This biweekly Rare Disease Video Recap covers key developments across the space, including regulatory actions, reimbursement decisions, and new pathways shaping evidence requirements. The update also highlights clinical and translational progress in advanced modalities, including individualized genetic medicines.
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Top Stories Covered In This Video
Chapters
0:00 Introduction
0:08 Disc Medicine (bitopertin): FDA issued a complete response letter for erythropoietic protoporphyria (EPP), citing uncertainty that the surrogate endpoint predicts clinical benefit
0:53 NICE (England), Immedica (pegzilarginase): NICE recommended the first disease-modifying therapy for arginase-1 deficiency (ARG1-D) for routine NHS use
1:27 HanchorBio (HCB101): FDA granted orphan drug designation for gastric cancer for an anti-SIRPα-CD47 fusion protein
2:03 UCB (Kygevvi): EMA CHMP issued a positive opinion, recommending EU marketing authorisation under exceptional circumstances for TK2 deficiency
2:45 FDA (Plausible Mechanism Pathway): Draft guidance proposed a bespoke route for individualized genome-editing and RNA-based rare-disease therapies
3:18 Affinia (AFTX-201): EMA granted orphan drug designation for BAG3-associated dilated cardiomyopathy gene therapy
3:48 IntraBio (acetylleucine): EMA COMP recommended orphan medicinal product designation for CACNA1A disorders
4:24 CHOP and Penn Medicine (personalized CRISPR therapy for CPS1 deficiency): One-year update reported ongoing clinical improvements and tolerance after three infusions in 2025
5:07 How to reach us
Transcript
Welcome to the latest edition of Rare diseases Updates, covering breakthroughs in the past two weeks. Brought to you by LucidQuest.
First, in the US, the FDA issued a complete response letter to Disc Medicine for bitopertin in erythropoietic protoporphyria, or EPP. Disc’s filing leaned on Phase 2 data from a randomized, placebo-controlled study of 75 patients, using whole-blood metal-free protoporphyrin IX, PPIX, as the primary endpoint. The FDA said it is unknown whether changes in this surrogate endpoint predict clinical benefit, and that trials showed no evidence linking lowered PPIX to improved sun tolerance. This decision may affect prescriber choices and payer reviews as stakeholders wait for fuller data.
Next, in England, NICE recommended pegzilarginase for routine NHS use as the first disease-modifying therapy for arginase-1 deficiency, also called ARG1-D. NICE pointed to small, short studies and noted a commercial agreement between NHS England and Immedica. NICE described broader clinical benefits as suggestive and said more research is needed. The recommendation could influence prescribing and reimbursement decisions in the near term.
Third, in the US, the FDA granted orphan drug designation to HanchorBio’s HCB101 for gastric cancer. HCB101 is an Fc-based anti-SIRP alpha–CD47 fusion protein that is being evaluated in ongoing early-phase studies, with cohorts and combinations varying. As a reminder, safety and efficacy still need to be established through clinical investigation, but the designation signals continued investment in new immuno-oncology modalities.
Turning to the EU, the EMA’s Committee for Medicinal Products for Human Use, CHMP, issued a positive opinion for UCB’s Kygevvi, doxecitine and doxribtimine, in thymidine kinase 2 deficiency, or TK2 deficiency. CHMP recommended marketing authorisation under exceptional circumstances, with a European Commission decision expected later in 2026. The opinion covers adults and children with symptom onset on or before age 12, based on two studies reporting survival and functional outcomes. If authorised, this could shape clinical adoption and payer assessments, pending full data requirements.
Back to the US, the FDA published draft guidance describing a proposed route to market for individualized genome-editing and RNA-based treatments in rare diseases, sometimes referred to as a plausible mechanism pathway. The draft emphasizes the importance of natural history context, meaningful clinical outcomes, and confirmatory evidence. If finalized, the framework could create a clearer regulatory option for highly individualized genetic medicines.
In additional EU regulatory news, the EMA granted orphan drug designation to Affinia Therapeutics’ AFTX-201 for BAG3-associated dilated cardiomyopathy. AFTX-201 is an investigational AAV gene therapy intended as a one-time intravenous administration to deliver a BAG3 transgene, supporting development in a rare, serious genetic heart disease.
Also in the EU, EMA’s Committee for Orphan Medicinal Products, COMP, issued a positive opinion recommending orphan medicinal product designation for IntraBio’s acetylleucine for CACNA1A disorders. IntraBio described these as rare, progressive neurological conditions with no approved therapies, and said it is preparing to initiate a multinational Phase III trial in 2026. The company expects European Commission action in the second quarter of 2026.
Finally, in the US, Children’s Hospital of Philadelphia and Penn Medicine reported a one-year update since treating a child with CPS1 deficiency using what they describe as the world’s first personalized CRISPR gene therapy for this condition. CHOP reported a base editor delivered via lipid nanoparticles to correct a CPS1 variant in the liver, administered as three infusions from February through April 2025. They reported meaningful ongoing clinical improvements and no serious side effects to date, while noting it is not described as a cure and that monitoring continues.
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Why it matters
- FDA’s stance on surrogate endpoints can delay rare-disease approvals even when trials meet primary endpoints, pushing programs toward clinical outcome measures (Disc Medicine, bitopertin). [1]
- NICE coverage plus commercial terms can unlock routine access in ultra-rare disease despite limited evidence bases (pegzilarginase, ARG1-D). [2]
- EU “exceptional circumstances” and orphan pathways remain central tools for ultra-rare disorders, but post-authorisation evidence expectations often remain high. [4]
- FDA’s draft pathway for individualized therapies may reshape how personalized gene-editing and RNA medicines are reviewed, especially where RCTs are impractical. [5]
- Orphan milestones for gene therapy (Affinia) and neurology programs (IntraBio) highlight continued EU incentives across modalities. [6], [7]
🗓️ Explore weekly details and sources
- Weeks 12–18 February 2026
- Week 19–25 February 2026
📚 Find your one-stop page for the full Rare Disease archive.
FAQ
What was the FDA’s main issue with Disc Medicine’s bitopertin submission in EPP?
FDA questioned whether the surrogate endpoint (PPIX reduction) is reasonably likely to predict clinical benefit, and noted no evidence tying PPIX lowering to improved sun tolerance in the submitted trials. [1]
What did NICE recommend for pegzilarginase in ARG1 deficiency, and what were the evidence limits?
NICE recommended pegzilarginase for routine NHS use in England, while noting evidence came from small, short studies (with more research needed). [2]
Does FDA orphan designation mean HCB101 is proven effective in gastric cancer?
No, orphan designation provides incentives, but safety and efficacy still must be demonstrated in clinical trials before approval. [3]
What is the significance of CHMP’s “exceptional circumstances” route for Kygevvi in TK2 deficiency?
It supports a marketing authorisation recommendation when comprehensive evidence collection is difficult due to rarity, with the EC making the final decision later in 2026 (per the report). [4]
What exactly happened for Affinia’s AFTX-201 in Europe?
EMA granted orphan drug designation for AFTX-201 for BAG3-associated dilated cardiomyopathy, an incentive intended to support development for rare, serious conditions. [6]
What exactly happened for IntraBio’s acetylleucine in Europe?
EMA COMP issued a positive opinion recommending orphan medicinal product designation for acetylleucine for CACNA1A disorders, with an EC decision expected in Q2 2026 (per the company). [7]
Entities / Keywords
Disc Medicine, bitopertin, erythropoietic protoporphyria (EPP), PPIX, complete response letter
NICE, NHS England, Immedica, pegzilarginase, arginase-1 deficiency (ARG1-D)
HanchorBio, HCB101, SIRPα, CD47, orphan drug designation, gastric cancer
UCB, Kygevvi, doxecitine, doxribtimine, thymidine kinase 2 deficiency (TK2d), CHMP, exceptional circumstances
FDA draft guidance, Plausible Mechanism Pathway, individualized genetic medicines, genome editing, RNA-based therapies
Affinia Therapeutics, AFTX-201, BAG3-associated dilated cardiomyopathy (DCM), AAV gene therapy, EMA orphan designation
IntraBio, acetylleucine, levacetylleucine, CACNA1A disorders, EMA COMP opinion
CHOP, Penn Medicine, CPS1 deficiency, personalized CRISPR, base editing, lipid nanoparticles
