Use of exploratory IND for Early phase clinical trials using PET or SPECT imaging

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1 Use of exploratory IND for Early phase clinical trials using PET or SPECT imaging Whistler, BC September 6-10, 2007 Gilles D. Tamagnan, Ph.D. Institute for Neurodegenerative Disorders Molecular NeuroImaging, LLC Associate Professor Yale University

2 Imaging Biomarker Development and Application Pre-clinical In vitro binding In vivo Baboons Clinical Quantitation test/retest Human - dosimetry Phase 1 Displacement /occupancy Multicenter imaging Single Center Imaging Phase II- IV Imaging Biomarker Compound synthesis Radioligand Validation and eind Application CLIP Program CLIC Program

3 Obstacles to Developing Imaging Biomarkers for CNS Drug Development Most radiopharmaceuticals fail in development (inadequate brain penetrance, poor signal:noise, unstable in vivo, etc) Expensive and time-consuming to develop- need in vitro, in vivo, and toxicology assessments Requires validation in human studies- determine optimal quantitative measures and test/retest reproducibility Difficult to use imaging biomarkers in multicenter trials requiring robust quantitative measures owing to technical factors related to instrumentation, acquisition protocol, radiochemistry, regulatory issues, etc.

4 In its March 2004 Critical Path Report, the FDA explained that to reduce the time and resources expended on candidate products that are unlikely to succeed, new tools are needed to distinguish earlier in the process those candidates that hold promise from those that do not

5 Investigators, and Reviewers Exploratory IND Studies January 2006 Pharmacology/Toxicology

6 For the purposes of this guidance the phrase exploratory IND study is intended to describe a clinical trial that - is conducted early in phase 1, - involves very limited human exposure, and - has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies).

7 Exploratory IND Approach Exploratory IND studies usually involve very limited human exposure and have no therapeutic or diagnostic intent. Such studies can serve a number of useful goals. For example, an exploratory IND study can help sponsors Determine whether a mechanism of action defined in experimental systems can also be observed in humans (e.g., a binding property or inhibition of an enzyme) Provide important information on pharmacokinetics (PK) Select the most promising lead product from a group of candidates5 designed to interact with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD) properties Explore a product s biodistribution characteristics using various imaging technologies

8 1. Clinical studies of pharmacokinetics or imaging Microdose studies are designed to evaluate pharmacokinetics or imaging of specific targets and are designed not to induce pharmacologic effects. Because of this, the risk to human subjects is very limited, and information adequate to support the initiation of such limited human studies can be derived from limited nonclinical safety studies. A microdose is defined as less than 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect of the test substance with a maximum dose of <100 micrograms (for imaging agents, the latter criterion applies). FDA currently accepts the use of extended single-dose toxicity studies in animals to support single-dose studies in humans. Because micro dose studies involve only single exposures to microgram quantities of test materials and because such exposures are comparable to routine environmental exposures, routine genetic toxicology testing is not needed. For similar reasons, safety pharmacology studies are also not recommended.

9 CONCLUSION Existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with any IND application, depending on the goals of an investigation, the specific human testing being proposed, and the expected risks. Sponsors have not taken full advantage of that flexibility, and limited, early phase 1 studies, such as those described in this guidance, are often supported by a more extensive preclinical database than is needed for those studies alone. The common theme throughout this guidance is that, depending on the study, the preclinical testing programs for exploratory IND studies can be less extensive than for traditional IND studies. This is because for the approaches discussed in this guidance, which involve administering sub-pharmacologic doses of a candidate product or products, the potential risks to human subjects are less than for a traditional phase 1 study.

10 Radiotracer eind Status List NAME TARGET (S) STATUS MNI 308 ß-amyloid protein In human use, expind MNI 187 ß-amyloid protein In human use, expind INER selective NET In human use, expind mzient selective SERT In human use, expind AV39, AV83 ß-amyloid protein In human use, expind CLINDE AV51, AV94 and AV151 Peripheral BZ receptor (inflammation) ß-amyloid protein In human use, expind In human use, expind MNI 330, ß-amyloid protein In human use, expind MNI-200 Adenosine A2a eind preparation MNI 337 ß-amyloid protein eind preparation MNI 168 ß-amyloid protein eind preparation

11 In vitro assessments In vitro binding determine affinity for target and selectivity Autoradiography and functional assays (if appropriate)

12 In Vivo Non-human Primate Studies In vivo baboon studies Initial injection to assess brain penetrance, washout, metabolites. Follow-up injections to develop quantitative outcome measures (bolus vs continuous infusion paradigm) Displacement studies to assess tracer specificity and selectivity Dose response at target

13 Exploratory IND in USA Based on baboon studies preparation of an expind for human studies expind allows testing of radiotracers in humans (approx N=30-50) without toxicology. In prior exploratory IND submissions no tox has been provided and required

14 Human Validation Studies Human studies with an expind Initial studies to assess brain penetrance, specific uptake, metabolites to establish quantitative outcome measure Test retest reliability Dose response and displacement studies with specific and selective receptor agents Human dosimetry

15 Human Studies - Applications Subsequent human studies will require a full IND with a complete tox package For promising radiotracers the tox package can be initiated while the human validation studies are underway Subsequent human studies will depend of the needs of the sponsor

16 mzient Serotonin transporter

17 CONTENTS I. Introductory Statement of Purpose and General Plan.. II. Research Plan and Study Protocol... III. Chemistry: Preparation and Controls.. IV. Pharmacology and Toxicology... V. Preclinical Experimentation (TAC, Vital Signs Data)... VI. Human studies VII. Environmental Assessment. VIII. Case report form... IX. References... X. Appended material. Biosketches of Investigators Chemistry Documents

18 I. Introductory Statement of Purpose and General Plan The four main objectives of this Phase I eind application are: To assess the dynamic uptake and washout of 123-I mzint in brain using single photon emission computed tomography (SPECT) in healthy subjects To perform blood metabolite characterization of 123-I mzint in healthy subjects to determine the metabolic fate and nature of metabolites in assessment of 123-I mzint as a single phtoton computed tomography (SPECT) brain imaging agent To evaluate the effects of different doses to the sertraline on the specific binding of 123-I mzint in healthy subjects evaluated with serial, dynamic SPECT imaging at baseline and after 14 days of sertraline treatment To determine the preliminary whole body distribution and elimination following intravenous injection of 123-I mzint in healthy subjects

19 DMF---Chemistry Chemistry Validation: Successful labeling runs Purity, Identity, Strength, Sterility, no Pyrogen at release and at end of expiration

20 III. Chemistry Preparation and Controls A-Master Production and Control Record (MPCR) 1-Descriptive name of drug: [123I]mZINT, 2β- Carbomethoxy-3β -[3'-((Z)-2- iodoethenyl)phenyl]nortropane Synonyms: [123I]-MNI-148, [123I]-mZIENT 2-Structure Final dosage form and route of administration: Sterile, apyrogenic solution for intravenous administration 3-List of components by name (in final vial)

21 4-Quantitative Composition of Drug Each dose contains: mzint, ascorbic acid, saline Calculations:Assuming a dose of 15 mci and specific activity of nlt 5,000 mci/µmol, maximum amount of carrier in the dose = (15 -mci) / -(5,000 mci/mmol) = mmol, which corresponds to the mass amount of (0.003 mmol) (395.2 mg/mmol) = 1.2 μg. 5-Theoretical yield and limits Theoretical yield is 100% assuming loss-free incorporation of the radiolabel into the radiolabeled compound and lossfree processing. Actual yields in radiochemical preparation of [123I]mZINT can be expected to be in the range of 29 61% (see Table 2). 6-Description of source and preparation of new drug substance 7-Description of containers, closures, and packaging materials

22 8- Labels and labeling 9- Preparation and quality control instructions See attached batch record 10-Specifications for approval or rejection 11- Special notations and precautions B. Preliminary Data 1- Process Validation 2- Stability Data and Expiration Dating 3- Bacterial Endotoxin (LAL) Pyrogen Test Limits 4- Solvents and metal residuals C. Facilities for Preparation and Quality Control 1- Preparation Area 2- Approved Components Area 3- Quarantine and Rejected Components Area

23 D. Procedures for Quality Control 1- Radiochemical Purity 2- ph 3- Pyrogen 4- Sterility test 5- Strength 6- Visual Inspection E. Component Specifications

24 Preclinical Experimentation In vitro studies Assays of mzint employed for the human NET, SERT and DAT were determined in transfected HEK-293 cells Baboon studies A series of SPECT investigations were conducted involving bolus injection of 123- I mzint in ovariectomized female baboon (Papio anubis). Images were acquired after administration of 11.5 (± 2.0) mci of 123-I mzint injected as an intravenous bolus in two baboons (weight 13.0 ± 1.2 kg). A total of seventeen 123-I mzint SPECT studies were performed evaluating the regional brain uptake and washout of radioactivity and the effects of displacement with citalopram over different doses with reboxetine and methylphenidate as control studies. These experiments are summarized in the following table: Safety data Following the induction of anesthesia through the end of the study heart rate, respiratory rate, blood pressure and temperature were monitored every fifteen minutes. Vital sign data from each mzint injection is included in Appendix 3 of this submission, Briefly, there were no systematic effects noted on vital signs following 123-I mzint injection. Brain uptake and washout Image Processing: Images were reconstructed using a standardized 3-D reconstruction and attenuation correction using empiric mu and Chang 0 attenuation algorithm. Time activity curves for specific and non-displaceable regional brain uptake and target: cerebellar ratios were obtained. Conclusion: Serial dynamic SPECT images demonstrate excellent penetrance into brain with initial visualization of cortical regions, thalamus, caudate, midbrain, and cerebellum, largely corresponding to initial brain blood flow. Specific activity in regions of high SERT density, including the thalamus, midbrain, and caudate, peak later and washout slower than cortical regions and cerebellum. Uptake ratios (thalamus:cerebellum) increase over 3 hours with ratios achieving a peak plateau of 5-6: 1.

25 mzient 4 Following 5 mg/kg citalopram iv

26 mzient 04 ratio to cerebellum Ratio to cerebellum citalopram 5mg/kg Elapsed (min midbrain parietal cingulate ctx thalamus temporal caudate Specific uptake mzient 04 citalopram 5mg/kg midbrain parietal cingulate ctx thalamus r temp l temp Elapsed

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28 Specific uptake (decay corrected) mzint 25 sertraline min Elapsed midbrain thalamus Specific displacement thalamus 90.9% midbrain 88.8%

29 Displacement of mzient by iv sertraline administration In baboon Sertraline dose (i.v) % displacement thalamus % displacement midbrain 0.1 mg/kg mg/kg mg/kg

30 Image from healthy subject imaged 8 h post 123-I mzient injection HmZINT 03 analysis HmZINT Decay-corr specific uptake Elapsed midbrain frontal thalamus striatum brainstem Ratio to cerebellum Elapsed midbrain frontal thalamus Brainstem

31 Dose-dependent Occupancy at SERT in Human Subjects Following Treatment with Sertraline Thalamus Midbrain Brainstem no rx 25 mg 50 mg 150 mg Plasma Sertraline (ng/ml)

32 Neuro-inflammatory Imaging CLINDE

33 Peripheral Benzodiazepine Receptor Clinde N N Cl N SnBu 3 Na 123 I Peractic acid Cl N 123 I O O N N

34 Cuprizone Treatment Increases 123-I CLINDE Uptake

35 Cuprizone Treatment Increases 123-I CLINDE Uptake in Mice

36 123-I CLINDE Imaging In a Non-human Primate in a Targetless Model

37 123-I CLINDE in Rhesus at Baseline and Following Chronic Ethanol Exposure: Two-fold Increase in Radiotracer Uptake Baseline Post-ethanol

38 Preliminary Human Studies Under exploratory IND # Bolus injection (5 mci) with serial dynamic acquisitions: 6 x 10 min 3 x 20 min 3 x 20 min Venous plasma obtained at midpoint of each scan Iterative reconstruction with standardized post hoc filter

39 Healthy Subject min post injection - Shows no specific uptake

40 Decay-corrected Cnt density Decay-corrected TAC CLINDE08 HS time (min) R Temp L Temp Midbrain Cerebellum R Frontal L Frontal Thalamus.1 R striatum.1 L Striatum.1

41 123-I CLINDE in Parkinson Subject - Uptake in striatum, Thalamus, midbrain

42 Current CLINDE studies Healthy subjects - n=6, PD subjects - n=5 AD subjects - n=4 MS subjects - n=5 Planned HIV

43 Amyloid Imaging

44 Amyloid Imaging IMPY, PIB, AV-1, FDDNP, AV-45, BAY , F-PIB AV 39, AV 83 AV 151 and analogs in human use with eind MNI 187, MNI-308 and analogs in human use with eind

45 ß-Amyloid imaging in AD 11 C PIB PET 18 F-AV-1 PET AD Control 18 F-AV-45 PET Control AD

46 Development of Amyloid ligands eind submission; Compare simultaneously 2 or 3 compounds in same subject No tox studies In-vitro binding and ex-vivo autoradiography One baboon study with each compound (allows us to evaluate vital signs in non human primate): we want to see brain uptake and speed of washout

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48 MNI187 β-amyloid imaging AD Subject Healthy Subject

49 Physician-Sponsored expind Application: PHASE I EVALUATION OF [ 123 I] AV-151, [ 123 I] AV-94 AND [ 123 I] AV-51 AS A BRAIN SPECT TRACER OF BETA- AMYLOID PROTEIN DEPOSITION IN ALZHEIMER S SUBJECTS

50 123-I AV94 AD subject imaged min post bolus injection

51 123-I AV94 AD subject imaged min post bolus injection

52 123-I AV94 AD subject imaged min post bolus injection

53 THANK YOU

54 Molecular NeuroImaging, LLC Job Description: Chemist Radiochemistry Senior Posting Date: September 2008 Requirements: Ph.D. (or MS) with Experience in working with short-lived radioisotopes.