+ + + + +




+ + + + +






 + + + + +



MAY 20, 2005


+ + + + +


      The meeting came to order at 2:00 p.m. in room 1113 of 5515 Security Lane, Rockville, MD.  Dr. Mahendra Rao, Chair, presiding. 




MAHENDRA RAO, M.D., Ph.D., Chair

GAIL DAPOLITO, Executive Secretary

ROSANNA L. HARVEY, Committee Management Specialist




JAMES J. MULE, Ph.D., Member



This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly the Food and Drug Administration makes no representation as to its accuracy.


                                         2:08 p.m.

            MS. DAPOLITO:  Okay, good afternoon.  This is Gail.  We're going to try and get started with the members and hope the others will sign on soon.  Dr. Rao, I know Dr. Harland said he'd be a little delayed.  We're trying to reach Dr. Allan now.

            DR. RAO:  You have a quorum anyway?

            MS. DAPOLITO:  We can get started.  We should have a quorum by the time we need to vote.  We'll go ahead and get started, if that's okay with you.

            DR. RAO:  That's absolutely fine.

            MS. DAPOLITO:  Okay.  All right.  I'll just go ahead and take a roll again.  Dr. Rao is here, Dr. Mulé is here, and Dr. Murray.  Do we have Dr. Allan or Dr. Harlan at this time?  No.  Okay. 

            At the site with me are Drs. Keith Webber and Dr. Kathy Carbone, Gail Dapolito, and Rosanna Harvey.  We have two members of the public joining us, too, and a member of my staff of the advisory committee staff, Christine Walsh. 

            There's the site on the NIH campus.  Would you please say who's there?

            DR. ROSENBERG:  Amy Rosenberg.

            DR. DONNELLY:  Ray Donnelly.

            MS. DAPOLITO:  Dr. Puri's at a third site.

            DR. PURI:  Hi, I'm here.

            MS. DAPOLITO:  Okay.  I will read - Dr. Rao, if it's okay with you, I'll read the conflict of interest statement.

            DR. RAO:  Please do.

            MS. DAPOLITO:  Okay.  The following announcement addresses conflict of interest issues associated with today's meeting of the Cellular, Tissue and Gene Therapies Advisory Committee, formerly the Biological Response Modifiers Advisory Committee, on May 20, related to the review and discussion of the Intramural Research Programs of the Division of Therapeutic Protein and the Clinical Proteomics Program. 

            Based on the agenda made available, it has been determined that the committee discussions present no potential for a conflict of interest. 

            Before I turn the meeting back over to you, Dr. Rao, I'd like to ask the members of the committee, do they have all the handouts, the agenda and the slides and their copy of the site visit report?

            DR. RAO:  I do.

            MS. DAPOLITO:  Okay.  Because if not, we can e-mail it to you or fax it out right now, but you should have everything, I hope.  There's another note on the agenda. 

            We did switch the order of the speakers for the Division of Therapeutic Proteins.  It will be Dr. Rosenberg, Dr. Johnson, and then Dr. Donnelly.  That's all I have.  Dr. Rao?

            DR. RAO:  Welcome everyone.  I think we'll just get right to it.  The first speaker is going to be Dr. Puri, who is the Director of Division of Cellular and Gene Therapies and he'll give us an update on the Clinical Proteomics Program.  Dr. Puri?

            DR. PURI:  Yes.

            DR. RAO:  Begin any time.

            DR. PURI:  Oh, okay.  Thank you very much.  I would like to thank the committee for your valuable time and help in the evaluation of our research program of our colleagues in the Division of Cellular and Gene Therapies. 

            Evaluations and recommendations are extremely valuable to us and I highly appreciate it.  As -- Dr. Emmanuel Petricoin is not here today, I will basically describe the Proteomics Program and where we are with the --

            MS. DAPOLITO:  Dr. Puri, may I interrupt you for a minute?

            DR. PURI:  Sure.

            MS. DAPOLITO:  Hello, this is Gail.  Who just - may I ask who just came on the line?

            DR. ALLAN:  I'm afraid to say.  It's John Allan.

            MS. DAPOLITO:  Hi, Dr. Allan.  Welcome.  Okay.  Dr. Puri - I'm sorry, we interrupted Dr. Puri in his brief presentation.  I'm sorry, Dr. Puri.

            DR. PURI:  That's okay.  I'm going to continue on that train that as Dr. Petricoin is not here today, I'll briefly describe the Proteomics Program and tell you a little bit about where we are with the program. 

            The site visit committee heard from Dr. Petricoin the details of the research program during his presentation.  His main focus of his work is on the establishment of proteomics technology, -- to the development of a standard for the technology, even in the diagnosis and implication of response to drug therapies.

            Dr. Petricoin's presentation mainly focused on tissue proteomics, looking at the possible for proteomic profile, but not much on the serum proteomics identifying biomarkers for early diagnosis of cancer, particularly ovarian cancer, that he has published and it was provided to you in the briefing document.

            Dr. Petricoin's research projects were undertaken under the umbrella of FDA/NCI Clinical Proteomics Program, which was published over four years ago by the Center for Biologics Evaluation and Research, FDA, and the National Cancer Institute Center for Cancer Research for invention, government, and employment of proteomic technologies for translation from bench to bedside. 

            Dr. Petricoin was a Co-Director from the FDA side.  Lance Liotta was a Co-Director from the NCI side. 

            Dr. Petricoin had recently moved on to a local university, George Mason University, where he's now a Co-Director at Center for Applied Proteomics and Molecular Medicine and Professor of Life Sciences at George Mason University and his appointment there began on April 1, 2005.

            After his departure, his fellows are still with us.  They're trying to complete their ongoing activities and also they are helping their colleagues to learn some aspects of this technology, particularly tissue proteomics.

            Some of -- colleagues, -- division of  cellular and gene therapy colleagues are learning this technology from his fellows and a technical person. 

            We intend to maintain this resource in the Division of Cellular and Gene Therapies and this technology is what we consider very important in the correct tradition of our complex biological projects, such as cellular and gene therapy and combination of products.

            NCI has expressed interest in continuing a joint collaboration on this technology.  Therefore, Dr. Carbone, who is our Scientific Director of Research at CBER, and I recently met with the new Director at Center for Cancer Research, Dr. Bob Wiltrout and a clinical person  - the Clinical Director is Dr. Lee Hellman - about a couple of weeks ago to express our interest in this collaboration.

            The Division of Cellular and Gene Therapy and CBER intends to commit significant space, equipment, and some personnel to continue this collaboration, particularly in the area of critical path need for biomarket development to assess safety, toxicity, efficacy of cellular and gene therapy products for cancer, and linking the outcome of biomarkers with the clinical outcome.

            They're also interested in the development of biomarkers for product quality and manufacturing our cellular and gene therapy products and combination products. 

            At this point this might spark some of the -- at this point and open any discussion for any questions.  We'll appreciate any committee insights and recommendations of the Clinical Proteomics Program at CBER.  Thank you.

            DR. RAO:  Thank you, Dr. Puri.  We have time for a couple of questions and maybe I can lead off with a question.  Is there a plan to replace Dr. Petricoin's position or hire, recruit somebody into his position, or is it to absorb this into another program?

            DR. PURI:  I believe so, yes.  The answer to that question is yes.  We have a plan that we are under negotiation with the National Cancer Institute of their level of their commitment, but DCGT is willing to commit at least to one person, to bring perhaps an additional - preliminary part to bring a tenure track person that will not only be expert in the proteomics technology, but also a protein biochemist that can also help in correct -- similar to a vaccines product that we have, that person can also bring the expertise on some analytical tools that the proteomics technology uses.

            DR. EPSTEIN:  Raj, can I comment?

            DR. PURI:  Sure.

            DR. EPSTEIN:  This is Sue Epstein and you might want to mention that that one person would have additional support.

            DR. PURI:  Right.  We also have - I didn't want to go into a whole lot of details, but we had a couple other people within the Division of Cellular and Gene Therapies. 

            They're one of the technical staff and a staff scientist.  They were left behind when their principal investigator moved on to a different position about a couple of years or so ago. 

            The plan is that we could certainly support that new tenure track person with these two people to mobilize that particular group so we can establish this program and --

            DR. RAO:  Is the take home message then that the new group will be smaller or the same size that what was Dr. Petricoin's current level of support?

            DR. PURI:  Actually, Dr. Petricoin's current level of support was two FTEs, including himself.  The new plan is that -- three FTEs, now. 

            -- anything at this point are NCI's commitment, but we are negotiating with Bob Wiltrout and Lee Hellman and -- by looking into this whole program and their level of support. 

            I think in the next couple of weeks, we will have a follow-up meeting with them, trying to come up with the overall plan.

            DR. RAO:  The reason I asked was because the recommendation from the committee was reviewed, and we'll hear a little bit I guess on this, seemed to be extremely positive on the direction and the necessity of that kind of program.

            DR. CARBONE:  This is Kathy Carbone.  Can I say something here, Raj?

            DR. RAO:  Yes.  Go ahead.

            DR. CARBONE:  I want to emphasize that we agree fully and we agree that without this kind of expertise, we simply can't do our job as well as we need to do it.  Putting these under the rubric and coordinating better across the program's genomics and proteomics and the regulatory mission, we think it's imperative. 

            Now, we have to do this in a setting of not only not increasing resources, but shrinking resources.  I want to compliment Raj and Suzanne from OCTGT with coming up with possibilities that involve shifting resources around, because this is basically it for a proteomics resource at CBER.

            We have to do what we need to do because we do value this very highly.

            DR. MULE:  This is Jim Mule.  Just a couple of other questions.  Now, I know Dr. Puri mentioned not getting into too much detail, which I agree with, but as part of the report, with the administration of the program, it would be good to know precisely who has left with Chip and what impact that has, I mean, in the overall sort of continuation of the efforts to not necessarily slow things down, but try to keep the pace going. 

            Specifically, it's Lowenthal and I'm not exactly sure how you pronounce the name, Wolfco (phonetic)?

            DR. CARBONE:  I think the bottom line is everybody.

            DR. PURI:  Everybody is left?

            DR.  RAO:  Everybody is here.

            DR. PURI:  Everybody is here, or they left?

            DR. RAO:  No, they are here, but some of them will be leaving, they're here --.

            DR. PURI:  Okay.

            DR. CARBONE:  The bottom line, though, Raj, is they're all going, and they're all going to be gone by August, correct?

            DR. PURI:  Right.  By August.

            DR. CARBONE:  Yes.  They're all going.  They're leaving with Chip, essentially, and we have to recreate from the ground up and --

            DR. MULE:  Okay.  That's good to know.  Then on the NCI side, has an individual been identified by Wiltrout and Lee as to how that connection can be maintained, if it can?

            DR. PURI:  Yes, Jim.  They're approving, I think, one other name I have been interacting with, at least in the -- branch.

            DR. MULE:  Okay.

            DR. PURI:  I had met and CBER is involved in the clinical proteomics program with Lance.  Now, Lance is gone.  I think Bob Wiltrout also mentioned that at least, perhaps, would be one other person that replacing and putting him in this collaboration.

            DR. MULE:  Okay.  Thank you.

            MS. DAPOLITO:  Can I interrupt for just a second?  This is Gail. 

            (UNIDENTIFIED SPEAKER):  Yes. 

            MS. DAPOLITO:  Dr. Harlan, did we hear you come on?

            DR. HARLAN:  You did. 

            MS. DAPOLITO:  Okay.

            DR. HARLAN:  I'm sorry I was late.

            MS. DAPOLITO:  That's okay.  Welcome.  Okay, so Dr. Rao, all the members are in attendance that are going to be.

            DR. RAO:  Oh, great.

            MS. DAPOLITO:  Thanks.

            DR. RAO:  If there are no further questions, maybe we can move on to the individual research programs and the presentation?

            MS. DAPOLITO:  Okay.

            DR. ROSENBERG:  Okay, so I think I am next here on the agenda.  I have provided everyone with the materials that attest to the accomplishments of our two investigators since their last site visit.

            Of course, my short presentation time really precludes me from going into those details, so I am going to really address the recommendations.

            As a general remark, I just want to say that because we haven't seen the final draft of the site visit report, we'll be addressing the site visit recommendations as we understand them from the debriefing and from brief descriptions we've been permitted to get of the final draft report.

            First, I will address the recommendations for Dr. Donnelly, and then those for Dr. Johnson.  Dr. Donnelly provides the agency, as you know, with critical expertise in the area of type-1 interferons, their chemistry and biology, as well as their activities in regulating cytokine networks.

            This, of course, is based on his highly regulatory related research.  It's very clear that Dr. Donnelly has made key strides in his research and in his regulatory area since the last site visit and we heartily agree with the recommendation to promote Dr. Donnelly.

            We certainly wish we could give more support to him, but this is very unlikely, given the fact that we are dealing with a substantial budget cut this year.

            We certainly concur with your recommendations on Dr. Donnelly.  We'd love for you to put in some strong language about the ability to offer such investigators additional support.

            Now, we'll go to Dr. Johnson's recommendations.  Again, Dr. Johnson's expertise in entomology (phonetic) and signal transduction is vital to the agency's regulatory mission.  I think that's easy to see from the kinds of products that we regulate and are regulated in the larger CBER context.

            Dr. Johnson's scientific program is exemplary and it's highly regulatory related.  He's made very impressive progress since the last site visit, both in terms of the number and quality of publications, as well as novel findings.

            I want to point out that he has made this immense scientific progress despite a very heavy regulatory and supervisory load.  He was the Chair of three BLAs from June 2001 to July 2002 and he's been Chief of the Laboratory of Chemistry since May 2004.

            I think you received information about how extensive responsibility that is and what kind of a time commitment it is.  I mean, it's extensive. 

            Now, let's get to the recommendations.  Basically, there were several recommendations that focused on the following.  One, that he had not yet published some key findings.  The second concerned attendance at national and international meetings.  The third concerned review duties for journals.  The fourth concerned collaborations.

            I would point out that he received no criticisms of his research, either the quality or the direction, and that there was really a substantial endorsement of his research programs.

            We are substantially in agreement with the findings and we do appreciate the committee's advice.

            DR. RAO:  Somebody joined in.  Maybe they can introduce themselves?  Hello?

            DR. ROSENBERG:  Maybe somebody was just shifting a microphone.  I don't know.

            DR. RAO:  Okay.  Amy, are you done?

            DR. ROSENBERG:  Oh, not at all.

            DR. RAO:  Okay.  Then please go ahead.

            DR. ROSENBERG:  Yes.  The first concern was that there was unpublished data for two additional manuscripts and I would like to point out that since the site visit, he has published these findings. 

            One is published in molecular and cellular biology and the other is in press.  It will be out in June, again in molecular and cellular biology.  We believe that this concern has really been very successfully addressed.

            Regarding his service as a reviewer for journals, he does serve as a reviewer for three very high-quality journals that are research appropriate, and so we believe that this concern regarding this service has been addressed.

            Regarding the collaborations and the extent of collaborations, I think if you go through his CV and you look at his bibliography, rather, and you go through the publications, you will see that he has been extremely collaborative in the past in numerous publications that were done collaboratively.

            He is in fact now establishing new collaborations in the continuing investigation of the small serine theorine kinase.  We think that this actually - this concern has been successfully addressed.

            Now regarding attendance at national and international meetings, we substantially agree.  This is an important thing for him to be able to do, especially given how beautiful the work is that he has done, to be able to share this, to be able to project it out, to be able to really maximize the impact of it.

            I just would like to point out that everybody has to prioritize their responsibilities and their time and I think in the case of Dr. Johnson that his ability to attend these kinds of meetings has been very strongly influenced by the amount of regulatory responsibilities that we have put on him and he has executed brilliantly.

            I also would like to point out that this concern will be addressed within a very short time frame, we think substantially less than a year. 

            In sum, I think just to conclude, that Dr. Johnson is really - he's an ideal researcher regulator.  He really executes both programs brilliantly. 

            He's got a cutting-edge, highly regulatory related research program, and he's assumed extensive regulatory and supervisory responsibilities.  Retaining him is absolutely critical to our regulatory mission. 

            We believe that he has in fact addressed the most substantive issues in the site visit evaluation and that the issues concerning the attendance at scientific meetings can be accomplished and addressed successfully in  time frame far shorter than two years. 

            We would appreciate further discussion on this in the closed session.  That concludes my presentation.

            DR. RAO:  Thank you, Amy.  I want to ask the committee whether they'd like to hold questions until they've heard from Dr. Johnson and Dr. Donnelly, or would they like to ask specific questions for Dr. Rosenberg right now?

            DR. MULE:  This is Jim Mule.  I personally would prefer holding off until we hear the presentations.

            DR. RAO:  Great.  I would second that.  If there's no burning question, we can maybe move on to the other two presentations.

            MS. DAPOLITO:  Dr. Rao, this is Gail.

            DR. RAO:  Yes.

            MS. DAPOLITO:  Just to keep in mind if there are some questions that would best be saved for the closed session.  I'll leave that up to you and Dr. Mule.

            DR. RAO:  That's right.

            MS. DAPOLITO:  Okay.  Thank you.

            DR. JOHNSON:  This is Gibbes Johnson.  I will just give a brief description of the regulatory work, efforts, and scientific work and efforts since the January 19, 2005 site visit.

            I'll just review the regulatory work we've been doing in the Laboratory of Chemistry since that site visit.  We're very near completion of a BLA review for an enzyme replacement therapy.  We've also done a pre-BLA review for another enzyme replacement therapy, which we'll be receiving soon.

            Both of these are priority six-month reviews, so we've been very busy with that.  We've also had 20 BLA supplements, four pre-I&D reviews, and three I&Ds and just since I prepared these slides yesterday and today, we've had four more I&Ds come in, so we're very, very busy right now.

            Let me just move on to the research program.  My laboratory studies the characterization of signal transfusion protein kinases.  It has a strong relevance to the FDA mission since disregulation of protein kinases, result in many diseases, and numerous FDA-regulated drugs target these kinases. 

            CDER currently regulates 12 drugs with target to ErbB family of receptor tyracine (phonetic) kinases, including Herceptin (phonetic) against ErbB2 and another example is a synthetic EGF receptor kinase active site inhibitor arresa (phonetic).

            Studies, or discovery and studies on the protein kinase such as TK provide insight into the molecular mechanisms underlying human infertility disorders associated with impairment of postmyotic male germ chromatin condensation, germ cell chromatin condensation, and this is the common defect in infertile male patients.

            I would just like to move and describe the two main projects that are ongoing in the lab and where we're trying to -- project deals with mechanisms of activation and signaling of the ErbB receptors, which includes the EGF receptor, ErbB2, ErbB3, and ErbB4.

            One of our future goals is to identify the EGF receptor active site -- critical to the ligand induced regulation of kinase specificity and signaling.

            Last year, we published, in JVC, that ligand actually not only activates the kinase, but it regulates specificity, which is critical to downstream signaling.

            We're also interested in investigating the potential role of a protein called PELP1, which is a coactivator of the estrogen receptor in EGF receptor signaling.  Preliminary evidence suggests or indicates that it's a substrain for the EGF receptor.

            We also have a knock-in mouse, which expresses only kinase inactive EGF receptor and we're using that to investigate the role of the intrinsic EGF receptor kinase activity and EGF receptor function in vivo and this will also help us predict potential clinical toxicities that may be observed with EGF receptor inhibitors in clinical trials.

            A last part of this project is we're also studying - trying to elucidate the ErbB2 auto inhibition and activation mechanisms.  ErbB2, unlike the other members of this family, does not have a ligand.

            Now I'll turn to another research project involving the characterization of the novel protein kinase SSTK, which we discovered in about 2000.  We're interested in elucidations and mechanism of SSTK action in spermiogenesis because this kinase is essential to male fertility. 

            We're interested in determination of the molecular mechanisms of the kinase's enzymatic regulation, determination of the effect of SSTK gene deletion on hormones whose production is controlled by the pituitary. 

            We're also further characterizing the female SSTK knock-out mouse phenotype and we're characterizing a novel protein, which we cloned and discovered, called SSTK interactive protein and are studying its function as a substrait (phonetic) and regulator of SSTK's action.

            We've also had two papers published in Molecular and Cellular Biology, one published just this month, and another one in press the June 15th issue.

            The first one is on the initial characterization and discovery of SSTK and its demonstration that it's essential for male fertility.

            The second one is an ongoing publication studying Calorin (phonetic), which is a row -- for rack and several of the other row guanine exchange nucleotype factors, and NGF receptor signaling and NGF-induced neuronal differentiation.  That will be in MCB in the next issue. 

            That concludes my presentation.

            DR. RAO:  Thank you, Dr. Johnson. 

            DR. DONNELLY:  Good afternoon.  This is Ray Donnelly speaking.  I thought I'd just give a brief update on the research activities in my laboratory since the site visit.  As Amy mentioned during her presentation, a lot of the work in my laboratory overlaps with the regulatory review work that I do here at the FDA for products, specifically for the interferons, interferon alpha and some of the more recent variants of interferon alpha that are being developed for clinical study.

            As you heard a lot about during the site visit back in January, one of the two primary projects in my laboratory is a characterization of several novel interleukin-10 (phonetic) related cytokines. 

            These include IL-19, 20, 22, 24, 26, and a small group of cytokines that we refer to as interferon lambda, that are also known as IL-28 and IL-29. 

            I believe that several of these cytokines probably represent novel biologic products that we will ultimately be charged with regulating in the not-too-distant future.

            I think it's important to understand as much as we can about the biology of these cytokines and the genes that are induced by these cytokines so that we're well-positioned to be able to understand and provide good guidance with regards to clinical development of these cytokines as biologic products.

            In terms of this first project, in the future, we are planning to determine which cell types and tissues express receptors for these cytokines, how broadly are the receptors distributed on different cell types and tissues. 

            Also, we'd like to identify specific genes that are activated by signaling through the receptor complexes for these cytokines. 

            Finally, in collaboration with Howard Young at the NCI Frederick (phonetic), we have embarked on a series of studies to develop transgenic mice that express the IL-22 receptor, or the interferon lambda receptor, on lymphoid cells specifically, and then ultimately, to test whether or not that provides an advantage in terms of an anti-tumor effect in various tumor models that they have in place there.

            As I've already mentioned, on some of the what we believe to be the clinical relevance of this, I think some of the benefits or potential benefits of these types of studies is that we may be able to identify novel markers of interferon activity, because as I talked to you about during the site visit, interferon lambda shares largely the same signaling pathway as interferon alpha and beta and seems to induce essentially the same gene expression profile.

            Along similar lines, we're interested to know whether IL-22 and/or interferon lambda are associated with certain diseases.

            For example, IL-22 seems to be elevated in patients with psoriasis.  There may be a good rationale for developing antagonists of IL-22 in certain disease states, such as psoriasis or psoriatic arthritis.

            With regards to interferon lambda, I think one of the obvious clinical applications that we hope to see in the not-too-distant future is whether it will provide an alternative to classical type-1    interferons, specifically, interferon alpha, as a treatment for chronic viral infections and in particular, chronic hepatitis C and hepatitis B virus infections.

            We actually have, since the site visit, developed some in vitro data to demonstrate that the interferon lambda will and does inhibit the expression of an HCV relicon in a liver cell culture system.

            That's all I wanted to say with regards to project number one.  Regarding project number two, which I really didn't talk about in any detail during the site visit, but it was presented to you in the briefing package, we have actually for several years been characterizing the IL-4 IL-13 signaling pathway in macrophages and monocytes. 

            I believe that that's important because, as I'm sure many of you are aware, IL-4 and IL-13 have been implicated in the pathogenesis of many diseases, so-called TH2 type predominant diseases, such as asthma or pulmonary fibrosis.

            By understanding how IL-4 and IL-13 signal and their role in regulating gene expression in macrophages and monocytes, we believe that it may have application or implications for understanding and developing better therapeutic strategies for controlling those diseases that I mentioned, asthma --.

            In that context, we are now trying to identify genes that are specifically inducible by signaling through the IL-4 IL-13 pathway and to see if we can identify again potential pharmacodynamic markers of IL-4 and IL-13 signaling that could be exploited perhaps in the future -- IL-4 and IL-13 antagonists is doing what it should do; that is, blocking IL-4 or IL-13 signaling.

            I think I'll close with that.  I just wanted to comment that we have published quite a bit over the last few years with regards to the first project that I talked about, the IL-10 related cytokines. 

            We have two papers now submitted for publication, one in JVC and one in the Journal of Immunology, on this second project, and so I believe we're making progress in both areas.  That's all that I have to say.

            DR. RAO:  Thank you, Dr. Donnelly.  I have a question for the committee, if there are any specific questions that you feel you need in open session, or would you like to just do this all in closed session?

            DR. MULE:  I just have two general questions, one for Dr. Johnson and one for Dr. Donnelly, if I could. 

            DR. RAO:  Go ahead.

            DR. MULE:  Dr. Johnson, can you maybe tell us where you are with the phenotype of the knock-out mouse?

            DR. JOHNSON:  Well, we characterized the defect in the --

            DR. MULE:  This is the SSTK knock-out?

            DR. JOHNSON:  Exactly.

            DR. MULE:  Yes.

            DR. JOHNSON:  How far have I come since the site visit, or do you just want a general overall of --

            DR. MULE:  No, how far have you come since the site visit?  Because you may recall the high level of interest the committee had with respect to that knock-out from the standpoint it could open up numerous possibilities for collaboration once the publication went forward with that particular mouse.

            DR. JOHNSON:  Well, I've been contacted by several individuals since then, but the paper has only been out about a week.

            DR. MULE:  Okay.

            DR. JOHNSON:  You're asking - do you want me to tell you more about the phenotype or what else we know?

            DR. MULE:  No, not necessarily.  Just essentially, what level of effort now will be put on that knock-out from the standpoint of additional collaborations?

            DR. JOHNSON:  Well, as much as I can.  Now, I only have one person working on that and he does regulatory work also. 

            DR. MULE:  Right.

            DR. JOHNSON:  We will - I've made some efforts to contact an expert actually in nuclear architecture and chromatin remodeling to try to help us understand the defect in the DNA condensation.

            I was also contacted the other day about ‑ somebody, an expert in actual spermatozoa capacitation as to whether the knock-out might be also influencing that process.

            There are several other interesting aspects of the phenotype.  You may not remember, but we've now got statistical data to indicate that we get approximately somewhere about two and a half to three males for every female in the offspring of the knock-outs, and that has now got a statistical significance of about .01.

            DR. MULE:  I see.

            DR. JOHNSON:  The male knock-outs are smaller.  I've also contacted a couple individuals at NIH who are interested in behavioral studies and are going to - I'm trying to convince them to maybe put them in some of their behavioral studies.

            DR. MULE:  Fair enough.  I'm very pleased actually to hear about these additional interactions, because the reality is, once that paper becomes older than a week old, you're going to have a number of requests, is my guess, and it's going to be a very valuable tool for your further progress and interaction.  It's very good, at least for me, to hear the status of that knock-out.  I thank you for that.

            Dr. Donnelly, do you have more information about the interferon lambda toxicity profile as it might compare to some of the other type-1 interferons?

            DR. DONNELLY:  In terms of in vivo studies in animals?

            DR. MULE:  Yes.  In vivo.

            DR. DONNELLY:  No, although I've actually been contacted by a fellow via e-mail.  I haven't even had the - this is just very recently - a fellow in I believe it's the NCI; it may actually be NHLB - who is a veterinarian who studies an HCV chimp model and he heard a presentation I gave here at the NIH a few weeks ago and became very excited about interferon lambda. 

            He is interested in actually testing it in a chimp model, because I think that's the next best thing to an actual -- study in human beings.  There is a chimp model that replicates the HCV virus.  Whether that will be - we just haven't explored it yet.

            DR. MULE:  Exactly, because clearly, it would be very exciting if lambda offered a different perhaps, or better, therapeutic profile than what we currently have, whether it be in virus infections or tumors, but also critical to that is going to be how it compares on a toxicity profile with the other interferons.

            It's very exciting and I think we all look forward to seeing some of that information down the road.

            DR. DONNELLY:  I agree.  I thank you for your comments.  I think - as I mentioned, there was a - we had a, here at the NIH, a conference on type-1 interferons that I participated in about a month ago.

            One of the speakers there was a person you may know, Jay Hooknagel --

            DR. MULE:  Oh, yes.

            DR. DONNELLY:  Who is an international expert on HCV, so his presentation was quite interesting, but he also - he and I spoke afterwards and he also was enthusiastic about the prospect of an alternative interferon that obviously has a different receptor distribution than the interferon alpha beta receptor distribution that could be used for this purpose.

            DR. MULE:  Exactly.

            DR. DONNELLY:  -- addition, he is interested in it as well.

            DR. MULE:  Great.  Well, Dr. Rao, that's all I had.

            DR. RAO:  Does anybody else have any other questions?  If not, Gail, do we need to ask for an open public hearing and comments right now?

            MS. DAPOLITO:  I have had no prior requests.  There are two guests at my site and I will ask if anyone had any interest in addressing the committee.  No?  I get a no, so we have no open public hearing speakers.  We can continue.

            DR. RAO:  Okay, then I would like to enter into closed session and give Gail a couple of minutes to reorganize things.

            MS. DAPOLITO:  Thank you.

            (Whereupon the open session went off the record at 2:48.)