BMRN BioMarin Pharmaceutical Inc

BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) today announced data analysis for Kyndrisa demonstrating consistent evidence of efficacy in comparable patients across three randomized, placebo-controlled studies that were conducted contemporaneously.  Kyndrisa is currently under review with U.S. and European health authorities for the treatment of patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping.  This analysis is included in materials prepared by BioMarin for the November 24, 2015 Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) meeting and can be found on the FDA website at:

http://www.fda.gov/AdvisoryCommittees/Calendar/ucm467180.htm

The analysis examined the pooled study population from the three placebo-controlled studies to identify patients whose baseline characteristics were comparable among all three studies with respect to two key baseline predictive factors: 6-minute Walk Distance (6MWD) and Rise From Floor (RFF). The goal of the evaluation was to determine whether results in comparable populations from the three studies all conducted contemporaneously were consistent with one another.

The treatment effect at week 48 for the pooled population of 128 study subjects from the three studies representing the middle 50% of all subject patients baseline 6MWD (between 313 meters and 419 meters) was 31.3 meters (p < 0.01).  The treatment effect at week 48 for the pooled population of 125 study subjects from the three studies representing the middle 50% of all subject patients baseline RFF (between 4.2 seconds and 13.3 seconds) was 25.8 meters (p = 0.015).

This analysis shows that the results of study 044 are consistent with the results of the two other studies and provides support for those two randomized studies.  In patients who are comparable to each other, similar outcomes have been documented in and across all three studies.

“This analysis contributes important insights into understanding the results of the three studies that serve as the basis for the Kyndrisa application,” commented Hank Fuchs, M.D., Chief Medical Officer of BioMarin. “With the results of this analysis the late stage Kyndrisa clinical program can be summarized as consisting of 3 well controlled randomized studies with over 500 patient years of safety data where the efficacy results include one statistically significant study on an established clinical endpoint with p= 0.01 (study 117), one supportive study with p= 0.07 (study 876) and one study (study 044) in which patients who are comparable to patients in the other two studies have similar results. We look forward to the opportunity to review in great detail the evidence of effectiveness based on this pooled data analysis at our Advisory Committee meeting.”

POOLED ANALYSIS DETAILS:

To enable comparison across studies, a group of patients enrolled in each of the 3 studies was identified based on similar baseline 6MWD and baseline RFF across the pooled population. The entire range of baseline characteristics for both 6MWD and RFF was examined, and the middle 50% of subjects from these analyses of the pooled population were selected for analysis. This approach removes the 25% most severely affected and the 25% least severely affected subjects from the analysis, and includes a sufficient sample size between treatment groups to enable interpretable results.

Based on this selection criterion, subjects had either a baseline 6MWD between 313 to 419 meters or a RFF between 4.2 and 13.3 seconds. Using these two groupings of subjects, the treatment effect was analyzed in the pooled study population, and by each study individually. These analyses show that improvement in 6MWD observed in the pooled population is similar as in the 044 study. This result is true for populations defined by either baseline 6MWD (Table 1) or baseline RFF (Table 2).  Parameter estimates, 95% confidence intervals, and nominal p-values are provided for descriptive purposes.

Table 1. Treatment Effect at Week 48 in 6MWD By Study and Pooled in Subjects from Studies 117, 876, and 044 with Baseline 6MWD between 313 meters and 419 meters

	Study
	Pooled044/117/876(N=76/52)			Study 044(N=56/32)	Pooled117/876(N=20/20)			Study 117 (N=8/13)			Study 876 (N=12/7)
Mean difference (meters) Kyndrisa vs. Placebo		31.3		19.9		55.6			72.8		37.1
95% CI		(9.3, 53.2	)	(-8.8, 48.7)		(19.8, 91.3	)		(12.4, 133.1	)	(-5.0, 79.2)
P value		0.006		0.171		0.003			0.021		0.080

Note: For pooled analysis, model includes study ID, treatment, visit, treatment by visit, baseline 6MWD, baseline 6MWD by visit. For analysis within each study, model includes treatment, visit, treatment by visit, baseline 6MWD, baseline 6MWD by visit. N’s are presented as 6 mg/kg drisapersen/placebo.

Table 2. Treatment Effect at Week 48 in 6MWD By Study and Pooled in Subjects from Studies 117, 876, and 044 with Baseline RFF between 4.2 seconds and 13.3 seconds

	Study
	Pooled044/117/876(N=79/46)			Study 044(N=58/28)	Pooled117/876(N=21/18)			Study 117(N=10/12)	Study 876(N=11/6)
Mean difference (meters) Kyndrisa vs. Placebo		25.8		18.1		36.6		31.4	35.6
95% CI		(5.1, 46.6	)	(-9.2, 45.6)		(4.2, 69.0	)	(-22.3, 85.1)	(-3.1, 74.3)
P value		0.015		0.191		0.028		0.236	0.069

Note: For pooled analysis, model includes study ID, treatment, visit, treatment by visit, baseline 6MWD, baseline 6MWD by visit. For analysis within each study, model includes treatment, visit, treatment by visit, baseline 6MWD, baseline 6MWD by visit. N’s are presented as 6 mg/kg drisapersen/placebo.

This analysis is not intended to provide stand-alone statistically robust evidence of treatment benefit observed in the 044 study.  The purpose of the analysis is to demonstrate that the strong findings in studies 117 and 876 are consistent with the outcome of the 044 study when patients whose baseline predictive characteristics are similar across all three studies.  Taken together, these data substantiate the efficacy findings of studies 117 and 876.

The PCNS advisory meeting is scheduled for November 24 at 8:00 a.m. to 5:30 p.m. EST. The briefing materials and webcast information can be found on the FDA website at: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm467180.htm

The Prescription Drug User Fee Act (PDUFA) action date for completion of FDA review of the Kyndrisa NDA is December 27, 2015.

About Duchenne Muscular DystrophyChanges in the dystrophin gene (mutations) that lead to the near absence of dystrophin protein result in the most severe form of dystrophin deficient muscular dystrophy, Duchenne muscular dystrophy, also known as just Duchenne.  Boys living with Duchenne experience progressive muscle weakness, causing serious medical complications including serious heart or respiratory-related complications, resulting in death in early adulthood.

Primarily affecting boys, Duchenne affects approximately 1 in every 3,500-5,000 male children, making it the most common fatal genetic disorder diagnosed in childhood.

There is currently no FDA approved therapy designed specifically to treat Duchenne.

About Kyndrisa and Exon SkippingKyndrisa is an antisense oligonucleotide that induces exon skipping to provide a molecular patch for dystrophin transcripts produced by certain mutated dystrophin genes. Exons are the parts of a gene that contain the instructions for generating a protein. In applicable cases, skipping an exon near the mutation allows for the production of a truncated but functional dystrophin protein.

About BioMarinBioMarin is a global biotechnology company that develops and commercializes innovative therapies for patients with serious and life-threatening rare and ultra-rare genetic diseases. The company's portfolio consists of five commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visit www.BMRN.com.

Forward-Looking StatementThis press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including, without limitation, statements about: expectations regarding the FDA’s review of the Kyndrisa NDA; outcomes of FDA Advisory Committee Meeting regarding Kyndrisa; the possible impact that the post-hoc analysis described in this release may have on the advisory committee members or the FDA; and the possible approval of Kyndrisa. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the actual conduct and result of the FDA advisory committee meeting; results and timing of current and planned clinical trials of Kyndrisa; the content and timing of decisions by the FDA, and other regulatory authorities concerning Kyndrisa; and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's 2014 Annual Report on Form 10-K, as amended, and the factors contained in BioMarin's reports on Form 8-K. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise.

Kyndrisa™ is our trademark, and BioMarin® is a registered trademark of BioMarin Pharmaceutical Inc.

Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558

Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451