In mid-2025, we published an article sharing our insights and commitment to the following five gene therapy clinical development programs actively pursuing Accelerated Approval: Ultragenyx's UX111 for MPS IIIA, REGENXBIO's RGX-121 for MPS II, uniQure's AMT-130 for Huntington's disease, Rocket Pharmaceuticals' RP-A501 for Danon disease, and Sangamo's ST-920 for Fabry disease.
A lot has happened since then, and we're providing that update below.
UX111 (Ultragenyx / MPS IIIA)
In July 2025, Ultragenyx received a Complete Response Letter (CRL), not on clinical grounds, but due to CMC-related issues identified during manufacturing facility inspections. The BLA was resubmitted in January 2026, still seeking Accelerated Approval, now supported by clinical data out to 8.5 years and updated biomarker evidence. A PDUFA date is expected in Q3 2026. The Accelerated Approval pathway and the rationale for surrogate endpoints remain intact.
RGX-121 (REGENXBIO / MPS II)
RGX-121, an AAV gene therapy under development for Hunter syndrome, received a CRL from the FDA in February 2026. While there appeared to have been prior alignment on the development approach and surrogate endpoint, the FDA's position changed materially at the time of review. According to REGENXBIO, the CRL cited three primary concerns:
- The comparability of the external control cohort.
- Whether the proposed biomarker is reasonably likely to predict clinical benefit to support Accelerated Approval.
- Aspects of the patient population included in the dataset.
The decision occurred in the midst of broader safety scrutiny — in January 2026, FDA placed a clinical hold on the Sponsor's RGX-111 gene-therapy program for Hurler syndrome after a brain tumor was detected in a participant treated in an early-stage study. The tumor was discovered during routine MRI monitoring several years after treatment, and an investigation into whether the event was related to the therapy is ongoing. Because RGX-111 and RGX-121 use related AAV vectors in pediatric lysosomal storage disorders, the hold was extended to RGX-121 shortly before its PDUFA date.
This CRL underscores the sensitivity of CNS gene-therapy programs that rely on biomarkers, small datasets, and external controls.
AMT-130 (uniQure / Huntington's Disease)
This one has another significant update. Following a Type A meeting in January 2026, the FDA walked back its prior position (according to the Sponsor) and instead stated that it cannot agree that Phase I/II data, compared to an external control, are sufficient to support a marketing application, and strongly recommended a prospective, randomized, double-blind, sham surgery-controlled study. This is a meaningful shift from the earlier FDA alignment that was the basis for our original article. uniQure is planning a Type B meeting in Q2 2026 to discuss Phase III design. The path to Accelerated Approval for AMT-130 may have fundamentally changed.
RP-A501 (Rocket Pharmaceuticals / Danon Disease)
The Accelerated Approval pathway remains the goal for this program, with biomarker-based co-primary endpoints anchoring the program. Though 2025 progress was disrupted after a patient in the Phase 2 pivotal trial passed away from an acute systemic infection, prompting a clinical hold. The hold was lifted in under three months with FDA confirmation that Rocket satisfactorily addressed all identified issues, and the trial resumed at a recalibrated dose with a modified immunomodulatory regimen. Dosing of the next cohort of patients is expected in the first half of 2026.
ST-920 (Sangamo / Fabry Disease)
The FDA-Sangamo alignment on Accelerated Approval seems to be holding strong. Sangamo initiated a rolling BLA submission in December 2025, with full BLA completion expected under the Accelerated Approval pathway in Q2 2026. Earlier this month, Sangamo submitted the preclinical and clinical modules to the FDA, and the companion antibody assay diagnostic was accepted by the FDA's CDRH for Premarket Approval review, a meaningful parallel milestone. The program is advancing on all fronts.
The Bigger Picture
The first quarter of 2026 has brought several high-profile regulatory decisions involving rare disease therapies that have sparked discussion across the biotech and rare disease communities, particularly regarding accelerated approval and evolving evidentiary expectations. Press releases say "FDA walked back its position" or "FDA moved the goalposts," with the above examples at the forefront.
However, whether these Sponsors fully met their commitments leaves the story incomplete. From where we sit, having worked with dozens of Sponsors navigating this exact landscape, the pattern is rarely as simple as FDA moving the goalpost. FDA agreements are frequently, if not always, conditional. What gets communicated as "FDA agreed" or "FDA is aligned" is often "FDA agreed in principle, under very specific conditions, pending data we have not yet generated, not have presented a design to generate." That distinction matters at the time of review. The question worth asking in each of these cases is not only what FDA said, but what the Sponsor delivered, whether the data fully supported the hypothesis, and whether the alignment that was described in press releases was ever as firm as it appeared.
Nonetheless, these decisions, Sponsor announcements, and hearsay continue to raise practical questions for other Sponsors developing therapies for rare and ultra-rare conditions, particularly where development relies on surrogate endpoints, small patient populations, external controls, or non-traditional study designs.
Questions Sponsors Are Asking
- How is the FDA currently evaluating surrogate endpoints and biomarkers in rare disease programs, and what determines whether they are sufficient to support approval?
- In rare and ultra-rare populations, what level of clinical evidence is acceptable when traditional trial designs are not feasible?
- Under what circumstances does accelerated approval remain an appropriate pathway for rare diseases?
- What trial designs are acceptable when patient numbers are extremely limited?
- As FDA leadership emphasizes flexibility, how will this be reflected in the review divisions' regulatory decisions?
Ultimately, Sponsors want clarity on how FDA's current thinking, particularly regarding biomarkers, external controls, and evidentiary standards, will shape the development and approval pathways for the next round of rare disease therapies they'll see.
(Read more about RareMoon's insights into these questions in an upcoming blog.)
Emerging Themes Across These Updates
Although it is premature to draw firm conclusions from these regulatory decisions several common themes are becoming apparent.
- Surrogate endpoints remain under close scrutiny, particularly where the link between the proposed biomarker and meaningful clinical benefit has not been clearly established or is not supported by robust mechanistic and epidemiological evidence.
- External controls must be robust and prospectively justified. Natural history data are increasingly viewed as a core development asset, requiring formal study designs and FDA alignment well before BLA submission.
- Early and effective regulatory engagement is not the same thing. Sponsors can check the box on meeting frequency yet still arrive at review misalignment. The quality of the dialogue, the specificity of the agreements, and how thoroughly those agreements are followed through is critical.
- FDA programs, pilot initiatives, and formal meeting structures exist specifically to build collaboration and alignment on biomarkers, endpoints, and control strategies. Sponsors who use these tools strategically, and early, may be in a stronger position than those who engage reactively.
Other Programs on Our Radar
Bitopertin: Erythropoietic Protoporphyria
Disc Medicine's NDA for bitopertin in erythropoietic protoporphyria also received a CRL in February 2026. The program sought accelerated approval based on reductions in protoporphyrin IX (PPIX), proposed as a surrogate biomarker.
While the FDA acknowledged the biomarker reductions observed in clinical trials, the Agency concluded that the data did not adequately demonstrate that reductions in PPIX were reasonably likely to predict meaningful clinical benefit. The FDA also indicated that results from the ongoing Phase III Apollo study could serve as the basis for traditional approval.
This decision reinforces continued scrutiny of surrogate endpoints in rare disease programs, even where biomarker changes are biologically plausible.
EBVALLO (tabelecleucel): EBV-Positive Post-Transplant Lymphoproliferative Disease
The regulatory path for EBVALLO, an allogeneic T-cell therapy for Epstein-Barr virus-positive post-transplant lymphoproliferative disease, continues to be closely watched. The therapy received a second CRL in January 2026 after resubmission of the BLA.
Notably, the Agency appeared to reverse their position; the single-arm clinical dataset, which, according to the Sponsor, was previously considered adequate to support the BLA filing, is no longer sufficient to provide evidence of effectiveness for accelerated approval. The Sponsor has indicated plans to re-engage with the FDA to determine the appropriate path forward.
This case highlights the importance of early alignment on dataset adequacy and the potential for evolving expectations during review, particularly for accelerated approval applications supported by small studies.
Other Near-Term Decisions
- Kresladi (marnetegragene autotemcel) from Rocket Pharmaceuticals, a gene therapy for leukocyte adhesion deficiency-I (LAD-I), with a target FDA action date of March 28, 2026.
- Tividenofusp alfa from Denali Therapeutics, an investigational enzyme therapy for Hunter syndrome currently under Priority Review, with an FDA decision expected on April 5, 2026.
- Orca-T, an investigational allogeneic cell therapy for hematologic malignancies including AML, ALL, and MDS, being developed by Orca Bio, with a PDUFA action date of April 6, 2026.
Additional decisions are expected throughout the year as the rare disease pipeline matures and more advanced-therapy programs reach regulatory milestones. These reviews may further clarify FDA's current approach to surrogate endpoints, natural history controls, and evidentiary standards in rare disease development.
As always, RareMoon will continue to monitor these signals closely and remains available to support Sponsors seeking early alignment with FDA on development strategy, endpoint selection, and regulatory pathways.