The Rare Responsibility of 2025

The Rare Responsibility – Special Edition 2025

Dear Impossible Readers,

Earlier this year, I began this blog with The Rare Responsibility. Now, it feels only natural to conclude 2025 with some of the rare discoveries that shaped it.

At the core of that shift was Huntington’s disease. For decades, Huntington’s has been the emblem of a devastating, stubborn genetic disorder. However, in 2025, we finally obtained credible clinical and mechanistic evidence indicating that it is possible to alter the course of the disease in humans. On one hand, a gene therapy programme showed promising early-stage human data. Patients treated with a direct brain-delivered therapy displayed significantly slower progression compared to historical or matched controls. Although the cohort was small, and long-term safety and durability remain uncertain, this represents the strongest indication yet that we can modify Huntington’s in humans.

Yet, Huntington’s was not the only headline. 2025 also saw the first case of personalised gene editing. A baby with carbamoyl phosphate synthetase 1 (CPS1) deficiency received a custom CRISPR‑based treatment tailored to their specific mutation. This was not part of an extensive commercial programme. In fact, it was essentially a one-patient medicine with significant implications. It demonstrated that we can move from individual genomic diagnosis to personalised genome editing, under compassionate or emergency use, and achieve meaningful clinical benefits. It is now an active, patient-centred reality.

However, before a personalised cure can be crafted, the mutation must be discovered. This brings us to the diagnostics front, where Solve-RD, a pan-European collaboration, made significant progress. By re-analysing genomic data from thousands of previously undiagnosed patients using improved pipelines and updated variant-interpretation tools, the team identified over 500 new rare disease diagnoses. This is not just an academic achievement. It highlights that a significant part of the rare disease challenge lies in diagnosis. Without knowing who has what, treatments, no matter how advanced, remain out of reach. In 2025, we recognised that diagnosing rare diseases is not limited by a lack of data, but by a lack of interpretation. And that is changing rapidly.

Alongside the progress in diagnosis and early testing, 2025 was equally significant for regulatory approvals. Approximately 14 new drugs received FDA approval, primarily for rare diseases. These included treatments for hereditary angioedema (both acute and preventive), neurofibromatosis type 1 (plexiform neurofibromas), tenosynovial giant cell tumour, diffuse midline glioma, and long-waited options for Barth syndrome, IgA nephropathy, a subset of phenylketonuria, myasthenia gravis, and haemophilia A/B. These approvals not only signify scientific progress but also demonstrate regulatory and commercial willingness to develop therapies for small patient populations.

Beneath the headlines, the clinical-trial engine itself has accelerated. According to industry intelligence, in the first half of 2025, there were around 6,071* Phase I–III interventional trial starts worldwide. Using a conservative industry estimate that roughly 35% of pipeline programmes target rare diseases, that indicates over 2,100* rare disease trials began in just six months. Extrapolating to the whole year, we are likely to see approximately 4,200* new rare disease trial starts in 2025. Meanwhile, the global number of active rare disease trials (across all phases) is likely to remain in the low tens of thousands. A remarkable scale for what was once a niche category.

This scale matters because it is not just about more trials, but about smarter ones. Gene therapy, genome editing, and RNA modalities are no longer artisanal, one-off efforts. Manufacturing and quality control are being standardised. Instead of handcrafted gene vectors or RNA molecules made patient-by-patient, we are beginning to see repeatable workflows, modular production lines, and manufacturing units that function more like foundries.

The industrial maturity brings us to a significant indicator of capital and confidence. In October 2025, Novartis announced it would acquire Avidity Biosciences for $12 billion in cash. Avidity is a pioneer in Antibody‑Oligonucleotide Conjugates (AOCs), a delivery platform designed to target RNA therapeutics directly to muscle tissue. Its pipeline includes three late-stage neuromuscular programmes: del-zota (for Duchenne muscular dystrophy), del-desiran (for myotonic dystrophy type 1), and del-brax (for facioscapulohumeral muscular dystrophy). Notably, Novartis made the deal even as Avidity spun off its early-stage precision cardiology programmes into a separate company, SpinCo, indicating that Novartis is increasing its focus on genetically defined neuromuscular diseases. The acquisition not only provides Novartis with new drug candidates but also a platform. It affirms that RNA‑delivery technology is considered sufficiently significant to justify a multi-billion-dollar purchase.

Beyond the Novartis–Avity acquisition, 2025 was a notably busy year for rare disease deals and strategic partnerships. Sanofi broadened its focus on rare immunology and precision haematology by acquiring Blueprint Medicines for several billion dollars, with Ayvakit, a systemic-mastocytosis therapy, at its core. Merck KGaA boosted its rare oncology efforts by buying SpringWorks Therapeutics, while BioMarin expanded into metabolic and genetic disorders by adding Inozyme Pharma to its portfolio. Meanwhile, Alexion, AstraZeneca’s division dedicated to rare diseases, continued to invest heavily in gene therapy platforms, acquiring next-generation AAV capsid technology to support future ultra-rare indications. Overall, these developments show that rare diseases are no longer niche markets but are now key to long-term innovation strategies in the biopharmaceutical industry.

Yet, amid all this progress, a realistic outlook persists. Not all experiments will succeed. Many early clinical results, such as the Huntington gene therapy, come from small patient groups and require long-term follow-up. Manufacturing scale is improving, but the high cost of goods remains a significant barrier to cell and gene therapies. Regulatory endpoints for very rare diseases cannot always depend on conventional large-scale clinical trials. Digital or molecular endpoints may be necessary, although these methods are still being tested and refined. While Novartis’ Avidity deal sends a strong signal, it also reveals a truth. Not all companies will take on the risk of low-volume, high-complexity manufacturing. The capital structure needed for ultra-rare therapies may differ from Big Pharma’s usual approach.

In short, 2025 marked the year when rare disease treatment stopped being an accident. It was no longer about individual, heroic founders or niche gene-therapy studios. Instead, platforms matured, capital aligned, data interpretation expanded, and regulatory systems began to adapt. The coming years will not just be about demonstrating that rare diseases are solvable. They will focus on proving that treating rare diseases is sustainable.

All the best,
Yours Possibly

*OpenAI (2025) ChatGPT (GPT-5.1 model). Assistance to estimate the number of rare disease clinical trials (Phase 1–3) for the year 2025.

P.S. Do not forget to vote in 2026!