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BioMarin Pharmaceutical Cerliponase PDUFA

01/27/2017 - 00:00

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Brineura (formerly known as Cerliponase alfa) for CLN2, late-infantile form of Batten disease: On July 28th, 2016, the Company announced that the U.S. Food and Drug Administration (FDA) had accepted for review the submission of a Biologics License Application (BLA) for Brineura, an investigational therapy to treat children with CLN2 disease, a form of batten disease. The Prescription Drug User Fee Act (PDUFA) goal date for a decision is January 27, 2017. BioMarin also has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Brineura, and it is undergoing validation at the Agency. The FDA granted Brineura Priority Review status, which is designated to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Brineura was previously granted Orphan Drug Designation and Breakthrough Therapy Designation by the FDA. (See BioMarin press release from July 27, 2016 for further details.)
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Source: press release, 8/04/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=983076

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BioMarin Announces Update to Brineura™ (Cerliponase Alfa) Program for Treatment of CLN2 Disease, a Form of Batten Disease
Additional Data Submitted to BLA following FDA Request, PDUFA Action Date Extended to April 27, 2017

Additional 8 Months of Treatment (81-Week Data) Show Maintenance of Efficacy, Consistent with Previously Submitted 48-Week Data

SAN RAFAEL, Calif., Sept. 06, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced a program update for cerliponase alfa, a recombinant human tripeptidyl peptidase 1 (rhTPP1) to treat children with CLN2 disease, a form of Batten disease. CLN2 disease is a rapidly progressing, fatal neurodegenerative disease with no approved treatments, where the majority of affected children lose their ability to walk and talk by approximately six years of age. After 81 weeks, patients treated with cerliponase alfa continue to have motor-language (ML) scores representing substantial attenuation of disease progression compared to natural history. These data are consistent with the data at 48 weeks submitted with the original Biologics License Application (BLA), and demonstrate durable and consistent treatment response. During their initial review of the BLA, the U.S. Food and Drug Administration (FDA) requested an updated efficacy data cut from the ongoing extension study, which the company provided. The FDA designated this submission as a major amendment to the application, thus extending the PDUFA action date by three months to April 27, 2017.

FDA has not communicated their rationale for declaring this submission a major amendment. This review division has extended PDUFA timelines for breakthrough products in the past. The Agency has advised that they plan to hold an advisory committee meeting at a date to be confirmed per their usual practice of notification in the Federal Register.

The additional data continue to show that the Hamburg Motor + Language CLN2 scores1 of a majority of treated patients are stable. Natural history of the disease shows an average of 2.1 points of decline over 48 weeks and an expected 3 points of decline over 81 weeks.2 Updated analysis of the estimated rate of decline including approximately 8 months of additional data continues to show substantial attenuation of disease progression with cerliponase alfa treatment. The mean (95% Confidence Interval) rate of decline of the Motor Language score in points per 48 weeks for the Intent to Treat (ITT) population (n = 23) as of 03 June 2016 was 0.32 (0.13, 0.52) (p < 0.0001 compared to a 2-point decline derived from available natural history), which was based on 81 weeks of treatment. This rate is improved from the corresponding rate of decline reported in the original BLA of 0.48 (0.16, 0.81), which was based on 48 weeks of treatment.

The primary analysis, agreed to with FDA, is a responder analysis where patients with decline in CLN2 score (<2 points over 48 weeks) are defined as responders. The response rate at 81 weeks (< 2 point decline in CLN2 score) remained 87%, as reported in the original BLA.

Consistent with previous data cuts, cerliponase alfa administered via intracerebroventricular infusion every 14 days was well tolerated, and no patients discontinued treatment due to adverse events (AEs). Most AEs were Grade 1 or 2, and the majority are consistent with severe, chronic neurologic disease in pediatric patients. The most common events associated with treatment included: pyrexia, hypersensitivity, seizure, epilepsy, vomiting and headache. No new safety signals were observed.

"We continue to work with the Agency to respond to their requests regarding available natural history data, clinical scales used to characterize the treatment effect, and durability of response," said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. "We believe that the continued maintenance of benefit, as well as the supporting responder analysis provides substantial evidence of effectiveness. We look forward to receiving further feedback from the Agency as the review progresses."

Children with CLN2 disease typically begin to present symptoms between the ages of two and four, with the majority of affected children losing their ability to walk and talk by approximately six years of age. Initial symptoms can include language delay and seizures, followed by movement disorders, motor deterioration, dementia and blindness. During the later stages of the disease, feeding and tending to everyday needs become very difficult, and death often occurs between 8 and 12 years of age. BioMarin estimates the incidence of CLN2 disease is approximately one in 200,000 with approximately 1,200 to 1,600 children in BioMarin's commercial territories.

Marketing Applications

The FDA and European Medicines Agency (EMA) granted cerliponase alfa Orphan Drug Designation. In addition, the FDA granted cerliponase alfa Priority Review Status and Breakthrough Therapy designation.

BioMarin has submitted a Marketing Authorization Application (MAA) to the EMA for cerliponase alfa, and it is undergoing validation at the Agency, an update is expected shortly. The EMA has granted BioMarin's request for accelerated assessment. Accelerated assessments are granted on the grounds that a product may satisfy an unmet medical need and is of major interest from the point of view of therapeutic innovation and public health. Accelerated assessment has the potential to shorten EMA's review procedure. However, at any time during the MAA assessment, the EMA may decide to continue the assessment under standard assessment timelines, and most applications that initially qualify for accelerated assessment are ultimately reviewed on a standard timeline.
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Source: press release, 9/06/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=987982

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FDA Accepts BLA for BioMarin's Cerliponase Alfa for CLN2 Disease, Form of Batten Disease
Potential First Treatment for Fatal, Rare, Brain Disease in Children

FDA Grants Priority Review Status and Breakthrough Therapy Designation

PDUFA Action Date is January 27, 2017

MAA Submitted to European Regulatory Authorities

SAN RAFAEL, Calif., July 27, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) announced today that the U.S. Food and Drug Administration (FDA) accepted for review the submission of a Biologics License Application (BLA) for cerliponase alfa, an investigational therapy to treat children with CLN2 disease, a form of Batten disease. The Prescription Drug User Fee Act (PDUFA) goal date for a decision is January 27, 2017. BioMarin also has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for cerliponase alfa, and it is undergoing validation at the Agency.

The FDA granted cerliponase alfa Priority Review status, which is designated to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Cerliponase alfa was previously granted Orphan Drug Designation and Breakthrough Therapy Designation by the FDA.

The company also announced that the preliminary approved brand name for cerliponase alfa is Brineura™.

"CLN2 disease is a rapidly progressing, fatal neurodegenerative disease with no approved treatments. The FDA recognized the potential of cerliponase alfa to help address this devastating condition, and we look forward to working closely with the Agency over the coming months," said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. "We thank the community for its continued support, as well as the patients and families who dedicated their time to the clinical development of cerliponase alfa."

"This is an historic milestone for the Batten disease community. For the first time since it was originally described more than a century ago, there is a potential treatment for our children with CLN2 disease," said Margie Frazier, PhD, Executive Director of the Batten Disease Support and Research Association. "We appreciate BioMarin's continued commitment to pursue a therapy for this devastating disease and to advancing it quickly through the development process."

Children with CLN2 disease typically begin to present symptoms between the ages of two and four, with the majority of affected children losing their ability to walk and talk by approximately six years of age. Initial symptoms can include language delay and seizures, followed by movement disorders, motor deterioration, dementia and blindness. During the later stages of the disease, feeding and tending to everyday needs become very difficult, and death often occurs between 8 and 12 years of age.

Early Access Program

BioMarin is planning to implement an early access program to provide access to treatment for additional CLN2 patients prior to obtaining marketing approval. The program will be limited in scope and number of participants and will be conducted under a protocol. BioMarin expects that the program will be conducted initially at centers that have participated in the cerliponase alfa study. Those sites have experience administering this drug directly to the brain and would ensure continued patient monitoring.

The timing of the start of the program is on track, and the initial site is expected to be open during Q3 2016. The exact timing will vary by country of the sites participating. The overall scope and details of this program are still being determined. BioMarin must adhere to specific legal procedures for each country and has begun these preparations with the goal of being ready to dose patients in Q3 2016.
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Source: press release, 7/27/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=981569

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