PTC’s Phase III Data Sets Up PKU Competition With BioMarin
Executive Summary
Phase III data for PTC’s sepiapterin shows statistically significant reduction of blood phenylalanine levels in patients with phenylketonuria. BioMarin has the only two approved drugs for PKU.
Rare disease-focused PTC Therapeutics, Inc. unveiled Phase III data for its phenylketonuria (PKU) candidate sepiapterin (PTC923) on 17 May that looks capable of positioning the oral synthetic drug to compete with BioMarin Pharmaceutical Inc.’s two approved PKU therapies. But, while PTC highlighted data from a subset of more severe PKU patients, at least one analyst questioned whether the sample size would be large enough to win sepiapterin a broad label indication.
In a 98-patient readout from the Phase III APHENITY trial, PTC reported a mean 63% reduction in phenylalanine (Phe) at six weeks compared to minimal reductions among patients receiving placebo (p<0.0001). The New Jersey specialty firm noted that in patients with classical PKU, the mean Phe reduction was 69%, but that was from a sample of six patients, whereas the overall primary endpoint data are based on results from 49 patients receiving the study drug.
“These are outstanding results and clearly differentiate sepiapterin for the treatment of PKU patients of all ages and severity in terms of absolute Phe reduction in the overall primary analysis population,” PTC CEO Matthew Klein told a same-day call.
PTC, which acquired sepiapterin through its May 2020 purchase of Censa Pharmaceuticals Inc., said it plans to discuss the Phase III data with regulators to determine a path toward filing the drug for approval. (Also see "Deal Watch: Roche And Vividion Will Investigate E3 Ligases In Cancer, Immunology" - Scrip, 20 May, 2020.) PKU, a rare disease with an estimated 58,000 patients worldwide, is an inherited metabolic disorder caused by a genetic defect that limits the body’s ability to break down phenylalanine, an amino acid found in most foods. Buildup of Phe can lead to irreversible problems, including intellectual disability, seizures and delayed development, the company noted.
Competition In PKU
In PKU, sepiapterin would compete with BioMarin’s Kuvan (sanopterin, also available generically) and Palynziq (pegvaliase), a subcutaneous injectable available in multiple formulations. (Also see "BioMarin Expands PKU Dominion With EU Approval Of Palynziq " - Scrip, 7 May, 2019.) Oral Kuvan brought in $228m globally in 2022, although only $44m in the US, while Palynziq tallied $255m globally, including $188m in the US.
Klein said the BioMarin drugs leave the PKU patient population still underserved. “The vast majority of patients are not well-served and there's therefore a large potential market opportunity,” the exec told the investor call. “We believe these APHENITY results position sepiapterin to address the persistent large unmet need across all PKU segments. This includes therapy-naive patients, including classical PKU patients, [as well as] patients who have failed, are not well-controlled or do not tolerate existing therapies.”
In addition to the primary endpoint data, PTC also pointed out that the study showed that 84% of patients met the US guidelines for blood Phe levels (less than 360 micromoles per liter, or μmol/L) and 93% met the EU standard (less than 600μmol/L).
“These are really important results that substantiate, again, a meaningful, broad-based treatment effect,” Klein asserted. “For reference, the proportion of patients achieving target blood Phe levels in the Kuvan placebo-controlled trial was 32% for less than 360μmol/L and 54% for less than 600μmol/L.”
Wide Variance In Revenue Projections For PKU Therapy
SVB Securities analyst Joseph Schwartz wrote in a 17 May note that the APHENITY data overall were positive, but wondered if data from six patients with classical PKU (≥1,200μmol/L Phe blood level) “will be sufficient to include this patient group on the label.”
Schwarts also was concerned about PTC’s “rather loose” method for classifying classical PKU patients and the lack of data on genetic mutations. “While the baseline characteristics among the Classical PKU patients were slightly higher than the larger population (761μmol/L Classical PKU vs. 646μmol/L overall PKU), the two means were strikingly within the same range and meaningfully below the 1,200μmol/L threshold,” he said, “making us wonder if PTCT could get an expanded label to Classical PKU patients with small patient numbers and without genetic information.”
SVB still anticipates market entry in 2024 for sepiapterin, the analyst said, and its current peak revenue estimate is $400m in 2030. “Our assumptions are based on sepiapterin penetrating both Kuvan-response and Kuvan-non-responsive patients,” he added.
Analyst projections of peak revenues for sepiapterin varied widely following the Phase III data release, although analysts uniformly said the drug looks headed for US approval. Cantor Fitzgerald is modeling what analyst Kristen Kluska called a “conservative” projection of $767m in 2030 for the US and five-largest European markets (UK, Germany, Italy, France and Spain).
“We think the company has made a strong case for this opportunity, considering 1) the larger number of patients who aren’t adequately controlled/on any therapies and 2) showing the drug is more efficacious than standard of care,” Kluska said in her 17 May note.
Raymond James analyst Danielle Brill offered a cautionary take, pointing out that while sepiapterin appears to offer superior efficacy to Kuvan, the PTC drug “is administered at higher doses and for longer duration than comparative Kuvan datasets, which could inflate response rates independent of apples-to-apples efficacy differences between the two drugs.” Brill’s same-day note predicts a US filing in the second half of 2023, approval and launch in the US during the second half of 2024 and peak sales of around $250m for sepiapterin.
Truist’s Robyn Karnauskas pushed her projections much higher, saying based on discussions with physicians who treat PKU patients that worldwide peak sales of sepiapterin could reach $1bn, while conceding in her 17 May note that consensus estimates of peak sales are around $330m.
Sepiapterin Part Of Considerable Late-Stage Pipeline
Following the Censa deal’s closing in 2020, PTC built up a war chest exceeding $1bn, thanks partly to the sale of some its royalty rights tied to Roche Holding AG’s spinal muscular atrophy drug Evrysdi (risdiplam) for $650m, and claimed its days as a finance-raising company were over. (Also see "PTC Eyes Transition From Capital-Raising To Money-Making Company" - Scrip, 18 Aug, 2020.) Despite that cash position, plus revenue from its approved Duchenne muscular dystrophy products Emflaza (deflazacort) and Translarna (ataluren), the struggle to fund a pipeline heavy with late-stage candidates ultimately drove it to sell substantial equity to Blackstone last October for an upfront commitment of $500m. (Also see "Finance Watch: PTC Secures Up To $1bn In Funding From Blackstone" - Scrip, 4 Nov, 2022.)
Besides sepiapterin, PTC’s late-stage pipeline includes the gene therapy Upstaza (eladocagene exuparvovec) for aromatic L-amino acid decarboxylase (AADC) deficiency; vatiquinone in Phase III for both mitochondrial disease-associated seizures and Friedrich’s ataxia; and PTC518 in Phase II for Huntington’s disease. It is also seeking approval in the US of Translarna for DMD and of Upstaza for AADC deficiency, although both drugs are approved in Europe for those indications. (Also see "PTC Confident About Commercial Prospects For Gene Therapy Upstaza" - Scrip, 20 May, 2022.)