拜玛林 (BMRN) 2026财年第三季度业绩电话会议：营收突破10亿美元，更新业绩指引

BioMarin Pharmaceutical Inc. (BMRN) 在2026年第三季度季度营收首次突破10亿美元，同比增长32%。代谢疾病产品组合的扩展推动了这一增长，而订单交货时机以及中东局势扰动促使管理层更新了全年业绩指引。

核心要点

• 2026年第三季度营收突破10亿美元，同比增长32%，标志着 BioMarin 首次实现单季度营收突破十亿美元大关。
• 在收购 Amicus 后，受益于 GALAFOLD 以及 POMBILITI 和 OPFOLDA 的首个完整季度贡献，代谢疾病业务营收增长44%至7.44亿美元。
• VOXZOGO 营收增长12%至2.45亿美元，全球接受治疗的儿童患者数量增长了约17%。
• BioMarin 将2026年营收指引更新为38亿美元至39亿美元，这主要反映了约7000万美元延期的国际订单以及与中东冲突相关的扰动。
• 全年非GAAP稀释每股收益指引调整为2.80美元至3.10美元，其中包含了对 Alesta 的收购、BMN 450 许可协议以及更新后的营收指引影响。
• FDA 已为 VOXZOGO 用于治疗软骨发育不良指定了2027年5月30日的 PDUFA 目标日期。管理层估计全球潜在目标患儿群体约为14,000人。

核心财务数据

业务与运营表现

GALAFOLD 患者数量同比增长约13%，在成熟市场和新兴市场均实现增长。BioMarin 正专注于诊断、开始治疗以及深耕现有市场。

POMBILITI 和 OPFOLDA 患者数量增加了约69%，同时营收增长了58%。管理层将换药归因于该疗法的临床疗效优势和不断扩大的循证证据。影响其他庞贝病疗法的供应瓶颈，也在某些欧洲市场的新起始治疗中占据了相当大的比例。BioMarin 预计相关营收贡献将在2027年及以后进一步建立，但竞品供应问题的持续时间和财务影响仍存在不确定性。

VOXZOGO 接受治疗的患者数量增长了约17%，超过了12%的营收增幅，这是因为预计在第三季度交货的一笔大型国际订单顺延到了第四季度。VOXZOGO 季度营收的75%以上来自美国以外地区，且该产品近期又在三个国际市场获得了用于治疗软骨发育不全的批准。

BioMarin 表示，根据换药数据，截至9月底，约85%的美国患儿仍坚持使用 VOXZOGO。两岁以下儿童占美国新起始治疗患者的大多数。管理层预计 VOXZOGO 的营收将在2027年继续增长，这得益于国际市场的拓展以及潜在的软骨发育不良适应症上市，但部分增幅会被现有及潜在的竞争所抵消。

在代谢疾病领域的其他产品方面，PALYNZIQ 的患者数量增长了9%，营收增长了2%。受益于美国以外市场的订单，VIMIZIM 的营收增长了18%，而 NAGLAZYME 的营收在第二季度迎来有利的订单交货时机后有所下滑。

研发管线最新进展

BMN 450 是一款用于治疗法布雷病的在研 I/II 期长效酶替代疗法（ERT）。BioMarin 表示，它有可能成为该适应症中首个皮下注射 ERT，并可能惠及基因突变不适用 GALAFOLD 的患者。该资产已获得 FDA 的孤儿药资格认定。

通过收购 Alesta 获得的 BMN 440 是一款口服 ENPP1 抑制剂，目前正在健康志愿者和低磷酸酯酶症成年患者中进行 I/IIa 期研究。BioMarin 预计将于2027年获得包含药代动力学、药效学、安全性及初步机制验证的数据。

对于 BMN 333，II/III 期项目正在进行的 II 期部分测试了三种剂量，并将评估至少六个月后相比于 VOXZOGO 的年化身高增长速度。管理层的首要目标是支持一项优效性研究。如果未达到初始设想，公司可能会考虑非劣效性或更低给药频率的方案，但公司表示，其价值主张必须超越单纯的便利性。

POMBILITI 与 OPFOLDA 为期五年的 PROPEL 扩展研究数据显示，在晚发型庞贝病成年患者中，运动功能得以维持，肺功能相对稳定。未发现新的安全性信号。

管理层指引

管理层表示，营收指引的修改反映的是时间差问题，而非潜在的患者需求变动。一家国际客户表示计划延期总计约7000万美元的多笔订单。BioMarin 预计将在2026年第四季度末至2027年第一季度之间完成其中大部分订单，但确切时间仍存在不确定性。

每股收益指引还纳入了2026年与 Alesta 相关的约3.20亿美元已收购研发中费用及后续费用，以及与 BMN 450 相关的约8300万美元（主要为预付款项类的已收购研发中费用和运营费用）。

Amicus 的整合协同效应进展超预期。BioMarin 目前预计该交易将在完成交割后的九个月内实现每股收益增厚，并表示有望在2026自然年度实现增厚，同时维持2028年约2.20亿美元的协同效应目标不变。

风险与关注焦点

• 国际采购模式可能会导致大额订单在不同季度之间发生移动，从而在患者需求稳定的情况下造成营收波动。
• 过去两个月，中东冲突加剧了客户的流动性和现金流扰动。
• 影响庞贝病竞争疗法的供应限制持续多久，以及其对 POMBILITI 和 OPFOLDA 需求的持久影响仍不确定。
• VOXZOGO 在软骨发育不全领域面临着现有和潜在的新竞争，包括随着更多疗法进入市场而可能导致的份额流失。
• BMN 333 必须确立剂量-反应曲线的形态，并证明更高的游离 CNP 暴露量能够带来显著的生长优势。
• BMN 440 和 BMN 450 仍处于早期临床开发阶段，未来的进展取决于安全性、药理学及疗效数据。

分析师问答要点

管理层表示，BioMarin 仍专注于与其在遗传学、监管、生产和商业化方面的能力相契合的临床阶段业务拓展。骨骼和代谢疾病仍是重点领域，不过公司也可能会考虑其他遗传性疾病。

关于 POMBILITI 和 OPFOLDA，管理层强调长期增长应来源于临床证据、患教与医教、从既往疗法转药以及全球市场拓展。青少年市场的机会被描述为一个催化剂，但与更广泛的商业化机会相比规模相对较小。

关于 VOXZOGO，管理层重申预计其将在2027年实现增长。国际拓展、两岁以下适宜人群标签的扩展以及潜在的软骨发育不良适应症上市有望对业绩形成支撑，而竞争可能会抵消部分增长。

对于 BMN 333，管理层表示 II 期分析将结合年化身高增长速度数据与暴露-反应模型。测试的三种剂量预计将使游离 CNP 暴露量分别增加约3倍、5倍和7倍，使研究能够评估反应曲线是否会达到平台期以及在何处达到平台期。

业绩电话会议完整文字记录

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完整财报电话会议逐字稿

管理层陈述

Operator

Hello, everyone. Thank you for joining us, and welcome to the BioMarin Third Quarter 2026 Conference Call. After today's prepared remarks, we will host a question-and-answer session. [Operator Instructions]

I will now hand the call over to BioMarin's Head of Investor Relations, Traci McCarty. Please go ahead.

Traci McCarty

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, Chief Executive Officer; Cristin Hubbard, Chief Commercial Officer; Greg Friberg, Chief R&D Officer; and Brian Mueller, Chief Financial Officer. I will now turn the call over to Alexander to provide our quarterly highlights. Alexander?

Alexander Hardy

Thank you, Traci, and thank you all for joining us today. Starting on Slide 5. Strong demand across our diversified portfolio of innovative therapies drove 32% year-over-year growth in the third quarter, surpassing $1 billion in quarterly revenues for the first time in our history. Also last week, we announced the addition of a new investigational Fabry asset to our clinical portfolio, recently renamed BMN 450, the fourth new asset added to our pipeline in 2026. This highlights the focused and deliberate expansion of BioMarin's clinical stage pipeline, BMN 450 has the potential to become the first subcutaneous enzyme therapy to treat people with Fabry and I will provide more detail in a moment.

Moving to our third quarter results. The metabolic conditions business delivered revenue growth of 44% compared to the third quarter of last year, driven by strong contributions from both GALAFOLD, POMBILITI and OPFOLDA. Together, they totaled more than $200 million in combined revenues in the quarter, while at the same time, the pace of Amicus cost synergies realization exceeded our expectations. We are energized by the addition of our Amicus colleagues, and we're working together to expand the reach of both GALAFOLD and POMBILITI and OPFOLDA, of bringing these therapies to more patients around the world. I am also pleased with the continued global expansion of VOXZOGO as the number of children treated increased by 17% worldwide.

Building on this momentum, we are pleased to share that May 30, 2027 is the PDUFA date for VOXZOGO for the treatment of hypochondroplasia, the first targeted therapy to potentially be approved for the indication and a potential seventh first in disease medicine for BioMarin. The team is well prepared for strong launches in hypochondroplasia in the U.S. and Europe, and we anticipate both regions will benefit from our global leadership in skeletal conditions. Before I turn the call over to Cristin, I want to say a few words about the work we are doing to expand our pipeline, including the most recent addition to our clinical portfolio.

BMN 450 is a Phase I/II compound that builds on our GALAFOLD experience and has the potential to expand the therapeutic reach to those with Fabry whose variants are not amenable with GALAFOLD. BMN 450 is a strategically compelling addition to our metabolic conditions BU, addressing treatment burden and a priority unmet need with a differentiated long-acting subcutaneous profile. It also reflects our growing commitment to the Fabry community, building on the Amicus acquisition as well as the expertise and relationships established with GALAFOLD.

In summary, we delivered strong financial results in the third quarter and made meaningful progress across every part of our business. In a moment, Brian will speak to some expected order timing dynamics and geopolitical headwinds that we are observing, resulting in today's updated guidance. In 2026, we have delivered on the strategic expansion of our innovative pipeline, including the addition of BMN 450, BMN 440 for hypophosphatasia, BMN 430 for a new syndrome and BMN 820 for FSGS. Our business development execution having delivered 5 deals in 2 years, demonstrates our capabilities across the value chain as a rare disease leader operating at scale.

Our commercial portfolio is now more diversified and more resilient following the successful acquisition of Amicus as well as our pipeline with the more recently acquired earlier stage assets. We look ahead with enthusiasm for what's to come as we advance the next wave of therapies from our clinical stage pipeline and to reporting on a number of key updates in 2027. Combined with the strength of our more diversified commercial portfolio, we are confident in our ability to create lasting value for patients and all of our stakeholders, and we look forward to updating you on our progress. I will now turn the call over to Cristin for more detail on our commercial performance. Cristin?

Cristin Hubbard

Thank you, Alexander. The third quarter again showed the strength and growing diversity of our portfolio. Our team stayed focused on expanding diagnosis, increasing access and helping more patients start and stay on therapy. Now turning to Slide 7. We have begun to implement the initiatives that we outlined last quarter for GALAFOLD and POMBILITI and OPFOLDA. For GALAFOLD, those levers are expanding diagnosis and treatment and deepening market penetration globally. For POMBILITI and OPFOLDA, there are increased patient switching and global market expansion complemented by improvements in diagnosis and treatment. New geographies take time. So this quarter, we focused on the fastest levers, finding and treating more patients in existing markets.

We are pleased with the progress we've made in a short amount of time. Both medicines delivered strong revenue in the quarter. GALAFOLD was $152 million, 10% higher than the $138 million Amicus reported for the third quarter of 2025. POMBILITI and OPFOLDA revenue was $49 million, 58% higher than the $31 million Amicus reported for the same period last year. The number of patients treated with GALAFOLD increased by approximately 13% year-over-year, with growth across both established and newer markets. For example, in the quarter, 1 international market increased patients on therapy by 20% year-over-year, reflecting the ongoing success of Family Cascades testing initiatives bolstered by expanding newborn screening programs.

The number of patients on POMBILITI and OPFOLDA increased by approximately 69% year-over-year. Switching continues to be supported by its differentiated clinical profile as we help physicians better identify disease progression on prior therapies. The expanding body of clinical and real-world evidence reinforces that profile including the 5-year PROPEL extension data presented at the World Muscle Society Congress in October, which Greg will speak to in a moment. We are also seeing an increasing penetration in Europe, where POMBILITI and OPFOLDA is now the market share leader in terms of patients on therapy in 4 markets. This leadership reflects the growing confidence in the profile of POMBILITI and OPFOLDA.

In the third quarter, we also began supporting patients in certain European markets who are affected by recent supply constraints for other Pompe therapies. We have released additional supply so that patients who need it can get treatment without interruption. As a result, patients who switched to POMBILITI and OPFOLDA during the quarter due to supply constraints represented a meaningful share of new patient starts in these markets. We would expect to see some additional patients in the fourth quarter due to supply constraints for the other Pompe therapies, with the revenue benefit from this dynamic building in 2027 and beyond.

Now we can't predict how long the constraints for other Pompe therapies will last where if it will result in material revenue increases from POMBILITI and OPFOLDA, but reliable supply from BioMarin could become a factor in treatment choice. Now turning to Slide 8. Total metabolic conditions revenue was $744 million and grew 44% year-over-year, driven largely by the first full quarter of GALAFOLD and POMBILITI and OPFOLDA. The number of patients on therapy grew across every one of our marketed metabolic conditions brands. Moving to the other products and metabolic conditions. The quarter reflected continued patient demand, along with the order timing patterns we have consistently described. Reflecting Palynziq's distinct product profile, patients on therapy increased 9% year-over-year globally, led by the adolescent launch in the U.S., and we observed minimal switching to Beach for analogs.

In fact, we've been pleased that some patients who switched to oral therapies have returned to PALYNZIQ treatment. Revenue grew 2% as the U.S. order timing normalized after a strong second quarter. It can take many months for a patient to titrate to a maintenance dose so we expect the adolescent revenue contribution to build into 2027 and beyond. Vimizim grew 18% year-over-year, benefiting from orders outside of the U.S. while Naglazyme revenue was lower as expected, following order timing benefits in the second quarter. Because order timing shifts between quarters, our full year metabolic conditions guidance is the best indicator of expected underlying performance.

Turning to Slide 9. In the third quarter, VOXZOGO revenue grew 12% year-over-year to $245 million despite a large order previously expected in Q3 now anticipated in Q4. Patient demand outpaced revenue in Q3 as the number of children treated with VOXZOGO globally increased approximately 17%. More than 75% of revenue in the third quarter was generated outside of the U.S. and we expect this segment to be a leading area of expansion in achondroplasia. We are pleased to share that we recently received approval to treat children with achondroplasia in 3 additional international markets with VOXZOGO.

Briefly on the U.S. Children under 2 represented the majority of new patient starts in the quarter and approximately 85% of the U.S. children remained on VOXZOGO as of the end of September based on our switching data. We served that the pace of switching trended downward each month during the third quarter. When we survey families about why they stay on VOXZOGO, they say it's because they are confident and is working for their child and because daily dosing has become an established well-tolerated routine. Further confidence for families and treaters comes from the growing body of clinical and real-world data supporting VOXZOGO's long-term safety and efficacy profile as reflected in the data package we submitted for full approval.

Beginning in the fourth quarter, we plan to focus our updates on VOXZOGO revenue rather than providing U.S. switching metrics. As VOXZOGO market mix changes with the anticipated launch for hypochondroplasia next year, along with continued international expansion in achondroplasia, U.S. switch data becomes less relevant to VOXZOGO's overall revenue performance. leadership in achondroplasia sets the foundation for a potential launch of VOXZOGO in hypochondroplasia, where we estimate a global total addressable patient population of approximately 14,000 children.

Our launch preparation is focused on 3 things. First, we are sharing the evidence. The first full Phase III results published in the New England Journal of Medicine evidence and presented as a late-breaking oral at SP showed statistically significant improvements in growth velocity, height and arm spend. Second, our medical affairs team is increasing diagnosis and patient identification, helped by the first international consensus recommendations for diagnosing hypochondroplasia published this quarter and by disease education that has reached more than 1,200 pediatric endocrinologists and geneticists in the U.S.

And third, we're laying the foundation for rapid access, engaging payers early on the pivotal data and building on VOXZOGO's established coverage and real-world experience in contemplation. With the potential addition of hypochondroplasia, we remain confident in VOXZOGO's durability. More than 5,000 infants and children in 58 countries have been treated with VOXZOGO and its evidence base continues to expand. Together with the potential of BMN 333 should data be supportive, these opportunities underpin our ambition to remain the leader in skeletal conditions. With that, I'll turn the call over to Greg for an R&D update.

Gregory Friberg

Thank you, Cristin. Turning to Slide 11. We are quite pleased to have 4 new assets under development, having leveraged externally sourced innovation to add multiple new programs to our pipeline this year. These additions span preclinical through Phase III development setting the stage for some exciting potential updates in the coming quarters. Today, I have the opportunity to provide more details and talk about our newest addition, BMN 450, a potential first subcutaneous enzyme replacement therapy for Fabry disease, having just announced the license agreement last week.

I'm also excited to share a little more detail on BMN 440, the first potential oral treatment for hypophosphatasia. And finally, I'll review the 5-year outcome data for POMBILITI and OPFOLDA that were presented at the World Muscle Society further underscoring the benefit of this therapy for those with late onset Pompe disease. Now moving to Slide 12 and BMN 450, which we are thrilled to add to our growing clinical pipeline. It is an investigational long-acting ERT for Fabry disease and is designed to extend the half-life and improve stability relative to currently available ERTs. Approved ERTs for Fabry are all administered by intravenous infusion and BMN 450 has the potential to be the first subcutaneous ERT in the space, giving patients and physicians an option to reduce the treatment burden.

Importantly, we believe BMN 450 also has the potential to be mutation agnostic and to address a broader patient population than that of GALAFOLD, which is indicated for the estimated 35% to 50% of patients with amenable mutations. We are encouraged that in preclinical studies, BMN 450 demonstrated differentiated efficacy across key measures, including renal function, vascular health and peripheral nerve system outcomes, which may offer potential for an improved therapeutic profile. It has received orphan drug designation from the FDA and is currently in Phase I/II testing.

Entering at Phase I/II is fortuitous as it allows us to shape the program moving forward, including the selection of dosing and patient populations. We bring deep experience developing and manufacturing ERTs and the regulatory pathways for ERTs in Fabry are well established. Following the ongoing study, we will assume sole responsibility for subsequent clinical development, manufacturing and commercialization outside of Korea. We look forward to updating you as the program progresses.

Now turning to Slide 13 and BMN 440, which we added in the third quarter through the Alesta acquisition. Because of the disease and the mechanism may be new to many of you, I want to spend a moment on each. Hypophosphatasia, or HPP is a rare genetic condition caused by mutation in the ALPL gene that codes for the enzyme tissue nonspecific alkaline phosphatase. When this enzyme is deficient, inorganic pyrophosphate or PPI, accumulates upstream and acts as a direct inhibitor of bone mineralization leading to fractures and exerting both direct and indirect effects on muscle leading to weakness.

PPI reduction is known to track with clinical benefits on bone health and mobility in patients. BMN 440 is a direct inhibitor of the ENPP1 enzyme directly upstream of PPI and thus can be thought of as a substrate reduction therapy for HPP. Preclinical data support this approach at ASBMR in October data from a mouse model of later onset HPP showed that oral treatment with BMN 440 reduced PPI and normalized the phosphate to PPI ratio. It also improved bone mineralization, muscle strength and mobility measures. The promise of this approach is to deliver an oral alternative to ERT therapy for pediatric and adult onset HPP with the added potential to better address systemic symptoms that bone selective ERTs cannot.

This is especially important because adult onset patients are often affected by muscle weakness, pain and fatigue, more so than bone problems. At ASBMR in October, a study with adult HPP patients demonstrated that the burden of this condition in adults extends beyond the skeleton to physical functioning, fatigue, sleep and pain. There are no approved therapies for adult onset HPP in the U.S. or Europe. BMN 440 is now in a Phase I/IIa study in healthy volunteers and adults with HPP. We expect data in 2027 that will characterize pharmacokinetics, pharmacodynamics and safety, establishing initial human proof of mechanism and informing dose selection and design for our next study.

Turning to Slide 14. At the World Muscle Society Congress in October, we presented 5-year data for the PROPEL open-label extension study in adults with late onset Pompe disease. This analysis followed 82 people who received POMBILITI and OPFOLDA continuously from the start of Propel. Most had received prior enzyme replacement therapy, having received it for an average of 7.6 years per year previous to enrollment. Over 5 years on POMBILITI and OPFOLDA, motor function was maintained and pulmonary function remained relatively stable. In ERT-experienced patients, 6-minute walk distance was maintained while in the ERT-naive patients, it actually improved over time.

Reductions in creatine kinase, a marker of muscle damage or sustained for the duration and there were no new safety signals. These data support durable outcomes through 5 years in patients who had already been treated and add to the growing body of evidence supporting the rationale of switching to POMBILITI and OPFOLDA. Sustaining motor function and limiting pulmonary decline for 5 years in a progressive disease like late onset Pompe is quite clinically meaningful. As a reminder, POMBILITI and OPFOLDA is indicated in the U.S. for adults who are not improving on their current ERT therapy. So long-term results in this population are especially relevant. With that, I will turn the call over to Brian. Brian?

Brian Mueller

Thank you, Greg. Please refer to today's press release for detailed third quarter 2026 results, including reconciliations of GAAP to non-GAAP financial measures as well as our upcoming Form 10-Q. As Alexander and Cristin have already covered the key revenue details for Q3, I will cover the financial impact of our 2 recent business development transactions, some revenue timing and geopolitical dynamics that we are observing and the expected associated earnings per share impacts in 2026.

Turning to Slide 16. We were pleased that third quarter revenue exceeded $1 billion, a first for BioMarin. Also on revenue, beginning this quarter, royalty and other revenues include amounts earned from Ascendis under the global settlement that we announced in August. Third quarter results include the Alesta acquisition, which closed on August 31, and drove approximately $290 million of pretax expenses or approximately $1.48 per share on a pretax basis, mostly related to acquired in-process research and development or IP R&D. The impact of the Alesta charges on pretax income for Q3 and the full year results in a timing-related tax element between Q3 and Q4. As a result, Q3 includes a $0.24 earnings per share tax benefit that will normalize in Q4 and net to 0 for the full year.

We continue to expect the acquisition to reduce full year non-GAAP diluted earnings per share by approximately $1.55 as announced in our October Form 8-K. Non-GAAP diluted earnings per share during the quarter was $0.23, which reflects the IP R&D charges related to the Alesta acquisition. Also underlying results, revenue grew 32% year-over-year, while non-GAAP SG&A expense increased 12%. The non-GAAP SG&A increase primarily reflects the addition of Amicus, including the commercial teams that support GALAFOLD and POMBILITI and OPFOLDA.

Turning to Slide 17 and our updated full year 2026 guidance. We are updating our full year total revenue guidance range to between $3.8 billion and $3.9 billion. The driver of the change is order timing and not underlying patient demand. During the third quarter, a single international customer indicated they intend to defer multiple expected orders totaling approximately $70 million. Certain of these orders are already under contract for shipment, and we expect to fulfill the majority of the orders between late Q4 and Q1 2027. However, we cannot predict the exact timing. And while this type of order movement is normal for our large global business and one of the reasons that we don't guide quarterly the magnitude and timing uncertainty so close to year-end has led us to update full year guidance accordingly.

A second factor is the prolonged conflict in the Middle East. We have been managing through moderate disruption thus far in 2026. However, customer liquidity and customer cash flow disruption have increased over the last 2 months, we are sharing this dynamic today because on a full year basis, we are usually able to offset various headwinds and tailwinds in our business. However, with just 2 months to go in the year, there are less of those available. The expected order timing just discussed and the observed Middle East disruption are reflected in today's updated guidance. To be clear, this guidance change is not driven by patient demand in these markets and our updated guidance is based on timing of revenue between Q4 and next year.

The underlying business is performing strongly as underscored by third quarter results today. We're also updating non-GAAP diluted earnings per share guidance to a range of $2.80 to $3.10, reflecting the 2 business development transactions that were not included in our August guidance as well as the bottom line impact of today's updated revenue guidance. The Alesta acquisition reduces full year non-GAAP diluted earnings per share by approximately $1.55 and the BMN 450 license agreement reduces it by approximately $0.32. The Alesta impact reflects approximately $320 million of acquired IP R&D and ongoing operating expenses this year, including transaction and transition costs.

The BMN 450 impact reflects approximately $83 million of primarily upfront acquired IP R&D expense and ongoing operating expenses, which we expect to record in the fourth quarter. We recognize that the bridge from our Q2 to Q3 guidance is complex. Excluding the 2 recent business development deals and today's updated revenue guidance due to order timing, the midpoint of our updated earnings per share range is effectively unchanged from August, reflecting the delivery of our underlying business profitability goal. In summary, the third quarter reflected strong top line execution across a broader portfolio, and we continued investing in future value creation through the acquisition of new clinical assets.

At the same time, Amicus cost synergies are ahead of schedule, and we continue to expect approximately $220 million of non-GAAP cost synergies to be realized fully in 2028. Thank you for your attention. We will now open the call to your questions. Operator?

Operator

[Operator Instructions] Your first question is from the line of Jessica Fye with JPMorgan.

分析师问答

Unknown Analyst

This is Adam on for Jess. I just wanted to ask, and sorry if I missed this, but the -- says you realize accelerated cost synergies in 3Q while maintaining the [ 229 ] target for 2028. Could you elaborate on that? And what should investors carry into the 2027 OpEx assumptions as we model that out?

Brian Mueller

Adam, this is Brian Mueller. Thanks for the question. And yes, you heard that accurately. We came out in the Q2 report in early August with our long-term views on the Amicus integration, we quantified the synergies and started to talk about the accretion of the deal in those metrics were partially dilutive post-acquisition here in 2026. Substantial accretion beginning next year in 2027 and then growing to full synergy realization in 2028. The integration is going really well. We're executing really proud of both the BioMarin and Amicus teams and now we're one team. And the cost synergies are ahead of schedule.

So we're not updating or quantifying any additional metrics at this time. We'll talk more about the '27 accretion when we guide to '27. But we can say that the cost synergies are ahead of schedule. We initially said that within the first calendar year post closing, the deal would be accretive. We can now pull that forward and be confident that the deal is accretive actually within 9 months. and still a quarter to go here, but I'll also share that we're currently tracking to even calendar year accretion in '26.

Operator

Your next question is from the line of Sean Laaman with Morgan Stanley.

Sean Laaman

The patient growth was around 69%, but you've acknowledged that uptake benefited from the competitor supply constraint. Alexander, can you quantify the underlying growth, excluding that disruption? And I might have missed it. And how many of those starts are likely to remain durable once competitor supply normalizes.

Brian Mueller

Thanks very much, Sean. I'm going to hand it over to Cristin.

Cristin Hubbard

Thanks much, Sean, for the question. This is Cristin. Yes, as you noted, the performance in the third quarter for POM OP was indeed strong. revenue up 58% and patients up 69% year-over-year relative to what Amicus reported in the same quarter. And I think what's really important to note on POM OP is that the switching really is based on the clinical profile of the medicine. Now we're watching this growing body of clinical and real-world evidence saw in the prepared remarks, the PROPEL extension study that Greg spoke to, which I think has been a really important momentum builder for us.

But as noted, we have also seen what we call a meaningful share of new patient starts based on the supply shortage we're hearing from other Pompe therapies. Now it's -- this is happening in certain European markets. We aren't sure how long this will last or the depth of the problem. But what we've done is worked really hard to ensure that we have additional supply so that we can not only support our patients that are on POMBILITI and OPFOLDA and not fold up, but importantly, any new patients that want to come on as a result of these shortages. So we really do think that this is an important moment for POMBILITI and OPFOLDA.

We're building great momentum, and it's just the beginning of some of the initiatives we put in place. I do want to note, however, that revenue growth will lag as we had many of these new starts in the quarter. So we will see that revenue build more into 2027 and beyond. But it's an exciting time for POMBILITI and OPFOLDA, and we're excited to carry with this momentum.

Operator

Your next question is from the line of Eliana Merle with Barclays.

Eliana Merle

Just on the achondroplasia base, something we've been hearing about recently. I guess, 1 of the more outspoken competitors in the space is just around the safety I've inhibiting FGFR2 in the developing brand and potential implications of that. I guess do you have any thought on the debate here and how this could play out commercially even just from a perception perspective. And then just second quick follow-up. For BMN 440, an interesting opportunity there, could you elaborate what would constitute proof of concept at the data next year.

Gregory Friberg

This is Greg Friberg. I'll take a stab at both of those. Yes. With regard to -- I think the comment you made about FGFR2 inhibition in the brain. My ops are much more philosophical, which is direct development is hard. I think that when we are looking at small versus large molecules, they have their risks, they have their opportunities, they have their challenges. But really, this issue of whether or not a small molecule crossing the blood-brain barrier leads to any sort of untoward side effects. These are hypothetical at this point. I would just comment that the FDA has established guidance on how they look at this. They take structured processes, they evaluate the risk benefit of these drugs very carefully.

And we know that, that's incredibly important, particularly in children who are going to be on these treatment for multiple years. At the end of the day, Clinical data is the antidote to all of these potential concerns and really -- from that standpoint, we're quite proud of the data package that we have with VOXZOGO. We've got, as Cristin commented on, over 5,000 patients, 10,000 patient years, 50 countries, we know that the benefit risk profile is one that we can stand behind. It's one of the -- we like to say it's the best-in-class evidence package. That, of course, has given us the opportunity to put forward the full approval data package that has additional information that will be ruled on by the FDA with the February 28 PDUFA date.

I really can't speculate beyond that how the FDA will view this. But certainly, the idea of a chronic safety and efficacy package that we bring with VOXZOGO, we see that as a winning argument that we will be putting forward and continuing to publish on for patients and physicians.

With regard to your second question, 440 and the proof-of-concept data, we have an ongoing Phase I/II study right now. As a quick reminder, this is a single dose and a multidose study rolled together. It's in both healthy volunteers as well as the subset of HPP patients. And the data that we will have to present publicly next year will include both PK as well as what we're calling proof of mechanism data. So this is data. Again, looking at enzymatic activity and biomarker activity what will come thereafter once we've been able to select doses and schedules, will be a Phase II study that will look at harder clinical end points. More to come, but we're really excited about this opportunity.

As a quick reminder, as a small molecule, a substrate reduction therapy for HPP, the promise and the opportunity here isn't just that we have a more convenient therapy, but potentially one that also reaches compartments like the muscle and the bone that can affect in particularly the adults, the kind of side effects that are -- and adverse events from their disease that are really burdening them the most. That is muscle pain and limitations of mobility that again, some of the more bone targeting large molecules may not be able to.

Operator

Your next question is from the line of Cory Kasimov with Evercore ISI.

Adithya Jayaraman

This is Adi on for Cory. We noticed the January PDUFA for pump in adolescent -- is that opportunity already included in your $1.2 billion peak sales outlook? Or would it be upside? And also more broadly, now that you've had more time to the acquired business, where else do you see the biggest opportunity to bring more Fabry and Pompe patients onto treatment beyond switching from existing therapies? .

Cristin Hubbard

So we do believe that there's a lot of opportunity here to continue to -- and did you ask specifically about POM OP or also GALAFOLD? Sorry, just so that I'm clear on the question, POM OP specifically.

Adithya Jayaraman

Yes. For both of them. For POM OP, we noticed that SMD has already filed. So on both.

Cristin Hubbard

Yes. So we believe that opportunity is relatively small in the scheme of things. But we believe that the overall opportunity on POMBILITI and OPFOLDA is quite a bit bigger. In so much, as I just mentioned in the previous comments, we really are seeing momentum build for this therapy, not only is it the evidence that we're seeing but also importantly, just the experience. So where we see the opportunities where we can really help build this is certainly to share the real-world evidence as we generate it. Certainly, the adolescent is a catalyst opportunity, I should say, for POMBILITI and OPFOLDA. But really, as we continue to expand this not only in the kind of in the indications that we have today, as we geographically expand this as well. So the real switching opportunities here are to make sure that the data continue to be generated and that we educate on that meaningful data that we importantly empower both physicians and patients to understand when their current treatment might be waning or they might be -- they are doing as well on the treatment that they're on.

And so that they're advocating on their own behalf to ensure that they get that switch to happen. And then as I've mentioned, I think that this geographic expansion, given that POMBILITI and OPFOLDA is still in its early days, it's important that we continue to build momentum in countries not only where we are today, but importantly, in the countries we aren't yet. And so our regulatory team, our commercial teams in the field are preparing for this, which will help to build that growth into the future.

Operator

Your next question is from the line of Paul Matteis with Stifel.

Paul Matteis

I appreciate it. I wanted to ask a couple on BMN 333 data next year. Understanding that your thesis here is that you could show clinical superiority I was wondering what would be an outcome next year that would definitively derisk that profile and make you confident in going that path for a pivotal study. And then maybe just as a second question to that, let's say, this drug does show good clinical activity, but maybe the question around power for superiority looks a little bit riskier. Would you still forge ahead with maybe some sort of noninferiority or -- path?

Gregory Friberg

Thanks, Paul, this is Greg. I'll tackle that one for you. With regard to the 333 study that's ongoing, just as a reminder for folks, we are running the Phase II portion of our combined Phase II/III program, which is looking at a variety of doses. In this case, it's 3 doses of 333. And looking at the AGV at 6 months, or greater and trying to determine how that compares to the control arm of VOXZOGO. That not only will be studied within the protocol, but also will be supplemented by a wealth of historic data again that we have at our disposal. .

Now again, it's not a question of whether a dose response exists, but it really is a question of the shape of that curve. We know that those 3 doses are going to give us significantly increased AUC exposures of free CNP and will allow us to test the hypothesis. So we have a basin model that's in place that will determine a posterior probability not only of those 3 doses, but really looking at it with regard to exposure response as well. And while we're not releasing what the math behind that model is we feel that, again, if we meet those criteria, we will have a good degree of confidence that moving forward with a superiority study, testing the winter dose against VOXZOGO is a very good bet.

That being -- as I said, again, what we know so far is, of course, that we've been able to get not only PK but increases in PD as well with the cyclic GMP. And we're quite confident, again, that we have the right molecule, and we're running the right study. just for posterity sake, since you're asking the question, should it not be achieved? Our Phase III study also will provide an opportunity to consider alternative hypotheses like noninferiority or less frequent dosing, and that would not materially slow down our development time lines. That's not our hypothesis. We think that we have the right study and the right molecule. We're looking forward to turn over the cards to that initial dose ranging study sometime next year.

Paul Matteis

So Greg, just to clarify, next year's readout is not really a growth velocity readout. It's more of a PK/PD readout. Is that right?

Gregory Friberg

It is a growth velocity readout. In this case, the PD is AGV. It's 6 months or greater data.

Please clarify, Paul. Yes, I was going to say it's AGV indeed. So the PD is AGV. Technically, that's an intermediate endpoint and final is all type, which we're thrilled to again have for VOXZOGO would be the primary endpoint for full approval. But when I mentioned PK/PD, I meant exposure response with regard to AGV.

Operator

Your next question is from the line of Alex Hammond with Wolfe Research.

Alexandria Hammond

So since the fold acquisition, you've added BMN 440 as well as 450 both early-stage clinical assets -- is that now the template? Or would you use that $4 billion to $5 billion of firepower you expect in mid-2027 on other commercial or late-stage deal? I guess, after these deals, what gaps remain in your pipeline? .

Unknown Executive

Alex, thanks very much for your question. Yes, we're -- as you can tell, we're very excited about the deals we've done and to add 4 assets to our pipeline in 2026 so far. We continue to remain focused on clinical stage deals at the moment. So programs that fit with our capabilities around genetics, around regulatory expertise around manufacturing, around commercialization. Particularly, as you can tell, interested in assets that fit with our business units, skeletal conditions and metabolic conditions. But we're interested also in other genetic conditions, but clinical stage assets, absolutely. And we do -- as Brian said, we're -- the accretion has been very impressive, the implementation of the Amicus acquisition and our fire power is increasing. So we -- we will continue to do these clinical stage deals for the foreseeable future.

Operator

Your next question is from the line of Philip Nadeau with TD Cowen.

Unknown Analyst

This is Rishi on for Phil. Really great progress. Two questions for me. First is -- so UV well was given a positive opinion from the CHMP of the EMA last month. So with the possible launch in Europe, or approval in Europe coming up. How do you anticipate this to play into the competitive dynamics with VOXZOGO as quantitatively as possible? And then my second question is you previously -- moving on to hypochondroplasia. You've previously given metrics on your efforts to increase diagnosis rates and age of -- and reduced age of diagnosis saying 90% increase in diagnosis rates, 70% reduction in the age of diagnosis. Just do you have any updates on those metrics now?

Cristin Hubbard

Thanks for the question, Rishi. So I'll take those. So -- in Europe, I can say that we are very much anticipating the launch there, have that into our plans. Our competitive readiness, of course, assumes that. We've not given guidance for the next year. And so at next point-- sorry, in the next year, we'll be able to provide more color on that, but I will say that we are ready for it, have it in our baseline plans and are looking forward to seeing what that looks like. Now on the second one on the HCH metrics, what we have shared is the real focus areas as we're nearing the launch. As you know, the PDUFA is coming in May in the U.S.

And we're really focused on right now sharing the Phase III data making sure that we're increasing diagnosis and then ensuring rapid access, so having the right conversations with payers. Now with regard to the specific metrics that you've asked for, we don't have an update on those today. But I will say that as we get closer to the launch timing, we very much will be sharing more on our plans and specifically the metrics that we'll be tracking and sharing as we move forward. So very excited about that as next year.

Operator

Your next question is from the line of Joon Lee with UBS.

Unknown Analyst

The DMS 333 has a bit of a moving target as we're expecting longer follow-up data from the combination of people growth hormone and by year-end. What would you be most focused on? And how would you position 333 vis-a-vis the competition?

Gregory Friberg

Thanks, Joon. This is Greg. Maybe I'll take a stab at that. Really, our thoughts with regard to the growth hormone combination are consistent with what we've been communicating in the last few quarters. I think the question is not whether adding growth hormone to an achondroplasia patients regimen would result in a spurt of additional growth. The question is whether or not that would be, number one, safe, of course, number two, whether or not it would be persistent, whether or not, again, that would be an increase that would continue over time. .

And of course, the larger question, which gets back to the root of why growth hormone is not typically used in achondroplasia patients to begin with is whether or not the final adult hide of these patients will be impacted. The concern, of course, is that growth plates may close prematurely over time. These are hypothetical risks, but it highlights the fact that additional data is needed. Now when you slice and dice the data every 3 to 6 months, it's hard to get a look at that. That being said, again, the last look at the data did suggest that perhaps those effects were starting to wane with the addition of growth hormone to CNP, our feeling 333 is that having a single agent, again, one that for remember, patients who are not growth hormone deficient, a single agent that gives you similar results would be preferable.

That is also consistent with the thesis of what we think that 333 can deliver. Again, higher levels of CNP, we're looking to optimize and have the best-in-class CNP that if there were a future state where combinations were available, you'd always want to combine with the best CNP anyways.

Operator

Your next question is from the line of Olivia Brayer with Cantor Fitzgerald.

Olivia Brayer

Brian, on the updated revenue guidance, can you maybe just help us better understand what's happening with that single customers' ordering patterns not sure whether you're able to disclose which country it is. But do you still expect growth from VOXZOGO in 2027, no matter how that order timing actually shakes out, whether it be in late 4Q versus the early 1Q of 2027 time frame that you mentioned? And then on hypochondroplasia, congrats on the PDUFA. So assuming a summer launch, anything you guys can say at this point about how quickly you expect that to meaningfully contribute to Box over sales? And is that something that you think you'll be ready to quantify come January?

Brian Mueller

Thanks, Olivia, it's Brian. I'll start with your first question, and then I'll let Cristin comment on -- so first, for those of you that know the company well, quarterly order timing dynamics in our business is very common, something that we regularly manage through. We've got this diverse global business. 2/3 of it is outside of the United States. That international business is largely single payer national health care systems that tend to order large quantities on an inconsistent basis. But they roll up to this robust business that we have. And over the course of any given year, again, these dynamics are something that we consistently manage through. There are usually puts and takes over the course of the year, and we'll comment on those at the quarters and perhaps adjust expectations as necessary.

However, at this point in time, with this single customer that flagged their intention to defer these handful of orders that totaled $70 million for the fourth quarter. It was just large enough and uncertain enough for us to recognize the uncertainty in today's guidance update. But very important, as I mentioned a few moments ago, it's not tied to patient interest in the therapy. It's entirely timing. Some of the orders are contracted for shipment. It's just that the contract runs into January in that instance. So just timing before Q4 and Q1 and for the lack of offsets here. So we just wanted to share the update and take a measured approach here.

Cristin Hubbard

And Olivia, with regard to your second question about hypochondroplasia. So yes, very excited about this as we near into next year. And specifically, the team working on diagnosis and patient identification. Our medical affairs teams are out there now we're educating on the Phase III data that we have. We're educating on the condition itself. And what we're really working on, both in our customer interactions, but also using different sources of data and being able to switch some of that data together because we have more access to data in the U.S. We are working on identifying patients and offices and finding out where they actually are. So what we will do as we near the launch and we gear up for it early in next year, we will be sharing more about specifically what our expectations are around that and how we feel like we'll be able to deliver on it and report out on it as we move forward.

Olivia Brayer

Okay. That's helpful. Can you guys actually comment on whether you expect VOXZOGO to grow in 2027? Or is it too early given the dynamics with the ordering patterns?

Gregory Friberg

Yes. Thanks for the reminder, there Olivia. We do expect VOXZOGO to continue to grow in 2027. And there is an element which includes the hypo and launch offsetting some of the potential loss of share to current and additional potential competitors. But just a reminder that more 75% of the VOXZOGO business is outside of the U.S. continuing to launch in new markets. We're continuing to deeply penetrate some of those international markets. We will remain the only achondroplasia therapy with a label for patients, children under 2 years old. And that exclusivity over what we believe is at least the next couple of years with the importance of starting therapy is early for birth for the international treatment guidelines, that sets up this potential switch market. And so we've got a number of growth drivers and plan to continue to invest and grow VOXZOGO.

Operator

Your next question is from the line of Chris Raymond with Raymond James.

Christopher Raymond

I wanted to maybe ask a similar question. The last one was asked maybe a little bit more explicitly. So Brian, I heard you say that there was a $70 million order from Q3 that got shifted. Full year '26 guidance was lower by $25 million. So the math, I guess, is it as simple as saying so Q4 should benefit by $45 million and I know you guys don't guide to '27 yet, but should we also then think then there's an additional benefit of $25 million in Q1 '27, just given the shift and you mentioned that it spans both Q4 and Q1 of next year.

And then maybe a follow-up to that question is on 333. Just hearing what you're saying about the option maybe to size the Phase III portion to look at non-inferiority what kinds of unmet needs are you thinking about addressing under that scenario if you have a Phase II data set that maybe points to noninferiority as the right way to go for 333.

Brian Mueller

Chris, this is Brian. I'll start. So first, just to clarify 1 element because I think you touched on some of the Q3 to Q4 dynamics as well. Just to be clear, Cristin mentioned an order that shifted from Q3 into Q4. That was, again, a single large international customer. And that order actually was VOXZOGO. So that's part of the VOXZOGO being a little less than expectations this quarter. That's again, a single order, but that one is planned for Q4. And it's different and not included in the $70 million that I referenced. That is another batch of orders that was previously expected in Q4, where the customer has now flagged that they may take delivery of those in Q1 or early '27. In the latter, the $70 million is the driver for today's guidance update. We took a risk-adjusted approach. We still have a chance to deliver some of these orders. So that's the lowering of the midpoint. But separate from that first item in Q3, hopefully, that helps. .

Christopher Raymond

Yes, I just want to make sure I understand. So lowering VOXZOGO by $25 million for the full year. The assumption is that some of that will spill over into Q1. Is that correct? Can you just clarify?

Brian Mueller

Through this lowering of guidance, which allows and recognizes the uncertainty through some of the Q4 slippage, if you will. And by the way, a little more than half of that $70 million is VOXZOGO in this market. So yes, if those slip into about Q4 into Q1, they would benefit Q1 or early '27. But we'll talk more about '27 when we guide to '27 in these types of markets. If there's a -- if there's a timing deferral of a quarter, that could play forward into the next year where follow-on orders get delayed. So we're still building up the revenue plan for '27.

Gregory Friberg

And Chris, this is Greg again. With regard to your 333 question, I think your question behind the question, of course, is what is the compelling value argument that we bring with 333 to the table. And we firmly believe that the superiority argument, the pharmacodynamics that we can bring forward, give us a chance again to demonstrate that there is more growth to be had and more pull-through to markers of health and wellness with a molecule like 333. Out of an abundance of politeness since I think it's 4 consecutive earnings calls that I've gotten a question about the noninferiority. I answered it. again, for directness stake, but we would believe that we would need to add something beyond simple convenience to make a value argument for what society would value from 333. .

Operator

Your next question is from the line of Joe Schwartz.

Joseph Schwartz

I have a couple of questions on 333. With only about 10 kids per arm in Phase II, what growth advantage over VOXZOGO would convince you that it's real. And how does the model you've used to power Phase III address the potential for growth velocity to plateau if it doesn't increase commensurate with the CGMP increases you've seen at some point over the curve.

Gregory Friberg

Thanks, Joe. Let me answer the question this way. We believe that the size of the study that we put in place and the models that we're using, again, we'll be looking at AGV for the individual cohorts, but we will also have the ability to match that to exposure analysis that we're going to have more than enough statistical power based on our model to have comfort moving forward to Phase III. You had a second part of the question as well, though. Can you remind me?

Joseph Schwartz

Yes. I guess what it's getting at is that other CNPs have not seen growth move up in line with the G&P increases that have been seen because there's been a plateau. And I know that you're hoping that exposure plus more activity at the receptor might be able to move beyond that. But I'm just wondering how, if at all, the Phase III powering is planning for that potential to play out?

Gregory Friberg

So the Phase II is powered off an effect size. Again, as I was mentioning, the Phase II will give us confidence that, yes, we have a dose that can reach it. And just to take a step back, the big question isn't whether there's a dose response relationship to increasing levels of free CNP. It's really about the shape of the curve where and if a plateau occurs, and of course, whether you can push your way up that curve. I think the direct answer to your question is we've picked 3 doses that give us sufficient increases in AUC for free CNP.

That's roughly 3x, 5x, 7x. That's again, probably a conservative estimate in terms of free CNP. These are doses that have not been tested in humans to this point. So again, that kind of spread of exposure, we do believe that we will definitively ask the question appropriately with this study that we've got the right reagent in 333 that can test that. Beyond that, I'm not going to get ahead of the data. We do think that, that data though will be incredibly informative and will help us identify whether that hypothesis holds true.

Operator

This concludes the Q&A portion of our call. I will now turn the call back to Alexander Hardy for closing remarks. Thank you.

Alexander Hardy

Thank you, operator. We delivered another standout quarter with 32% top line growth and the first quarter in our history in which total revenue surpassed $1 billion. Our focused and deliberate expansion of BioMarin's clinical stage pipeline is delivering results with 4 new programs added in the last 12 months and spanning preclinical through Phase III development. We expect our leadership in skeletal conditions to support a strong launch of VOXZOGO for hypochondroplasia following its potential approval next May, which should mark BioMarin's seventh force disease medicine. As you look ahead with enthusiasm, we advance a next wave of therapies from our clinical stage pipeline, prepared to report on a number of key updates in 2027. .

Combined with the strength of our more diversified commercial portfolio, we're confident in our ability to create lasting value for patients and all of our stakeholders. Thank you for your continued support and look forward to keeping you updated on our progress.

Operator

This concludes today's call. Thank you for attending. You may now disconnect.