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BioMarin Pharmaceuticals Inc.

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Cerliponase alfa for CLN2, late-infantile form of Batten disease: Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 (rhTPP1), for the treatment of patients with late-infantile neuronal ceroid lipofuscinosis type 2 (NCL-2), a form of Batten disease is currently in a Phase 1/2 study. This study is expected to be concluded by year-end with results expected in the first quarter of 2016.
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Source: press release, 10/29/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=939338

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Henry J. Fuchs, M.D., EVP and CMO, gave guidance for full data from the BMN-190 study. He stated, "We intend to share this very encouraging data with European regulatory authorities over the coming months while we complete the study and we plan to share the full data set in the fourth quarter of this year."
Source: Q4 2014 earnings conference call, 2/25/15.

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Cerliponase alfa (BMN 190) for the treatment of late infantile CLN2 disease, a form of Batten disease, is currently in Phase 1/2 studies. In January 2015, BioMarin shared interim data from nine patients who have been followed for at least six months and up to 15 months. Preliminary data suggest that treatment with cerliponase alfa appears to result in stabilization of the disease compared to the natural history based on a standardized measure of motor and language function. Complete Phase 1/2 results are expected in the fourth quarter of 2015.
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Source: press release, 2/25/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=898344

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January 12, 2015

BioMarin Provides Preliminary Data From Ongoing Phase 1/2 Pivotal Study of BMN 190 for Treatment of CLN2 Disorder, a Form of Batten Disease

Preliminary Results Show Evidence of Disease Stabilization

SAN RAFAEL, Calif., Jan. 12, 2015 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced interim results from its Phase 1/2 pivotal study for BMN 190 or cerliponase alfa, a recombinant human tripeptidyl peptidase 1 (rhTPP1), to treat of patients with late infantile CLN2 disease, a form of Batten disease. Interim data indicates that in all nine of the BMN 190 patients who have been followed for at least six months and up to 15 months, the treatment appears to show stabilization of the disease compared to the natural history based on a standardized measure of motor and language function.

The primary end point of the study is a standardized mobility and language score using a CLN2-specific rating scale. The scale separately measures performance of mobility and language with normal function in each being a score of three and no function being a score of zero. The highest score possible is six.

According to data from a natural history study of the disease, patients generally lose one point every six months and generally lose most language and mobility functioning over a two to four year period in this rapidly progressive disease. In the nine BMN 190 patients treated for more than six months and up to 15 months, six patients showed no net change in their CLN2 rating scale score, while the other three showed a decline of one point.

In addition, seven of the nine patients in the BMN 190 study for more than six months were matched to between one and 12 individuals from the natural history data set according to baseline age and disease severity. (For two of the BMN 190 patients, there is no matched patient in the natural history database based on age and disease severity.) All seven BMN 190 patients with six months of treatment and at least one control match had better walk/talk scores as of their last evaluation than their natural history counterparts.

Additional detailed information on the interim preliminary results from the nine patients who have been on BMN 190 for more than six months and their matched natural history counterparts can be found at http://www.bmrn.com/pdf/JPMPresentation011215.pdf.

"This trial represents the essence of BioMarin's commitment to patients with fatal rare diseases and no treatment options. This initial look at the data is encouraging, and this therapy may make a meaningful difference for children with this form of Batten disease. We look forward to working with the regulatory authorities to determine if this single study will support regulatory approval as quickly as possible," said Jean-Jacques Bienaimé, Chief Executive Officer.

There is no approved treatment that can prevent, stop, or reverse CLN2 disorder. Palliative care—to reduce seizures—and physical rehabilitative care—to help children retain muscle function for as long as possible—are currently the available treatment options for patients with this rare disease.

"This interim data represents an important step on a journey to develop a treatment for CLN2 disorder that may be able to slow the course of this fatal disease," said Angela Schulz, M.D. Ph.D., Department of Paediatrics, University Medical Center Hamburg-Eppendorf. "We appreciate the commitment of the children and their families who are participating in this study."

"We welcome BioMarin's update on nine of the 24 patients participating in this clinical trial and appreciate the efforts they are making in developing a treatment for this deadly ultra-rare disease," said Andrea West, Chief Executive, Batten Disease Family Association.

"We are pleased about the progress that BioMarin is making in developing a treatment for CLN2 disorder," said Margie Frazier, Ph.D., Executive Director, Batten Disease Support and Research Association. "This is a notable moment, which holds promise for the children and families who are affected by this disease."

The Phase 1/2 pivotal study is an open-label, dose-escalation study in patients with late infantile CLN2 disease, a form of Batten disease. The primary objectives are to evaluate the safety and tolerability of BMN 190 or cerliponase alfa and to evaluate effectiveness using a CLN2 disorder-specific rating scale score in comparison with natural history data after 48 weeks of treatment. Secondary objectives are to evaluate the impact of treatment on brain atrophy in comparison with CLN2 natural history after 48 weeks of treatment and to characterize pharmacokinetics and immunogenicity. The study enrolled 24 subjects at five clinical sites for a planned treatment duration of 48 weeks. Complete results are expected in Q4 2015.
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Source: press release, 1/12/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=890846

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2H 2015: Results from Phase 1/2 trial with BMN 190 for the treatment of Batten's disease
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Source: press release 2/26/14. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=828597

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BMN 190 for LINCL (Batten disease): The company announced that the first patient had been dosed in the Phase 1/2 trial for BMN 190, a recombinant human tripeptidyl peptidase 1 (rhTPP1) for the treatment of patients with neuronal ceroid lipofuscinosis type 2 (NCL-2), a form of Batten disease. This is the first time that a patient with Batten Disease has been treated with an enzyme replacement therapy in a clinical trial setting. The Phase 1/2 study is an open-label, dose-escalation study in patients with NCL-2. The primary objectives are to evaluate the safety and tolerability of BMN 190 and to evaluate effectiveness using an NCL-2-specific rating scale score in comparison with natural history data after 48 weeks of treatment. Secondary objectives are to evaluate the impact of treatment on brain atrophy in comparison with NCL-2 natural history after 48 weeks of treatment and to characterize pharmacokinetics and immunogenicity. The study will enroll approximately 22 subjects for a treatment duration of 48 weeks.
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Source: press release, 10/24/13. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=800324

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September 23, 2013
BioMarin Doses First Patient in Phase 1/2 Trial With BMN 190 for the Treatment of Neuronal Ceroid Lipofuscinosis Type 2, a Form of Batten Disease

SAN RAFAEL, Calif., Sept. 23, 2013 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) announced today that it has dosed the first patient in the Phase 1/2 trial for BMN 190, a recombinant human tripeptidyl peptidase 1 (rhTPP1) for the treatment of patients with neuronal ceroid lipofuscinosis type 2 (NCL-2), a form of Batten disease. This is the first time that a patient with Batten Disease has been treated with an enzyme replacement therapy in a clinical trial setting.

"This program is representative of the company's core competency of developing life-altering enzyme replacement therapies for serious unmet medical needs," said Hank Fuchs, M.D., Executive Vice President and Chief Medical Officer of BioMarin. "We are inspired and motivated by the patient and physician community and encouraged by the pharmacological activity demonstrated in preclinical models. We hope to leverage our expertise in enzyme replacement therapy development to deliver a viable treatment option to patients with this form of Batten Disease."

"The completion of dosing of the first patient in the trial of BMN190 marks the beginning of an important journey. This neurodegenerative disease of childhood is devastating for patients and families. While we hope to make a large difference in their outcome, we are moved and grateful for the support of affected families worldwide," said Angela Schulz, M.D. Ph.D., Children's Hospital, University Medical Center Hamburg-Eppendorf. "Clinical trials are the only means to ascertain whether the promise of this new therapeutic approach will be fulfilled. Without the families' selfless dedication to the important principles of science, this would not be possible."

"We are encouraged by this important milestone, and support the clinical trial process as the best way to bring much needed therapies to underserved patient populations," said Tracy VanHoutan, founder of the Noah's Hope Batten Disease research fund, and 2nd Vice President of the Batten Disease Support and Research Association, the largest organization in the world dedicated to family support and medical research in Batten Disease.

The Phase 1/2 study is an open-label, dose-escalation study in patients with NCL-2. The primary objectives are to evaluate the safety and tolerability of BMN 190 and to evaluate effectiveness using an NCL-2-specific rating scale score in comparison with natural history data after 48 weeks of treatment. Secondary objectives are to evaluate the impact of treatment on brain atrophy in comparison with NCL-2 natural history after 48 weeks of treatment and to characterize pharmacokinetics and immunogenicity. The study will enroll approximately 22 subjects at up to ten clinical sites for a treatment duration of 48 weeks.
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Source: press release, 9/23/13. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=792413

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A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease
Estimated Enrollment: 22
Study Start Date: September 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01907087?term=BMN190&rank=1

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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: I/II

Event Type: Data: Phase I/II trial results

Dates: 2016-01-01 - 2016-03-31

Results:

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BioMarin Announces Positive Data From Cerliponase Alfa Program for Treatment of CLN2 Disease, a Form of Batten Disease, at 12th Annual WORLDSymposium(TM) 2016
80% Reduction in Clinical Disease Progression in One Year Compared to Natural History (p <0.0001)

Company Plans to Submit Marketing Applications Starting Mid-Year 2016

SAN RAFAEL, Calif., March 02, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced positive 48-week results from its Phase 1/2 pivotal study 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. The average rate of clinical decline for motor and language function in patients receiving cerliponase alfa treatment — the primary efficacy endpoint — was approximately 80% less than the expected rate of decline in the untreated population, preserving essential function in the majority of treated patients (p <0.0001). Treatment with 300 mg cerliponase alfa administered via intracerebroventricular (ICV) infusion every other week was generally safe and well-tolerated in 24 patients and resulted in disease stabilization in 65% (15 of 23) of patients treated over a 48-week period, based on the Hamburg Motor + Language CLN2 rating. 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.

In the phase 1/2 study, 87% of patients experienced attenuation of their disease compared to the expected rate of decline observed in available natural history data. The primary endpoint of the study is a standardized mobility (motor) and language score using a CLN2 disease-specific rating scale. The scale separately measures performance of mobility and language with normal function in each being a score of 3 and no function being a score of 0. The highest score possible is 6. Natural history of the disease shows an average of 2.1 units of decline over 48 weeks in 41 untreated patients followed longitudinally.1 The mean decline in 21 evaluable subjects receiving cerliponase alfa treatment was 0.43 units over 48 weeks (p < 0.0001 compared to a 2-point/48 week decline derived from available natural history). Of the 23 evaluable subjects, two were not included in the rate of decline evaluation, as these subjects entered the study with the maximum motor-language score of 6, were not actively declining prior to treatment initiation and remained at 6 during the treatment period.

Brain Magnetic Resonance Imaging (MRI) measurement showed that cerliponase alfa treatment attenuated cortical grey matter volume loss. In 23 treated patients, the mean total cortical grey matter volume decrease is 9.7% over 48 weeks. In a separate study of six untreated children with CLN2 disease, cortical grey matter volume decreased by 14.5% each year.2

An interim analysis from an ongoing extension study suggests durability of therapeutic effect. The mean change from baseline in the first nine patients receiving cerliponase alfa treatment was an improvement of +0.2 units over 72 weeks compared to the expected decline observed in a natural history cohort of approximately -3.13 units. Of those nine patients, three gained 1 point, five remained with a stable score and one lost 1 point. In the four patients who received cerliponase alfa for up to 88 weeks, the mean change from baseline was a decline of -0.5 units compared to the expected decline observed in a natural history cohort of approximately -3.83 units.

Additional analysis of cerliponase alfa for the treatment of CLN2 disease will be presented at the International Child Neurology Congress in Amsterdam at the beginning of May.

"BioMarin is humbled by the substantial benefit that cerliponase alfa has shown for many of the children with CLN2 disease in this trial. Maintaining one or two points on the CLN2 disease-specific rating scale could mean the important difference between a child being able to continue to walk and talk or not," said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. "We have pushed out a medical frontier by developing a potential first enzyme replacement therapy administered directly into the brain ventricles for a form of Batten disease. We are planning to apply for regulatory approval in the U.S. and Europe with this study, which is a very rapid registration approach justified by compelling data in this devastating disease."

"We have seen a highly significant impact for the children participating in this study. This demonstrates the important proof of principle that enzyme replacement therapy administered directly to the brain ventricles can be effective and presents a desperately awaited ray of hope for CLN2 patients worldwide," said Angela Schulz, M.D. Ph.D., Department of Paediatrics, University Medical Center Hamburg-Eppendorf. "It is a privilege to be part of the development of a therapy that has the potential to alter the course of CLN2 disease. I am thankful to the children and their families who uprooted their lives to participate in this groundbreaking study."

"We are hugely grateful to BioMarin for its continued commitment to developing a treatment for CLN2, late infantile batten disease. For all those families who firmly held onto the hope of a treatment, this is very welcome and exciting news for a better future," said Andrea West, Chief Executive, Batten Disease Family Association.

"BioMarin continues a tradition of being a pioneer in enzyme replacement therapies with the development of a treatment for this form of Batten disease. The company is making an important effort to move through the regulatory process as quickly and efficiently as possible to make this needed therapy widely available," said Margie Frazier, Ph.D., Executive Director, Batten Disease Support and Research Association.

Safety Results from Study 190-201

Cerliponase alfa administered via intracerebroventricular infusion every 14 days was well tolerated, and no patients discontinued treatment due to adverse events (AEs). 23 of 24 patients who received more than one dose of drug completed the 48-week study and then chose to enroll in an extension study and continue to receive treatment. One subject discontinued treatment after one dose of drug due to inability to comply with all study procedures. 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 (46%), hypersensitivity (33%), seizure (33%), epilepsy (17%), vomiting (13%) and headache (13%).

Seven (29%) of the subjects experienced a total of ten serious adverse events (SAEs) assessed as related to cerliponase alfa by the study investigators, which included eight events of hypersensitivity and two events of infusion-related reactions. Eight of the ten related SAEs were Grade 1 or 2 in severity, and two were Grade 3 (hypersensitivity). Seven (29%) patients experienced 15 device-related adverse events: 14 out of 15 were Grade 1 or 2. The only device-related SAE was a single report of a Grade 3 SAE (propionibacterium infection), which was detected by routine cerebrospinal fluid monitoring, was treated, and patient resumed drug treatment. There were no reports of anaphylaxis or anaphylactoid reactions, and no deaths during the study.

Efficacy Results from Study 190-201

Table 1- 4 http://investors.bmrn.com/releasedetail.cfm?ReleaseID=958565

BioMarin plans to submit marketing applications with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) by mid-year 2016 with anticipated actions by the FDA and EMA in the first half of 2017.

The FDA and EMA granted cerliponase alfa Orphan Drug Designation. In addition, the FDA granted cerliponase alfa with Breakthrough Therapy designation. BioMarin will seek to shorten the regulatory review time by requesting Priority Review in the U.S and Accelerated Assessment in Europe. 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. Accelerated Assessment is designated by the EMA to drugs that are considered to be medicinal products of major therapeutic interest.
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Source: press release, 3/02/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=958565

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