EOP2 prachiti Vichare - It is an End of Phase II meeting request for FDA that is requested by the companies to plan and execute their Drug Development process. PDF

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It is an End of Phase II meeting request for FDA that is requested by the companies to plan and execute their Drug Development process....

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Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

02/27/2017

Prachiti Vichare

Food and Drug Administration, Center for Drug evaluation and Research, Division of Dermatology and Dental Products, 5901-B Ammendale Road, Beltsville, MD 20705-1266

Re: End of Phase 2 Meeting Request for AIN457 Dear Madam, Novartis Pharmaceuticals is requesting an End of Phase 2 meeting; we request you to arrange this meeting at the division’s earliest convenience to discuss our further post-marketing plans for our phase 3 trials for developing our compound AIN457. Our product, AIN457 can be used to treat moderate-to-serious plaque psoriasis. AIN457 is our novel drug and based on our pre-clinical data, phase I, phase II clinical data we believe that AIN457 is safe so far and provides therapeutic benefits to patients suffering from moderate-to-severe plaque psoriasis. AIN457 is a first drug discovered to treat plaque psoriasis. A detailed information package that summarizes our rationale and proposed plan for phase III clinical study will be sent to the division. Any questions or any additional inquiries, please do not hesitate to contact the undersigned Mr. Joseph Tribbiani, Manager, Regulatory Affairs at 857-478-1088. Sincerely, Ross Geller CEO of Novartis

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Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

Contents INTRODUCTION:....................................................................................................................................3 PRODUCT NAME AND APPLICATION NUMBER:...........................................................................3 CHEMICAL NAME AND STRUCTURE...............................................................................................3 PROPOSED INDICATION:.....................................................................................................................4 TYPE OF MEETING BEING REQUESTED:........................................................................................4 PURPOSE OF THE MEETING:.............................................................................................................4 OBJECTIVE OF THE MEETING:.........................................................................................................4 REQUESTED MEETING AGENDA.......................................................................................................5 QUESTIONS..............................................................................................................................................5 SPONSOR MEETING ATTENDEES......................................................................................................7 AGENCY STAFF REQUESTED TO PARTICIPATE IN THE MEETING.........................................7 INFORMATION PACKAGE...................................................................................................................8 SUGGESTED DATES AND TIMES FOR THE REQUESTED MEETING........................................8 PROPOSED FORMAT OF THE MEETING..........................................................................................8

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Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

INTRODUCTION: AIN457, a novel product developed by Novartis pharmaceuticals is used in the treatment of moderate-to-severe plaque psoriasis. It is a monoclonal antibody I.e., Human interleukin 17-A antibody, a pro-inflammatory cytokine linked to disease exacerbation. AIN457 inhibits the release of IL-17A which reverses the disease progression and offers new treatment options for patients suffering from psoriasis. It comes in two forms such as powder for injection and solution for injection either using by prefilled syringe or pen(auto-injector)

PRODUCT NAME AND APPLICATION NUMBER: 2.1 Product name: AIN457 2.2 BLA Application Number: 100814

CHEMICAL NAME AND STRUCTURE 3.1 Chemical Name: Secukinumab 3.2 Molecular Weight and Mechanism of Action: a) Mechanism of Action: Secukinumab is a human interleukin-17A antibody. During an inflammatory response IL-17 family is released by T helper 17 cells which generally targets endothelium and epithelium. People suffering from psoriasis have increased levels of IL17A. Secukinumab when administered, selectively binds to IL-17A and blocks it from binding to its receptor and helps in preventing the inflammatory process which causes psoriasis b) Molecular Weight: 148 kDa 3.3 Molecular Formula: C6584H10134N1754O2042S44 3.4 Formulation: Composition of one vial of lyophilized AIN457 (150 mg powder solution) contains: a) AIN457 - 150 mg b) Sucrose – NF-92.43 mg c) L-Histidine USP – 4.66 mg d) Polysorbate 80 NF – 0.60 mg 3.5 Route of Administration: Subcutaneous Injection

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Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

PROPOSED INDICATION: AIN457 (Cosentyx) is a human interleukin 17A antagonist which is used to treat moderate-tosevere plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

TYPE OF MEETING BEING REQUESTED: Type B PURPOSE OF THE MEETING: Novartis Pharmaceuticals is requesting an EOP2 meeting in order to obtain agency’s current thinking and feedback on proposed clinical program for: a) Phase III studies b) Dosage optimization c) To evaluate phase III plans and protocols d) To assess the pediatric safety and effectiveness e) Additional information to support the marketing application f) Chemistry, manufacturing, and controls g) Regulatory and Statistical parameters Discussing these parameters will further ensure our firm for a successful BLA application.

OBJECTIVE OF THE MEETING: The main objective of the meeting is to reach a covenant for the following: a) Proper design, control, and management of phase III trials. b) Evaluation of Phase I and Phase II trials, any additional data necessary from earlier phases in order to proceed to phase III trials. c) Duration of the Phase III trials, any additional trials required to ensure safety and efficacy of phase III trials, risk evaluation, and mitigation strategies. d) Dose optimization and regulation. e) To discuss any additional studies needed, and discuss the progression of PK studies. f) Any additional nonclinical studies to be conducted in order to ensure safety and efficacy and capability of nonclinical studies that have already been conducted. g) Documentation and Regulatory requirements.

REQUESTED MEETING AGENDA We request the meeting to last for approximately 60 minutes. The proposed meeting agenda for the drug AIN457 is as follows: Objective of the meeting, Brief introduction of participants

5 mins

Non-clinical discussion

10 mins Confidential Page 4

Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

Clinical discussion

25 mins

CMC, Regulatory discussion Summary of the entire discussion and Conclusion

15 mins 5 mins

QUESTIONS 9.1 Nonclinical a) Animal studies were conducted to evaluate the carcinogenic and mutagenic potential for AIN457. Some literature studies recommend that IL-17A promotes cancer cell invasion in vitro, whereas other some of the reports indicate IL-17A promotes T-cell mediated tumor rejection. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown. Does the agency require additional studies to be carried out in any other rodents or similar species in order to cross check the malignancy results? b) The sponsor has conducted pre and post-natal development study in pregnant CD-1 mice with a subcutaneous dose on gestation and post-partum days. No treatment-related side effects were observed in parent generation except minor changes such as a decrease in lymphocyte levels and company considers these changes were not due treatment. Does the agency agree with this findings? Background of the study: Subcutaneous doses of 0,15 50 and 150 mg/ kg/ dose BZN035 were administered to pregnant CD-1 mice on gestation days 6, 11 and 17 and also on postpartum days 4, 10, and 16. No treatment-related effects on parent generation clinical condition, body weight, feed consumption, maternal performance was observed in the study. The NOAEL was identified to be 150 mg/ kg/ dose. There were no treatment-related effects on survival, growth, development, behavior or reproductive performance of the offspring (F1 generation). Treatment-related minor changes were noted in lymphocyte population in blood, thymus, and spleen. These minor changes in lymphocyte populations were not considered significant since there were no treatment-related effects on T cell- dependent antibody responses (TDAR) noted in this study. 9.2 Clinical 1) Novartis intends to conduct Phase III trials with double-blind, multi-Centre and in 1400 patients to evaluate safety and efficacy of secukinumab in the intended population. Does the agency agree with Phase III study plan? 2) Novartis pharmaceuticals tend to conduct a pivotal Phase III trial which enrolls subjects of 18 years of age and older who have plaque-type psoriasis with psoriasis area and severity index of ≥ 12 (PASI). Subjects will be randomized and will receive SC dose of injection of 150 mg and 300 mg at weeks 0, 1,2 and 3 followed by maintenance dose starting at week 4 through week 48. In Confidential Page 5

Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

one of the trails, EU-sourced Enbrel (etanercept) will be used as an active comparator product. This product is an unapproved product in the US, does the agency agree with the use of such product in our phase III clinical trials and can teenagers, above the age of 18 can be tested in the trails? 3) Novartis plans to conduct a PK comparability study in healthy volunteers to bridge from the lyophilised to a liquid formulation for the pre-filled syringe. Healthy male subjects were randomly assigned to receive a single injection of SC secukinumab 150 mg using either the autoinjector or a standard needle and syringe. The PK parameters of secukinumab were calculated using non-compartmental analysis. An ANOVA model was applied to compare the 2 injection methods with regard to secukinumab C(max) and the AUC from 0 and 49 days after administration (AUC(0-49d)) Is this the appropriate bridging approach? 9.3 CMC a) A bioequivalence study was conducted by the sponsor and the PK time points at week 4 and week 12 were compared and it was observed that concentration resulting from auto-injector was almost similar to those from prefilled syringe. A detail study report has been attached to the information package. Provided analytical (CMC) - comparability between the pre-filled syringe and the auto-injector, does the agency agree that the following assessments studies are adequate and sufficient to support the approval of a commercial auto-injector? -Auto-injector design verification -auto-injector manufacturing process validation -auto-injector design validation (stimulated clinical use with injection pads) -auto-injector clinical use study (actual patient self-injection) 9.4 Regulatory

a) The Phase III clinical data submitted to EU agency which showed the highest level of safety and efficacy and got approval by EU in 2015. Can the Phase III data submitted to EU can be used as a supporting material for phase III submission of AIN457? b) The company is planning to conduct post-marketing studies for 2 years after it gets approved. The detailed study plan is attached along with the information package. Does the agency agree with the intended plan?

SPONSOR MEETING ATTENDEES    

Ross Geller, Senior Manager, Regulatory Affairs Chandler Bing, Quality Head Biologics, and BPO Quality Rachel Zayn, Technical Project Leader Harvey Specter, MD, Chief Medical Officer, Executive Vice president Confidential Page 6

Novartis Pharmaceuticals AIN457

RGA6200 FDA Meeting Request

 Robert Maldey, Ph.D., Global Regulatory CMC  Gabriel Macht, Ph.D., Pharmacology, and Toxicology, Pharmacological Sciences  Scott Ackles. Ph.D., Vice President, Clinical Development

AGENCY STAFF REQUESTED TO PARTICIPATE IN THE MEETING       

Matthew White, Regulatory Project Manager Monica Geller, MD, Director of Division of Dermatology and Dental Products Sam Winchester, Ph.D., Product Quality Reviewer Jared kall, MS Regulatory Health Project Manager, Safety Sarah Joseph, Ph.D., Review Chief, DMA Christopher Sparks, Lead Nonclinical Reviewer Donna Eastwood, MD Clinical Team Leader Division of Dermatology and Dental Products  Any other officials that the Agency views would be critical to this meeting.

INFORMATION PACKAGE Prior to the scheduled meeting, Novartis Pharmaceuticals will provide a briefing package not less than 30 days which will contain details of Phase I and Phase II clinical study outcome, Phase III design and other CMC information, regulatory information and Long-term clinical studies that the company plans to conduct.

SUGGESTED DATES AND TIMES FOR THE REQUESTED MEETING Novartis Pharmaceuticals is eager to discuss and co-operate with the Agency. Any date from 28th March to April 7th will be ideal, from morning (09:00 hours) to evening (17:00 hours). The Brief information package is ready at our end and will be dispatched as soon as the response is received from the Agency. Considering the review time requirements; if the meeting is not scheduled for the above-mentioned date, a meeting could also be scheduled for 28th of April.

PROPOSED FORMAT OF THE MEETING Novartis Pharmaceuticals requests to conduct the meeting face-to-face at the Divisions office. If not possible, teleconference meeting would be the second option, as per the Agency’s recommendation and availability.

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