Top Stories
FDA partial clinical hold on PepGen FREEDOM2 trial raises questions for EDO oligonucleotide platform in myotonic dystrophy type 1
The FDA placed a partial clinical hold on PepGen’s FREEDOM2-DM1 Phase 2 trial of PGN-EDODM1 in patients with myotonic dystrophy type 1, a rare neuromuscular disease with no approved treatments. The hold relates to previously submitted preclinical pharmacology and toxicology studies and did not cite any concerns with blinded clinical data from the Phase 1 FREEDOM study, according to PepGen’s announcement. Notably, dosing continues at 10 mg/kg in the UK and Canada, where the Data Safety Monitoring Board recommended dose escalation. No US patients had been enrolled in FREEDOM2. PepGen reiterated that it expects to report 5 mg/kg cohort data in Q1 2026 and 10 mg/kg data in H2 2026. The Phase 1 FREEDOM study had demonstrated a mean splicing correction of 53.7% after a single 10 mg/kg dose, suggesting robust target engagement for the EDO platform’s approach to restoring MBNL1 splicing function. Both Orphan Drug and Fast Track designations from the FDA remain in place. As MarketScreener reported, this represents the second FDA hold affecting PepGen’s EDO programs following the December 2024 CONNECT2-EDO51 hold in Duchenne muscular dystrophy, raising broader questions about whether the platform’s preclinical package satisfies current FDA expectations for novel oligonucleotide delivery systems.
CHMP formally rejects Daybue for Rett syndrome in EU, creating transatlantic regulatory split as Acadia seeks re-examination
The EMA’s Committee for Medicinal Products for Human Use adopted a negative opinion on Acadia Pharmaceuticals’ marketing application for trofinetide (Daybue) in Rett syndrome patients aged two years and older, as Fierce Pharma detailed. The CHMP concluded that treatment effects in the pivotal LAVENDER trial were “too small” at 12 weeks and the study did not assess several key symptoms of the disorder. Patient discontinuations over time complicated long-term efficacy interpretation. Acadia plans to request formal re-examination, a process allowing the committee to reconsider with additional expert input. The rejection creates notable regulatory divergence: the FDA approved Daybue in 2023 based on the same LAVENDER data, and approvals followed in Canada and Israel. Rett syndrome affects approximately 1 in 10,000-15,000 female births worldwide, and more than 1,000 patients globally are currently on treatment. AllSci noted that with no disease-specific therapy approved in Europe, treatment continues to rely on supportive care, while gene therapies from Neurogene (NGN-401) and Taysha (TSHA-102) advance through clinical development as alternative approaches to the MECP2 mutation underlying the disorder.
Tenaya Therapeutics and Alnylam launch $1.13B biobuck collaboration to identify genetic targets in rare cardiovascular diseases
Tenaya Therapeutics and Alnylam Pharmaceuticals entered a research collaboration to discover novel gene targets for disease-modifying cardiovascular therapies, combining Tenaya’s iPSC-derived cardiomyocyte disease modeling with Alnylam’s RNAi platform. Tenaya will validate up to 15 gene targets over a two-year term, receiving up to $10 million upfront plus cost reimbursement, with Alnylam eligible to pay up to $1.13 billion in development and commercial milestones should validated targets reach approved therapies, as Nasdaq reported. Tenaya’s stock rose 38% on the news. Tenaya’s existing pipeline includes TN-201 for MYBPC3-associated hypertrophic cardiomyopathy and TN-401 for PKP2-associated arrhythmogenic right ventricular cardiomyopathy, both rare inherited cardiac conditions. The collaboration positions Alnylam to expand beyond its established ATTR franchise into broader genetic cardiology, while Tenaya gains non-dilutive funding and potential proof-of-concept data from RNAi validation of its proprietary targets. Alnylam will handle all downstream development and commercialization.
Pipeline Watch
Guggenheim Securities analysts attributed the FREEDOM2 hold in part to an understaffed FDA, according to Fierce Biotech. The FREEDOM2 hold follows the December 2024 CONNECT2-EDO51 hold in DMD, which was never resolved before PepGen voluntarily discontinued its Duchenne program after disappointing dystrophin levels of only 0.59% of normal at 10 mg/kg. The DM1 program’s stronger target engagement data — 53.7% splicing correction — may support a more constructive resolution with the agency. PepGen held $148.5 million in cash at year-end 2025.
The Alnylam collaboration extends beyond Tenaya’s existing HCM and ARVC gene therapy candidates into novel genetic mechanisms of cardiovascular disease. Tenaya’s target identification platform has generated more than 150 genetic targets to date, per the company, and Alnylam gains access to iPSC-based cardiomyocyte validation for its RNAi platform. The two-year discovery term and $10 million upfront payment are modest, but Nasdaq noted the $1.13 billion milestone structure reflects the breadth of up to 15 targets under evaluation.
Atrium emerged as a spinout from Novartis’s $12 billion Avidity Biosciences acquisition with $270 million in funding and two preclinical cardiovascular AOC candidates targeting rare cardiac conditions. Novartis retained Avidity’s Duchenne and myotonic dystrophy programs, while Atrium’s cardiology assets combine tissue-targeting antibodies with RNA therapeutics in a novel delivery approach distinct from conventional gene therapy vectors.
Sanofi secured global rights to Sino Biopharmaceutical’s dual JAK/ROCK inhibitor in a deal valued at up to $1.53 billion, with applications in hematology that may include rare blood disorders. The combined mechanism potentially offers differentiated efficacy compared to selective JAK inhibitors facing class-wide safety concerns. Development strategy and indication selection will determine positioning against existing JAK inhibitors, reported Fierce Pharma.
Competitive Landscape
The CHMP rejection means no disease-specific therapy is available for Rett syndrome patients in Europe, leaving supportive care as the standard while gene therapy candidates from Neurogene and Taysha advance through clinical development. AllSci reported that Anavex’s small-molecule blarcamesine also remains in development for the indication, potentially offering an alternative regulatory path in Europe if Daybue’s re-examination fails.
| Company | Therapy | Modality | Status |
|---|---|---|---|
| Acadia | Daybue (trofinetide) | Small Molecule | US Approved / EU Rejected |
| Neurogene | NGN-401 | AAV Gene Therapy | Phase 1/2 (BTD, RMAT) |
| Taysha | TSHA-102 | AAV Gene Therapy | Phase 1/2 (BTD, RMAT) |
| Anavex | Blarcamesine | Small Molecule | Phase 2/3 |
PepGen’s FREEDOM2 hold in DM1 follows its December 2024 CONNECT2 hold in DMD, forming a pattern of FDA preclinical concerns around the Enhanced Delivery Oligonucleotide platform. Competitors advancing conventional antisense oligonucleotides or AAV gene therapies in myotonic dystrophy may benefit from comparatively clearer regulatory pathways. The international trial design — dosing continues in the UK and Canada under separate regulatory frameworks — may provide supportive data while the US hold is addressed.
Two recent deals — Tenaya-Alnylam ($1.13 billion biobucks for genetic target discovery) and the Novartis-Avidity spinout creating Atrium ($270 million for rare cardiac AOCs) — signal growing pharma interest in rare inherited cardiovascular conditions beyond the established ATTR-CM market. The deals reflect distinct modality bets: RNAi versus antibody-oligonucleotide conjugates for delivering genetic medicines to heart tissue.
Forward Looking
- PepGen’s FREEDOM2 5 mg/kg cohort data readout expected in Q1 2026 will provide the first multi-dose efficacy signal for PGN-EDODM1 in DM1 and may influence FDA’s assessment of the partial clinical hold.
- Acadia’s CHMP re-examination of Daybue will clarify whether the committee’s evidentiary bar for Rett syndrome can be met with additional analyses or whether separate EU trial programs will be required for rare neurological indications.
- Tenaya-Alnylam’s two-year target validation timeline will test whether iPSC-based cardiomyocyte screening can efficiently identify druggable genetic targets for RNAi therapeutics in rare inherited cardiac conditions.
- PepGen’s resolution of the FREEDOM2 hold will signal whether FDA preclinical expectations for novel oligonucleotide delivery platforms have shifted broadly or remain specific to the EDO chemistry.