Navepegritide

iStock, Golden Sikorka Therapies from industry leaders BioMarin and Ascendis Pharma supply a key hormone that promotes bone growth. In order to move the field forward, challengers are looking to address the underlying cause of the rare, genetic disease. In November 2021, the FDA approved BioMarin’s Voxzogo for children 5 years and older with achondroplasia, giving hope to more than 10,000 patients and their families across the U.S. Voxzogo marked the industry’s first-ever therapy for the rare, genetic disorder characterized by short stature in children. Despite qualifying as a rare disease—it affects one in 15,000 to one in 40,000 newborns— achondroplasia is the most common cause of dwarfism. Now, nearly four years later, the achondroplasia community is once again awaiting regulatory action that could open up a new treatment option for the disease. On November 30, the FDA is set to make a decision on Ascendis Pharma’s TransCon CNP, which the biotech is proposing as a weekly treatment for children with achondroplasia. “When Ascendis Pharma announced TransCon CNP results, BioMarin’s stock fell 17%,” Sadaf Javed, manager of Forecasting and Analytics at DelveInsight, told BioSpace in an email. Javed said that despite the drawbacks of cross-trial comparisons, TransCon CNP’s pro to be “competitive” in terms of efficacy, safety and convenience. In particular, its once-weekly schedule is a “strong differentiator,” she added, compared to Voxzogo, which is given via daily subcutaneous injections. The market for TransCon CNP and Voxzogo is ample. There are around 24,000 clinically eligible patients from birth to 18 years of age globally, according to Jefferies analyst Andrew Tsai. With Voxzogo so far achieving around 17% market penetration, or 4,000 patients. “This therefore implies a global market opportunity in [achondroplasia] of just north of $5B assuming full penetration,” Tsai told BioSpace in an email. Even as BioMarin and Ascendis jockey for leadership in the achondroplasia arena, many other players are gunning for a share of this sizeable market, looking to stand out through better efficacy and safety, novel mechanisms or convenience. Spurring Growth Both Voxzogo and TransCon CNP work by mimicking the function of a naturally occurring hormone called the C-type natriuretic peptide (CNP), a signaling molecule involved in a key achondroplasia pathway. Achondroplasia, Javed explained, is caused by a gain-of-function mutation in the FGFR3 gene, which leads to the over-activation of the FGFR3 receptor. This, in turn, suppresses the activity of cells that are crucial for bone development, “effectively stalling bone growth at the growth plate,” she continued. These molecular underpinnings explain the key symptoms of achondroplasia: short limbs, hydrocephalus, curved spine and bowed legs. Patients with achondroplasia also suffer from physical developmental delays and, when left unchecked, back pain, breathing problems, obesity and recurrent infections. CNP enters the picture partway through the FGFR3 cascade. The hormone “naturally counteracts FGFR3 activity,” to promote bone growth, Javed said, opening up a promising treatment mechanism for achondroplasia. With Voxzogo’s approval in 2021 , BioMarin verified the clinical and regulatory value of the CNP pathway and “set the bar on an approvable endpoint” for achondroplasia, Tsai added. Indeed, Phase III data submitted by the biotech to the regulator to support the approval showed that Voxzogo treatment improved annual growth velocity by 1.57 cm per year at 52 weeks, compared with placebo. Over the years, BioMarin has only strengthened Voxzogo’s profile, drawing from “more than 6,000 patient-years of data” across the drug’s clinical development and real-world use, Chief Commercial Officer Cristin Hubbard told BioSpace in an email. This continued effort led to another victory in October 2023, when the FDA approved the drug’s expansion into children under 5 years of age. “Voxzogo is the first and only approved medicine for achondroplasia starting at birth,” Hubbard said. Current consensus guidelines, published just this year in Nature Reviews Endocrinology and arranged by a global consortium of experts and patient advocates, highlight the value of timely treatment. “Treatment should be initiated as early as possible,” the consensus statement read, pointing to new data suggesting that starting intervention within the first months of life could lead to better growth improvements. Despite Voxzogo’s strong clinical profile, the achondroplasia market is hardly open-and-shut. Hubbard herself concedes that there remains unmet need with thousands of children worldwide still in need of treatment. If approved this fall, Ascendis’ longer-acting CNP analog could help fill this need. In the Phase II ACcomplisH study, TransCon CNP led to an annualized growth velocity of 5.42 cm per year, as opposed to 4.35 cm per year in placebo comparators. The difference was statistically significant in favor of Ascendis’ drug, according to a November 2023 publication in The Lancet , which also demonstrated a favorable overall safety profile. “Ascendis’ likely approval of TransCon CNP for achondroplasia poses a major threat to BioMarin’s top-selling drug,” Javed said, however noting that BioMarin continues to hold not only a geographical advantage—with a commercial footprint of around 50 countries—but also a stronger label. “[The] majority of children in the United States are actually diagnosed prenatally and often, the decision to treat is made prenatally,” she added. “BioMarin is the only one that is indicated in infants.” Ascendis declined to comment for this article, citing the ongoing regulatory review for its drug application. Striking at the Root Despite being the preferred pathway of the two market leaders, the CNP cascade has some drawbacks, keeping the field open for alternative approaches. For one, the CNP hormone is a vasodilator—a compound that widens the blood vessels—and therapeutic analogs come with concerns of low blood pressure, Javed explained. The molecule’s composition also poses a practical problem. CNP is a peptide hormone with a relatively short half-life, necessitating daily or weekly injections to maintain its therapeutic benefits. This, according to Javed, “can be burdensome” for patients. Looking beyond CNP, some drugmakers, including California-based BridgeBio, are striking at the root of achondroplasia. BridgeBio is developing infigratinib, a small-molecule drug that works by blocking the mutant FGFR3 receptor, in turn hitting achondroplasia “directly at its genetic source,” Justin To, CEO of Skeletal Dysplasias at the company, told BioSpace by email. In November last year, the company published data from the Phase II PROPEL 2 study, touting a 2.5 cm per year increase in annualized growth velocity at 18 months of follow-up. Of note, infigratinib also demonstrated a significant improvement in body proportionality, defined as the ratio between the patients’ upper and lower body segments. “Notably, Voxzogo and TransCon CNP weren’t effective on proportionality, which is of key importance to the patient/doc community,” Jefferies’ Tsai said, “so I think there is a real opportunity here for [infigratinib] to differentiate with broad and meaningful benefit.” Aside from the proportionality edge, BridgeBio also hopes to compete on convenience. “We have heard from both families of children with achondroplasia and clinicians that there is a significant need for an oral treatment option,” To said. “If approved, [infigratinib] would be the first oral treatment option for children with achondroplasia.” BridgeBio is currently running the fully-enrolled Phase III PROPEL 3 study of infigratinib in achondroplasia, with topline data expected early next year . Aside from BridgeBio, Tsai also pointed to Tyra Biosciences’ FGFR3 blocker TYRA-300 as another promising upcoming achondroplasia treatment. The drug, also called dabogratinib, “is being positioned as a more selective FGFR3 inhibitor,” he continued, potentially even “more selective than infigratinib.” While primarily studying dabogratinib for bladder cancer, Tyra is also trialing the drug in mid-stage studies for achondroplasia. Therapies that target the molecular root of achondroplasia, such as dabogratinib and infigratinib, “could translate to superior efficacy vs. existing CNP analogs,” Tsai said. Of course, BioMarin, currently the undisputed achondroplasia leader, isn’t just sitting back and letting its challengers speed on ahead. Tsai, in particular, has his eye on BMN-333, a long-acting CNP formulation, which is currently in early-stage testing. BMN-333, he said, “has been designed to sustain elevated CNP levels” and improve upon Voxzogo’s once-daily dosing regimen. BioMarin’s Hubbard noted that the company is set to start a pivotal Phase II/III study for BMN-333 in the first half of 2026. But the biotech will continue to work on Voxzogo, even looking to position the drug as a treatment for other skeletal growth conditions. For instance, BioMarin has a late-stage program for hypochondroplasia , a genetic disorder that also results in dwarfism. Voxzogo is also being tested for two other genetic disorders, Noonan syndrome and Turner syndrome , that, aside from physical abnormalities, result in developmental defects. The Noonan and Turner programs are in Phase II. “It’s the everyday milestones that families share that drive us,” Hubbard said. “Reaching a car door, riding a roller coaster, turning on a light switch, putting up his or her own hair. These moments, and the clear unmet need, are why we remain deeply committed to leading innovation in rare conditions.”

iStock, Grandbrothers From more than 30 target action dates in the last three months of the year, BioSpace has narrowed the list to six regulatory decisions that could have far-reaching implications for biopharma and patients. As 2025 enters its home stretch, the FDA is also nearing the end of its calendar. But that doesn’t mean that the industry is in for a quiet year-end—quite the opposite, in fact. In the last three months of 2025, the FDA is set to decide on at least 30 regulatory applications, many of which could help shift the treatment landscape for hard-to-treat diseases or push the boundaries for novel modalities. One upcoming verdict, for instance, could mark another industry first for CAR T therapies, while another could mean the comeback of a previously-pulled cancer drug. Here, BioSpace rounds up six of these most highly anticipated decisions in Q4, looking at the data backing their bids and what their approvals could mean for the industry. After Delay, Regeneron Awaits Two Eylea HD Verdicts Regeneron is looking to boost the pro high-dose Eylea with a move into macular edema after retinal vein occlusion (RVO) and a monthly dosing regimen across all its approved indications. The FDA is currently reviewing these applications and is expected to release its verdict in the fourth quarter. No specific decision date has yet been indicated. The regulator had an initial target action date of Aug. 19, but extended the review period due to issues at a third-party manufacturing site, Regeneron announced earlier that month. The production plant in contention was previously owned by the CDMO giant Catalent, which was acquired by Novo Nordisk’s parent company for $16.5 billion in February 2024 . An FDA report made public in August revealed uncontrolled and unaddressed contaminations at this site, including with bacteria and cat hair. Regeneron has nevertheless reassured investors that aside from these third-party problems, the FDA has not flagged any problems with the submission. “Based on our discussions, we believe that there’s nothing significant left to be done,” CEO Leonard Schleifer said during the company’s Q2 earnings call . “We are expecting, once the resolution of the filling issues has occurred, to receive favorable action, we hope, from the FDA.” To support its application for high-dose Eylea, Regeneron filed data from the Phase III QUASAR study, which demonstrated that the high-dose formulation was non-inferior to the currently approved standard-dose version of Eylea when used to treat patients with macular edema after RVO, according to a readout in December 2024. Adverse events were comparable between the two formulations. High-dose Eylea is currently approved for wet age-related macular degeneration, diabetic macular edema and diabetic retinopathy. GSK’s Blenrep Comeback Bid Nears Moment of Truth By Oct. 23, the FDA is expected to release its decision on GSK’s proposal to bring Blenrep back to the market, this time as a second-line treatment for relapsed/refractory multiple myeloma. Blenrep, an antibody-drug conjugate targeting the CD38 protein, was originally approved in August 2020 under the FDA’s accelerated pathway. But soon after failing its confirmatory Phase III study in November 2022, GSK withdrew the product from the market. Then, last year, GSK started setting the stage for Blenrep’s comeback with data from the Phase III DREAMM-7 trial. A readout in February 2024 demonstrated a significant 59% drop in the risk of death or disease progression in patients treated with Blenrep plus bortezomib and dexamethasone, as compared with a similar regimen using Johnson & Johnson’s Darzalex. Then, in June that same year, the pharma reported findings from another late-stage study, DREAMM-8, touting significantly better progression-free survival for Blenrep versus Takeda’s Velcade. GSK is using these two studies to support its regulatory application for Blenrep, but in July this year, the FDA’s internal reviewers flagged “high rates of ocular toxicity and dose modifications” in both trials. The DREAMM studies also had “limited dose exploration” which in turn highlight the unaddressed need for a “careful evaluation” of Blenrep’s risks in its proposed indications, according to the reviewers. An external advisory committee in July agreed with this assessment and voted 7–1 against Blenrep , finding an unfavorable benefit-risk pro the drug in its proposed indication. “The efficacy data were strong but the toxicity data were also very strong,” panelist Neil Vasan said at the time. Shortly after the vote, the FDA extended Blenrep’s review by three months. BMS’ Breyanzi Could Become First CAR T Therapy for Marginal Zone Lymphoma Bristol Myers Squibb is proposing its CAR T therapy Breyanzi for the treatment of marginal zone lymphoma (MZL), potentially blazing the trail for the therapeutic class in this indication. The FDA has a target decision date of Dec. 5. To support its application, BMS filed findings from the Phase II TRANSCEND FL study, a single-arm, open-label trial that enrolled more than 270 patients with relapsed or refractory follicular lymphoma or MZL. Data presented at the 2025 International Conference on Malignant Lymphoma in June demonstrated a 95.5% overall response rate in patients with MZL, including 62.1% who saw a complete response. The safety pro TRANSCEND FL was consistent with what had previously been established for Breyanzi. Rates of cytokine release syndrome and neurologic complications were “low,” according to BMS, with no grade 4 or 5 cases detected. If it wins the FDA’s blessing, Breyanzi would be the first CAR T therapy indicated for MZL, according to an August 2025 news release from the company. It would also mark the second time that Breyanzi notched a regulatory record: In March 2024, it became the first CAR T to win approval for chronic lymphocytic leukemia and small lymphocytic leukemia in relapsed/refractory patients. Breyanzi works by binding to the CD19 protein, in turn triggering the activation and action of CAR-T cells, as well as the release of pro-inflammatory signals to destroy the target tumor. It is also approved for large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. The drug’s label carries a boxed warning for cytokine release syndrome, neurological toxicities and secondary hematological malignancies. Arrowhead Makes Case for RNAi Therapy in Rare Cholesterol Disease After delivering four firsts for the rare disease space in August, the FDA by Nov. 18 could grant another—this one for Arrowhead Pharmaceuticals’ plozasiran , an RNA interference therapeutic for familial chylomicronemia syndrome (FCS). Afflicting 1 to 2 people per million , FCS is an ultra-rare, heritable disease that manifests as excessively high levels of triglyceride levels, typically reaching over 880 mg/dL, according to Arrowhead . In turn, patients with FCS suffer from cardiometabolic and other complications such as diabetes, hepatic steatosis, abdominal pain and even cognitive problems. There are currently no treatments that can adequately control FCS in the U.S., according to Arrowhead. Arrowhead’s answer to FCS is plozasiran , an investigational therapy that reduces the production of the ApoC3 protein, which is naturally produced in liver cells and serves as a component of triglyceride-rich lipoproteins. ApoC3 prevents the breakdown and clearance of these fatty molecules. By reducing ApoC3 production, plozasiran helps normalize lipid levels in FCS patients. Arrowhead is supporting its application with data from the Phase III PALISADE trial. A readout in November 2024 demonstrated that 25 mg of plozasiran—the proposed commercial dose—led to a roughly 80% reduction in triglyceride levels. In at least half of the treated patients, triglyceride levels stayed below 500 mg/dl, a threshold linked with worse acute pancreatitis risk. Plozasiran treatment also resulted in lower cholesterol levels. Arrowhead is also developing plozasiran for severe hypertriglyceridemia and dyslipidemia. Ascendis Eyes Approval in Rare Bone Growth Disorder Also awaiting a rare disease decision is Ascendis Pharma, which is advancing TransCon CNP, also known as navepegritide, for the treatment of children with achondroplasia. The FDA is set to release its verdict by Nov. 30. Achondroplasia is a rare, genetic disease characterized by dwarfism due to faulty bone development. Ascendis is targeting a specific disease type caused by mutations in the FGFR3 gene, resulting in manifestations in different tissues across the body. Aside from bone problems, patients with this specific type of achondroplasia also suffer from muscular, neurological and cardiorespiratory problems. Around 250,000 people worldwide are affected by this disease, according to Ascendis. TransCon CNP works by providing sustained exposure to the C-type natriuretic peptide, a molecule that helps stimulate bone growth and counter the inhibiting effects of FGFR3 mutations. Through this mechanism, Ascendis contends that its drug candidate could help ease the burden of symptoms and complications in achondroplasia. Ascendis tested the TransCon CNP in ACcomplisH, a randomized, double-blinded and placebo-controlled Phase II study that enrolled 42 patients who received 6 μg, 20 μg or 50 μg of the drug. Results, published in The Lancet in November 2023, showed that patients on TransCon CNP saw significant improvements in annualized growth velocity, alongside other key benefits, such as a stabilized quality of life and better physical functioning. In a June 2025 statement , Ascendis Chief Medical Officer Aimee Shu said the biotech’s clinical development program for TransCon CNP is the “first ever to demonstrate improvements beyond linear growth at 52 weeks compared to placebo.” Cytokinetics Could Challenge BMS in Cardiomyopathy Market Closing out this list is Cytokinetics and its cardio candidate aficamten, which is currently under FDA review for obstructive hypertrophic cardiomyopathy (oHCM). The FDA’s target decision date is Dec. 26. Aficamten blocks the cardiac myosin protein, which plays a role in heart contraction, allowing the oral drug candidate to address a key symptom of oHCM. Data from the Phase III MAPLE-HCM study, presented in August at the 2025 European Society of Cardiology Congress, demonstrated a significant improvement in exercise capacity over metoprolol, a beta-blocker used as standard-of-care in the disease. At the time, analysts at Truist Securities said aficamten’s results position it to be “potentially best-in-class” in oHCM. They called the MAPLE-HCM data “robust,” noting that outperforming metoprolol could help aficamten distinguish itself in the oHCM market. Cytokinetics filed for aficamten’s approval in late 2024, at which time the FDA provided an initial target action date of Sept. 26, 2025 . In May, however, the regulator extended its review by three months to review an additional risk mitigation strategy submission. If approved, aficamten will compete with BMS’s Camzyos, also a cardiac myosin inhibitor that won approval for oHCM in 2022 . The pharma is testing the drug in a non-obstructive form of the heart disease, but a readout in April this year was disappointing : Camzyos was unable to significantly outperform placebo in terms of exercise capacity outcomes, nor did it lead to better physical function.