MIR'S. A LOT OF PATIENTS IN MY EXPERIENCE I'VE ENROLLED 23 OF THESE 77 PATIENTS A LOT OF THE PATIENTS ACTUALLY WANT TO GET THE MRI'S BECAUSE THEY WANT TO SEE HOW THEIR KNEES ARE ACTUALLY DOING. AND THEY FEEL THE MRI IS A VERY OBJECTIVE WAY TO EVALUATE THAT. OKAY. SO HERE IS WHAT I HINTED AT. WE HAVE 77 PATIENTS THROUGH JUNE 18TH. THE ENROLL. WAS SUSPENDED ON MARCH 5TH AT THE REQUEST OF THE IDMC. AND THAT WAS PENDING FDA REVIEW AND THE FDA DID ALLOW, LOOKED AT THE ADVERSE EVENTS THAT WERE REPORTED AND ALLOWED CONTINUATION OF THE STUDY ON THE 7TH. THIS HAS GONE BACK TO THE FIVE SITES, ALL FIVE SITES, IS THAT CORRECT NOW HAVE FULL REAPPLIED TO THEIR IRB'S AND THEY'VE GOTTEN REIRB APPROVAL FOR REINROLLING WHICH THEY'RE DOING. IF I USE THE TERM SERIOUS ADVERSE EVENTS BY DEATH THERE ARE NO SERIOUS ADVERSE EVENTS. THERE WERE A FEW I WOULD SAY MODERATE OR SEVERE ADVERSE EVENTS AND I'LL GO OVER THOSE BUT THEY WERE ALL SELF LIMITED. THIS JUST SHOWS THAT WE DON'T REALLY HAVE MUCH OF THE ANALYSIS AT THIS POINT. THE MRI'S ALL THESE DATA BEING ACCUMULATED RIGHT NOW. THERE WILL BE AN INTERIM ANALYSIS SIX MONTHS AFTER THE LAST PATIENT IS ENROLLED AND WE WOULD EXPECT, WHEN WOULD WE PROBABLY EXPECT THE LAST PATIENT ENROLL. BASED ON KNOWLEDGE OF ENROLLMENT. AUGUST, SIX MONTHS AFTER AUGUST, THERE WILL BE AN INTERIM ANALYSIS AND I GUESS SHORTLY AFTER THAT WE'LL COME BACK TO THIS COMMITTEE AND SHOW PERHAPS THE RESULTS OF THE BLIND. NOW THIS IS THE BEST I CAN GIVE YOU SINCE I'M PRETTY BLINDED TO THIS STUDY. THIS IS MY DATA ON MY BLINDED PATIENTS. I BELIEVE IT'S MADE UP OF 23 PATIENTS AND THIS JUST DESCRIBES THERE'S NO KNEE INFUSION, GREEN IS MODERATE ONE AND THERE WAS ONE SEVERE ONE. THE SEVERE ONE RESOLVED FOR ME, RESOLVED IN 48 HOURS. THEY CALLED THE HOW WAS, WE SAID TAKE SOME ANTI-INFLAMMATORIES, REST AND PUT SOME ICE ON IT 48 HOURS. THAT GOT BETTER. THIS IS A REASONABLE PROFILE WHEN YOU'RE GIVING EVEN CORTICO STEROID INJECTIONS TO PATIENT THAT HAVE ARTHRITIS OF THEIR KNEE. THESE MEASURES COME IN WITH PAIN IN THEIR KNEE. THEY COME IN WITH INFUSIONS THEY HAVE TROUBLE WALKING, THAT'S WHY THEY'RE GETTING THE KNEE INJECTIONS, THEY MAY HAVE A CANE. IT'S NOT VERY DIFFERENT THAN MY 2340EUR8 PROFILE OF PATIENTS, MANY GET DRAMATIC RELIEF. AS SOON AS YOU GET THE CORTICO STEROID INJECTION OR THE, WHICH ALSO HAS A LOCAL ANESTHETIC THEY GET DRAMATIC RELIEVE FROM THE LOCAL ANESTHETIC WHEN IT GOES AWAY THE PAIN GETS WORSE UNTIL THE CORTICO STEROID KICKS IN. THEY HAVE SYMPTOMS LIKE THIS A DAY OR TWO LATER AND WE CAN ADVISE THEM APPROPRIATELY. THIS IS NOT VERY DIFFERENT. UNLESS AGAIN, IT'S BLINDED DATA BUT I HAVE THIS DATA. I DON'T KNOW WHOSE WHO BUT IT BASICALLY DESCRIBE THAT THESE ARE THE VISUAL ANALOGUE SCALES ON THE AVERAGE OF THEY PATIENTS AFTER THEY'VE GOTTEN THE INJECTIONS. SOME PLACEBOS AND GOTTEN THE TREATMENT VERSUS THE PLACEBOS. TWO OF THE PATIENTS AND THIS IS ANECDOTAL. TWO OF THE PATIENTS ARE SO HAPPY WITH THEIR INJECTIONS THAT THEY WANT TO GO TO KOREA AND GET THEIR OTHER OTHER KNEE INJECTED. I SAID THAT'S AGAINST THE RULES AND ONE CALLED OGDEN UP AND SAID I'LL PAY FOR MY FLIGHT TO KOREA CAN I GO THERE AND GET THE INJECTION OUT OF THE STUDY. THEY COULD BE PLACEBOS BUT I KNOW TWO PEOPLE WHO WERE INCREDIBLY HAPPY WITH THEIR STUDIES. THEIR ANALOGUE SCALES WENT DOWN PRACTICALLY TO ZERO. AND GRADE THREE OSTEOARTHRITIS IS NOT ONE OR TWO. IT'S NOT MILD ARTHRITIS IT'S FAIRLY SEVERE SYMPTOMS AND FAIRLY SEVERE DEGREE OF ARTHRITIS WITH JOINT SPACE NOW AND IT'S VERY OBVIOUS IT'S TYPICALLY MORE THAN 50% JOINT SPACE NOW OF THE KNEE. SO ANYWAY, THERE WERE A FEW OF THESE SWELLING EPISODES. THERE WAS ONE OR TWO PATIENTS THAT HAD TO GO ON A TEAM THEY TOOK EXTRA MEDICATIONS THAT CAUSED A LITTLE BIT OF CONCERN FOR I GUESS YOU WOULD USE MUD RATE AND SEVERE SIDE EFFECTS. NOT SERIOUS. SERIOUS IS THE BAD ONE. MODERATE AND SEVERE. AND THAT CAUSED A LITTLE CONCERN BY THE IDMC COMMITTEE TO REVIEW THESE. BECAUSE OF THAT I WAS PART OF LOOKING AT OUR OWN DATA AND I HAD FAIRLY WHAT I SHOWED YOU THERE AND I FELT THAT MAYBE WE SHOULD PUT A FEW MORE CAUTIONS TO THE INVESTIGATORS AND GIVE A LITTLE BIT MORE DATA TO THE PATIENTS ABOUT THAT THEY MIGHT EXPECT SWELLING. A LOT OF THESE PATIENTS MAY NEVER HAVE GOTTEN THE CORTICOID STEROID INJECTION. THEY DIDN'T KNOW WHAT TO EXPECT. I DON'T KNOW IF YOU CAN READ THIS. WE EXPECT 50% OF THE PATIENTS WILL GET THESE SIDE EFFECTS OF SWELLING OF THE KNEE JOINTS. THE EFFECTS WERE TEMPORARY AND TREATABLE. DOES EVER HAVE THESE SLIDES BY THE WAY? I DIDN'T ASK THAT AT THE BEGINNING. IS THIS DATA GIVEN TO EVERYBODY AT THE BEGINNING? CERTAINLY ANY INFORMATION HERE WE CAN GO OVER AND GIVE TO ANY OF THE MEMBERS HERE. YOUR PHYSICIAN IS AWARE OF THESE EFFECTS AND CAN PROVIDE TREATMENT. LET ME TALK ABOUT THAT. SO WE REDEFINE THE STOPPING CRITERIA THAT ANY LOCALIZED AND CUTANEOUS IMMUNE RESPONSE MIGHT BE EXPECTED AND WE DON'T HAVE TO STOP THE STUDY FOR JUST A LOCALIZED SWELLING OF THE KNEE. AND THEN WE ADDED A HANDOUT TO THE PATIENTS THAT DESCRIBES THESE MEASURES JUST TO FURTHER HELP PATIENTS OUT AND FURTHER TO ENSURE SAFETY. APPLY A GENERAL COMPRESSIVE DRESSING WITH AN ELASTIC BANDAGE FOR 48 HOURS, ISOLATE THE KNEES FOR THE NEXT 24 HOURS, AVOID STRENUOUS ACTIVITIES AND SPORTS AT LEAST ONE OF THE PARTIALS THAT I SAW WHEN I WAS LOOK -- PATIENTS THAT I SAW WHEN I WAS LOOKING AT IT FROM OF THE SITE WAS DOING GYMNASTICS AND RUNNING TWO DAYS LATER AND THEN THEY DEVELOPED TREMENDOUS AMOUNT OF SWELLING. YOU DOPE -- DON'T WANT TO DO THAT. WE'RE TRYING TOIVE THESE PEOPLE. WE DON'T WANT THEM TO GO TO A SPORTS APPROACH IMMEDIATELY AFTER GETTING THE INJECTIONS. CAUTIONS ABOUT PAIN AND SWELLING. THEY CAN TAKE ADVIL AND ALEVE, IF THIS PERSISTS THEY NEED TO CALL THE STUDY STAFF AND THE LOCAL DOCTORS. THIS JUST SHOWS THE BROCHURES WERE REVISED TO DESCRIBE EVERYTHING I JUST TOLD YOU AND THAT'S GIVEN TO THE PATIENTS. SO I THINK THAT IF I HAD TO DO THIS AGAIN, I WOULD JUST PUT A LITTLE BIT MORE OF THESE GUIDANCE TO THE CENTERS TO PATIENTS. IF YOU GET THIS INJECTION, YOU FEEL GREAT. DON'T START RUNNING RIGHT AWAY. IT'S NOT GOING TO WORK. WE DON'T EXPECT THIS TO WORK RIOT AWAY. WE'RE TRYING TO HAVE A MEDICATION THAT IS GOING TO EVENTUALLY REDUCE INFLATION SWELLING AND POTENTIALLY RELIEVE ANALGESIA TO ME. WE CAN'T MAKE ANY OTHER CLAIMS AT THIS POINT BUT WE DON'T WANT PATIENTS TO GET INJECTIONS AND START RUNNING. THIS IS BETTER ADVICE FOR THE PATIENTS AND FOR THE INVESTIGATORS AT THE DIFFERENT SITES. JUST MORE WAY TO DO THINGS. I THOUGHT WE HAD A LOT OF THIS IN THERE. WE WERE JUST FURTHER EMPHASIZING THAT NOW. SO THANK YOU ALL FOR YOUR ATTENTION. ANY QUESTIONS? >> DR. LOTZ? >> YES. I HAVE, THANKS FOR THE SUMMARY. IT WAS A VERY DETAILED DISCUSSION AND I APPRECIATE THIS. I HAVE A COUPLE MORE QUESTIONS. IF YOU COULD PERHAPS SUMMARIZE AGAIN THE I GUESS WE'RE TALKING ABOUT TWO PATIENTS WHICH HAD THE MOST PROFOUND INFLAMMATORY RESPONSE. HOW SOON AFTER THE INJECTION THIS OCCURRED AND HOW SOON AFTER THE INJECTION WERE THE RESULTS. >> DO YOU WANT TO DO THIS. THESE WERE NOT MY TWO PATIENTS. SOMETIMES WITH A DON'T LIKE TALKING ABOUT OTHER PEOPLE. >> SO THE ONES, YOU'RE TALKING ABOUT THE ONES THAT HAD THE WORST RESPONSE TO THE TREATMENT. THEY WOULD WITHIN 24 HOURS, AND I THINK IF YOU LOOK ARE LOOK AT, HE SHOWED A LITTLE BIT ON HIS SLIDE OF THE VAST SCORE AND THE INFUSION. YOU CAN SEE THAT AT OTHER SITES AS WELL, 24 HOURS THERE'S A NOTICEABLE SORT OF INFLAMMATION ACROSS THE BOARD. ALMOST ALL THE PATIENTS AFTER GETTING INJECTIONS AND SO THESE PATIENTS WHO RESPONDED WORSE, THEY WITHIN 24 HOUR, THEY'RE GETTING THAT SAME THING EXCEPT MAYBE TO A MORE SIGNIFICANT DEGREE. MOST PATIENTS THAT GOES AWAY WITHIN A FOR DAY. THESE WORSE PATIENTS A COUPLE OF THEM, THEY ACTUALLY TOOK UP TO 30 DAYS OR A LITTLE OVER 30 DAYS FOR IT COMPLETELY TO RESOLVE. >> EXAMINED OR THEY JUST CALLED AND THIS WAS A TELEPHONE INTERJEW. >> OH NO. >> NO, THEY CAME INTO THE OFFICE AND SAW THE PHYSICIANS. AND THEY WERE GIVEN WHATEVER APPROPRIATE MEDICAL TREATMENT IT WAS. >> I CAN DO -- >> THAT'S HOW THE ASSESSMENT. >> YES. THEIR VISUAL ANALOGUE SCORE GOT FAIRLY HIGH. EIGHT OR NINE. THEY WERE INITIALLY TREATED WITH ANTI-INFLAMMATORIES AND THEN ONE OF THE TWO WAS TREATED WITH VICODIN, A NARCOTIC. ONE OF THOSE ALSO THEN, THE OTHER ONE THAT DIDN'T GET THE NARCOTIC GOT A CORTICO STEROID DOSE PACK. AND THEY, SO THOSE WERE THE MOST SEVERE ONES. AND ONE OR BOTH OF THEY WERE PUT ON CRUTCHES FOR A LIMITED PERIOD OF TIME FOR ABOUT A WEEK TO TWO. AND THEN IT RESOLVED BY A MONTH AFTER THOSE MEASURES. THOSE ARE THE MOST SEVERE. >> SO THIS WAS BOTH BASED ON PATIENTS SELF ASSESSMENT BASED ON THE RESPONSES TO THE QUESTIONS -- AS WELL AS CLINICAL EXAM. >> THIS WERE DEFINITELY, THEY WERE ALL CLINICALLY EXAMINED MULTIPLE TIMES. I MEAN, THEY WERE BROUGHT BACK MULTIPLE TIMES TO MAKE SURE. >> THE SYNOVIAL FLUID ANALYZED? >> I CAN'T TELL YOU THAT ANSWER. THE QUESTION IS WAS THE SYNOVIAL FLUID ANALYZED IN THOSE PATIENTS. >> SO THE ANSWER'S NO. THE PATIENTS ON THAT CHART ARE SEEN FAIRLY OFTEN BY THE STUDY, THE DIFFERENT STUDY COORDINATORS AT EACH SITE. WHEN THIS HAPPENED, THESE THINGS HAPPENED, THEY WERE SEEN BY THE ACTUAL TREATING PHYSICIANS AT THE SITES. >> BY THE PERSON WHO DOES THE INJECTION AND THE PERSON WHO DOES THE INJECTION IS ALSO, WOULD BE A RHEUMATOLOGIST OR PRIMARY CARE PHYSICIAN STANDING THERE ASSESSING SEVERITY OF THE TRANSFUSIONS. >> YES. THEY WERE ORTHOPEDIC SURGEONS. THERE'S NO ONE THAT ISN'T AN ORTHOPEDIC SURGEON AND THEY ARE TYPICALLY USED TO GIVING INJECTIONS AND ASSESSING SWELLING. CERTAINLY WHAT COULD I IMAGINE COULD BE THE WORSE THING. THEY WOULD NOT GET BETTER FROM THIS. THE WORSE THING I COULD IMAGINE IS AN INJECTION, IT'S WORSE THAN THIS BUT INJECTION COULD LEAD TO AN INFECTION THEORETICALLY AND IF THAT HAPPENS THAT WOULD NEVER GET BETTER WITH ANTIBIOTICS. IN FACT THESE COULD GET BETTER. >> THE FACT THAT THESE ARE INDICATING THAT OBVIOUSLY THIS WAS NOT AN INFECTION. PERHAPS TO CLARIFY IN THE FUTURE IT MIGHT BE WORTHWHILE TO ASPIRATE THESE INFUSES AND ANALYZE THEM. >> I THINK THAT'S A GOOD SUGGESTION, SINCE IT DIDN'T HAPPEN TO ME BUT I WOULD HAVE DONE IT. SO IT DIDN'T HAPPEN TO ME, I WASN'T THERE. BUT WE COULD MAKE SOME SORT OF, IF I WERE TO DO IT, I WOULD SAY I SUSPECT GREATER THAN 30CC'S OR 50CC'S OF FLUID ACCUMULATION IN THE KNEE THAN ASPIRATE THAT COULD BE GETTING INTO THE PROTOCOL. I THINK THAT IS APPROPRIATE MEDICINE. I THINK THAT'S WHAT YOU WOULD DO FOR ANYBODY. >> I THINK IT'S MOST USEFUL FOR YOU BECAUSE THEN YOU GET A BETTER UNDERSTANDING OF WHAT TYPE OF MECHANISM MAYBE. >> WE DIDN'T THINK OF DOING THAT, BUT THAT PROBABLY MAKES SENSE. WHY IS THIS PATIENT GETTING A MUCH MORE INFLAMMATORY RESPONSE. I'M NOT SURE WE'RE SAYING 30 OR 50CC'S. GREATER THAN 30 BECAUSE THAT'S SUBJECTIVE BECAUSE SOMETIMES YOU DON'T KNOW HOW MUCH FLUID IS IN THE KNEE. >> I THINK IT WOULD BE HOW MUCH OF AN INCREASE ABOVE BASELINE. YOU HAVE SOME PATIENTS THAT RUN A HIGHER SYNOVIAL FLUID VOLUME THAN OTHERS. YOU'RE LOOKING AT YOUR PATIENT PROFILES PROBABLY THEREBY SOME PATIENTS WHO HAVE NORMAL SYNOVIAL FLUID VOLUME WHERE OTHERS MAY HAVE 10 OR 20CC. EXTENT OF CHANGE FROM BASELINE TO THE EVENT AFTER THE INSWREKION THAT SHOULD GUIDE AND ASPIRATION SHOULD BE TRIED. >> ALL RIGHT. SO GREATER THAN 30CC CHANGE OF FLUID FROM BASELINE AND BASELINE FLUID SHOULD BE RECORDED. DR. LOTZ WHAT WOULD YOU SUGGEST WE ONLYIZE, I HAVE MY OWN IDEAS BUT WHAT WOULD YOU SUGGEST WE ANALYZE IN THAT FLUID? ANYTHING DIFFERENT THAT WE WOULDN'T NORMALLY DO FOR INFLAMMATORY CYTOKINES. >> DIFFERENTIAL, I THINK SINCE YOU HAVE THE SAMPLES I WOULD CERTAINLY SUBMIT THEM TO CULTURE AND PERHAPS MEASURE THE LEVELS AS WELL AS INFLAMMATORY MEDIA LEVELS. >> OKAY. I THINK THOSE ARE EXCELLENT SUGGESTIONS. >> DO YOU KNOW ANY PATIENT THAT HAD FUSIONS BEFORE YOU STARTED? >> I CAN'T GIVE YOU THAT NUMBER BUT I WOULD, MY ESTIMATE WOULD BE, I CAN'T GIVE YOU EXACT NUMBERS. MY STILL IS CLOSE TO 50%. I DON'T THINK YOU SHOULD CORRELATE 50% OF POSTED FUSIONS WITH THAT. >> WITHIN THIS STUDY YOU ACTUALLY KNOW, RIGHT. YOU SCANNED EVERYTHING. EVERYBODY HAS A SCAN. DO YOU ACTUALLY KNOW IN THE THIS STUDY WHEN THE FUSION RATE IS AND WHETHER IT MIGHT CORRELATE TO ANY OF THESE REACTIONS. >> SOMETIMES THEY MAY THE MRI WOULD BE SMALL FUSION. WHAT DOES THAT MEAN. I GES WE COULD BACK TO THE ACTUAL SCANS AND DO THAT. >> IF YOU LOOK AT YOUR DATA I LOOKED LIKE AT THREE MONTHS YOU HAD ABOUT WHAT, 40% WITH PERSIST EMPT FUSION. SO THE QUESTION IS, IS IT MORE, IS IT LESS. AND WHEREVER WE. AND THEN GET BACK TO IT, IF IT IS MORE IF YOU COULD CORRELATE THEM IN THE INITIAL SCAN OR MRI WITH WHAT THEY HAD AT THREE MONTH, THEN YOU MIGHT SAY WELL HERE'S A GROUP THAT MAYBE WE OUGHT TO BE LOOKING AT THE FLUID AGAIN NOT JUST THOSE THAT HAVE A BIG INFLAMMATORY RESPONSE BUT THOSE THAT HAVE PERSIST EVEN FLUID IN THE KNEE AND I THINK YOU MIGHT LEARN SOMETHING FROM THAT. >> THAT'S ALSO A GOOD IDEA. WE GO BACK TO THE INITIAL SCANS, NOT DEBUNKING THE RADIOLOGIST BUT WE ACTUALLY NEED THE RADIOLOGIST FOR THIS SPECIFIC PURPOSE TO TRY TO GET A QUANTITATIVE ASSESSMENT FOR THE AMOUNT OF FLUID AND YOU RELATE THE RESPONSE TO THE WELLING EPISODES, THESE PAINFUL EPISODES AND ULTIMATE EFFICACY AND THAT MAY TELL US SOMETHING ABOUT WHO TO TREAT AND WHO NOT TO TREAT. ETCETERA JUST ANOTHER PARAMETER. WE HAVE TO LOOK AT IT BECAUSE THERE MAY BE A SLIGHT VARIANCE IN WHEN THEY GOT THEIR MRI SCAN VERSUS IN THE STUDY, THAT CAN CHANGE THE AMOUNT OF FLUID. >> BUT NOT A LOT. THE OTHER QUESTION I HAD WAS DR. LEE SAID THAT THERE WAS THE ANY RESPONSE TO IT EXCEPT INJECTION IN THE ANIMAL MODEL, THERE WAS NO INFLAMMATORY RESPONSE, DID I HEAR YOU CORRECTLY? LET ME ASK THE QUESTION ABOUT SUBCUTANEOUS INJECTION AND YOU SAID IN YOUR CLINICAL STUDIES THERE WASN'T ANY CUTANEOUS RESPONSE, NO INFLAMMATORY RESPONSE. >> THAT'S WHAT I SAID. SO THE DIFFICULTY WE HAVE THERE IS FOR THE SUBCUTANEOUS STUDIES, THERE WERE, WHEN THEY HAD THE BOLUS OR THE FEW DAYS OR WEEK AFTER THE INJECTION, THE ANIMALS WERE NOT SACRIFICED AT THAT MONEY AND THE TISSUE ANALYZED. SO THEY WERE SACRIFICED AT A LATER TIME POINT. >> THE NEXT QUESTION OF COURSE WOULD HAVE BEEN THE SKIN IS A LOT MORE REACTIVE THAN THE KNEE JOINT EXAMINE HOW DO -- AND HOW DO YOU EXPLAIN THE DIFFERENCES. >> SOMEBODY DOES AN INJECTION AND THEY MISS THE KNEE JOINT, COULD THAT HAPPEN? SURE THAT COULD HAPPEN. THEORETICALLY MAYBE MORE OF THIS IS GETTING SUBCUTANEOUSLY THAN YOU WOULD EXPECT. WHAT IS THE REACTION THERE. >> OR TWO THINK. ONE, I COULDN'T ROLE EXPLAIN IT ON THE INFORMATION THAT I HAD P I WOULDN'T HAVE EXPECTED REACTIVITY ON THE SKIN AND I WOULD HAVE EXPECTED MORE THAN WHAT I SAW IN THE ACTUAL JOINT. THE SECOND IS DEPENDING ON THE VISCOSITY OF WHAT YOU'RE INJECTING YOU'RE GOING TO HAVE SOME LEAKAGE ON THE WAY OUT POTENTIALLY AND WHAT DOES THAT MEAN IN TERMS OF SKIN INFLAMMATION AND WHAT ARE YOU GOING TO GET IN TERMS OF REACTIVITY. I WOULD LIKE TO HAVE KNOWN WHAT THERE WAS IN THE SUBCUTANEOUS ANIMAL MODEL AS TO THE SAME TIME FRAME AND WHAT YOU WERE ACTUALLY LOOKING AT. >> I ASKED A SIMILAR QUESTION BEFORE AND I WAS HAPPY TO HEAR THAT EVEN UPON SUBCUTANEOUS INJECTION OF THE COMPLETE DOSE EVENTUALLY RESULTS CUTANEOUSLY SO I THINK THAT'S REASSURING TO KNOW. >> DR. MONT A FEW REQUESTS. I'M ANXIOUS TO SEE ONE TRIAL CLOSE IN A SIX MONTHS ANALYSIS AS TO WHO THESE PATIENTS ACTUALLY ARE THAT GOT THE REACTION. BUT EVERYONE SYMPTOMS ARE RESOLVED THE REDNESS AND SWELLING. >> YES. >> IT IS SELF LIMITING AND THE FDA DID LOOK AT IT UNBLINDED BEFORE YOU STARTING THE TRIAL IN MAY SO WE ARE REASSURED IN THAT. THE FIRST SCAN DONE AFTER INJECTION THAT'S A THREE-MONTH SCAN. >> THAT'S A ONE-MONTH. >> ONE-MONTH. >> ONE-MONTH SO YOU SHOULD HAVE A SCAN ON ALMOST EVERY ONE OF THESE PATIENTS. >> BUT THE SCAN I THINK IS ONE MONTH. >> YOU SHOULD HAVE A SCAN ON EVERY ONE OF THESE PATIENTS, THE TREATMENT AT ONE MONTH PLAN. SOME OF THESE PATIENTS SWELLING WAS STILL GOING ON AT THE TIME. IF IT WAS GOING ON MORE THAN 30 DAYS THOSE PATIENTS YOU COULD ACTUALLY TELL WHAT WAS SWELLING. YOU COULD ACTUALLY KNOW SUBQUEUE -- SUBCUTANEOUS AND THAT'S SCANNABLE BY YOUR PROTOCOL. IS THAT DATA AVAILABLE TO THE MONITORING BOARD TO GO LOOK AT OR YOU GUYS GO LOOK AT. I SHOULD BE MUCH MORE REASSURED IF SOMEBODY LOOKED AT THAT TO KNOW WHAT'S GOING ON. IT REASSURES ME IT'S SELF LIMITING AND IT OBVIOUSLY IS NOT AN INFECTION BECAUSE WITHOUT ANTIBIOTICS IT ALL WENT AWAY. IT STILL WOULD BE NICE TO SEE THE BASELINE SCAN CORRELATED TO ANYTHING IN TERMS OF WHO GOT THE REACTION AND THAT ONE MONTH SCAN IF THERE WAS STILL SWELLING GOING ON IF YOU COULD TELL WHERE THE SWELLING WAS, WHERE THE FLUID WAS AND TRY TO DEFINE. BUT AGAIN I'M NOT MUCH REASSURED TO HEAR THAT EVERYONE'S SYMPTOMS HAVE DISAPPEARED. >> SO I KNOW FROM TALKING TO THE GROUP 100% OF THE ADVERSE EVENTS HAVE REVOLVED. WE HAVE THE TWO MONTH BREAK. YOUR POINT I WOULDN'T HAVE THOUGHT OF BECAUSE BASICALLY WE'RE NOT SUPPOSED TO REVIEW THE MRI SCANS UNTIL SIX MONTHS AFTER. >> HERE'S A CLINICAL INDICATION. >> HERE'S A CLINICAL INDICATION. SO I DO THAT. >> I DON'T WANT YOU TO UNBLIND YOUR STUDY. GO LOOK AT THE SWELLING AND THE MRI. YOU HAVE MRI AND NOT KNEE SWELLING AND NOT LOOK AT IT. >> WE SHOULD LOOK AT EVERYBODY. WE SHOULD LOOK AT THE MRI'S, SWELLING OR NO SWELLING AND DO THAT BLINDED. IT SHOULD BE BLINDED WHETHER THE PERSON HAS SWELLING OR NOT TO SEE WHAT'S GOING ON. >> THE INJECTION SITE COULD CHANGE THE REACTION VERSUS -- SHOULD BE BETTER TO BE STRAIGHTFORWARD FOR SOMEONE WITH EXAMINING KNEES. AND PERHAPS THAT SHOULD BE MADE MORE CLEAR FOR GOING FORWARD TO CAREFULLY DISTINGUISH THIS SO WE DON'T HAVE THIS DISCUSSION IN THE FUTURE WITH A MISSED INJECTION INTO THE JOINT SPACE OR SYNOVIAL REACTION OR CUTANEOUS REACTION. >> I THINK THEY COMMENTS ARE GREAT BECAUSE I CAN IMAGE COMING BACK HERE AND SAY WE MADE A BEAUTIFUL ANALYSIS OF WHAT HAPPENED TO THE PATIENTS THAT WERE SWOLLEN COMPARED TO THE ONES THAT WEREN'T SWOLLEN. IF WE START SEEING THE ONES THAT WERE SWOLLEN WERE MORE THESE INJECTIONS GONE SUBQUEUE THAIN JUST WE WON'T BE ABLE TO MA THAT FOR SURE BUT AT LEAST WE HAVE NICE CHARACTERIZATION OF THAT SO A PATIENT IN FUTURE APPLICATION OF THIS MEDICATION OR ANYTHING IN THE FUTURE HAVING PROBLEMS LIKE THIS GETS AN MRI AND IF YOU SEE THIS APPEARANCE ON THE MRI, IT MIGHT TELL YOU SOMETHING. >> OR IT MIGHT BE A GOOD THING. IT MIGHT BE A YEAR FROM NOW THOSE PEOPLE MIGHT HAVE MORE CARTILAGE IN WHICH CASE THAT WOULD ACTUALLY BE A GOOD THING. AGAIN I WOULD GO PUSH TO LOOK AT SOME OF THOSE MRI AND'S CORRELATE. >> WE'RE ALLOWED TO DO THAT NOW. THAT'S EASY. >> I LOOK FURTHER TO SEEING ANY OTHER DATA. ANY OTHER COMMENTS FROM THE RAC MEMBERS? ANY MORE COMMENTS FROM THE PHONE? HOW ABOUT FROM THE PUBLIC? >> I HAVE A QUESTION FOR YOU. THIS IS MIKE BROOK MEYER IN CALIFORNIA. >> GO MIKE. >> ONE OF THE PREMIER BOTTLES CERTAINLY FOR ARTHRITIS IS THE INFECTIOUS ARTHRITIS MODEL AND ONE OF THE FINDINGS YOU HAVE IS THE AMOUNT OF VIRAL GENOME THAT COULD BE FIND THE AMOUNT OF VIRAL ACTIVITY TENDS TO GO UP AND DOWN WITH THE AMOUNT OF INFLAMMATION. IS THERE ANY CONSIDERATION IN TAKING SAMPLES EVEN JUST BANKING SAMPLES FOR FUTURE ANALYSES TO LOOK FOR EVIDENCE OF ENVIRONMENT ACTIVATION IN THIS SYSTEM? >> DO YOU MEAN TO TAKE THAT OGDEN? TAKE BANKING SAMPLES. >> WITH THE GENOMIC TECHNOLOGY IT JUST TAKES A MIL OR SO OF FLUID TO BE SURE THAT YOU CAN GO BACK LATER AND SORT OUT POSSIBLE PROBLEMS. YOU MAY DISCOVER SOMETHING VERY INTERESTING. >> YES. REGARDING THAT ACTIVATION OF A RETRO VIRUSES WE ARE DOING THE -- TWO YEAR FOLLOW UP. UNTIL THOUSAND WE HAVEN'T DETECTED ANY ACTIVATED VIRAL DNA. >> THAT'S WHAT I WANT TO HEAR BASICALLY THAT YOU HAVE CONSIDERED THIS AS A POSSIBLE COMPLICATION. >> BUT THIS WAS DONE ON BLOOD SAMPLES NOT ON JOINTS. >> YES. I WOULD LOOK AT JOINT FLUID AS WELL. >> THAT'S A GOOD SOMETHINGION. >> HAVE YOU DONE IT ON JOINT FLUID. >> YES, WE HAVE -- JOINT FLUID. >> DR. ROSS SITTING THERE AT THE TABLE IS AN EXPERT ON RETRO VIRUS DETECTION AND SHE MAY BE WILLING TO GIVE YOU IDEAS ABOUT HOW TO GO ABOUT THAT. WITH THE INCREASING CONSIDERING OF RETRO VIRAL GENOME IN THE HUMAN GENOME, YOU MAY FIND SOMETHING VERY INTERESTING HERE. >> IT'S ALWAYS BEEN QUITE AMAZING TO ME THAT GOATS AND MICE HAVE RETRO VIRUS BUT HUMANS DON'T. >> WHAT I HEAR IS IF THERE'S GREAT SWELLING AROUND THE JOINT AND IF IT TURNS OUT ON THE MRI YOU SEE IT'S ACTUALLY FLUID IN THE JOINT I THINK THERE'S A CONSENSUS THAT EVEN FROM A SCIENTIFIC STANDPOINT, AND I WOULD PAUSE IT IT WOULD BE FROM A CLINICAL STANDPOINT IT WOULD TAKE SOME FLUID FROM THE KNEE TO SEE WHAT THE REASON IS. FROM THAT YOU CAN ACTUALLY TELL ABOUT VIRUS, YOU CAN TELL ABOUT INFLAMMATORY MEDIATORS, YOU CAN TELL A NUMBER OF THINGS THAT MIGHT HELP YOU WITH YOUR STUDY AS WELL AS PLANNING YOUR FUTURE STUDIES. I THINK THAT'S THE RECOMMENDATION I HEAR OVERALL FROM THE VARIOUS FOLKS AROUND THE TABLE AND ON THE PHONE. >> I THINK THAT'S VERY REASONABLE AND IT'S ACTUALLY PRETTY EXCITING TO DO THAT ANALYSIS. LOOKING FORWARD TO THAT. >> ANY OTHER COMMENTS? I THANK YOU FOR COMING TO PRESENT THE DATA AND LOOK FORWARD TO SEEING ULTIMATE RESULTS AND THE UPDATE STUDY. WITH THAT, ANY OTHER DISCUSSIONS OR AGENDA ITEMS? I MOVE THAT WE CLOSE THIS 129TH MEETING OF THE RAC AND THANK YOU