AU
`
`EXHIBIT NO?.!J
`
`RECOMBINANT DNA ADVISORY COMMITTEE
`
`Minutes of Meeting
`
`March 16, 2005
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`National Institutes of Health
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
`
`CONTENTS
`
`I.
`
`Call to Order and Opening Remarks ...................................................................................................2
`
`II. Minutes of the December 16, 2004, RAC Meeting .............................................................................3
`A. Committee Motion 1 ......................................................................................................................3
`
`Ill. Update on Human Gene Transfer Protocol #9906-322: A Phase I Study of NGF Ex Vivo Gene
`Therapy for Alzheimer's Disease (AD) ................................................................................................3
`
`IV. Update on Human Gene Transfer Protocol #0401-623: A Phase I/Il, Dose-Escalating,
`Randomized and Controlled Study to Assess the Safety, Tolerability, and Efficacy of CERE-11lO
`(AAV-Based, Vector-Mediated Delivery of Beta-NGF) in Subjects with Mild to Moderate AD...........
`
`V. Discussion of Human Gene Transfer Protocol #0501-689: A Phase I, Open-Label Study of
`CERE-120 AAV Serotype 2-Neurturin (NTN) to Assess the Safety and Tolerability of Intrastriatal
`Delivery to Subjects with Idiopathic Parkinson's Disease (PD).......................................................... 4
`A. Protocol Summary ...................................................................................................................... 4
`B. Written Reviews by RAC Members and Ad Hoc Reviewer ......................................................... 5
`C. RAC Discussion........................................................................................................................... 6
`D.
`Investigator Response ................................................................................................................. 6
`E. Public Comment.......................................................................................................................... 7
`F. Synopsis of RAC Discussion and RAC Recommendations ........................................................ 7
`G. Committee Motion 2..................................................................................................................... 8
`
`VI. Discussion of Human Gene Transfer Protocol #0501-691: Phase I Trial of Systemic
`Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express
`Sodium Iodide Symporter (NIS), with or without Cyclophosphamide, in Patients with
`Recurrent or Refractory Multiple Myeloma (MM) .......................................................................
`A. Protocol Summary ...............................................................................................................
`B. Written Reviews by RAC Members and Ad Hoc Reviewer .................................................
`C. RAC Discussion ...................................................................................................................
`D.
`Investigator Response .........................................................................................................
`E. Public Comment...................................................................................................................
`F. Synopsis of RAC Discussion and RAC Recommendations ...............................................
`G. Committee Motion 3 ............................................................................................................ .
`
`.8
`.8
`.9
`10
`10
`11
`11
`11
`
`VII. Data Management Report ....................................................................................................... .......... 12
`
`VIII. Presentation of American Association for the Advancement of Science Award to RAC Members.. 13
`
`IX. General Clinical Research Center (GCRC) Resources for Long-Term Followup.............................14
`
`X. Discussion of Human Gene Transfer Protocol #0411-681: Phase la/lb Trial of Anti-Prostate-
`Specific Membrane Antigen (PSMA) Designer T Cells in Advanced Prostate Cancer after
`Nonmyeloablative (NMA) Conditioning .............................................................................................15
`A. Protocol Summary ......................................................................................................................15
`B. Written Reviews by RAC Members and Ad Hoc Reviewer ........................................................15
`C. RAC Discussion..........................................................................................................................17
`D.
`Investigator Response ................................................................................................................17
`E. Public Comment..........................................................................................................................18
`F. Synopsis of RAC Discussion and RAC Recommendations .......................................................18
`G. Committee Motion 4....................................................................................................................19
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`XI. Update and Discussion of Human Gene Transfer Protocol #0312-691: Administration of a
`Replication-Deficient AAV Gene Transfer Vector Expressing the Human CLN2 cDNA to the
`Brain of Children with Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) (Batten Disease) ......19
`A. RAC Discussion ..........................................................................................................................20
`B. Public Comment..........................................................................................................................21
`
`XII. Closing Remarks and Adjournment.......................................
`
`Attachment I.
`
`Recombinant DNA Advisory Committee Roster
`
`21
`
`A-I-i
`
`Attachment II.
`
`Public Attendees ....................................................................................................... A-li-i
`
`Attachment Ill. Abbreviations and Acronyms ................................................................................... A-Ill-i
`
`[Note: The latest Human Gene Transfer Protocol List can be found at the Office of Biotechnology
`Activities' Web site at <www4. od. nih. gov/obalrac/protocol.pdf>.]
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`NATIONAL INSTITUTES OF HEALTH
`RECOMBINANT DNA ADVISORY COMMITTEE
`MINUTES OF MEETING'
`
`March 16, 2005
`
`The Recombinant DNA Advisory Committee (RAC) was convened for its 99th meeting at 8:00 am. on
`March 16, 2005, at the Bethesda Marriott Hotel, 5151 Pooks Hill Road, Bethesda, MD. Dr. Diane Wara
`(Chair) presided. In accordance with Public Law 92-463, the meeting was open to the public from
`8:00 am. until 5:30 p.m. on March 16. The following individuals were present for all or part of the
`meeting.
`
`Committee Members
`
`Steven M. Albelda, University of Pennsylvania Medical Center
`W. Emmett Barkley, Howard Hughes Medical Institute
`Martha C. Bohn, Northwestern University
`Neal A. DeLuca, University of Pittsburgh
`Stephen Dewhurst, University of Rochester Medical Center
`Thomas D. Gelehrter, University of Michigan Medical School
`Philip R. Johnson, Jr., The Children's Hospital of Philadelphia
`Terry Kwan, TK Associates
`Bernard Lo, University of California, San Francisco
`Nicholas Muzyczka, University of Florida
`Glen R. Nemerow, The Scripps Research Institute
`Madison Powers, Georgetown University
`Naomi Rosenberg, Tufts University
`Robert D. Simari, Mayo Clinic and Foundation
`Richard G. Vile, Mayo Clinic College of Medicine
`Diane W. Wara, University of California, San Francisco
`
`Office of Biotechnology Activities (OBA) Director/RAC Executive Secretary
`
`Amy P. Patterson, Office of the Director, National Institutes of Health (NIH)
`
`Ad Hoc Reviewers/Speakers
`
`Raymond T. Bartus, Ceregene, Inc.
`Elaine S. Collier, National Center for Research Resources (NCRR), NIH
`Ronald G. Crystal, New York Presbyterian Hospital/Cornell University
`Howard J. Federoff, University of Rochester (via teleconference)
`Theodore Friedmann, University of California, San Diego
`Diane E. Griffin, Johns Hopkins University (via teleconference)
`Richard A. Knazek, NCRR
`Stephen J. Russell, Mayo Clinic
`Mark H. Tuszynski, University of California, San Diego
`Elias A. Zerhouni, NIH
`
`1 The Recombinant DNA Advisory Committee is advisory to the National Institutes of Health (NIH), and its
`recommendations should not be considered as final or accepted. The Office of Biotechnology Activities should be
`consulted for NIH policy on specific issues.
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`Nonvoting Agency Representatives
`
`Kristina C. Borror, Office for Human Research Protections, U.S. Department of Health and Human
`Services (DHHS)
`Stephanie L. Simek, U.S. Food and Drug Administration (FDA), DHHS
`
`NIH Staff Members
`
`Rosemarie Aurigemma, National Cancer Institute (NCI)
`Robert Baughman, National Institute of Neurological Diseases and Stroke (NINDS)
`Sandra H. Bridges, National Institute of Allergy and Infectious Diseases
`Liza Dawson, John E. Fogarty International Center
`Kelly Fennington, OD
`Linda Gargiulo, 00
`Dennis Hickstein, NCI
`Tom Holohan, OD
`Robert Jambou, 00
`Laurie Lewallen, OD
`Catherine McKeon, National Institute of Diabetes and Digestive and Kidney Diseases
`R. Rita Misra, NCI
`Karen Musynski, NCI
`Marina O'Reilly, 00
`Eugene Rosenthal, 00
`Sonia Skarlatos, NHLBI
`Karen Schweikart, NCI
`Thomas Shih, 00
`Danilo Tagle, NINDS
`Anthony Welch, NCI
`Gisele White, 00
`Bradley C. Wise, National Institute on Aging
`
`Others
`
`There were 92 attendees at this 1-day RAC meeting. Attachment I contains a list of RAC members, ad
`hoc reviewers and speakers, and nonvoting agency and liaison representatives. Attachment II contains a
`list of public attendees.
`
`Call to Order and Opening Remarks/Dr. Wara
`
`Dr. Wara, RAC Chair, called the meeting to order at 8:00 a.m. on March 16, 2005. Notice of this meeting
`under the NIH Guidelines for Research Involving Recombinant DNA Molecules was published in the
`Federal Register on February 8, 2005 (70 FR 6720). Issues discussed by the RAC at this meeting
`included public discussions of three protocols, a data management report, updates of three protocols
`reviewed by the RAC in prior years, and a presentation on General Clinical Research Center (GCRC)
`resources for long-term follow-up. In addition, Dr. Elias Zerhouni, M.D., Director of NIH, presented the
`RAC with the Scientific Freedom and Responsibility Award from the American Association for the
`Advancement of Science.
`
`Dr. Patterson reminded RAC members of the rules of conduct that apply to them as Special Government
`Employees.
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`Minutes of the December 16, 2004, RAC Meeting/Drs. Barkley and Gelehrter
`
`Dr. Gelehrter stated that the minutes of the December 2004 RAC meeting had been well prepared and
`were complete and accurate, with a few minor typographical errors that had already been communicated
`to the OBA.
`
`A. Committee Motion I
`
`It was moved by Dr. Gelehrter and seconded by Dr. Barkley that the RAC approve the minutes of the
`December 16, 2004, RAC meeting. The vote was 15 in favor, 0 opposed, and 0 abstentions.
`
`Ill. Update on Human Gene Transfer Protocol #9906-322: A Phase I Study of Nerve Growth
`Factor (NGF) Ex Vivo Gene Therapy for Alzheimer's Disease (AD)
`
`Presenter: Mark H. Tuszynski, M.D., Ph.D., University of California, San Diego
`
`[Note: Dr. Wara noted that this update was presented as background for the review of Protocol #0501-
`689; see Section V below.]
`
`Dr. Tuszynski reviewed the clinical results of this protocol to date, presenting the results of cognitive
`testing and positron emission tomography (PET) scan studies. He noted the findings are in press and will
`be published in the journal Nature Medicine. Dr. Tuszynski stated that nerve growth factor (NGF) therapy
`holds potential for treating progressive disorders of the nervous system. The premise on which this
`treatment is based is that the natural proteins of the brain prevent the death of and augment the function
`of responsive cell populations. In an adult monkey study, ex vivo NGF delivery protected cholinergic
`neurons, which degenerate and die in AD.
`
`He presented an update of protocol 9906-322, which used a murine leukemia viral (MLV)-based vector
`system to transduce primary autologous fibroblasts in patients with AD. The fibroblasts were implanted
`into the nucleus basalis region of the brain to provide an ex vivo cell source for trophic support of
`degenerating neurons. The clinical assessment group included six subjects with a mean age of 67.1
`years and a diagnosis of early, probable AD. Subjects were recruited in the early stages of the disease to
`allow for informed consent and because early intervention in the degenerative process holds better
`potential for neuroprotection. All subjects safely completed the cell injection procedure with the first two
`subjects received treatment on one side of the brain and the next four subjects received bilateral
`injections at escalating doses. Dr. Tuszynski noted that the outcomes should be interpreted cautiously,
`because the study is a small Phase I trial with no placebo controls and no blinding. Results indicated a
`statistically significant change in the rate of cognitive decline in mean Mini-Mental Status Examination
`scores. The PET scans of the subjects that received bilateral injections showed a significant increase in
`cortical activity following NGF delivery relative to the first baseline. This indicates a reversal of the
`expected pattern of decline over time for AD patients. Dr. Tuszynski reported that there have been no
`adverse events (AEs) from either the growth factor or the gene delivery system with follow-up from 2 to 4
`years.
`
`IV. Update on Human Gene Transfer Protocol #0401-623: A Phase 1111, Dose-Escalating,
`Randomized and Controlled Study to Assess the Safety, Tolerability, and Efficacy of CERE-
`110 (AAV-Based, Vector-Mediated Delivery of Beta-NGF) in Subjects with Mild to Moderate
`AD
`
`Presenter: Raymond T. Bartus, Ph.D., Ceregene, Inc.
`
`[Note: Dr. Wara noted that this update was presented as background for the review of Protocol #0501-
`689,- see Section V below.]
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`Dr. Raymond Bartus noted that David Bennett, M.D. of Rush Medical College, is the principal investigator
`(P1) for this Phase I, dose-escalating trial. CERE-ilO is a genetically engineered adeno associated virus
`serotype 2 (AAV-2) vector that expresses NGF in the nucleus basalis, the same target discussed by Dr.
`Tuszynski. The open-label trial has two dose levels with three subjects receiving each dose level. The
`study's primary purpose is to assess the safety and tolerability of the different doses of CERE-1 10 when
`administered to subjects with mild to moderate AD. Secondary objectives are to evaluate efficacy
`through assessment of cognitive functioning, using the Activities of Daily Living and Dementia Quality of
`Life scales, to determine the biodistribution of CERE-1 10 in urine and serum by PCR, and to evaluate
`immunogenicity by determining the antibody response to AAV and NGF. To date, three subjects have
`been enrolled and follow-up ranges from nine weeks to eight months. No AEs have occurred.
`Biodistribution data in serum and urine are negative.
`
`Dosing of Cohort 1 was completed in January of 2005. A cumulative review of the data by the DSMB was
`held in March. Cohort 2 will be administered their first doses in April of 2005. In response to questions,
`Dr. Bartus clarified that the subjects were not prescreened for pre-existing AAV antibodies. He said the
`subjects in this trial were impaired to an extent similar to those in Dr. Tuszynski's trial. In closing, he
`noted that PET scans will be conducted later in the study, after a clinically meaningful time period has
`elapsed.
`
`V.
`
`Discussion of Human Gene Transfer Protocol #0501-689: A Phase I, Open-Label Study of
`CERE-120 (AAV-2-NTN) to Assess the Safety and Tolerability of Intrastriatal Delivery to
`Subjects with Idiopathic Parkinson's Disease (PD)
`
`Principal Investigator: William J. Marks, Jr., M.D., University of California, San Francisco
`Raymond T. Bartus, Ph.D., Ceregene, Inc.; Jeffrey H. Kordower, Ph.D.,
`Other Presenters:
`Rush Presbyterian-St. Luke's Medical Center; Paul S. Larson, M.D.,
`University of California, San Francisco; C. Warren Olanow, M.D.,
`Ceregene, Inc.; Jeffrey M. Ostrove, M.D., Ceregene, Inc.; Philip Starr,
`M.D., Ph.D., University of California, San Francisco
`Ceregene, Inc.
`Drs. Bohn and Johnson and Ms. Kwan
`Howard J. Federoff, M.D., Ph.D., University of Rochester (via
`teleconference)
`
`Sponsor:
`RAC Reviewers:
`Ad hoc Reviewer:
`
`[Note: Drs. Lo, Muzyczka, S/man, and Wara recused themselves because of conflicts of interest. Or,
`DeLuca chaired this portion of the RAC meeting.]
`
`A.
`
`Protocol Summary
`
`PD is a slowly progressive, neurodegenerative disorder that currently afflicts approximately 1 million
`people in the United States. PD is caused by the loss of function and death of dopamine neurons in the
`substantia nigra, a region of the brain that controls balance and coordinates muscle movement. Because
`these neurons no longer make dopamine and start to die, the lines of communication between the brain
`and the body become progressively weaker. Eventually, the brain is no longer able to direct or control
`muscle movement in a normal manner. The four primary symptoms of PD often appear gradually but
`increase in severity over time: (1) tremor or trembling in the hands, arms, legs, jaw, and face; (2) rigidity
`or stiffness in the limbs and trunk; (3) slowness of motor movements; and (4) postural instability or
`impaired balance and coordination. People with PD may have trouble walking, talking, or completing
`simple tasks that depend on coordinated muscle movements.
`
`Treatment for PD currently aims at temporarily replenishing or mimicking dopamine's actions. However,
`as the disease progresses, the drugs gradually lose effectiveness and increasingly cause side effects
`such as uncontrolled movements. Importantly, no available therapy addresses the underlying cause of
`PD. Several neurotropic factors can augment the function of nigrostriatal dopaminergic neurons and
`protect them from degeneration. These factors include a family of proteins called glial cell line-derived
`neurotropic factor ligands such as glial cell line-derived neurotropic factor (GDNF) and neurturin (NTN).
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`GDNF and NTN share structural and functional similarities and demonstrate comparable beneficial effects
`in animal models of PD.
`
`To be most safe and effective, neutrophic factor therapy should cover as much of the target area as
`possible with the therapeutic protein without affecting non-target sites. In non-clinical studies, CERE-120,
`an adeno-associated virus vector (AAV2) expressing NTN, has been shown to effectively deliver the
`neurotrophic factor to the nigrostriatal system and protect nigral dopaminergic neurons from degeneration
`in both rodent and non-human primate models of PD. The animal studies also have shown that CERE-
`120 administration is safe and well tolerated.
`
`This proposed Phase I clinical trial will investigate the safety and tolerability of CERE-120 surgically
`delivered to the striatum of research participants with PD. Safety will be determined by evaluation of
`spontaneously reported adverse events, clinical laboratory test results, magnetic resonance imaging,
`neuropsychometric tests, and thorough clinical evaluations. All research participants will be monitored for
`signs of inappropriately targeted CERE-120 transduction or an immune reaction to the product. The
`primary enrollment criterion is a diagnosis of advanced PD. Participants also must have no other
`significant neurological or medical abnormalities contraindicating surgery or study participation. After
`completion of the study, all participants will undergo annual, lifelong monitoring.
`
`The trial will include two cohorts of 12 to 18 subjects. The first cohort will receive doses of 2.0x1011 vector
`genomes (vg) and the second will receive 8.0x111 vg, divided into four targeted locations per striatum.
`Initially, subjects will be enrolled sequentially, so that the second subject will be administered CERE-120
`no less than 28 days after the first subject has undergone the dosing procedure. The third and fourth
`subjects will be treated no less than 28 days after the second subject has undergone the dosing
`procedure and the fifth and sixth subjects no less than 28 days after the fourth. At least 28 days after the
`sixth subject in the low-dose cohort has undergone the dosing procedure, the first subject in the high-
`dose cohort will be treated with CERE-120. Enrollment in the high-dose cohort will follow the same
`paradigm as that employed in the low-dose cohort.
`
`Study assessments will be performed during a 30-day eligibility evaluation period, a baseline
`assessment (0 to 7 days before surgery), and during the surgical dosing procedure (day 0). For the
`first 28 days after surgery, subjects will visit the research facility approximately every 7 days after the
`completion of the dosing procedure, and thereafter at 2, 3, 6, 9, and 12 months. Adverse event
`assessments, clinical laboratory tests, and assessments of disease status will be performed at each visit.
`Clinical assessments of PD will be administered at the visits scheduled for months 1, 3, 6, 9, and 12.
`Long-term assessments will be performed annually thereafter.
`
`B. Written Reviews by RAC Members and Ad Hoc Reviewer
`
`Twelve RAC members voted for in-depth review and public discussion of the protocol. Key issues
`included the absence of a rescue strategy and the use of a novel neurotrophic factor that has not been
`used previously in the human brain in gene transfer research. RAC reviewers Drs. Bohn, Kwan, and
`Johnson and ad hoc reviewer Dr. Federoff submitted written reviews, to which the investigators
`responded in writing and during this meeting.
`
`Dr. Bohn read into the record a disclosure that one of her research interests relates to the development of
`regulated vectors for Parkinson's disease and that she is participating in a large, multi-center program
`funded by NINDS, for which Dr. Federoff is the P1. She noted that a good therapy for late-stage PD is
`needed and the protocol was the first one proposing to deliver a secretable growth factor to large areas of
`the brain. However, she expressed concern about the lack of an apparent rescue strategy to remove the
`NTN gene expression in the brain, especially since multiple brain areas are to be targeted and AAV2
`vectors have been observed to be transported to non-targeted brain regions. Given that several PD trials
`involving GDNF protein delivery were stopped and cerebellar toxicity was detected in monkey studies,
`she asked the investigators to explain how they planned to respond should any adverse events result
`from NTN delivery which may persist for many years. She asked for more information on the supporting
`animal studies and their applicability to this protocol, the levels and distribution of NTN and the receptors
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`it would be acting through. She suggested that the use of eight needle tracks was aggressive surgically
`and reflected a design more compatible with a Phase II than a Phase I study. Regarding the inclusion of
`pro-NGF sequence in the NTN construct, she noted that studies have suggested that pro-NGF may
`induce neuronal cell death. She asked how much pro-NGF-NTN is produced and binds the receptors
`involved in cell death. Her additional concerns addressed the criteria for the possible addition of subjects
`to the cohorts, the need for a description of the evaluations of the autopsy material, the relationship of
`pre-immune antibodies to vector transduction. She requested an explanation for the detection of vector
`DNA in the cerebellum, brain stem, and lymph nodes in the absence of NTN mRNA expression.
`
`Dr. Federoff asked whether the investigators had assayed for potentially novel biological properties of the
`pro-NGF-NTN construct, and for any immune responses to the new epitope created in the fusion protein.
`Regarding the potential for efficacy in late stage Parkinson's patients, he asked about the number of
`target cells and GFRa1 receptors still remaining at that disease stage. Dr. Federoff also asked about the
`sensitivity of the detection of trafficking of CERE-120 outside the nervous system. Because expression of
`CERE-120 may not have reached steady state levels at 28 days, Dr. Federoff asked for the rationale for
`the 28 day serial enrollment. Noting that both peak toxicity and the chronicity of the bioactive molecule
`should be of concern in toxicology studies, Dr. Federoff stated that none of the data presented addressed
`the longer-term toxicity that might accrue from accumulated and persistent bioactivity of NTN. He asked if
`the modeling done by the investigators was sufficiently predictive to give them confidence that a pro-
`inflammatory environment will not be created by a gene that can't be turned off.
`
`Ms. Kwan stated that the non-technical abstract and the informed consent documents were well written,
`with technical terms kept to a minimum. She also noted that the documentation of the request for
`autopsy was one of the best that has been submitted to the RAC. However, based on some optimistic
`wording in the informed consent document, she expressed concern that subjects might anticipate a
`greater relief or treatment value from the protocol than is justified. She asked the investigators to clarify
`the wording to indicate whether the period between doses is 28 days. She asked for an expanded written
`explanation for the research subjects explaining that the expression of NTN can't be stopped because
`cells may be permanently changed when gene transfer is performed. Ms. Kwan requested that public
`discussion include an explanation as to why the introduction of the vector in this Phase I protocol should
`begin with such an extensive application and she wondered whether this attempt to try to obtain benefit
`was a paradigm shift away from the definition of Phase I research.
`
`Dr. Johnson disclosed that he had invented two uses of AAV, a commercial-scale production of AAV
`vectors and a vaccine vector that was patented by his former employer and licensed to Targeted
`Genetics Corporation. His former employer receives royalties from Targeted Genetics Corporation and
`some royalty monies are passed on to him. Dr. Johnson noted that the protocol is provocative and
`complex, and since he's not a neurobiologist, he restricted his review primarily to the use of AAV as the
`vector for gene delivery, which he described as straightforward.
`
`C. RAC Discussion
`
`During the meeting, the following additional questions and issues were raised
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Dr. DeLuca asked in which regions of the brain the clinical inoculations would take place.
`
`Dr. Federoff asked if there might be exuberant sprouting of neurons in places where the growth
`factor has been produced and is bioactive.
`
`Dr. Albelda asked why the investigators decided to use bilateral injections, since injecting one
`side only might be safer and provide an internal control for efficacy.
`
`Dr. Bohn asked the investigators to consider increasing the 28-day delay between cohorts.
`
`Dr. Vile inquired about the basis of the restriction of protein expression even with very high doses
`of the virus.
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`Minutes of the Recombinant DNA Advisory Committee - 3/16/05
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`•
`
`Dr. Nemerow asked about the control in the MPTP monkey model and whether the investigators
`had ever tried empty vector as a control.
`
`D.
`
`Investigator Response
`
`Dr. Bartus and his colleagues responded to RAC questions and concerns with the following
`information:
`
`Regarding the lack of a rescue strategy, the investigators considered potential risks. Since no
`adverse events were observed in extensive nonclinical safety/toxicity studies, they considered
`hypothetical risks and the specific adverse effects associated with intraventricular administration
`of other growth factors. The investigators described the treatment strategies they considered
`specific and effective for symptoms that might arise. These include pharmacological treatments
`that have been effective in subjects who were administered GDNF. (GDNF is structurally and
`functionally similar to NTN.) Information on these potential risks will be provided to each subject
`in the informed consent document.
`
`In response to questions about the region of the brain selected, the investigators explained that it
`is a single targeted site, the nigrastriatal system. They initially considered one injection in the
`caudate and three in the putamen, but refined the protocol to focus only on the putamen. By
`injecting only into the anterior putamen, the investigators can infuse higher doses and lower the
`risk of the experimental material spreading to the ventricles. Based on volumetric and kinetic
`studies of NTN distribution, bilateral injections into four sites in each brain hemisphere was
`considered to provide the most appropriate test of safety. An extensive review of the literature
`indicates that a complication rate from needle tracks, such as hemorraghic strokes, is 1 to 3
`percent, and these events are often transient. The investigators routinely implant eight needle
`tracks per side when conducting fetal nigra transplant studies and have not seen any side effects
`or complications in protocols similar to the one proposed.
`
`Regarding the retention of GFRa1 expressing neurons in late stage PD, there is a 55-60% loss of
`nigra neurons in late stage PD. The data are not specifically available on expression of GFRa1 in
`Parkinsons disease, however, in animal models that induce nigral neuronal degeneration, there
`are persistent trophic responses, presumably mediated by GFRa1. In other neurodegenerative
`disorders such as Alzheimer's disease, also characterized by progressive neuronal degeneration
`over time, growth factor receptors remain expressed well after the onset and progression of
`neuronal decline.
`
`Regarding the 28-day serial enrollment of participants, the investigators described the dosing
`schedule as a commonly used one and similar to that used in the protocol reviewed by the RAC
`the previous year for CERE-1 10. NTN expression reached maximal and stable levels by 28 days
`with no further increase up to seven months post-administration. No toxicity was detected in the
`rat studies out to one year and monkeys at seven months post-administration of the vector.
`
`Concerning the use of a pro-NGF-NTN fusion sequence, the study team stated that although
`NGF has been implicated in programmed cell death during development, GFLs such as NTN
`have not been shown to exert pro-apoptotic effects. Correspondingly, no evidence of cell death
`has been observed in any of the non-clinical studies conducted to determine the safety profile of
`CERE-120. The same pro-NGF sequence was expressed in the NGF vector used in the earlier
`trial in which pro-NGF was less than 1% of the expressed product and there was no evidence of
`neuronal injury.
`
`No cellular marker of inflammation or immune reaction in the brain, no humoral immune response
`to human NTN, and no change in hematology parameters were detected in any of the nonclinical
`studies in rats or monkeys. This empiric