The FDA has set target approval dates for three breakthrough therapies addressing rare genetic disorders, with decisions expected in the third quarter of 2025 that could transform treatment landscapes for patients with phenylketonuria, spinal muscular atrophy, and acromegaly.
Sepiapterin Offers New Hope for PKU Patients
PTC Therapeutics' sepiapterin, formerly known as PTC923, faces a July 29, 2025 PDUFA target action date for treating pediatric and adult patients with phenylketonuria (PKU). The therapy addresses a critical unmet need in PKU, an inherited metabolic disease caused by mutations in the phenylalanine hydroxylase (PAH) enzyme that leads to elevated blood phenylalanine levels and potential neurological damage.
Sepiapterin employs a dual mechanism of action, converting intracellularly to tetrahydrobiopterin (BH4), a PAH cofactor, while simultaneously acting as a chaperone to protect against PAH misfolding and increase PAH activity. This approach represents a significant advancement over current treatment options, which rely primarily on strict dietary protein restriction supplemented by BioMarin's existing therapies.
The phase III APHENITY trial demonstrated compelling efficacy results, with sepiapterin achieving a mean 63% reduction in blood phenylalanine levels in PKU patients. Notably, 84% of patients achieved phenylalanine control below 360 μmol L⁻¹, substantially outperforming existing treatments. BioMarin's Kuvan (sapropterin) shows only a 30% response rate with a 29% decrease in blood phenylalanine levels over six weeks, while Palynziq (pegvaliase) demonstrated approximately 62% improvement over eight weeks in its phase III PRISM-2 trial.
Perhaps most significantly for patient quality of life, over 97% of participants in the open-label extension study's phenylalanine tolerance protocol could liberalize their diet, experiencing a mean 126% increase in protein intake. The European Medicines Agency issued a positive opinion on sepiapterin in April 2025, with EU marketing authorization expected later this year.
Myostatin Inhibition Shows Promise in SMA
Scholar Rock's apitegromab, a human monoclonal antibody targeting myostatin activation, has received FDA priority review with a September 22, 2025 PDUFA date for spinal muscular atrophy treatment. The therapy selectively binds pro- and latent forms of myostatin in skeletal muscle, addressing the progressive muscular atrophy and weakness characteristic of SMA.
SMA results from mutations in the SMN1 gene that reduce levels of the SMN protein, leading to motor neuron degeneration. Current treatments, including Biogen's Spinraza (nusinersen) and Roche's Evrysdi (risdiplam), target SMN2 gene splicing to increase functional SMN protein levels. However, patients typically experience progressive decline in motor function despite these interventions.
The phase III SAPPHIRE trial demonstrated apitegromab's potential as an add-on therapy, showing a statistically significant 1.8-point improvement in Hammersmith Functional Motor Scale Expanded (HFMSE) scores in the combined 10 mg kg⁻¹ and 20 mg kg⁻¹ treatment arms among patients already receiving nusinersen or risdiplam.
Apitegromab may face future competition from other myostatin inhibitors in development, including Biohaven's taldefgrobep alfa and Roche's GYM329. While taldefgrobep's phase III RESILIENT SMA study showed clinically meaningful improvements, it missed statistical significance on its primary endpoint at week 48. Top-line data from GYM329's ongoing phase II/III trial are expected in 2025.
Oral Somatostatin Agonist Targets Acromegaly Market
Crinetics' paltusotine, an oral selective somatostatin receptor type 2 (SST2) agonist, has a September 25, 2025 PDUFA target date for acromegaly treatment and long-term maintenance therapy. Acromegaly, a chronic endocrine disorder characterized by excessive growth hormone production from benign pituitary tumors, causes excess insulin-like growth factor-1 secretion, progressive disfigurement, organ enlargement, and significant health complications.
The therapy's approval package includes data from two pivotal phase III trials. In PATHFNDR-1, which evaluated patients switching from injectable somatostatin receptor ligands, 83% of paltusotine-treated patients maintained IGF-1 levels within the normal range compared to 4% receiving placebo. The PATHFNDR-2 trial in medically untreated patients demonstrated that 56% achieved IGF-1 normalization at 24 weeks versus 5% in the placebo group.
Paltusotine could significantly impact a market currently dominated by injectable somatostatin receptor ligands such as octreotide and lanreotide. While Chiesi's Mycapssa provides an oral octreotide formulation for some patients, paltusotine's novel mechanism could offer an effective oral alternative for a broader patient population, including those initiating medical therapy.
Regulatory Outlook
All three therapies are also under review by the European Medicines Agency, suggesting potential global market access if approved. These approvals represent significant advances in rare disease treatment, offering patients new therapeutic options that could improve both clinical outcomes and quality of life compared to existing standard-of-care treatments.
