BioMarin Pharmaceutical Stock

BioMarin Pharmaceutical Inc. (BioMarin) operates as a global biotechnology company.

The company develops and commercializes targeted therapies that address the root cause of genetic conditions. The company’s robust research and development capabilities have resulted in multiple innovative commercial therapies for patients with rare genetic disorders. The company’s distinctive approach to drug discovery has produced a diverse pipeline of commercial, clinical, and pre-clinical candidates that address a significant unmet medical need, have well-understood biology, and provide an opportunity to be first-to-market or offer a substantial benefit over existing treatment options.

The company’s key business developments in 2023 include the U.S. Food and Drug Administration (FDA) approval of VOXZOGO for children with achondroplasia of all ages with open growth plates in the United States, European Commission (EC) approval to expand the indication for VOXZOGO to treat children with achondroplasia aged four months and older with open growth plates in the European Union (EU), and FDA approval of ROCTAVIAN in the U.S.

Commercial Products

VIMIZIM

VIMIZIM is an enzyme replacement therapy for the treatment of MPS IVA, a lysosomal storage disorder. MPS IVA is a disease characterized by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS) causing excessive lysosomal storage of certain complex carbohydrates known as glycosaminoglycans (GAGs), such as keratan sulfate and chondroitin sulfate. This excessive storage causes a systemic skeletal dysplasia, short stature, and joint abnormalities, which limit mobility and endurance. Malformation of the chest impairs respiratory function, and looseness of joints in the neck cause spinal instability and potentially spinal cord compression. Other symptoms may include hearing loss, corneal clouding, and heart disease. Initial symptoms often become evident in the first five years of life. The disease substantially limits both the quality and length of life of those affected.

VIMIZIM is approved for marketing in the U.S., the EU and other international markets.

NAGLAZYME

NAGLAZYME is a recombinant form of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) indicated for patients with MPS VI. MPS VI is a debilitating life-threatening genetic disease for which no other drug treatment exists and is caused by the deficiency of arylsulfatase B, an enzyme normally required for the breakdown of GAGs. Patients with MPS VI typically become progressively worse and experience multiple severe and debilitating symptoms resulting from the build-up of carbohydrate residues in tissues in the body. These symptoms include inhibited growth, spinal cord compression, enlarged liver and spleen, joint deformities and reduced range of motion, skeletal deformities, impaired cardiovascular function, upper airway obstruction, reduced pulmonary function, frequent ear and lung infections, impaired hearing and vision, sleep apnea, malaise and reduced endurance.

NAGLAZYME is approved for marketing in the U.S., the EU and other international markets.

PALYNZIQ

PALYNZIQ is a PEGylated recombinant phenylalanine (Phe) ammonia lyase enzyme, which is delivered through subcutaneous injection to reduce blood Phe concentrations. PALYNZIQ is the company’s second approved treatment for PKU. PKU is caused by a deficiency of activity of an enzyme, phenylalanine hydroxylase (PAH), which is required for the metabolism of Phe. Phe is an essential amino acid found in all protein-containing foods. Without sufficient quantity or activity of PAH, Phe accumulates to abnormally high levels in the blood, resulting in a variety of serious neurological complications, including severe mental retardation and brain damage, mental illness, seizures and other cognitive problems. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all PKU patients under the age of 40 in developed countries have been diagnosed at birth. PKU can be managed by a Phe-restricted diet, which is supplemented by nutritional replacement products, like formulas and specially manufactured foods; however, it is difficult for most patients to adhere to the strict diet to the extent needed for achieving adequate control of blood Phe levels.

PALYNZIQ is approved for marketing in the U.S. for adult patients with PKU who have uncontrolled blood Phe concentrations greater than 600 micromol/L on existing management. PALYNZIQ is also approved for marketing in the EU, Australia, and Brazil for patients ages 16 and older who have inadequate blood Phe control (blood Phe concentrations greater than 600 micromol/L) despite prior management with available treatment options.

In the U.S., PALYNZIQ is only available through the PALYNZIQ Risk Evaluation and Mitigation Strategy (REMS) program, which is required by the FDA to mitigate the risk of anaphylaxis while using the product. Notable requirements of the company’s REMS program include the following: prescribers must be certified by enrolling in the REMS program and completing training; prescribers must prescribe auto-injectable epinephrine with PALYNZIQ; pharmacies must be certified with the REMS program and must dispense PALYNZIQ only to patients who are authorized to receive it; patients must enroll in the REMS program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with PALYNZIQ; and patients must have auto-injectable epinephrine available at all times while taking PALYNZIQ.

BRINEURA

BRINEURA is a recombinant human tripeptidyl peptidase 1 (TPP1) for the treatment of patients with CLN2, a form of Batten disease. CLN2 is an incurable, rapidly progressive disease that typically ends in patient death by 10-12 years of age. Patients are initially healthy but begin to decline at approximately the age of three. BRINEURA is the first treatment approved to slow the progression of loss of ambulation in children with CLN2 disease and was one of the first therapies to go through an accelerated review procedure in the EU.

BRINEURA is administered via intracerebroventricular (ICV) infusion and intended to be used in combination with a delivery device, such as an injector or other delivery system.

BRINEURA is approved for marketing in the U.S. (for ages three and older) and in the EU (for all ages from birth) and in other international markets.

ALDURAZYME

ALDURAZYME is a highly purified protein that is designed to be identical to a naturally occurring form of the human enzyme alpha-L-iduronidase, a lysosomal enzyme normally required for the breakdown of GAGs. MPS I is a progressive and debilitating life-threatening genetic disease that is caused by the deficiency of alpha-L-iduronidase. Patients with MPS I typically become progressively worse and experience multiple severe and debilitating symptoms resulting from the build-up of carbohydrate residues in all tissues in the body. These symptoms include inhibited growth, delayed and regressed mental development (in the severe form of the disease), enlarged liver and spleen, joint deformities and reduced range of motion, impaired cardiovascular function, upper airway obstruction, reduced pulmonary function, frequent ear and lung infections, impaired hearing and vision, sleep apnea, malaise and reduced endurance.

The company developed ALDURAZYME through collaboration with Sanofi. Under the company’s collaboration agreement with Sanofi, the company is responsible for manufacturing ALDURAZYME and supplying it to Sanofi. Sanofi and BioMarin are members of BioMarin/Genzyme LLC, a 50/50 limited liability company (the BioMarin/Genzyme LLC) that holds the intellectual property relating to ALDURAZYME and other collaboration products and licenses all such intellectual property on a royalty-free basis to Sanofi and BioMarin to allow the company to exercise its rights and perform the company’s obligations under the agreements related to the BioMarin/Genzyme LLC; and engages in research and development activities that are mutually selected and funded by Sanofi and the company.

ALDURAZYME is approved for marketing in the U.S., the EU and other international markets.

VOXZOGO

VOXZOGO is a once daily injection analog of C-type Natriuretic Peptide (CNP) for the treatment of achondroplasia, the most common form of disproportionate short stature in humans. In patients with achondroplasia, endochondral bone growth, an essential process by which bone tissue is created, is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 gene (FGFR3). VOXZOGO acts as a positive regulator of the signaling pathway downstream of FGFR3 to promote endochondral bone growth.

VOXZOGO is approved for marketing for the treatment of achondroplasia in children with open growth plates of all ages in the U.S. and Japan, children with open growth plates aged four months and older in the EU, and patients in various age ranges for other markets, including Australia and Brazil.

The company continues to research VOXZOGO’s safety and effectiveness in children with achondroplasia. At the 2023 American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting, the company presented updated data demonstrating the long-term benefit of treatment with VOXZOGO and new observational data on disease burden in children with achondroplasia.

In the fourth quarter of 2023, the company began the pivotal program with VOXZOGO for the treatment of children with hypochondroplasia. The six-month run-in study will be followed by the 52-week randomized, double-blind, placebo-controlled phase of the 80-participant clinical trial, with the treatment study expected to begin mid-2024. The company is engaging global health authorities in the first half of 2024 regarding development programs in idiopathic short stature and multiple genetic short stature pathway conditions, with plans to begin pivotal studies later in 2024.

KUVAN

KUVAN is a proprietary synthetic oral form of 6R-BH4, a naturally occurring enzyme co-factor for PAH, indicated for patients with PKU. KUVAN is the first drug for the treatment of PKU, which is an inherited metabolic disease.

KUVAN is approved for marketing in the U.S., the EU and other international markets (excluding Japan). In certain international markets, KUVAN is also approved for, or is only approved for, the treatment of primary BH4 deficiency, a different disorder than PKU.

Generic versions of KUVAN are available in several countries around the world, including multiple generic versions in the U.S. The company is also aware that manufacturers are challenging the company’s patent portfolio related to KUVAN in several jurisdictions, and several generic versions of KUVAN have been approved either centrally by the EC or on a country-by-country basis throughout the EU.

ROCTAVIAN

ROCTAVIAN is an adeno associated virus (AAV5) vector gene therapy designed to restore factor VIII plasma concentrations in patients with severe hemophilia A. Hemophilia A, also called factor VIII deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. According to the World Federation of Hemophilia rankings of severity of hemophilia A, the normal range of factor VIII activity levels is between 50% and 150%, expressed as a percentage of normal factor activity in blood, the mild hemophilia A range of factor VIII activity levels is between 5% and 40%, the moderate hemophilia A range of factor VIII activity levels is between 1% and 5%, and the severe hemophilia range of factor VIII activity levels is less than 1%. People living with hemophilia A are not able to form blood clots efficiently and are at risk for excessive bleeding from modest injuries, potentially endangering their lives. People with severe hemophilia often bleed spontaneously into their muscles or joints.

ROCTAVIAN was conditionally approved by the EC in August 2022 and approved by the FDA in the U.S. in June 2023. The company’s European launch of ROCTAVIAN is underway following ROCTAVIAN'S conditional approval for marketing in the EU for the treatment of severe hemophilia A in adult patients without a history of factor VIII inhibitors and without detectable antibodies to AAV5. The company plans to provide the European Medicines Agency (EMA) further clinical data in an effort to convert the company’s conditional approval to a standard marketing authorization. Please see ‘Government Regulation – Adaptive Pathways’ in this Annual Report on Form 10-K for additional information on conditional marketing authorizations.

The company has and continues to collaborate with payers around the world to secure reimbursement for ROCTAVIAN on terms which are intended to assist payers with realizing the value and sharing the risk of a one-time treatment. For example, the company has agreed with the German National Association of Statutory Health Insurance Funds an outcome-based prospective cohort model for ROCTAVIAN which will allow future reimbursement to be increased or decreased based on real-world data collected from the German Haemophilia Registry of patients treated with ROCTAVIAN. The company is also continuing its development efforts on ROCTAVIAN expansion opportunities.

Research and Development Programs

The company has multiple clinical and preclinical product candidates in various stages of development that are intended to address the root causes of genetic conditions with a significant unmet medical need. Generally, the company’s development programs have well-understood biology and provide an opportunity to be first-to-market or offer a substantial benefit over existing treatment options.

In 2023, the company conducted clinical trials on several product candidates for the treatment of various diseases and progressed pre-clinical activities, including studies intended to support Investigational New Drug (IND) application or Clinical Trial Application (CTA) submissions.

During the first quarter of 2024, the company’s management began a strategic portfolio review of all research and development (R&D) programs to determine which R&D assets have the highest potential patient impact and highest potential value creation for stockholders.

Sales and Marketing

The company has established a commercial organization, including a sales force, to support the company’s product lines directly in the U.S., Europe, South America and certain other significant markets. For other selected markets, the company has signed agreements with other companies to act as distributors of all the company’s products, other than ALDURAZYME. Most of these agreements generally grant the distributor the right to market the product in the territory and the obligation to secure all necessary regulatory approvals for commercial or named patient sales. Additional markets are being assessed at this time and additional agreements may be signed in the future.

Sanofi has the exclusive right to distribute, market, and sell ALDURAZYME globally and is required to purchase its requirements exclusively from the company.

In the U.S., the company’s products (other than ALDURAZYME) are marketed through its commercial teams, including sales representatives and supporting staff members, who promote the company’s products directly to physicians in specialties appropriate for each product. Outside of the U.S., the company’s sales representatives and supporting staff members market the company’s products (other than ALDURAZYME).

The company utilizes third-party logistics companies to store and distribute the company’s products. Moreover, the company uses third-party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with the company’s commercial activities.

Customers

Customers for the company’s products (other than ALDURAZYME) include a limited number of specialty pharmacies and end-users, such as hospitals and non-U.S. government agencies. The company also sells its products (other than ALDURAZYME) to the company’s authorized distributors and to certain larger pharmaceutical wholesalers globally, which act as intermediaries between the company and end-users and generally do not stock significant quantities of the company’s products. However, in certain countries, governments place large periodic orders for NAGLAZYME and VIMIZIM. PALYNZIQ is distributed in the U.S. pursuant to the REMS program through a limited number of certified specialty pharmacies. During 2023, 36% of the company’s net product revenue was generated by three customers. Sanofi is the company’s sole customer for ALDURAZYME and is responsible for distributing, marketing, and selling ALDURAZYME to third parties.

Government Regulation

The company’s products require approval from the FDA, the European Commission (EC) (on the basis of the scientific opinions issued by the EMA) and corresponding agencies in other countries before they can be marketed. The U.S. Foreign Corrupt Practices Act (FCPA), to which the company is subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.

The company also must adhere to cGMP regulations and product-specific regulations enforced by the FDA and other regulatory agencies through their facilities inspection program. In the U.S., for example, the company is subject to the CCPA along with the California Privacy Rights Act of 2020 (CPRA).

The company is also subject to the EU’s General Data Protection Regulation GDPR, which requires that personal data is only collected for specified, explicit and legal purposes as set out in the GDPR or local laws, and the data may then only be processed in a manner consistent with those purposes.

Trademarks

BioMarin, BRINEURA, KUVAN, NAGLAZYME, PALYNZIQ, VIMIZIM and VOXZOGO are the company’s registered trademarks. ROCTAVIAN is the company’s registered trademark in the European Union. ROCTAVIAN is the company’s trademark in the United States (U.S.). ALDURAZYME is a registered trademark of BioMarin/Genzyme LLC.

History

BioMarin Pharmaceutical Inc. was incorporated in Delaware in 1996. The company began its operations in 1997.