On February 25, 2021 BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) (BioMarin or the Company) reported financial results for the fourth quarter and full year ended December 31, 2020 (Press release, BioMarin, FEB 25, 2021, View Source [SID1234575664]).

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Net Product Revenues for the fourth quarter of 2020 were essentially flat as compared to the fourth quarter of 2019. The change in Net Product Revenues was primarily attributed to the following:

Kuvan Net Product Revenues decreased by $33.6 million, primarily due to the U.S. loss of market exclusivity in October 2020 resulting from generic competition; and
Aldurazyme Net Product Revenues decreased by $22.7 million due to timing of product fulfillment to Genzyme. Aldurazyme is marketed by Genzyme and BioMarin Aldurazyme revenues are driven by the timing of when the product is released and control is transferred to Genzyme. Revenues for the fourth quarter of 2020 were comparatively lower than 2019 due to such timing. Based on data provided to us by Genzyme, patients receiving commercial Aldurazyme increased by 10% during 2020; partially offset by
Naglazyme and Vimizim Net Product Revenues increased by an aggregate of $35.1 million primarily due to timing of sales in the Middle East and Latin America;
Palynziq Net Product Revenues increased by $17.9 million driven by a combination of revenue from U.S. patients achieving maintenance dosing and new patients initiating therapy; and
Brineura Net Product Revenues increased by $9.8 million driven by growth in the number of patients in all regions.
The increase in GAAP Net Income for the fourth quarter of 2020, compared to the same period in 2019 was primarily due to the following:

decreased research and development (R&D) expense of $16.1 million primarily due to lower clinical activity spend for valoctocogene roxaparvovec gene therapy programs and decreased tralesinidase alfa costs as the program was licensed to a third-party in 2019; and
an increase in the benefit from income taxes of $37.5 million primarily due to the change in the jurisdictional mix of earnings and the related tax impact from the completion of an intra-entity transfer of certain intellectual property rights to an Irish subsidiary where the Company’s ex-US regional headquarters are located during the third quarter of 2020; partially offset by
an increase in Cost of Sales of $30.2 million primarily due to inventory reserves and higher sales volumes of products with lower margins.
Non-GAAP Income for the fourth quarter of 2020 decreased to $39.5 million, compared to Non-GAAP Income of $46.4 million for the same period in 2019. The decrease in Non-GAAP Income for the quarter, compared to the same period in 2019, was primarily attributed to lower gross profits and higher SG&A expenses, partially offset by lower R&D expenses.

As of December 31, 2020, BioMarin had cash, cash equivalents and investments totaling $1.35 billion, which includes net proceeds of $535.8 million from the Company’s May 2020 convertible debt offering, as compared to $1.17 billion as of December 31, 2019. On October 15, 2020, the Company’s 1.50% senior subordinate convertible notes matured and were settled in cash for approximately $375.0 million.

Commenting on full-year 2020 results, Jean-Jacques Bienaimé, Chairman and Chief Executive Officer of BioMarin, said, "Despite the impact in 2020 from the COVID-19 pandemic and a delay in the potential approval of valoctocogene roxaparvovec for severe hemophilia A, demand for our current product portfolio continued to drive steady revenue growth and expansion of our pipeline. Excluding contributions from Kuvan, for which a generic became available during 2020, total revenues grew 13% in 2020, and generated $85 million of positive operating cash flows for the full year, underscoring the essential nature of our medicines."

Mr. Bienaimé continued, "The most recent Phase 3 data updates from our latest-stage development programs in achondroplasia and severe hemophilia A demonstrated significant efficacy. In the largest gene therapy trial ever conducted for the treatment of severe hemophilia A, we were pleased that valoctocogene roxaparvovec was the first in hemophilia A to demonstrate statistically significant evidence of annualized bleed rate superiority over standard of care recombinant FVIII. Based on these results, we are very encouraged that one infusion of valoctocogene roxaparvovec gene therapy may potentially address the high treatment burden for people with severe hemophilia A. We are targeting submission of the one-year Phase 3 results to the European Medicines Agency in the second quarter of 2021 and planning to dialog with the FDA to align on steps to obtain approval in the United States."

"Also in 2021, we look forward to the potential approval of vosoritide, which would be the first pharmacological treatment to address the underlying cause of achondroplasia, the most common form of dwarfism. We announced in the fourth quarter of 2020 that vosoritide demonstrated sustained growth effects for over two years in children with achondroplasia participating in our Phase 3 extension study. In addition to the large, Phase 3 program currently in the extension phase, we have built a multi-pronged dossier of additional studies to support our understanding of the unmet medical need for children with achondroplasia and the effects of vosoritide in this condition. In addition to the highly statistically significant placebo-controlled Phase 3 results, the program includes the long-term clinical results in 5 to 18 year-olds from our Phase 2 study, natural history data, and the ongoing study of newborns through 5 years. Many families are keen to seek early treatment for their children so we are hopeful that, if approved, vosoritide will become available later in 2021 upon potential approvals."

Key Program Highlights

Valoctocogene roxaparvovec gene therapy for severe hemophilia A: On January 10, 2021, the Company announced positive top-line, one-year data results from its ongoing global Phase 3 GENEr8-1 study of valoctocogene roxaparvovec, an investigational gene therapy for the treatment of adults with severe hemophilia A. Data from the study in the pre-specified primary analysis for Annualized Bleeding Rate (ABR) showed that a single dose of valoctocogene roxaparvovec significantly reduced ABR by 84% compared with prior treatment with prophylactic FVIII infusions. These results were from a pre-specified group of participants in a non-interventional prospective baseline observational study (rollover population; N=112) with a median follow-up of 60.1 weeks after dosing with valoctocogene roxaparvovec. 80% of the rollover participants were bleed-free starting at week five after treatment.
Additionally, at the end of the first year post-infusion with valoctocogene roxaparvovec, participants in the modified intent-to-treat (mITT) population (N=132) had a mean endogenous Factor VIII expression level of 42.9 (SD 45.5, median 23.9) IU/dL, as measured by the chromogenic substrate (CS) assay, supporting the marked clinical benefits observed with abrogation of bleeding episodes and Factor VIII infusion treatment rate. Factor VIII expression declined at a slower rate compared to the Phase 1/2 study, and remained in a range to provide hemostatic efficacy. In a subset of the mITT population that had been dosed at least two years prior to the data cut date (N=17), Factor VIII expression declined from a mean of 42.2 (SD 50.9, median 23.9) IU/dL at the end of year one to a mean of 24.4 (SD 29.2, median 14.7) IU/dL at the end of year two with continued hemostatic efficacy demonstrated by a mean ABR of 0.9 (median 0.0) bleeding episodes per year.

Valoctocogene roxaparvovec also significantly reduced the mean annualized Factor VIII usage in the rollover population by 99% from 135.9 (median 128.6) to 2.0 (median 0.0) infusions per year (p-value <0.0001).

In the U.S., the FDA recommended that the Company complete the Phase 3 study and submit two-year follow-up safety and efficacy data on all study participants. The Company plans to meet with FDA to review the two-year data request and share the Phase 3 GENEr8-1 results announced on January 10, 2021. BioMarin is targeting submission of the Marketing Authorization Application (MAA) with these results to the EMA in the second quarter of 2021 pending confirmation in presubmission meetings.

Vosoritide for children with achondroplasia: On December 21, 2020 the Company announced that children in the open-label long-term extension of the Phase 3 study of vosoritide, an investigational, once daily injection analog of C-type Natriuretic Peptide (CNP), maintained an increase in Annual Growth Velocity (AGV) through the second year of continuous treatment. An analysis, comparing all children randomized and treated with vosoritide for two years (n=52) to all children from the run-in study who were randomized to receive placebo with an untreated observation period of two years (n=38), showed improvement in one-year height change in the treated group relative to the untreated group that was similar in the second year of treatment, 1.79 cm, as in the first year of treatment, 1.73 cm. The cumulative height gain over the 2-year treatment period was 3.52 cm more than the untreated children.
In 2020, marketing applications for vosoritide were validated and accepted by EMA and FDA, respectively. The CHMP opinion is expected in Europe in June of 2021. The U.S. New Drug Application (NDA) for vosoritide is under review by the FDA with a Prescription Drug User Fee Act (PDUFA) target action date of August 20, 2021.

In January 2021, the Company received notice from FDA that the NDA for vosoritide had been granted Priority Review Designation. Under this designation, the vosoritide NDA may qualify for a Priority Review Voucher (PRV) upon approval. A PRV confers priority review to a subsequent drug application that would not otherwise qualify for that designation. The rare pediatric disease review voucher program is designed to encourage development of new drugs and biologics for the prevention or treatment of rare pediatric diseases.

Palynziq for PKU: On October 7, 2020 the Company announced that the FDA approved the supplemental Biologics License Application (sBLA) to increase the maximum allowable dose of Palynziq (pegvaliase-pqpz) Injection for treatment of adults with PKU to 60 mg daily. Previously, the maximum dose was 40 mg daily. In the Phase 3 PRISM studies, 19% of study participants required a 60 mg dose to achieve adequate response to Palynziq.
Palynziq is indicated to reduce blood Phe concentrations in adults with PKU, who have uncontrolled blood Phe concentrations greater than 600 μmol/L on existing management. Palynziq, a PEGylated recombinant phenylalanine ammonia lyase enzyme, is the first and only approved enzyme substitution therapy to target the underlying cause of PKU by helping the body to break down Phe.

BMN 307 gene therapy product candidate for PKU: The Company announced that it plans to dose escalate in PHEarless, the Phase 1/2 study of BMN 307 based on encouraging Phe lowering and safety signals observed in study participants who were treated with the lowest dose. Both the FDA and EMA granted BMN 307 Orphan Drug Status. Additionally, the FDA has granted Fast Track status to BMN 307. Product for use in the Phase 1/2 study was made at commercial scale from BioMarin’s award-winning gene therapy manufacturing facility.
BMN 331 gene therapy product candidate for Hereditary Angioedema (HAE): IND-enabling studies are ongoing with BMN 331, BioMarin’s third gene therapy candidate, for the treatment of HAE. BioMarin plans to leverage its broad expertise in developing gene therapies for severe hemophilia A and PKU to improve efficiencies in the development process of BMN 331.
DiNA-001 for MYBPC3 hypertrophic cardiomyopathy (HCM): Pre-clinical studies are underway with DiNA-001 following a collaboration announced in 2020 with DiNAQOR, a gene therapy platform company, to develop novel gene therapies to treat rare genetic cardiomyopathies. DiNAQOR received an undisclosed upfront payment and is eligible to receive development, regulatory and commercial milestones on product sales in addition to tiered royalties on worldwide sales.
BMN 255 for a subset of chronic renal disease: On January 11, 2021 the Company announced that it filed an IND in 2020 for BMN 255, a small molecule for a subset of chronic renal disease. BMN 255 was driven by genetic discoveries for both mechanism and for identifying individuals for treatment.
BMN 351 for Duchenne Muscular Dystrophy (DMD): IND-enabling studies are underway with BMN 351, an oligonucleotide therapy that has demonstrated a high-level of protein expression in experimental animals possessing skippable dystrophic mutations and at doses that are promising in regard to safety. The Company intends to determine timing of a potential IND filing at the end of the year based on results of ongoing IND-enabling studies.
BioMarin will host a conference call and webcast to discuss fourth quarter and full-year 2020 financial results today, Thursday, February 25, 2021 at 4:30 p.m. ET. This event can be accessed on the investor section of the BioMarin website at www.biomarin.com.