BioMarin Presents New Phase 3, Four-Year Data Underscoring Long-Term Safety and Efficacy of ROCTAVIAN® (valoctocogene roxaparvovec-rvox) at International Society on Thrombosis and Haemostasis 2024 Congress

Data from Longest and Largest Hemophilia Gene Therapy Study Show Durable and Sustained Bleed Control and Factor VIII Expression Maintained Four Years Post-ROCTAVIAN Infusion

Additional Data Show Meaningful Impact of ROCTAVIAN on Health-Related Quality of Life (HRQoL)

SAN RAFAEL, Calif., June 7, 2024 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) today announced that new data supporting the long-term safety and efficacy of ROCTAVIAN® (valoctocogene roxaparvovec-rvox) will be presented at the 32nd Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Bangkok, Thailand, June 22-26, 2024.

"We are pleased to share data at ISTH demonstrating that ROCTAVIAN continues to offer durable and sustained bleed control and endogenous factor VIII expression four years after the infusion, representing the longest and largest Phase 3 follow-up results of a gene therapy in hemophilia," said Hank Fuchs, M.D., president of Worldwide Research and Development at BioMarin. "Importantly, these Phase 3 data also indicate a plateauing of factor VIII levels after year three with the majority of patients remaining off prophylaxis, which shows ROCTAVIAN can offer long-term bleed protection for adults with severe hemophilia A and may provide relief from the burden of chronic infusions and injections."

Four-Year Data from Largest Phase 3 Hemophilia Gene Therapy Study Demonstrate Long-Term Safety and Efficacy of ROCTAVIAN
The Phase 3 GENEr8-1 trial demonstrated that durable bleed control and sustained factor VIII (FVIII) expression were maintained four years after treatment with ROCTAVIAN, with FVIII activity near stable compared with results reported previously and no new safety signals observed. Of the 134 patients who received ROCTAVIAN in the study, the rollover population of 112 patients had baseline annualized bleeding rate (ABR) data prospectively collected during a period of at least six months while on routine FVIII prophylaxis prior to receiving ROCTAVIAN, and two of the 112 patients discontinued the study prior to year four. During year four, 73.6% of the remaining participants (81/110) had zero treated bleeds. Over the entire study period to the time of the data cut, 24 of the 134 total participants resumed prophylaxis with either FVIII or emicizumab without any complications. Mean FVIII activity at the end of year four (n=130) was 27.1 and 16.1 IU/dL as assessed by one-stage assay (OSA) and chromogenic assay (CSA), respectively. These levels are near stable from the previously reported three-year data. Over four years, the mean ABR for treated bleeds for the rollover population was 0.8 bleeds/year, and the mean ABR for all bleeds was 1.3 bleeds/year.

Table 1. Rates of bleeding and FVIII use over four years post-ROCTAVIAN treatment in the rollover population (N=112)

Results Suggest Positive Impact of ROCTAVIAN on Health-Related Quality of Life
In an additional analysis from the Phase 3 GENEr8-1 study, ROCTAVIAN provided important improvements in health-related quality of life (HRQoL) over four years in people with severe hemophilia A, even for those with FVIII levels below 5%. These improvements were measured using the Haemo-QOL-A assessment, a questionnaire designed to measure HRQoL in people with hemophilia A and B. Four years after treatment, the average Haemo-QOL-A Total Score increased by 6.2 points from baseline, with improvements observed in Physical Functioning (4.8 points), Role Functioning (5.9 points), and Consequences of Bleeding (9.2 points). Based on FVIII activity at year four, average Haemo-QOL-A Total Score increased by 6.3, 5.8, and 6.9 points for participants with FVIII activity in ranges ≥40%, ≥5% to <40%, and <5%, respectively.

"People living with severe hemophilia A often experience burdens associated with lifelong treatment, such as the need for frequent infusions or injections, as well as health complications associated with bleeds," said Flora Peyvandi, M.D., Ph.D., ISTH president and study author. "These data demonstrate the meaningful, positive impact that ROCTAVIAN treatment can have on patients' quality of life, especially in helping them move more freely and reducing the burden of caring for bleeding episodes."

Phase 2 Data Show Seven-Year Safety and Efficacy of ROCTAVIAN
Additional data to be presented at ISTH, previously shared at the 2024 European Association for Haemophilia and Allied Disorders Congress, include Phase 2 results that demonstrated the majority of adults with severe hemophilia A treated with ROCTAVIAN maintained bleed control seven years after the infusion, with only two of seven participants resuming prophylaxis. At year seven, in the cohort that received ROCTAVIAN at a dose of 6x10^13 vg/kg (n=5), median FVIII activity remained in the mild hemophilia range (10.3 IU/dL per chromogenic assay), and the mean ABR decreased by 96% from baseline.

BioMarin's full list of presentations at ISTH includes:

Oral Presentations:

Kinetic Profiles of Anti-AAV5 Antibody Generation and Clearance in Neonatal, Infant, and Adult Hemophilia A Dogs
#OC 02.1
Saturday, June 22, 2024, 1:00 – 1:15 p.m. Indochina Time (ICT)

Seven-Year Follow-Up of Valoctocogene Roxaparvovec Gene Therapy for Haemophilia A
#OC 30.1
Monday, June 24, 2024, 9:30 – 9:45 a.m. ICT

Efficacy and Safety of Valoctocogene Roxaparvovec Four Years After Gene Transfer in GENEr8-1
#OC 30.2
Monday, June 24, 2024, 9:45 – 10:00 a.m. ICT

Health-Related Quality-of-Life Outcomes Four Years After Treatment with Valoctocogene Roxaparvovec
#OC 30.3
Monday, June 24, 2024, 10:00 – 10:15 a.m. ICT

Poster Presentations:

Results from the Taiwanese Cohort in GENEr8-1: Bleeding Rates, Factor VIII Usage, Quality of Life and Safety in Severe Hemophilia A Patients After Gene Therapy
#PB0229
Sunday, June 23, 2024, 1:45 – 2:45 p.m. ICT

Persistent and Stable Therapeutic Levels of Transgenic FVIII Expression Following AAV Delivery to Adult and Infant Hemophilic Dogs
#PB0221
Sunday, June 23, 2024, 1:45 – 2:45 p.m. ICT

Efficacy, Safety and Quality of Life Three Years After Gene Transfer with Valoctocogene Roxaparvovec in a Brazilian Cohort
#PB0558
Monday, June 24, 2024, 1:45 – 2:45 p.m. ICT

About Hemophilia A

Hemophilia A, also called factor VIII (FVIII) deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective FVIII, a clotting protein. Although it is passed down from parents to children, about one-third of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have hemophilia A.

About ROCTAVIAN

ROCTAVIAN is an adeno-associated virus vector-based gene therapy used for the treatment of adults with severe hemophilia A who do not have antibodies to adeno-associated virus serotype 5 (AAV5), which is determined by a blood test. The one-time infusion works by delivering a functional gene that is designed to enable the body to produce FVIII on its own, reducing the need for ongoing prophylaxis.

The European Commission (EC) granted conditional marketing authorization to ROCTAVIAN on August 24, 2022. The U.S. Food and Drug Administration (FDA) approved ROCTAVIAN on June 29, 2023.

More information on testing to determine eligibility to receive ROCTAVIAN can be found at https://www.ROCTAVIAN.com in the U.S. and https://www.ROCTAVIAN.de in Germany.

U.S. Important Safety Information

ROCTAVIAN U.S. Important Safety Information

Contraindications: Patients with active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B). Patients with known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent), or cirrhosis, and patients with known hypersensitivity to mannitol.

Infusion-related reactions including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during and for at least 3 hours after ROCTAVIAN administration. Administer ROCTAVIAN in a setting where personnel and equipment are immediately available to treat infusion-related reactions. Discontinue infusion for anaphylaxis.

Hepatotoxicity: The safety and effectiveness of ROCTAVIAN in patients with hepatic impairment has not been established. Perform liver health assessments prior to administration. The majority of patients treated with ROCTAVIAN experienced ALT elevations and required corticosteroids for ALT elevation. Assess patient's ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period. Live vaccines should not be administered to patients while on immunosuppressive therapy.

Monitor ALT weekly for at least 26 weeks and as clinically indicated, during corticosteroid therapy and institute corticosteroid treatment in response to ALT elevations as required. Continue to monitor ALT until it returns to baseline. Monitor factor VIII activity levels since ALT elevation may be accompanied by a decrease in factor VIII activity. One case of autoimmune hepatitis was reported during third year follow-up in a patient with history of hepatitis C and steatohepatitis.

It is recommended that patients abstain from consuming alcohol for at least 1 year after administration and thereafter limit alcohol use. Concomitant medications may cause hepatotoxicity, decrease factor VIII activity, or change plasma corticosteroid levels which may impact liver enzyme elevation and/or factor VIII activity or decrease the efficacy of the corticosteroid regimen or increase their side effects. Closely monitor concomitant medication use including herbal products and nutritional supplements and consider alternative medications in case of potential drug interactions.

Thromboembolic events: Factor VIII activity above ULN has been reported following ROCTAVIAN infusion. Thromboembolic events may occur in the setting of elevated factor VIII activity above ULN. Evaluate patients for risk of thrombosis including general cardiovascular risk factors before and after administration of ROCTAVIAN. Advise patients on their individual risk of thrombosis in relation to their factor VIII activity levels above ULN and consider prophylactic anticoagulation. Advise patients to seek immediate medical attention for signs or symptoms indicative of a thrombotic event.

Factor VIII inhibitors and Monitoring for inhibitors: The safety and effectiveness of ROCTAVIAN in patients with prior or active factor VIII inhibitors have not been established. Patients with active factor VIII inhibitors should not take ROCTAVIAN. Following administration, monitor patients for factor VIII inhibitors (neutralizing antibodies to factor VIII). Test for factor VIII inhibitors especially if bleeding is not controlled, or plasma factor VIII activity levels decrease.

Monitor Factor VIII using the same schedule for ALT monitoring. It may take several weeks after ROCTAVIAN infusion before ROCTAVIAN-derived factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes. Exogenous factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds. Consider more frequent monitoring in patients with factor VIII activity levels ≤ 5 IU/dL and evidence of bleeding, taking into account the stability of factor VIII levels since the previous measurement.

Factor VIII activity produced by ROCTAVIAN in human plasma is higher if measured with one-stage clotting assays compared to chromogenic substrate assays. When switching from hemostatic products prior to ROCTAVIAN treatment, physicians should refer to the relevant prescribing information to avoid the potential for factor VIII activity assay interference during the transition period.

Malignancy: The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. ROCTAVIAN can also insert into the DNA of other human body cells. Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following ROCTAVIAN administration. In the event that any malignancy occurs after treatment with ROCTAVIAN, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100.

Most Common Adverse Reactions: Most common adverse reactions (incidence ≥ 5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. Most common laboratory abnormalities (incidence ≥ 10%) were ALT, AST, LDH, CPK, factor VIII activity levels, GGT and bilirubin > ULN. Patients also experienced adverse reactions from corticosteroid use.

Isotretinoin, Efavirenz, and HIV Positive Patients: Isotretinoin is not recommended in patients who are benefiting from ROCTAVIAN. Efavirenz is not recommended in patients treated with ROCTAVIAN. Clinical studies of ROCTAVIAN did not include sufficient numbers of patients with HIV to determine whether the efficacy and safety differs compared to patients without HIV infection.

Females and Males of Reproductive Potential: ROCTAVIAN is not intended for administration in women. There are no data on the use of ROCTAVIAN in pregnant women or regarding lactation. For 6 months after administration of ROCTAVIAN, men of reproductive potential and their female partners must prevent or postpone pregnancy using an effective form of contraception, and men must not donate semen.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to BioMarin at 1-866-906-6100.

Please see the ROCTAVIAN full Prescribing Information for additional Important Safety Information.

About BioMarin

Founded in 1997, BioMarin is a global biotechnology company dedicated to transforming lives through genetic discovery. The company develops and commercializes targeted therapies that address the root cause of genetic conditions. BioMarin's unparalleled research and development capabilities have resulted in eight transformational 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. For additional information, please visit www.biomarin.com.

Forward-Looking Statements

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: data to be presented at the 32nd Congress of the International Society on Thrombosis and Haemostasis, including the oral and poster presentations; the development of BioMarin's ROCTAVIAN program generally; the safety profile, efficacy and potential positive impact of ROCTAVIAN for adults with severe hemophilia A; and the potential benefits of ROCTAVIAN for adults with severe hemophilia A, including offering long-term bleed protection, providing relief from the burden of chronic infusions and injections, helping treated patients move more freely and reducing the burden of caring for bleeding episodes. 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: results and timing of current and planned preclinical studies and clinical trials of ROCTAVIAN; any potential adverse events observed in the continuing monitoring of the patients in the clinical trials; the content and timing of decisions by the Food and Drug Administration, the European Commission and other regulatory authorities; BioMarin's success in the commercialization of ROCTAVIAN, including achieving adequate market share and reimbursement levels; whether ROCTAVIAN will have the impacts and benefits as anticipated; 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 Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, as such factors may be updated by any subsequent reports. 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.

BioMarin® and ROCTAVIAN® are registered trademarks of BioMarin Pharmaceutical Inc.

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