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MB-111 is a potential first-in-class in vivo ultracompact CRISPR therapy for Familial Chylomicronemia Syndrome and Severe Hypertriglyceridemia Dr. Brown brings deep expertise in nucleic acid drug development as Mammoth advances its lead program, MB-111, to IND-enabling stage and continues to build a leading company in genetic medicines BRISBANE, CA, USA I May 05, 2025 I Mammoth Biosciences, Inc. , a biotechnology company harnessing its proprietary next-generation CRISPR gene editing platform to create potential one-time curative therapies, today announced the nomination of its first clinical development candidate, MB-111, and the appointment of biotechnology industry veteran, Bob D. Brown, Ph.D., to its Board of Directors. MB-111 utilizes CasPhi — an ultracompact CRISPR in vivo gene editing system that is less than half the size of first-generation, Cas9-based systems — encapsulated in a lipid nanoparticle for delivery to the liver after IV administration. Share MB-111 utilizes CasPhi — an ultracompact CRISPR in vivo gene editing system that is less than half the size of first-generation, Cas9-based systems — encapsulated in a lipid nanoparticle for delivery to the liver after IV administration. MB-111 has the potential to be a first-in-class, one-time treatment for patients with very high triglycerides including familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG). MB-111 is designed to permanently disrupt the expression of the APOC3 gene in the liver, and thus to reduce expression of ApoC-III protein. ApoC-III is a critical driver of lipid metabolism and disrupting its production has been shown to reduce plasma triglycerides in patients with pathologically elevated levels, including those with FCS and SHTG. These patients suffer from recurrent episodes of acute pancreatitis, leading to frequent hospitalizations, as well as an increased risk of cardiovascular disease. Mammoth Biosciences is on track to initiate IND-enabling studies this year. “The nomination of our lead program as a development candidate is a major milestone for Mammoth and the gene editing field, as well as the first proof point of the therapeutic potential of our novel ultracompact CRISPR systems and gene editing technologies,” said Trevor Martin, Ph.D., co-founder and Chief Executive Officer of Mammoth Biosciences. “The preclinical data on MB-111 is compelling, and we’re excited about its potential to be a first-in-class genetic cure for debilitating diseases such as FCS and SHTG. We believe Dr. Brown’s extensive drug discovery and development experience, and track record of building leading companies in siRNA and antisense oligonucleotide therapeutics across rare and chronic diseases will be invaluable to our goal of increasing the number of patients who can derive benefit from Mammoth Biosciences’ genetic medicines.” Dr. Bob D. Brown brings over 30 years of experience in multidisciplinary biotechnology research and drug development, including in the US and ex-US jurisdictions. Most recently, Dr. Brown served as Chief Scientific Officer and Executive Vice President of R&D at Dicerna Pharmaceuticals, an RNAi-focused therapeutics company that was acquired by Novo Nordisk. At Novo, he served as President and Head of the Dicerna Transformation Research Unit and SVP. During his time at Dicerna, he led the discovery and early clinical development of numerous genetic medicines, including nedosiran for the treatment of primary hyperoxaluria, RG6346 for the treatment of chronic hepatitis B, belcesiran for the treatment of alpha-1 antitrypsin deficiency, and several other drug candidates now in the clinical development pipelines of large pharmaceutical companies. Prior to Dicerna, Dr. Brown held various positions at Genta, a clinical-stage antisense oligonucleotide therapeutics company, most recently as its Vice President of Research and Technology. Previously, he was a co-founder and Vice President of R&D of Oasis Biosciences, which was acquired by Gen-Probe. Dr. Brown is an inventor or co-inventor of more than 85 issued US patents, and earned a Ph.D. in molecular biology from the University of California, Berkeley and B.S. degrees in chemistry and biology from the University of Washington, Seattle. “I’m honored to join Mammoth Biosciences at such a pivotal moment, as CRISPR technology stands ready to transform healthcare and redefine the future of medicine,” said Dr. Brown. “I look forward to working with the exceptional Mammoth Biosciences team to harness the power of their groundbreaking platform to tackle some of the most pressing medical challenges and improve patients’ lives. Drawing on my experiences in drug discovery and clinical development, I aim to help advance Mammoth Biosciences’ ultracompact CRISPR gene editing therapies—starting with MB-111—toward clinical application.” About Mammoth Biosciences Mammoth Biosciences is a biotechnology company focused on leveraging its proprietary ultracompact CRISPR systems to develop potential long-term curative therapies for patients with life-threatening and debilitating diseases. Founded by CRISPR pioneer and Nobel laureate Jennifer Doudna and Trevor Martin, Janice Chen, and Lucas Harrington, the company’s ultracompact systems are designed to be more specific and enable in vivo gene editing in difficult to reach tissues utilizing both nuclease applications and new editing modalities beyond double stranded breaks, including base editing, reverse transcriptase editing, and epigenetic editing. The company is building out its wholly owned pipeline of potential in vivo gene editing therapeutics and capabilities and has partnerships with leading pharmaceutical and biotechnology companies to broaden the reach of its innovative and proprietary technology platform. Mammoth Biosciences’ deep science and industry experience, along with a robust and differentiated intellectual property portfolio, have enabled the company to further its mission to transform the lives of patients and deliver on the promise of CRISPR technologies. SOURCE: Mammoth Biosciences

iStock, PhonlamaiPhoto Beam Therapeutics and Verve Therapeutics have each built their lead candidates on a technique billed as a safer alternative to conventional CRISPR. Clinical results have so far been promising. Nine years ago this month, researchers led by Harvard University’s David Liu reported on a new gene editing technique, a variation on CRISPR/Cas9 that they dubbed base editing. Today, preliminary but encouraging results are trickling out from clinical trials on the first base editing therapies. Just last month, Beam Therapeutics announced that its candidate BEAM-302 can correct the disease-causing mutation in patients with alpha-1 antitrypsin deficiency. Weeks later, Verve Therapeutics released initial results from a Phase Ib trial showing that its VERVE-102 gene therapy reduced LDL cholesterol levels by half, on average, in four participants who received the highest dose. “I think the prospects and outlook [for base editing] look very positive right now,” Sami Corwin, an analyst at William Blair, told BioSpace . “We’ve seen it de-risked in three indications so far”—AATD, familial hypercholesterolemia and sickle cell disease (SCD). Beam owns the intellectual property behind base editing and, so far, has only licensed it to Verve, Beam President Giuseppe Ciaramella told BioSpace . But that may change: “Once you show success, I’m sure there are going to be some other companies that are going to be trying to use base editing to essentially do their own product,” he said. Base Editing Basics With CRISPR/Cas9 gene editing, researchers construct a guide RNA (gRNA) complementary to a targeted stretch of DNA. The gRNA is tethered to a Cas9 enzyme that snips a double-stranded break at the target, which is then repaired by the cell’s own machinery. It’s a process that carries risks, including that off-target breaks could be created and that breaks may not be properly repaired, creating unwanted mutations. “The problem is that [with] all of the nucleases, the only thing that they could do when they landed on the spot of DNA was making a double-stranded break, and . . . basically everything else is now left to the cell to sort out,” Ciaramella said. Double-stranded breaks “need to occur only under very controlled conditions when the cells are replicating because otherwise they can lead to all sorts of unpredictable editing outcomes.” The only CRISPR/Cas9-based therapy approved so far, Vertex and CRISPR Therapeutics’ Casgevy, relies on extracting bone marrow cells from a patient with SCD and editing them outside the body to disable a gene that suppresses production of fetal hemoglobin. The cells are then expanded and transplanted back into the patient, where they produce red blood cells with fetal hemoglobin as a stand-in for the adult hemoglobin that’s mutated in the disease. Casgevy is also approved for transfusion-dependent beta thalassemia. Base editing, like the original CRISPR/Cas9, uses a gRNA. However, it leverages a modified Cas9 that, rather than creating a double-strand break in the DNA, can chemically change an adenosine (A) base to a guanine (G) or a cytosine (C) to a thymine (T). Researchers can target either the coding DNA strand or its complementary partner for these edits, Ciaramella noted, which opens up more possibilities. “Essentially, we can achieve four edits with the two base editors that we’ve got.” Base editing is “actually much more versatile than maybe even people anticipated at the beginning,” when it was viewed mainly as a way to correct point mutations, Ciaramella added. For example, by making a change in the regulatory rather than the coding region of a gene, researchers can activate that gene. Beam: Running the Gamut After his group devised base editing, Liu and CRISPR pioneer Feng Zhang co-founded Beam specifically to develop therapeutics based on the technique. The company emerged from stealth in 2018 with $87 million in series A funding. The company has not confined itself to particular kinds of disorders or means of delivery. It has both in vivo and ex vivo programs for SCD and beta thalassemia alongside in vivo programs in alpha-1 antitrypsin deficiency (AATD) and glycogen storage disease 1a (GSD1a). Beam also has collaborations with Apellis and Pfizer, about which it’s revealed little. The candidate at the center of Beam’s March 10 announcement , BEAM-302, corrects a mutation that causes the body to produce a form of the AAT protein known as Z-AAT rather than the functional form, M-AAT. Z-AAT has deleterious effects on both the lungs and liver. BEAM-302 delivers base editing machinery to the liver, where AAT is made, via lipid nanoparticles. At sites in Australia, New Zealand, the Netherlands and the U.K., the company tested single intravenous doses of 15 mg, 30 mg and 60 mg in three-patient cohorts and found dose-dependent, durable increases in total AAT and decreases in Z-AAT, along with only minor adverse events. Total circulating AAT levels were high enough in the highest-dose group that those patients can be considered to no longer have progressive disease, Ciaramella said. He added, however, that these were only interim results and that the company is testing higher doses and considering redosing some patients. The AATD data “confirmed that the sensitivity and efficacy of the base editing technology was there,” Corwin said. Since the treatment was well-tolerated even at higher doses, the readout also suggested that an inflammatory response to another base editing candidate reported earlier by Verve was due to the lipid nanoparticle vehicle rather than the base editing machinery itself, she added. Other analysts also took note. Jefferies’ Michael Yee said in a note to investors that “safety has been a major area of focus in the context of issues from other LNP products for gene editing,” but that “BEAM safety looks clean.” He added that BEAM-302 “looks to have important benefits that differentiate from RNA editing and plasma-derived AAT therapy. . . . [W]e are seeing ‘correction’ of the disease with a one-time therapy.” With another program, Beam is seeking to set itself apart in the sickle cell disease space. Both bone marrow transplants and Casgevy treatment require patients to undergo a course of the chemotherapy drug busulfan to open up space in the marrow for the new blood-making cells that will be introduced. The treatment has side effects, including the possibility of impaired fertility. Beam’s ex vivo SCD candidate, BEAM-101, edits cells so that not only is fetal hemoglobin production switched on, but a receptor is tweaked to confer resistance to an antibody Beam devised. Rather than busulfan, patients are treated with the antibody, which starves unedited bone marrow cells of a growth factor needed to proliferate. “We can confer advantages of survival to the edited cells over unedited cells simply by changing a single amino acid in this receptor,” Ciaramella said. Beam presented positive safety and efficacy data on the first seven patients treated with BEAM-101 in a U.S.-based study at the American Society of Hematology meeting in December. Verve: A Focus on the Heart Boston-based Verve’s origin story begins with a competition entry that wasn’t selected, said CEO and co-founder Sek Kathiresan. The 2016 contest, run by the American Heart Association, promised $75 million in funding for an idea to tackle coronary heart disease. Kathiresan, then a professor at Harvard Medical School and director of Massachusetts General Hospital’s Center for Genomic Medicine, said he took inspiration from natural mutations that keep cholesterol levels low and thus protect people carrying the mutations from developing heart disease. Kathiresan wanted to develop a therapy that mimicked natural protective mutations. “The proposal was really: well, we understand what causes disease, which is cholesterol. We know a key way to stop this disease, which is to get cholesterol down and keep it down for a long time,” he told BioSpace . When the application was turned down, he forged ahead anyway, gathering the investors and initial team needed to found Verve in 2018. The company tested both base editing and traditional CRISPR/Cas9 on target genes in preclinical research, and “what ultimately led us to choose base editing was the possibility of it being a fair bit safer because it did not cut DNA in both strands, but rather just tried to make the single spelling change A to G at one spot,” he said. The editing was also precise: “we’re not really seeing any off targets elsewhere in the genome.” But for another of its programs, Verve settled on a different gene editor because it found base editing wasn’t the most effective way forward. The company now has three base editors in clinical trials, although the trial of VERVE-101 was paused last April after one patient developed grade 3 drug-induced thrombocytopenia within days of dosing. Verve, like Corwin, has since attributed those abnormalities to the lipid nanoparticle vector. Verve said at the time that it would instead prioritize VERVE-102, which like VERVE-101 treats heterozygous familial hypercholesterolemia, a genetic propensity to high cholesterol. VERVE-102 uses a different lipid nanoparticle from VERVE-101 that targets the PCSK9 gene for inactivation in liver cells. Last month, Verve announced IND clearance for VERVE-102 based on initial clinical data from outside the U.S. showing the therapy was well-tolerated. In its April 14 press release , the company reported a dose-dependent response and no serious adverse events in a Phase Ib trial, with a maximum LDL cholesterol reduction of 69% in the highest-dose cohort. Verve is now testing a still-higher dose and plans to begin a Phase II trial in the second half of this year, per its announcement. Meanwhile, VERVE-201, which targets the ANGPTL3 gene in liver cells, is in trials for the homozygous version of the condition as well as for patients whose hypercholesterolemia is not responding to other therapies. The first patient was dosed with VERVE-201 in a Phase Ib trial in Canada and the U.K. in November 2024. Getting this far has required breaking new ground in a few ways, Kathiresan said, from devising the mRNA and gRNA that would go into treatments to interfacing with the FDA. “We were actually the first to go in front of the U.S. FDA and propose in vivo gene editing in humans,” he notes, as other companies in the space have so far run their early trials in other countries, just as Verve did for VERVE-102. Gene editing and other gene therapies are usually associated with rare disease, often those with no other effective treatments. High cholesterol is both common and treatable, but Kathiresan argued gene editing could nonetheless fill an important unmet need. “Theoretically, current medicines can lower LDL at a single time point [by] 40, 50, 60%. . . . But the challenge is discontinuation. A year out after starting any cardiovascular medication, a third to 50% of people have discontinued,” he said. In contrast, with base editing, “you basically lower LDL and then keep it low for your whole life. And that can really have a dramatic impact on your risk for heart attack.” Ultimately, though, Kathiresan characterized base editing not as a silver bullet but as one tool companies can consider. “I think base editing will have a place. . . . But there will be other technologies as well that I think may be even better suited for a given target,” he said. “So I think right now the focus is really on the targets and the disease indications, and then, at least for us, finding the right gene editing tool for that target.”

First Quarter 2025 Total Revenues of $745 million (+15% Y/Y and +17% at Constant Currency Y/Y) First Quarter 2025 GAAP Diluted Earnings Per Share (EPS) of $0.95 (+107% Y/Y) First Quarter 2025 Non-GAAP Diluted EPS of $1.13 (+59% Y/Y) Conference Call and Webcast Scheduled Today at 4:30 p.m. ET SAN RAFAEL, Calif., May 1, 2025 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced financial results for the first quarter ended March 31, 2025. "During the first quarter, we saw continued high demand for our innovative medicines resulting in strong revenue growth and profitability," said Alexander Hardy, President and Chief Executive Officer of BioMarin. "Products in our pipeline also advanced according to plan. In April, we shared positive top-line results from the Phase 3 PALYNZIQ® study for the treatment of adolescents with phenylketonuria between the ages of 12 and 17. Also in April, we were pleased to conclude enrollment in the pivotal study in hypochondroplasia with VOXZOGO, keeping us on track to launch in 2027, should data be supportive." Mr. Hardy continued, "For the remainder of 2025, we look forward to continued momentum in our global expansion of VOXZOGO® for achondroplasia. Across our Enzyme Therapies, we plan to build upon strong PALYNZIQ performance in the quarter, as well as initiatives to drive uptake of our other therapies to reach an even greater number of patients around the world. In addition to our strong financial outlook, we expect to advance multiple new indications with VOXZOGO in our CANOPY clinical program, share early clinical results from both BMN 351 for Duchenne Muscular dystrophy and BMN 333, our long-acting C-type natriuretic peptide, as well as execute on our business development strategy. We are delivering strong growth and profitability while we continue to implement BioMarin's new strategy and operating model. We look forward to seeing the benefits of this transformation flow through our results in the coming quarters and beyond." First Quarter 2025 Financial Highlights Total Revenues for the first quarter of 2025 were $745 million, an increase of 15% compared to the same period in 2024, driven by strong 40% year-over-year VOXZOGO revenue growth from new patients initiating therapy across all regions. In the quarter, revenues from BioMarin's Enzyme Therapies (ALDURAZYME®, BRINEURA®, NAGLAZYME®, PALYNZIQ and VIMIZIM®) increased 8% compared to the first quarter of 2024, driven by a combination of increased patient demand and the timing of large government orders in all regions. The increase was partially offset by lower KUVAN® product revenues attributed to continued generic competition as a result of the loss of market exclusivity. GAAP Net Incom e increased by $97 million to $186 million in the first quarter of 2025 compared to the same period in 2024, an increase of 109%, primarily attributed to higher gross profit driven by the factors noted above. The increase was also attributed to lower operating expenses following the termination of certain early stage development programs following the company's 2024 strategic portfolio review and focused ROCTAVIAN strategy announced in the second half of 2024. These increases were partially offset by higher tax provision primarily due to increase in taxable income. Non-GAAP Income increased by $81 million to $221 million in the first quarter of 2025 compared to the same period in 2024, representing 58% growth. The increase in Non-GAAP Income was primarily due to the factors noted above. First Quarter 2025 Business Highlights Innovation Skeletal Conditions: In March 2025, BioMarin presented new data demonstrating favorable safety and strong adherence in real-world clinical practice with VOXZOGO in children with achondroplasia under the age of 3 years old at the 2025 American College of Medical Genetics and Genomics (ACMG) Annual Meeting. No treatment-related adverse events nor any dose interruptions were reported among 63 children followed for up to 23.7 months. These real-world findings further validate VOXZOGO's established safety profile and reinforce the therapeutic benefit seen in clinical studies. The study's safety results, including in infants as young as 1 month old, add to the growing body of evidence supporting early treatment initiation with VOXZOGO, consistent with new international treatment guidelines published in the journal Nature Reviews Endocrinology earlier this year. In April 2025, BioMarin completed enrollment in its pivotal Phase 3 study with VOXZOGO in hypochondroplasia and the company is on track to share topline data in 2026, with a potential launch in 2027. BioMarin plans to leverage its multiyear track record treating children with achondroplasia, a related condition, to raise awareness and treat children with hypochondroplasia across the globe. The CANOPY clinical program is continuing to advance VOXZOGO in additional new indications, including idiopathic short stature, Noonan syndrome, Turner syndrome, and SHOX deficiency. With BMN 333, BioMarin's long-acting C-type natriuretic peptide (CNP), the company enrolled multiple cohorts of healthy volunteers in its first-in-human study, with initial pharmacokinetic (PK) data expected by year-end. Detailed data from this study is expected to be presented at a scientific forum in the first half of 2026. Pre-clinical data with BMN 333 demonstrated sustained 100 pM concentrations for free CNP, representing an approximate 2-3 fold increase versus published data in an analogous pre-clinical model for other long-acting CNP analogs. Additionally, BioMarin recently met with FDA and reached agreement on an overall clinical development plan for BMN 333 in achondroplasia. Assuming the Phase 1 data are supportive, the company plans to initiate a registration-enabling study in 2026, supporting a previously disclosed target for 2030 approval. BioMarin plans to seek similar agreements with additional global regulators in the coming months. The company announced in April that its pivotal study with PALYNZIQ for the treatment of adolescents between the ages of 12 and 17 met its primary efficacy endpoint, demonstrating a statistically significant lowering in blood Phe levels. These data will support the planned submission of applications in the second half of 2025 to expand PALYNZIQ age eligibility in the United States and Europe. Other Clinical Pipeline Programs: BMN 351, BioMarin's next generation oligonucleotide for Duchenne Muscular Dystrophy, and BMN 349, an oral therapeutic for Alpha-1 antitrypsin deficiency (AATD)-associated liver disease, continue to advance. Initial data for BMN 351 is anticipated to be presented at a scientific congress in the second half of 2025 (including muscle dystrophin levels from the 6 mg/kg cohort after 25 weeks of dosing). During a recent strategic portfolio assessment of R&D programs, BioMarin determined that the evolving profile for BMN 370, a pre-clinical candidate for the treatment of von Willebrand disease, did not meet its threshold for further development and commercialization. The program has been discontinued and impacted employees have been redeployed within BioMarin. Growth Total VOXZOGO revenue in the first quarter increased 40% compared to the same period in 2024, representing continued strong global demand since its commercial launch in 2021. As of the end of the quarter, children with achondroplasia in 49 countries around the world were being treated with VOXZOGO. In the U.S., BioMarin is investing in focused initiatives to drive continued expansion. These efforts include increasing field personnel to broaden the prescriber base and adding awareness platforms to drive adoption of VOXZOGO treatment. This is expected to begin increasing the rate of U.S. expansion in the second half of the year. Outside of the U.S. (OUS), from where the majority of VOXZOGO revenue is generated, uneven ordering patterns, consistent with BioMarin's other brands, were observed. This OUS dynamic is expected to result in VOXZOGO full-year revenues being more weighted towards the second half of 2025. Enzyme Therapies revenues grew 8% in the first quarter Y/Y, driven by strong continued demand for PALYNZIQ. Strong PALYNZIQ performance as well as solid growth from BioMarin's other enzyme treatments are expected to continue throughout 2025. Value Commitment In the first quarter of 2025, BioMarin delivered strong results across the business. Total revenues for the first quarter grew 15% Y/Y. First quarter GAAP Operating Margin of 30.0% expanded 16.4 percentage points Y/Y while GAAP Diluted EPS of $0.95 increased 107% Y/Y. First quarter Non-GAAP Operating Margin of 35.7% expanded 11.9 percentage points Y/Y while Non-GAAP Diluted EPS of $1.13 increased 59% Y/Y. These measures of profitability increased at rates faster than revenue growth, representing the company's focus on operational efficiency. During the quarter, BioMarin continued to realize the benefits of cost transformation initiatives implemented in 2024, resulting in a decrease in GAAP and Non-GAAP R&D and SG&A expenses Y/Y. Throughout the remainder of 2025, BioMarin expects to increase investments in VOXZOGO indication expansion, clinical pipeline development, and commercialization initiatives supporting the company's Skeletal Conditions and Enzyme Therapies business units. The company generated operating cash flows totaling $174 million in first quarter 2025, an increase of 271% compared to first quarter 2024. Total cash and investments at the end of the first quarter were approximately $1.8 billion, and with anticipated increasing profitability, BioMarin is positioned to generate increasing operating cash flow into the future. Today, the company reaffirmed its previously communicated 2025 full-year financial guidance, which reflects the impact of tariffs that have already been enacted but does not reflect the impact of potential future pharmaceutical tariffs. BioMarin has immaterial exposure to U.S. tariffs for China, Mexico and Canada across its global supply chain operations and product sales. Forward-Looking Non-GAAP Financial Information BioMarin does not provide guidance for GAAP reported financial measures (other than revenue) or a reconciliation of forward-looking Non-GAAP financial measures to the most directly comparable GAAP reported financial measures because the company is unable to predict with reasonable certainty the financial impact of changes resulting from its strategic portfolio and business operating model reviews; potential future asset impairments; gains and losses on investments; and other unusual gains and losses without unreasonable effort. These items are uncertain, depend on various factors, and could have a material impact on GAAP reported results for the guidance period. As such, any reconciliations provided would imply a degree of precision that could be confusing or misleading to investors. 2025 Full-Year Financial Guidance (in millions, except % and EPS amounts) BioMarin will host a conference call and webcast to discuss first quarter 2025 financial results today, Thursday, May 1, 2025, at 4:30 p.m. ET. This event can be accessed through this link or on the investor section of the BioMarin website at . About BioMarin BioMarin is a global biotechnology company dedicated to translating the promise of genetic discovery into medicines that make a profound impact on the life of each patient. The San Rafael, California-based company, founded in 1997, has a proven track record of innovation with eight commercial therapies and a strong clinical and preclinical pipeline. Using a distinctive approach to drug discovery and development, BioMarin pursues treatments that offer new possibilities for patients and families around the world navigating rare or difficult to treat genetic conditions. To learn more, please visit .  Forward-Looking Statements This press release and the associated conference call and webcast contain forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including, without limitation, statements about: future financial performance, including the expectations of Total Revenues, Non-GAAP Operating Margin percentage, Non-GAAP Diluted EPS and Operating Cash Flow for, in certain instances, the full-year 2025 and future periods, as well as profitability growth in 2025, and the underlying drivers of those results, such as the revenue opportunity represented by treatments for Skeletal Conditions, namely VOXZOGO, the expected demand and continued growth of BioMarin's Enzyme Therapies portfolio, including PALYNZIQ, and the expectation regarding the full realization of the benefits of BioMarin's cost transformation program; plans regarding BioMarin's revamped corporate strategy and operating model in 2025 and beyond, including expected growth in the Skeletal Conditions business unit and execution of BioMarin's business development strategy, and its anticipated benefits; the timing of orders for commercial products; BioMarin's ability to meet product demand; the timing of BioMarin's clinical development and commercial prospects, including announcements of data from clinical studies and trials; the clinical development and commercialization of BioMarin's product candidates and commercial products, including (i) expected advancements of pipeline candidates, including BMN 333, BMN 349 and BMN 351, the anticipated initial data read-out for BMN 351 in the second half of 2025, the expected data and data presentation for BMN 333 in the first half of 2026 and plans to initiate a registration-enabling study for BMN 333 in 2026, as well as plans to seek similar agreements with additional global regulators in the coming months; (ii) plans to submit applications to expand PALYNZIQ age eligibility for the treatment of adolescents with phenylketonuria between the ages of 12 and 17 in the U.S. and Europe in the second half of 2025; (iii) expected topline data from the pivotal study in hypochondroplasia in 2026 and launch in 2027; (iv) the expectations regarding global expansion of VOXZOGO for achondroplasia and expected increase in the rate of U.S. expansion in the second half of 2025; (v) plans to advance five new VOXZOGO indications with BioMarin's CANOPY clinical program; and (vi) plans to reach greater number of patients around the world across BioMarin's Enzyme Therapies; the expected benefits and availability of BioMarin's commercial products and product candidates; and potential growth opportunities and trends. 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: BioMarin's success in the commercialization of its commercial products; impacts of macroeconomic and other external factors on BioMarin's operations, such as trade wars and potential future pharmaceutical tariffs; results and timing of current and planned preclinical studies and clinical trials and the release of data from those trials; BioMarin's ability to successfully manufacture its commercial products and product candidates; the content and timing of decisions by the U.S. Food and Drug Administration, the European Commission and other regulatory authorities concerning each of the described products and product candidates; the market for each of these products; actual sales of BioMarin's commercial products; 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 Annual Report on Form 10-K for the fiscal year ended December 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®, BRINEURA®, KUVAN®, NAGLAZYME®, PALYNZIQ®, ROCTAVIAN®, VIMIZIM® and VOXZOGO® are registered trademarks of BioMarin Pharmaceutical Inc., or its affiliates. ALDURAZYME® is a registered trademark of BioMarin/Genzyme LLC. All other brand names and service marks, trademarks and other trade names appearing in this release are the property of their respective owners. Non-GAAP Information The results presented in this press release include both GAAP information and Non-GAAP information. Non-GAAP Income is defined by the company as GAAP Net Income excluding amortization of intangible assets, stock-based compensation expense and, in certain periods, certain other specified items, as detailed below when applicable. The company also includes a Non-GAAP adjustment for the estimated tax impact of the reconciling items. Non-GAAP R&D expenses and Non-GAAP SG&A expenses are defined by the company as GAAP R&D expenses and GAAP SG&A expenses, respectively, excluding stock-based compensation expense and, in certain periods, certain other specified items, as detailed below when applicable. Non-GAAP Operating Margin percentage is defined by the company as GAAP Income from Operations, excluding amortization of intangible assets, stock-based compensation expense and, in certain periods, certain other specified items, divided by GAAP Total Revenues. Non-GAAP Diluted EPS is defined by the company as Non-GAAP Income divided by Non-GAAP Weighted-Average Diluted Shares Outstanding. Non-GAAP Weighted-Average Diluted Shares Outstanding is defined by the company as GAAP Weighted-Average Diluted Shares Outstanding, adjusted to include any common shares issuable under the company's equity plans and convertible debt in periods when they are dilutive under Non-GAAP. The company's presentation of percentage changes in total revenues at Constant Currency rates, which is computed using current period local currency sales at the prior period's foreign exchange rates, is also a Non-GAAP financial measure. This measure provides information about growth (or declines) in the company's total revenue as if foreign currency exchange rates had not changed between the prior period and the current period. BioMarin regularly uses both GAAP and Non-GAAP results and expectations internally to assess its financial operating performance and evaluate key business decisions related to its principal business activities: the discovery, development, manufacture, marketing and sale of innovative biologic therapies. Because Non-GAAP Income, Non-GAAP R&D expenses, Non-GAAP SG&A expenses, Non-GAAP Operating Margin percentage, Non-GAAP Diluted EPS, Non-GAAP Weighted-Average Diluted Shares Outstanding and Constant Currency are important internal measurements for BioMarin, the company believes that providing this information in conjunction with BioMarin's GAAP information enhances investors' and analysts' ability to meaningfully compare the company's results from period to period and to its forward-looking guidance, and to identify operating trends in the company's principal business. BioMarin also uses Non-GAAP Income internally to understand, manage and evaluate its business and to make operating decisions, and compensation of executives is based in part on this measure. Non-GAAP financial measures are not meant to be considered in isolation or as a substitute for, or superior to comparable GAAP measures and should be read in conjunction with the consolidated financial information prepared in accordance with GAAP. Investors should note that the Non-GAAP information is not prepared under any comprehensive set of accounting rules or principles and does not reflect all of the amounts associated with the company's results of operations as determined in accordance with GAAP. Investors should also note that these Non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time to time in the future there may be other items that the company may exclude for purposes of its Non-GAAP financial measures; likewise, the company may in the future cease to exclude items that it has historically excluded for purposes of its Non-GAAP financial measures. Because of the non-standardized definitions, the Non-GAAP financial measure as used by BioMarin in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by other companies. The following tables present the reconciliation of GAAP reported to Non-GAAP adjusted financial information: SOURCE BioMarin Pharmaceutical Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED