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BioMarin Provides Program Update on Vosoritide in Achondroplasia
New Data Shows Durable and Consistent Effects on Mean Annualized Growth Velocity
for up to 12 months with Increases of 46%-65% from Baseline

Phase 3 Randomized Controlled Study Planned to Start at End of 2016

SAN RAFAEL, Calif., April 20, 2016 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) today provided an update on its Phase 2 study of vosoritide, an analog of C-type Natriuretic Peptide (CNP), in children with achondroplasia, the most common form of dwarfism. After 12 months of daily dosing at 15 µg/kg/day, the cohort 3 patients (n=10) experienced a 46% or 1.9 cm/year increase in mean annualized growth velocity from baseline (p-value = 0.02). (See Table 2). These findings provide evidence of durability of effect consistent with previously presented 6-month data for these patients, which demonstrated an annualized increase of 50% or 2.0 cm/year in mean annualized growth velocity. In addition, 6-month data for 12 patients who were initiated on a lower dose and switched to 15 µg/kg/day showed an increase of 65% or 2.3 cm/year in mean annualized growth velocity from baseline (p-value = 0.002).

Vosoritide at 15 µg/kg/day was well tolerated and there were no treatment-related serious adverse events or adverse events leading to discontinuation. Consistent with the initial 6-month data, in the newly released data, all adverse events assessed as related to study drug were mild to moderate. Over 12 months of dosing at 15 µg/kg/day, injection site reactions and hypotension (asymptomatic decreases in blood pressure) were the most common drug related adverse events, reported by 90% and 40% of cohort 3 patients, respectively. All injection site reaction events were mild and the majority were resolved in one hour. All adverse events of hypotension were mild, transient and resolved without intervention. Safety data from lower dose cohort subjects who increased their dose to 15 µg/kg/day for at least 6 months was generally comparable to the 12-month safety data; however, two subjects experienced symptomatic events associated with a decrease in blood pressure, only one of which was deemed by the investigator to be related to study drug. Both subjects continued to receive their daily dose of vosoritide without dose modification. The phase 2 study is also evaluating a higher dose of 30 ug/kg/day. Preliminary data after several months of treatment has shown that this dose is similarly well tolerated with no new safety findings.

A consistent effect in increasing urinary cyclic guanosine monophosphate (cGMP), a urinary pharmacodynamic biomarker, provides further evidence of durable pharmacologic activity of the 15 µg/kg/day dose over the 12-month observation period in cohort 3.

"We're encouraged by the consistency of the data from six to 12 months in both safety and efficacy, and plan to initiate a Phase 3 study by the end of the year," said Hank Fuchs, MD, Chief Medical Officer at BioMarin. "By addressing the root cause of achondroplasia with vosoritide treatment and normalizing annualized growth velocity in children with achondroplasia, we ultimately hope to improve the medical complications of disproportionate bone growth."

"Children with achondroplasia are likely to experience a variety of medical complications caused by the condition," said Ravi Savarirayan, M.D., Ph.D. Professor, Department of Paediatrics, University of Melbourne and Lead Investigator for the vosoritide Phase 2 study. "A treatment like vosoritide has the potential to decrease medical complications and to increase function and quality of life."

While the Phase 2 efficacy endpoint centers on mean annualized growth velocity, BioMarin hopes that that longer treatment may lead to improvement in many of the complications that can be associated with achondroplasia, such as disproportionality, though longer time of treatment and/or a controlled study may be required to demonstrate this effect.

By the end of 2016, BioMarin is planning to initiate a single Phase 3 randomized controlled study over 12 months in children with achondroplasia ages 5-14 with a subsequent long-term open-label extension subject to discussions with regulatory authorities. In addition, BioMarin is planning a separate Phase 2 study evaluating the effect of vosoritide in infants and toddlers. Vosoritide has Orphan designation in both the United States and Europe.

Table 1 and 2
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Source: press release, 4/20/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=966001

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Vosoritide for achondroplasia: In June 2015, the Company published results from the Phase 2 study showing a 50 percent in mean annualized growth velocity (speed at which growth in children occurs) in the cohort of 10 patients receiving a 15 µg/kg dose of vosoritide daily for six months compared with their own pre-treatment growth velocity (P-value= 0.01). In addition, to support further exploration of a dose that may enable "catch-up" growth in the event of delayed treatment, a fourth cohort with 30 micrograms per kilogram daily completed enrollment in the fourth arm of the Phase 2 study. BioMarin will provide 12-month results with vosoritide at the 15 µg/kg dose, preliminary safety update on the 30 µg/kg dose and an update on Phase 3 plans at the R&D Day in April 2016.
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Source: press release, 2/25/16. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=957260

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Henry J. Fuchs, M.D., EVP and CMO, commented on the ongoing phase-II study with Vosoritide for achondroplasia. He stated, "Also expected at our R&D Day in New York in April, data from ongoing phase-II study with Vosoritide for achondroplasia as well as plans and timelines for our pivotal study. We have fully enrolled the fourth arm of the phase-II study with the 30 microgram per kilogram dose while the first three cohorts in the phase-II study move forward in the extension of the phase-II study with the 15 microgram per kilo dose."
Source: Q3 2015 earnings conference call, 10/29/15.

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Vosoritide for achondroplasia: In June, the Company published results from the Phase 2 study showing a 50 percent or 2.01 cm/year increase in mean annualized growth velocity (speed at which growth in children occurs) in the cohort of 10 patients receiving a 15 µg/kg dose of vosoritide daily for six months compared with their own pre-treatment growth velocity (p-value= 0.01). Based on these results, BioMarin intends to move into Phase 3 study discussions on the next stage of development with health authorities with a dose of 15 micrograms per kilogram daily. In addition, to support further exploration of a dose that may enable "catch-up" growth in the event of delayed treatment, a fourth cohort with 30 micrograms per kilogram daily has recently completed enrollment in the Phase 2 study. BioMarin will provide an update on Phase 3 design and plans, as well as 12 month results from the Phase 2 study at the R&D Day in April 2016.
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Source: press release, 10/29/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=939338

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BioMarin's Initial 6-Month Data from Phase 2 Study of Vosoritide (BMN 111) in Children with Achondroplasia Presented at the American Society for Bone and Mineral Research Annual 2015 Meeting

SAN RAFAEL, Calif., Oct. 12, 2015 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced that Dr. Melita Irving, Clinical Geneticist, Guy's and St Thomas' NHS Foundation Trust, Evelina Children's Hospital London, UK, presented the initial six-month data from the first three cohorts of a Phase 2 proof-of-concept and dose-finding study of vosoritide (BMN 111), an analog of C-type Natriuretic Peptide, in children with achondroplasia at the American Society for Bone and Mineral Research Annual 2015 Meeting in Seattle, Washington. Achondroplasia is the most common form of human dwarfism.

The initial six-month data from the first three cohorts showed a 50 percent or 2.01 cm/year increase in mean annualized growth velocity (speed at which growth in children occurs) in the cohort of 10 patients receiving a 15 µg/kg dose of vosoritide daily for six months compared with their own pre-treatment growth velocity (p-value= 0.01). Data suggests that vosoritide activity was sustained over six months of dosing as measured by increases in cyclic guanosine monophosphate (cGMP), a urinary marker of pharmacological activity. No serious or severe adverse events were observed and the most common adverse events reported were mild injection site reactions, asymptomatic hypotension and headache that were resolved without medical intervention (Grade 1). BioMarin previously announced these data in June this year and indicated that these data would be presented at an upcoming medical meeting.

"We are pleased to share this initial six-month data from the first three cohorts in a scientific forum, and we are grateful to the children, families and physicians who have participated in this study. By developing a therapy that addresses the root cause of achondroplasia, we hope to address the associated complications, such as disproportionate bone growth," said Hank Fuchs, M.D., Executive Vice President and Chief Medical Officer at BioMarin. "We are very encouraged with this initial data, and we look forward to working with health authorities and the patient community to advance vosoritide to the next stage of clinical development."

While the Phase 2 efficacy endpoint centers on annualized growth velocity after six months of treatment, BioMarin believes that growth velocity may be an important early indicator and that longer treatment may lead to improvement in many of the complications that can be associated with achondroplasia, such as disproportionality, though longer time of treatment is likely required to accumulate evidence to this effect.

Vosoritide is the designated generic name for BMN 111 and was issued by the International Nonproprietary Names (INN) system managed by the World Health Organization (WHO). Vosoritide has Orphan designation in both the United States and Europe.
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Source: press release, 10/12/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=936250

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BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study

- 50% Increase in mean annualized growth velocity in 15 µg/kg/daily dose group

- BMN 111 was well tolerated across all three dose cohorts

- Phase 2 findings support program advancement of 15µg/kg/daily dose into pivotal registration discussions with health authorities

- Investor conference call to be held today, June 17, 2015 at 1:30pm PT/(4:30pm ET)

SAN RAFAEL, Calif., June 17, 2015 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced positive results of a Phase 2 proof-of-concept and dose finding study of BMN 111 (vosoritide), an analog of C-type Natriuretic Peptide (CNP), in children with achondroplasia. Achondroplasia is the most common form of human dwarfism. Vosoritide has Orphan designation in both the United States and Europe.

Phase 2 Results and Safety Summary of First Six Months

Data from the 26 children participating in the Phase 2 study demonstrated a favorable safety profile and efficacy at the 15 micrograms/kilogram/daily dose. The 10 children in Cohort 3 treated with 15 micrograms per kilogram per day had a mean increase of 50% (p-value = 0.01) in their annualized growth velocity compared to their annualized prior 6 month natural history baseline growth velocity. Changes from baseline in proportionality as measured by upper to lower body ratio were not observed. No Serious Adverse Events (SAEs) were observed for the duration of the study. The complete data from the study will be presented at a medical meeting later in the year.

"We are very encouraged to have observed evidence of activity with vosoritide in children participating in our Phase 2 study," said Wolfgang Dummer, M.D., Ph.D., Vice President, Clinical Development of BioMarin. "In children receiving the highest dose of 15 micrograms per kilogram daily, we observed a 50% increase in mean annualized growth velocity compared to their own natural history control growth velocity. This increase in growth velocity, if maintained, could allow children with achondroplasia to resume a normalized growth rate." Dr. Dummer continued, "More importantly, vosoritide was well tolerated in all dose cohorts and we have observed no major safety concerns to date. Based on these results, we intend to move into pivotal registration study discussions with health authorities with a dose of 15 micrograms per kilogram daily. In addition, to support further exploration of a dose that may enable "catch-up" growth in the event of delayed treatment, we intend to study 30 micrograms per kilogram daily in ancillary studies. The next step in our development plan is to review this Phase 2 data with health authorities and our outside advisors to develop our path forward with registration enabling studies."

"We are looking forward to working with health authorities worldwide as we continue to develop vosoritide for patients with achondroplasia globally," said Jean-Jacques Bienaimé, Chairman and Chief Executive officer at BioMarin. "It is estimated that about 96,000 patients in our established territories are afflicted with achondroplasia, so approximately 25%, or 24,000, are under 18 years of age and in our addressable market."

Safety and Adverse Event Observations in the Phase 2 Study

No serious adverse events (SAEs) were reported in any cohort during the study.
The majority of AEs reported were mild (Grade 1) and included injection site reactions, headache, hypotension, back pain and cough.
Blood pressure (BP) and heart rate (HR) were monitored frequently and during every site visit. Symptomatic hypotension was not documented in the study. Each patient had approximately 100 measurements of BP in the course of the study. 17 asymptomatic hypotension events in 10 patients were recorded out of the majority of blood pressure measurements obtained. The 17 events were mild (Grade 1), transient, self-limited and resolved without medical intervention. Events occurred across all dose cohorts and at varying times after dosing with no evidence of dose dependency. One subject in Cohort 1 was reported to have "dizziness due to hypotension" and the event resolved without medical intervention in 5 minutes. The event occurred at home and no blood pressure measurement available during the episode of dizziness. The patient continued therapy with no further events.
No clinically significant changes in vital signs at any dose or time of exposure.
No bone related adverse events (AEs) were reported.
Table 1: BMN 111 (vosoritide) Summary of Efficacy Results from Phase 2 Study in Children with Achondroplasia
Efficacy Analysis: Annualized 6-Months Growth Velocity

Data table: http://investors.bmrn.com/releasedetail.cfm?ReleaseID=918431

Additional Highlights from BMN 111 (vosoritide) Study in Children with Achondroplasia

There was a dose-related increase in urinary excretion of cGMP measured over the 6 month duration of the study. cGMP is a biochemical marker that may indicate that BMN 111's biological effect will continue beyond 6 months.
In dose cohort 3, the median annualized increase from baseline was 2.7 centimeter/year or 66% annualized increase over baseline.
Phase 2 Study Design

Children in this study completed a minimum six month natural history 901 study to determine their respective baseline growth velocity prior to entering the Phase 2 study with BMN 111. The Phase 2 trial was an open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. In this three dose cohort study, patients were treated with either 2.5 µg/kg/daily, 7.5 µg/kg/ daily or 15 µg/kg/ daily, respectively. A total of 26 children with achondroplasia with an average age of 7.8 years were enrolled in the study. Based on the safety profile observed to date across the three dose cohorts, all subjects participating in the Phase 2 study have now been switched to the highest dose of 15 µg/kg/ daily for the duration of the 18 month extension study.

BMN 111 was recently designated the generic name vosoritide by the International Nonproprietary Names (INN) system managed by the World Health Organization (WHO).
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Source: press release, 6/17/15. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=918431

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BMN 111 for the treatment of achondroplasia has enrolled all patients in the Phase 2 study and data from the first three cohorts of the study are expected late in the second 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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2Q 2015: Data on first three cohorts in Phase 1/2 with BMN 111 for the treatment of achondroplasia
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Source: press release, 2/26/14. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=828597

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January 14, 2014
BioMarin Doses First Patient in Phase 2 Trial With BMN 111 for the Treatment of Children With Achondroplasia

SAN RAFAEL, Calif., Jan. 14, 2014 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) announced today that it has dosed the first child in the Phase 2 trial with BMN 111, an analog of C-type Natriuretic Peptide (CNP), for the treatment of children with achondroplasia. Achondroplasia is the most common form of disproportionate short stature or dwarfism.

"BMN 111 is representative of BioMarin's core competency of developing life-altering therapies that address unmet medical needs," stated Hank Fuchs, M.D., Chief Medical Officer of BioMarin. "In this Phase 2 study, we hope to see improvements in bone growth similar to what was observed in our preclinical models, and resulting improvements in the medical complications of achondroplasia that occur as a result of disproportionate bone growth. We believe treatment with BMN 111 for achondroplastic children will be well-tolerated and could potentially address the underlying cause of this condition and lead to benefits in the lives of these patients."

The Phase 2 study is an open-label, sequential cohort, dose-escalation study of BMN 111 in children who are 5-14 years old. The primary objective of this study is to assess the safety and tolerability of daily subcutaneous doses of BMN 111 administered for 6 months. The secondary objectives will include an evaluation of change in annualized growth velocity, changes in absolute growth parameters, changes in body proportions and other medically relevant and functional aspects of achondroplasia, such as sleep apnea and joint range of motion. Prior to enrolling in the Phase 2 study, all patients will have participated in a 6 month natural history study to determine baseline growth velocity data. This is an international study that will enroll approximately 24 subjects for a treatment duration of 6 months.
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Source: press release, 1/14/14. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=819163

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BMN 111 for Achondroplasia: The company announced that U.S. and European Regulatory Authorities have agreed that a Phase 2 study in Achondroplasia can start without additional data. BioMarin previously completed a Phase 1 study in adult healthy volunteers. The company expects to initiate its first study in pediatric patients in the fourth quarter of 2013 or the first quarter of 2014.
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Source: press release, 10/24/13. http://investors.bmrn.com/releasedetail.cfm?ReleaseID=800324

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Henry J. Fuchs, M.D., EVP and CMO, commented on the status of the BMN-111 program for Achondroplasia. He stated, "Now turning to BMN-111 for achondroplasia. As announced today, we are modifying our clinical program based on a request from the Food and Drug Administration for more pharmacokinetic and safety data in children. The FDA acknowledges that we have identified a range of doses that are relatively well-tolerated short-term. It has now requested additional pharmacokinetic and safety data in children with achondroplasia before proceeding to extended dosing in children. The FDA has placed the program on partial clinical hold. We will work with the appropriate health authorities on the implications for the program. We anticipate that we will initiate the clinical study in patients with achondroplasia in Q4 2013 or Q1 2014. Despite this minor delay, we are very much committed to this program and eager to proceed to the next phase of development."
Source: Q2 2013 earnings conference call, 7/25/13.

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Study-901 - A Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia
Estimated Enrollment: 200
Study Start Date: April 2012
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT01603095?term=BMN111&id=901&rank=...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Vosoritide (BMN-111)Endocrine and MetabolismAchondroplasiaC-type natriuretic peptide analogOveractive FGFR3 pathway

Mechanism of action: Vosoritide (BMN-111) a stabilized version of C-type natriuretic peptide (BMN-111), a natural human peptide that is a positive regulator of bone growth. Achondroplasia is a result of an autosomal dominant mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which causes an abnormality of cartilage and bone formation. In normal circumstances, FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. To counteract the effects caused by the activating FGFR3 mutation, BMN-111 binds to its own receptor which initiates intracellular signals that ultimately inhibit the overactive FGFR3 pathway. Daily subcutaneous injections of BMN-111 in mouse models of the disease have demonstrated the ability of this drug to correct the dwarf phenotype.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2017-05-01 - 2017-11-30

Results: Pending