Back & spine complications1,2

Ear infections, sleep apnea1,2

Cardiovascular complications1,2

Bowed legs1,2

Dental overcrowding1,2

Obesity1,2

MUTATION

BMN 111 PHASE 2 TRIAL includes:

• 26 children with achondroplasia

• BMN 111 tested in children (5-14 years old) whose growth plates were still open

• 6 months without BMN 111 to set a baseline for comparison

Primary objective: Evaluate drug safety and tolerability

Secondary objectives:

• Measure the changes in annualized growth velocity (speed at which growth in children occurs)

• Understand the way BMN 111 is metabolized

• Observe the changes in body proportions (may take years)

Exploratory objectives (in process—may take years to demonstrate):

• Bone density

• Dimensions of the spine

• Growth plate morphology

Roadmap to a New TherapyUnderstanding Achondroplasia and the Clinical Trial Process

Achondroplasia is the most common form of human dwarfism. In people with achondroplasia, a specific mutation in the FGFR3 gene causes irregular bone growth.1,2

Secondary Complications From Irregular Bone Growth

Typical Bone Growth3 Irregular Bone Growth in Achondroplasia1,2

BMN 111

BMN 111

Disproportionate short stature is the most obvious feature of achondroplasia, but irregular bone growth can also lead to potentially serious complications over a person’s lifetime that are not as easy to see.1

BMN 111: An investigational therapy developed by BioMarin. Currently in clinical trials, BMN 111 may work on the underlying problem to signal regular bone growth.

OUR GOAL: To give individuals with achondroplasia an option to reduce the impact of these complications on their lives.

Clinical Trial Process

BMN 111 PHASE 1 TRIAL included 48 healthy adult volunteers

Primary objective: To evaluate safety, tolerability, and how BMN 111 is metabolized by the body

Status: Completed

BMN 111 PHASE 3 TRIAL

Status: BioMarin is in the process of working with health authorities to design a Phase 3 trial that will allow BMN 111 to gain Regulatory approval

BioMarin is committed to pursuing these exploratory objectives in this trial and future trials.

Our work revolves around giving individuals with rare genetic conditions the power to have a say in the way they want to live their lives. At BioMarin, we understand that any potential therapy is a choice that should be carefully considered by individuals with achondroplasia, their families, and their doctors.

Length of time: Several months5

Length of time: Several months to 2 years5

Length of time: 1 to 4 years5

Length of time: 6 to 10 months4

Typical Review Process: Marketing authorization application (MAA) is submitted. Regulatory reviews all data and decides whether or not to approve the drug4

Typical Phase 1: Drug studied in a small group of people (healthy volunteers) to determine safety and side effects4

Typical Phase 2: Drug studied in a larger group (people with a certain condition) to determine effectiveness and safety4

Typical Phase 3: Drug studied for longer periods of time in large groups to gather more data on effectiveness and safety, compared to common treatments or placebo4

Clinical trials are conducted in phases—each phase designed for a different purpose. The following maps out an approximate time frame for trial phases in general.

PHASE 1Clinical Trial

Committed to Our Work in Achondroplasia

Committed to Rare Genetic Conditions

PHASE 3Clinical Trial

PHASE 2Clinical Trial

Regulatory Review

Nearly

20years developing

personalized therapies

5approved therapies

on the market

Working in nearly

60 countries

More than

2,000dedicated employees

Currently in

PHASE 2

• 6 months of daily BMN 111 injections under the skin

- Divided into 3 study groups (cohorts), each receiving a different dose

References:

1. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-172.

2. Pauli RM. Achondroplasia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington; 1993-2016. Initial posting October 12, 1998. Last updated February 16, 2012. Accessed February 3, 2016.

3. Gilbert SF. Osteogenesis: the development of bones. Developmental Biology. 6th ed. Sunderland, MA: Sinauer Associates; 2000. http://www.ncbi.nlm.nih.gov/books/NBK10056/. Accessed February 3, 2016.

4. The FDA’s drug review process: ensuring drugs are safe and effective. US Food and Drug Administration Web site. http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm. Updated November 6, 2014. Accessed February 3, 2016.

5. Step 3: clinical research. US Food and Drug Administration Web site. http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm. Updated November 23, 2015. Accessed February 3, 2016.

©2016 BioMarin Pharmaceutical Inc. All rights reserved.

• Changes in sleep apnea

• Changes in long-bone growth

• Elbow joint range of motion (functional improvement)

Status: Ongoing. A fourth cohort has been added and is fully enrolled—with patients receiving a higher dose than the first 3 cohorts

In the growth plate, cartilage cells (chondrocytes) undergo different stages of activity to form new bone. The FGFR3 gene mutation interferes at the stage in which chondrocytes multiply and line up. Therefore, the rest of process is impacted, resulting in irregular bone growth.1-3

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HOW TO FIND OUT MORE ABOUT BMN 111 Check for updates regularly at:

ClinicalTrials.govBioMarin.com

www.biomarin.com/products/

pipeline/bmn-111/

Search: NCT01603095

Resting chondrocytes

Resting chondrocytes

Multiply and line up

Limited chondrocyteproduction

Mature andincrease size

Limited chondrocytes to mature and increase size

Convert tonew bone

Limited chondrocytes

converted to bone