PRE IND Meeting Request Letter PDF

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Alexandria Pharmaceuticals

RA 6201 FDA Meeting Request

RSP4594

March 19, 2017 Food and Drug Administration Center for Drug Evaluation and Research Division of Neurology FDA, DMEDP, HFD-510 Document Room, 14-B-19 5600 Fishers Lane Rockville, MD 20857 Re:

Pre-IND Meeting Request- Type B RSP4594

Dear Dr. Dunn, Alexandria Pharmaceuticals is hereby requesting a pre-IND meeting, to be held at the Division’s earliest convenience, to discuss our plans for developing RSP4594, which has Clonazepam as the active pharmaceutical ingredient and is an anticonvulsant indicated for Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures and panic disorders. Our intention is to develop and seek approval for RSP4594 as a pharmaceutical alternative to currently approved products. Based on our non-clinical data, we believe that our product provides a therapeutic benefit to patients as provides a safer and more convenient method to administer treatment. A detailed information package that outlines our rationale and proposed plan for developing will be sent to the Division. Should you have any questions or require additional information, please do not hesitate to contact the undersigned at (123) 456-78901, Raeesa Potnis, Manager, Regulatory Affairs. Sincerely, Raeesa Potnis Manager, Regulatory Affairs, Alexandria Pharmaceuticals (123) 456-78901

TABLE OF CONTENT

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Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

1

INTRODUCTION...................................................................................................3

2

Product name and application number....................................................................3 2.1 2.2

3

Product Name......................................................................................................3 Application Number............................................................................................3

Chemical Name and structure..................................................................................3 3.1 3.2 3.3 3.4 3.5

Chemical Name...................................................................................................3 Molecular Description and Weight......................................................................3 Chemical Structure..............................................................................................3 Formulation..........................................................................................................4 Route of Administration......................................................................................4

4

Proposed indication.................................................................................................4

5

Type of meeting being requested.............................................................................5

6

Purpose of the meeting............................................................................................5 6.1

Rationale..............................................................................................................5

7

Objectives/outcomes expected from the meeting....................................................5

8

Requested meeting agenda......................................................................................5 8.1 8.2 8.3

Non-Clinical........................................................................................................6 Clinical.................................................................................................................6 CMC....................................................................................................................7

9

Sponsor Meeting Attendees.....................................................................................8

10

Agency staff requested to particiapte in the meeting...............................................9

11

Information Package................................................................................................9

12

Suggested Dates and Times for the requested meeting...........................................9

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Alexandria Pharmaceuticals RSP4594 1

RA 6201 FDA Meeting Request

INTRODUCTION

Alexandria Pharmaceuticals is a research and development based company which has a vast portfolio of pharmaceutical formulations and APIs. Alexandria Pharmaceuticals has been operating for over a decade has excelled in providing healthcare solutions specializing in a wide number of disease areas. The goal of the company is to provide better lifestyle and care to the patients and improve their quality of life. Alexandria Pharmaceuticals boasts of 25,000 employees working tirelessly towards this aim. Over the years, Alexandria Pharmaceuticals has continuously developed and marketed novel drugs which are targeted at efficiently meeting the patient's therapeutic needs and has become a name synonymous with innovation in the healthcare industry. Alexandria Pharmaceuticals is now focused on developing RSP4594 which has Clonazepam as the active pharmaceutical ingredient and is an anticonvulsant indicated for Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures and panic disorders. 2

PRODUCT NAME AND APPLICATION NUMBER

2.1Product Name. RSP4594 2.2Application Number Not Yet Assigned. 3

CHEMICAL NAME AND STRUCTURE

3.1Chemical Name 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one FDA13 \l 1033 ]

[ CITATION

3.2Molecular Description and Weight 3.2.1 Molecular Formula: C15H10ClN3O3 3.2.2 Molecular Weight: 315.713 g/mol

[ CITATION FDA13 \l 1033 ]

[ CITATION FDA13 \l 1033 ]

3.3Chemical Structure Figure 1 Chemical Structure of RSP4594

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Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

3.4Formulation Table 1 Formulation Table

Sr. No. 1.

Active Ingredient (in mg) Clonazepam

1. 2.

Lactose Magnesium Stearate

3.

Microcrystalline cellulose

35.27

70.56

91.15

4.

Corn Starch

0.01

0.02

0.03

5.

FD&C Yellow No. 6 Lake

0.02

0.02

0.02

Total

50

100

150

0.5 1 Inactive Ingredients (in mg) 10.2 20.4 4 8

2 40.8 16

3.5Route of Administration Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole. [ CITATION FDA13 \l 1033 ] 4

PROPOSED INDICATION

Seizure Disorders: RSP4594 is indicated alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, RSP4594 may be useful. Panic Disorder: RSP4594 is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. [ CITATION FDA13 \l 1033 ]

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Alexandria Pharmaceuticals RSP4594 5

RA 6201 FDA Meeting Request

TYPE OF MEETING BEING REQUESTED

This is a Type B Meeting Request: Pre-IND meeting. 6

PURPOSE OF THE MEETING

6.1Rationale

      

To review and reach agreement on the design of animal studies needed to initiate human testing. To discuss regarding the product formulation, analytical test methods and statistical data requirements. To identify and resolve scientific issues. To evaluate the safety profile of the drug. To ensure adequacy of manufacturing and control standards. To discuss the scope and design of Phase 1 testing, plans for studying the drug product in target populations and best approach for presentation and formatting of data in the IND. To increase the probability of a successful IND.

7

OBJECTIVES/OUTCOMES EXPECTED FROM THE MEETING

To determine if:    

Adverse effects/toxicities from nonclinical data are adequately addressed. The risks and benefits of the drug are adequately discussed and considered. The information provided support an acceptable margin of safety. The proposed clinical study design is justified by the supporting nonclinical data. To review and reach an agreement with the agency regarding the design of animal studies needed to initiate human testing and to agree upon an appropriate Phase I design. 8

REQUESTED MEETING AGENDA

Table 2 Meeting Agenda

Agenda Item

Estimated Time

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Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

I. Introduction II. Discussion of Submitted Questions

05 minutes

(A) CMC Issues (B) Nonclinical Issues (C) Clinical Trial Design (D) Regulatory Issues

10 minutes 20 minutes 10 minutes 10 minutes

(E) Closing Estimated Total

05 minutes 60 minutes

8.1Non-Clinical In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning. In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).[ CITATION FDA13 \l 1033 ] Does the Agency concur with the data given above? Does the Agency agree that the preclinical development program is sufficient to support the proposed clinical plan? 8.2Clinical

The effectiveness of clonazepam in the treatment of panic disorder will be demonstrated in two double-blind, placebo-controlled studies of adult outpatients Confidential Page 6 of 10

Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia. These studies are expected to show that clonazepam is significantly more effective than placebo in treating panic disorder on change from baseline in panic attack frequency, the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global Impression Improvement Score. Study 1 is a 9-week, fixed-dose study involving clonazepam doses of 0.5, 1, 2, 3 or 4 mg/day or placebo. This study will be conducted in four phases: a 1-week placebo lead-in, a 3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. A significant difference from placebo is expected to be observed consistently only for the 1 mg/day group. The difference between the 1 mg dose group and placebo in reduction from baseline in the number of full panic attacks is expected to be approximately 1 panic attack per week. At endpoint, 74% of patients receiving clonazepam 1 mg/day should be free of full panic attacks, compared to 56% of placebo-treated patients. Study 2 will be a 6-week, flexible-dose study involving clonazepam in a dose range of 0.5 to 4 mg/day or placebo. This study will be conducted in three phases: a 1-week placebo lead-in, a 6-week optimal-dose and a 6-week discontinuance phase. The mean clonazepam dose during the optimal dosing period is 2.3 mg/day. The difference between clonazepam and placebo in reduction from baseline in the number of full panic attacks is expected to be approximately 1 panic attack per week. At endpoint, 62% of patients receiving clonazepam should be free of full panic attacks, compared to 37% of placebo-treated patients. [ CITATION FDA13 \l 1033 ] Subgroup analyses are not expected to indicate that there are any differences in treatment outcomes as a function of race or gender. Does the agency agree that the proposed clinical study designs to evaluate the safety and efficacy of RSP4594 are acceptable? 8.3CMC

Clonazepam, a benzodiazepine, is available as scored tablets with a K-shaped perforation containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5 mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2 Lake. The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions Confidential Page 7 of 10

Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures. Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.[ CITATION FDA13 \l 1033 ] Does the agency agree that the chemical properties of RSP4594 are suitable for a tablet to be taken orally without any stability issues? 9

SPONSOR MEETING ATTENDEES

Name

Title

Affiliation

Ms. Raeesa Potnis

Manager, Regulatory Affairs Regulatory Affairs Department

Mr. Rick Grimes

Senior Chemist

Chemistry Department

Mr. Daryl Dixon

Senior Pharmacologist

Pharmacology Department

Dr. Michonne Anthony

Senior R&D Scientist

Research Scientist

Ms. Sawri Madkaikar

Senior Pharmacokineticist

Pharmacology Department

Mr. Gabriel Macht

Senior Biostatistician

Statistics Department

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Alexandria Pharmaceuticals RSP4594

RA 6201 FDA Meeting Request

10 AGENCY STAFF REQUESTED TO PARTICIAPTE IN THE MEETING

      

Deputy Director: James Smith, M.D., M.S. 301-796-1190 1317 WO 22/Rm. 3360 3372 Deputy Director for Safety: Jennifer Pippins, M.D. (Acting) 301-796-5067 WO 22/Rm. 3319. Chiefs, Project Management Staff: Julie Marchick, MPH. 301-796-1280 WO 22/Rm. 3350; Pamela Lucarelli 301-796-3961 WO 22/Rm. 3364 Administrative Officer: Nicole Cooper 301-796-1193 WO 22/Rm. 3218 Safety Regulatory Project Manager: Mehreen Hai, Ph.D. Chief, Project Management Staff- Division of Neurology: Jacqueline Ware, Pharm.D. Safety Regulatory Project Manager- Division of Neurology: Christine Phipps, Pharm.D. [ CITATION USF16 \l 1033 ]

11 INFORMATION PACKAGE The Information Package will be submitted to the FDA 30-days before the meeting date. 12 SUGGESTED DATES AND TIMES FOR THE REQUESTED MEETING Meeting is requested on: Monday, April 24th, 2017, 1:30 pm onwards. Tuesday, April 25th, 2017, 10:00 am onwards. Preferred Format of meeting: Face-to-face or Videoconference. 13 REFERENCES

[1 FDA Approved Labeling Text October 2013 NDA 017533 Klonopin (clonazepam) ] tablets, "www.fda.gov," 2013. [Online]. Available: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lb l.pdf. [Accessed 17 March 2017]. [2 U. F. a. D. Administration, "About FDA," 07 July 2016. [Online]. Available: Confidential Page 9 of 10

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RA 6201 FDA Meeting Request

] https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco /CDER/ucm290674.htm. [Accessed 17 March 2017].

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