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BioMarin Announces EMA Validation of Brineura™ (Cerliponase Alfa) Marketing Authorization Application for Treatment of CLN2 Disease, a Form of Batten Disease
CHMP Opinion and EU Decision Expected Q3 2017

SAN RAFAEL, Calif., Sept. 15, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) announced today that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for Brineura™ (cerliponase alfa) to treat children with CLN2 disease, a form of Batten disease. Validation of the MAA confirms that the submission is accepted and starts the formal review process by the EMA's Committee for Human Medicinal Products (CHMP).

Earlier this year, the CHMP accepted BioMarin's request for accelerated assessment of the MAA on the grounds that Brineura is of major public health interest with the potential to have a major impact on medical practice for CLN2 patients in Europe. Accelerated assessment has the potential to shorten the EMA's review procedure. However, applications which are initially granted accelerated assessment frequently revert to standard assessment timelines. Assuming a positive opinion from the CHMP and standard assessment timing, a decision from the European Commission is anticipated by the third quarter of 2017. The EMA previously granted Brineura Orphan Drug Designation.

"CLN2 disease is a rapidly progressing, fatal neurodegenerative disease with no approved treatments. Based on the positive results of the pivotal study, we are working to bring this meaningful therapeutic option to patients and families in Europe as soon as possible," said Hank Fuchs, MD, Chief Medical Officer of BioMarin. "We greatly appreciate the CLN2 community's ongoing support and look forward to continuing to work with regulatory authorities in the coming months."

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 eight and 12 years of age.

Marketing Applications

On July 27, 2016, the U.S. Food and Drug Administration (FDA) accepted for review the submission of a Biologics License Application (BLA) for cerliponase alfa. The Prescription Drug User Fee Act (PDUFA) goal date for a decision is April 27, 2017. 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 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.

Early Access Program

BioMarin has implemented an early access (compassionate use) program as planned to provide experimental drug for additional CLN2 patients prior to obtaining marketing approval. The program is limited in scope and number of participants, and is being conducted under a protocol. The program initially is being conducted at centers that have participated in the cerliponase alfa study. The program began in August 2016 in Hamburg, Germany and Columbus, OH, U.S.A. We continue to work on opening the other sites, while adhering to specific legal and regulatory procedures for each country. In order to assure fairness in inclusion, enrollment decisions will be made independent of BioMarin. In addition, the identities of participants are confidential to protect the privacy of the patients and families.
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Source: press release, 9/15/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=989247

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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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BioMarin Announces EMA Grants Accelerated Assessment for Cerliponase Alfa, Experimental Treatment for a Form of Batten Disease
EU and U.S. Marketing Application Submissions Planned for Mid-Year 2016

Company Seeking Priority Review in the U.S.

SAN RAFAEL, Calif., May 03, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced that the European Medicines Agency (EMA) has granted BioMarin's request for accelerated assessment for the planned cerliponase alfa Marketing Authorization Application (MAA). 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.

Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (rhTPP1) intended for the treatment of children with CLN2 disease, a form of Batten disease. CLN2 disease is a rapidly progressing, fatal neurodegenerative disease with no approved treatments.

The company expects to submit the cerliponase alfa MAA to the EMA and the Biologics License Application to the U.S. Food and Drug Administration (FDA) by mid-year. If the cerliponase alfa MAA is accepted by the EMA, then an opinion from the Committee for Medicinal Products for Human Use (CHMP) is anticipated in the first quarter of 2017, and, if positive, a decision from the European Commission could be received in the first half of 2017.

"We are pleased that the EMA has recognized the need to bring a therapy to children with this particular form of Batten disease as quickly as possible. This could be the first therapeutic option available for these children," said Jean-Jacques Bienaimé, Chairman and Chief Executive Officer of BioMarin. "We look forward to entering the regulatory review phase for cerliponase alfa on a global basis. CLN2 disease represents a significant unmet medical need for those affected, and our hope is to offer a life-altering treatment option to patients worldwide."

In the U.S., BioMarin is seeking to shorten the regulatory review time by requesting Priority Review. Priority Review status is designated by the FDA to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. The FDA will evaluate this request following submission of the planned Biologics License Application (BLA). Cerliponase alfa has been granted Orphan Drug Designation by the FDA and EMA and Breakthrough Therapy designation by the FDA.

Early Access Program

BioMarin is planning to implement an early access program to provide limited access to treatment for additional CLN2 patients prior to obtaining marketing approval. An early access program will be limited in scope and number of participants, and will be conducted under a protocol. We expect that the program will be conducted 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 program is expected to begin in at least one site by the end of Q3 2016, and the timing of additional sites will vary by country and individual site. The overall scope, eligibility criteria and details of this program are still being determined. BioMarin must adhere to specific legal procedures for each country and has begun these preparations at risk with the goal of being ready to dose patients by the end of Q3 2016. BioMarin will provide additional details about the scope and timing of this program as they become available.
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Source: press release, 5/03/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=968719

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Cerliponase alfa (BMN-190)Endocrine and MetabolismCLN2 disease (Batten Disease)Enzyme replacement therapyTPP1 enzyme activity

Mechanism of action: Cerliponase alfa (BMN-190) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. BMN-190 is an enzyme replacement therapy designed to restore TPP1 enzyme activity and break down the storage materials that cause CLN2 disease. In order to reach the cells of the brain and central nervous system, BMN-190 must be administered directly to the cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord. A small, simple device will be implanted in each patient’s head, under the skin of the scalp and through a small hole drilled in the skull, to allow for regular treatment directly to the brain. Animal research has shown that BMN-190 distributes widely in the brain and BMN-190 is able to get into the cells of the brain and break down the storage materials.

Phase of Development: Filed

Event Type: Regulatory EMA: CHMP Opinion (Estimate)

Dates: 2017-09-15

Results: Pending