Ultragenyx Pharmaceuticals Gets CRL for UX111 Gene Therapy for MPS IIIA

Ultragenyx Pharmaceuticals RARE announced that the FDA has issued a Complete Response Letter (CRL) for its biologics license application (BLA) for UX111. The AAV gene therapy is being developed as a treatment for patients with Sanfilippo syndrome type A (MPS IIIA). 

In the CRL, the FDA requested more information and enhancements concerning certain chemistry, manufacturing and controls elements and findings from recent manufacturing facility inspections. Per Ultragenyx Pharmaceuticals, the issues raised are facility- and process-related, not tied to product quality, and can be addressed quickly. It plans to work closely with the FDA in the coming months to resolve the observations, after which it expects to resubmit the BLA, triggering a review period of up to six months.

However, the FDA recognized the robustness of the submitted neurodevelopmental outcome data and the supportive nature of the biomarker findings. The CRL did not raise concerns about the clinical data or inspections but requested updated clinical data from current patients for inclusion in the resubmission. However, the regulatory setback has delayed the potential approval of UX111 for MPS IIIA to 2026.

Year to date, shares of RARE have plunged 30.5% compared with the industry’s 0.9% decline.

Basis for RARE’s BLA Submission for UX111 in MPS IIIA

Last year, Ultragenyx Pharmaceuticals submitted the UX111 BLA for MPS IIA under the FDA’s accelerated approval pathway.

The BLA submission was backed by data, including findings from the ongoing, pivotal phase I/II/III Transpher A study. Results show that treatment with UX111 led to a rapid and lasting reduction in heparan sulfate (HS) levels in the cerebrospinal fluid (CSF) of patients with MPS IIIA. Additionally, maintaining lower CSF HS levels over time was linked to improved long-term cognitive development, contrasting with the decline observed in natural history data. The investigational gene therapy was overall well-tolerated in the study. Adverse events related to treatment with the candidate were mostly mild to moderate in severity.

MPS IIIA is a rare, fatal lysosomal storage disease with no approved treatment that primarily affects the brain. Per Ultragenyx Pharmaceuticals, approximately 3,000 to 5,000 patients in commercially accessible geographies are affected by this disease, with a median life expectancy of 15 years. UX111 was added to RARE’s pipeline following an exclusive license agreement with Abeona Therapeutics in 2022.

The investigational gene therapy enjoys the Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease and Orphan Drug designations in the United States. In the EU, it has been granted the PRIME and Orphan Medicinal Product designations.

Other Key Clinical Programs in RARE’s Pipeline

Ultragenyx Pharmaceuticals has several other interesting gene therapy candidates in its pipeline. RARE and its partner, Mereo BioPharma, are jointly developing UX143 (setrusumab) monoclonal antibody forpediatric and young adult patients with osteogenesis imperfecta (OI) in two late-stage studies, Orbit and Cosmic.

The company is also evaluating UX701, an investigational AAV9 gene therapy, in a phase I/II/III Cyprus2+ study to treat Wilson disease. In 2024, Ultragenyx Pharmaceuticals announced that the phase III GlucoGene study, evaluating its investigational AAV8 gene therapy, DTX401, to treat glycogen storage disease type Ia patients aged eight years and older, achieved its primary endpoint with statistical significance. The GlucoGene study also met its key secondary endpoints. The next step for the company involves discussing these results with regulatory authorities to support a marketing application soon.

Last year, Ultragenyx Pharmaceuticals initiated dosing in the pivotal phase III Aspire study evaluating the efficacy and safety of GTX-102, its investigational antisense oligonucleotide, for Angelman syndrome.

RARE’ Zacks Rank and Other Stocks to Consider

Ultragenyx Pharmaceuticals currently carries a Zacks Rank #2 (Buy).

Some other top-ranked stocks in the biotech sector are Verona Pharma VRNA, Agenus AGEN and Bayer BAYRY. While VRNA and AGEN currently sport a Zacks Rank #1 (Strong Buy) each, BAYRY carries a Zacks Rank #2 at present. You can see the complete list of today’s Zacks #1 Rank stocks here.

In the past 90 days, Verona Pharma’s bottom-line estimates for 2025 have significantly improved from a loss of 7 cents per share to earnings of 22 cents. During the same timeframe, estimates for 2026 earnings per share have improved from $2.21 to $2.88. VRNA stock has soared 125.4% so far this year.

Verona Pharma’s earnings beat estimates in one of the trailing four quarters and missed the mark on the other three occasions, delivering an average negative surprise of 6.76%.

In the past 90 days, Agenus’ bottom-line estimates for 2025 have significantly improved from a loss of $4.66 per share to earnings of $1.56. During the same timeframe, estimates for 2026 loss per share have narrowed from $5.02 to $1.99. AGEN stock has surged 149.3% so far this year.

Agenus’ earnings beat estimates in two of the trailing four quarters and missed the mark on the other two occasions, delivering an average negative surprise of 22.71%.

BAYRY’s 2025 earnings per share estimate has increased from $1.19 to $1.27 for 2025 over the past 90 days, while that for 2026 has gone up from $1.28 to $1.34 over the same timeframe. Year to date, shares of Bayer have surged 65%.

BAYRY’s earnings beat estimates in one of the trailing four quarters, matched twice and missed on the remaining occasion, the average negative surprise being 13.91%.

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