A Tale of Four INDs

1. A Tale of Four INDs Richard J. Barohn, M.D. Gertrude and Dewey Ziegler Professor of NeurologyChair, Department of Neurology University Distinguished Professor Mazen Dimachkie, M.D. Professor of Neurology Chief, Neuromuscular Service University of Kansas Medical Center Neurology/Neurosurgery Grand Rounds May 17, 2013

2. “It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us.” - Charles Dickens A Tale of Two Cities www.wikipedia.org

3. Investigational New Drug (IND) Application • Provisions of the IND Regulation – 21 CFR 312 • IND is regulatory mechanism for new drug development

4. When an IND is needed • A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to 312.2(a) • Submit an IND if any exempt criteria are not met • Also certain FDA and NIH grants require an IND

5. When an IND not needed The IND regulations [21 CFR 312.2(b)] state that clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements for an IND if all of the following apply: • The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use, nor intended to be used to support any other significant change in the labeling for the drug. • The investigation is not intended to support a significant change in the advertising for a prescription drug product. • The investigation does not involve a change in route of administration, dosage level, or patient population, or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with use of the drug product. • The investigation is conducted in compliance with the requirements for institutional review (21 CFR Part 56) and informed consent (21 CFR Part 50). • The investigation is conducted in compliance with the requirements of 21 CFR 312.7, i.e., the drug may not be represented as safe or effective for the purposes for which it is under investigation, nor may it be commercially distributed or sold.

6. IND “Rules” • You, as investigators, can read rules and decide if you are exempt • But I recommend you write the FDA and “ask” for exempt status and ask for a written response back • Some IRBs require such a letter from FDA • IND application is sent to: Food and Drug Administration Email Contact: Center for Drug Evaluation and Research Dr. Russell Katz Central Document Room russell.katz@fda.hhs.gov 5901-B Ammendale Rd. Beltsville, MD 20705-1266

7. What are roles and responsibilities • Sponsor-Investigator: an individual who both initiates and conducts an investigation, and under whose immediate direction the drug is administered or dispensed. • Always an individual • Requirements of Sponsor-Investigator include both those applicable to an investigator and a sponsor • This role applicable to many KUMC IND’s. For more information on additional requirements of role, contact the HSC and Research Institute.

8. What is involved in IND submission • Content requirements for an IND submission are found in 21 CFR 312.23 • Essential forms for a submission: • 1571: must accompany every submission to the FDA for the IND • http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm083533.pdf • 1572: Statement of Investigator • 3674: related to clinicaltrials.gov posting

9. What is a 1571? • Important:by signing youagree not to begin any clinical investigations: • “…until 30 days after FDA’s receipt of the IND unless I receive earlier notification by FDA that the studies may begin…” And; • “…covered by the IND if those studies are placed on clinical hold or financial hold” • If you do not hear any response from the FDA for 30 days after the date they receive the submission, the IND is considered “in effect”.

10. What is involved in IND submission • Essential documents for a submission: • Cover letter/Introductory Statement /General Investigational Plan (2-3 pages) • Investigator’s Brochure (if available from manufacturer; not required for single center investigator initiated trial submissions) • Protocol • Draft Informed Consent Form • Cross Reference Letter (provided by manufacturer which gives submission right to reference all previous data related to drug submitted to the FDA – chemistry, pharmacology and toxicology, previous human experience)

11. KUMC Research Institute, 2013 What is involved after initial IND submission? • Continuing management of the IND is essential. Submissions to the FDA to keep them appraised of study activity includes: • Annual Reports (Sponsor; 312.33): due within 60 days of IND anniversary date (date the IND went into effect) • Unanticipated Problem Reports (Sponsor): to the FDA and any sub-sites • Revised Protocol (Sponsor): changes in risk/benefit of trial, change that impacts subject safety • Changes in the study team, study sites (Investigator)

12. Muscle Channelopathies • Inherited Disorders of Muscle • Molecular Defects in Na+, Cl-, or Ca2+ Channels • Produce either: • Episodic weakness (periodic paralysis) • Myotonia or paramyotonia

13. Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia Richard Barohn, Brian Bundy, Yunxia Wang, Laura Herbelin, Jaya Trivedi, Michael Hanna, Dipa Raja Rayan, Shannon Venance, Emma Ciafaloni, Mohammad Salajegheh, Giovanni Meola, Valeria Sansone, Alice Zanolini, Jeffrey Statland, Robert Griggs, CINCH Study Group Supported by FDA-OPD RO1 FD 003454 & RDCRN/NIH U54 NS059065-05S1 IND #77,021

14. Mexiletine in NDM Two-Period Crossover Design Mexiletine 200mg tid N =29 Placebo Wash- out Period NDM N = 59 Week: 1 2 3 4 6 7 8 9 N =30 Placebo Mexiletine 200mg tid Indicates the weeks to include for the primary endpoint analysis

15. Outcome Measures • Primary Outcome: • Stiffness: self-reported using an Interactive Voice Response Diary (IVR) • Telephone call in daily • Rate stiffness, weakness, fatigue and pain on 0-9 scale • Secondary Outcome: • Pain, Weakness, and Fatigue– IVR • Clinical Myotonia Assessment • Quality of life as measured by INQoL, SF36 • Quantitative measure of hand grip myotonia • Measurement of CMAP after short and long exercise • Grading of Myotonia on Needle EMG

16. Interactive Voice Response Diary • Primary outcome: • Mexiletine significantly improved stiffness on the IVR • Secondary measures • Mexiletine also significantly improved pain, weakness, and tiredness on the IVR

17. JAMA 2012;308(13):1357-1365

18. Conclusion • Mexiletine improved stiffness, pain, weakness and fatigue in NDM patients measured by IVR and quality of life measured by SF-36 • Stiffness scores: the largest treatment mean difference • Most frequent side effect • GI: 9/59 (15%) reported • Other outcome measures currently being analyzed • Lessons: • Investigator-initiated rare disease research can be done in multi-site consortium • Patient reported outcome measures can be primary endpoint • Generic drug availability can be problematic

19. Phase II Trial of Methotrexate in Myasthenia GravisFDA OPD - RO1 FD003538IND #101,306 Richard J. Barohn, MD, Mamatha Pasnoor, MD Laura Herbelin, BSc, Mazen Dimachkie, MD Jianghua He, PhD & the MG Methotrexate Muscle Study Group

21. Myasthenia Gravis • My Rx Recommendations – 2012 • 1st Line: Enlon • Pyridostigmine Prednisone Thymectomy (get in trial!) • 2nd Line: Azathioprine • Cyclosporine • IVIg • 3rd Line: MycophenolateMofetil • Plasmapheresis • 4th Line: Methotrexate Rituximab • 5th Line: Cyclophosphamide • Tacrolimus

22. Study Design • Randomized, double-blind, placebo-controlled study • To determine if oral methotrexate is a safe and effective therapy for myasthenia gravis (MG) patients who are on prednisone

23. Phase II Trial of Methotrexate in MGBarohn and Muscle Study GroupFDA OPD R01 FD003538 • A randomized, double-blind, placebo-controlled study • 50 patients • 25 receiving MTX/25 receiving placebo/12 mo study • Specific aim – determine if oral MTX is an effective therapy for MG patients who are prednisone-dependent • Hypothesis – adding MTX therapy will improve the MG manifestations so that prednisone dose can be reduced and clinical measures of MG severity will improve • The primary measure of efficacy will be the 9-month prednisone area under the curve (AUC) • 20 sites – KUMC, UTSW, UTSCSA, UC-Irvine, OSU, U. North Carolina, U. Virginia, UCSF – Fresno, U. Miami, U. Indiana, MGH, CPMC, U. Iowa, Toronto, Phoenix, Methodist, NM Center Houston, Penn State, U. Florida, U. Toronto

24. Outcome Measure - Primary 9 month (months 3-12) prednisone area under the curve • Measure of the area under the time/dose curve (AUC) • Measures the total prednisone doses of each patient in 9 months • Prednisone is tapered at month 3 if patient is improved • Standardized taper regimen is used • Reduction of prednisone AUC demonstrates improvement • Lower AUC in Methotrexate vs Placebo group

25. Quantitative MG Score Total QMG Score: ___________________________

26. Polyglutamation Assay – with Children’s Mercy Hospital Mara Becker, MD (PI) and Steve Leeder, PharmD, PhD MTX bioactivated to the polyglutamated form of methotrexate (MTXglun) by folylpolyglutamyl synthase (FPGS) Polyglutamation determines the biologic activity of methotrexate Amount of polyglutamation is variable from patient to patient Rheumatoid arthritis lit suggests patients with highly polyglutamated methotrexate respond better Additional blood draw at month 12 Personalized medicine approach

27. Status of enrollment • 57 subjects screened • 50 subjects enrolled, 6 screen failures: • ALT (2), too strong (2), 1 decided against, 1 thymoma • 5 drop-out: • 1 for Parkinson new diagnosis • 1 for ALT elevation • 1 myalgia • 1 personal (travel) • 1 did not feel well • Last subject to finish late 2013

28. Phase II Studies of Rasagiline in Amyotrophic Lateral Sclerosis36 patient open-label screening studyNo IND #80 patient placebo-controlled studyIND #104,360FDA OPD - RO1 FD003739 Principal Investigators: Richard J. Barohn, MD Yunxia Wang, MD Jon Katz, MD Russell Swerdlow, MD and the WALS and MSG

29. Why Rasagiline • Rasagiline has broad neuroprotective activity in neuronal cell culture system that may occur at a mitochondrial level • Mitochondrial dysfunction occurs in ALS patients • Another drug that is closely related to a compound that is effective in Parkinson’s disease, R-pramipexole, is believed to modulate at mitochondrial level, but Phase 3 ALS results are negative • Rasagiline prolongs survival in the SOD1 mouse model of ALS • Small Israeli ALS clinic experience (Drory) • European study starting - Ludolph

30. Rasagiline-Open Label Study Design • Phase II, open label; 2 mg/day for 12 months • No IND # : exempt • TEVA investigator initiated grant –PI: Yunxia Wang, MD, University of Kansas Medical Center • Sites: University of Kansas Medical Center California Pacific Medical Center Phoenix Neurological Institute University of Iowa University of Nebraska University of Minnesota University of Tennessee The Methodist Hospital System McGill University University of Pennsylvania

31. ALSFRS-R Speech 4 – Normal Speech processes5. (cont.) 3 – Detectable speech with disturbances 2 – Intelligible with repeating 1 – Speech combined with nonvocal communication 0 – Loss of useful speech Salivation 4 – Normal 3 – Slight but definite excess of saliva in mouth; may have nighttime drooling 2 – Moderately excessive saliva; may have minimal drooling 1 – Marked excess of saliva with some drooling 0 – Marked drooling; requires constant tissue or handkerchief Swallowing 4 – Normal eating habits 3 – Early eating problems – occasional choking 2 – Dietary consistency changes 1 – Needs supplemental tube feeding 0 – NPO (exclusively parenteral or enteral feeding) Handwriting 4 – Normal 3 – Slow or sloppy; all words are legible 2 – Not all words are legible 1 – Able to grip pen but unable to write 0 – Unable to grip pen 5a. Cutting Food and Handling Utensils (patients without gastrostomy) 4 – Normal 3 – Somewhat slow and clumsy, but no help needed 2 – Can cut most foods, although clumsy and slow; some help needed 1 – Food must be cut by someone, but can still feed slowly 0 – Needs to be fed 5b. Cutting Food and Handling Utensils (alternate scale for patients with gastrostomy) 4 – Normal 3 – Clumsy but able to perform all manipulations independently 2 – Some help needed with closures and fasteners 1 – Provides minimal assistance to caregivers 0 – Unable to perform any aspect of task 6. Dressing and Hygiene 4 – Normal function 3 – Independent and complete self-care with effort or decreased efficiency 2 – Intermittent assistance or substitute methods 1 – Needs attendant for self-care 0 – Total dependence 7. Turning in bed and adjusting bed clothes 4 – Normal 3 – Somewhat slow and clumsy, but no help needed 2 – Can turn alone or adjust sheets, but with great difficulty 1 – Can initiate, but not turn or adjust sheets alone 0 – Helpless Walking 4 – Normal 3 – Early ambulation difficulties 2 – Walks with assistance 1 – Nonambulatory functional movement only 0 – No purposeful leg movement Climbing Stairs 4 – Normal 3 – Slow 2 – Mild unsteadiness or fatigue 1 – Needs assistance 0 – Cannot do Dyspnea 4 – None 3 – Occurs when walking 2 – Occurs with one or more of the following: eating, bathing, dressing 1 – Occurs at rest, difficulty breathing when either sitting or lying 0 – Significant difficulty, considering using mechanical respiratory support Orthopnea 4 – None 3 – Some difficulty sleeping at night due to shortness of breath, does not routinely use more than two pillows 2 – Needs extra pillow in order to sleep (more than two) 1 – Can only sleep sitting up 0 – Unable to sleep Respiratory Insufficiency 4 – None 3 – Intermittent use of NIPPV 2 – Continuous use of NIPPV during the night 1 – Continuous use of NIPPV during the night and day 0 – Invasive mechanical ventilation by intubation or tracheostomy

32. Rasagiline – Open Label Study Design • Aims: • Determine whether rasagiline is safe in this patient population and if the drug has the potential to slow ALS disease progression • Determine if mitochondrial function biomarkers are affected by rasagiline prior and after the rasagiline treatment • Use of WALS Historical Controls

33. Six Month ALSFRS-R Rasagiline versus Historical Control

34. Mitochondrial Biomarker Assays • Mito membrane potential on lymphocyte mitos • JC1 ratio flow cytometry • Lymphocyte mitotracker flow cytometry • Apoptosis markers in lymphocytes • Phosphatidylserine-annexin assay • Oxidative stress markers in blood • Oxygen Radical Antioxidant Capacity (ORAC) assay • Bcl2/Bax ratios on blood protein lysates • Rationale: Bcl2/Bax RNA ratio changes in cell culture

35. Serum Biomarkers: Mito Membrane Potentials Lymphocyte JC-1 Ratio Flow Cytometry Lymphocyte Mitotracker Flow Cytometry Conclusions: After six months of treatment, mitochondria were relatively hyperpolarized. Possible Explanation: Rasagiline hyperpolarized mitochondria.

36. Lymphocyte Annexin Levels Flow Cytometry • Apoptosis (Annexin) • Significant apoptosis indicated p=0.03

37. Conclusion • There is scientific rational to study rasagiline in ALS • Rasagiline is safe in this population • We may be demonstrating mitochondrial target engagement • We may be demonstrating a biomarker measure of disease progression • Next steps: • Analyze 12 month data in May 2013 • Begin 80 patient placebo controlled study

38. Rasagiline 80 – Randomized Placebo Controlled Trial • IND# 104,360 • Funded by FDAOPD RO1-003739, Septmeber 2012 • PI is Richard J. Barohn; Co-PI’s: Yunxia Wang, Russell Swerdlow (KUMC), Jonathan Katz (CPMC) • 12 month placebo-controlled study • 3:1 randomization (60 on rasagiline 2 mg/day, 20 on placebo) • Using WALS Historical Controls bleed-in

39. Biomarkers in Ras 80 ALS Study • Lymphocytes • Swerdlow lab • Bcl2/Bax expression ratio in RNA samples • Higher ratios could be considered “protective” • Urine • Columbia lab – Dr. Santella • Isoprostane levels and urinary 8-oxodG levels in ALS subject urine samples • Lower levels could indicate reduced oxidative stress • Glutathione Brain MRI – Hoglund Brain Imaging Center • Low glutathione = oxidative stress • TDP 43 measurement in platelets • Agbas lab – KCUMB • Changes (up or down) in TDP43 levels could indicate effects on an ALS-associated protein

40. A Tale of 4 INDsPart Deux A randomized, double-blinded, placebo-controlled pilot study assessing the safety and tolerability of Arimoclomol in sporadic Inclusion Body Myositis (IBM) FDA-IND # 76,773

41. IBM microscopy

42. IBM: Prognosis • Relentless progression to disability: cane in 10/14 at 5 years+ and wheelchair in 3/5 at 10 years+ • 4% decrease of strength over 6 months • Median of 14 years from onset, 75% significant walking difficulties & 37% used a wheelchair • Patients treated with immunosuppression more severely disabled on last assessment • KU chart review 7.5-year mean duration, 56% assistive device & 20% requiring a wheelchair Dalakas & Sekul 1993 Rose et al 2001 Benveniste et al. 2011 Estephan et al. 2011

43. Arimoclomol • Developed by CytRx and now owned by Orphazyme • Analog of bimoclomol, a hydroxylamine derivative • Co-inducer of “heat shock” or “molecular chaperone” gene expression • Stabilizes the active phosphorylated trimer of the transcription factor, HSF-1 • May slow down the process of protein misfolding and aggregation in IBM

44. ArimoclomolMechanism

45. Design • Randomised double blind placebo controlled study (2:1) • Funded through GCRC Junior Investigator Grant and MRC • Kansas, USA: 12 patients • London, UK: 12 patients • Treatment phase: 4 months • Follow-up phase: 8 months • Treatment = Arimoclomol 100 mg PO TID

46. Outcome Measures • Primary is safety and tolerability: • Adverse event reporting • Labs • Secondary • Muscle strength testing: • QMA/MVICT 6 muscles bilaterally • MMT • IBMFRS • DEXA fat-free mass • Muscle biopsy – HSP 70 levels/histology

47. Results: Demographics Diagnosis of definite (10) or probable (14) IBM

48. Results:Adverse Events • 8 treatment-related adverse events in PBO • 14 treatment-related adverse events in arimoclomol • Constipation (3) • hyponatremia (2), loose stools (2) • 1 in each: GI problems, gas pains, nausea, cramps, dizziness/tinnitus, hypertension & RA • Most common gastrointestinal • One Serious Adverse Event but none of the adverse events led to drug discontinuation.

49. Results:MMT

50. IBM FUNCTIONAL RATING SCALE