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2027 Event Site
RNA interference has moved from a Nobel Prize-winning discovery to a validated drug platform, and John Harris MD, PhD used that progress to ask Anastasia Khvorova PhD, Francesco De Rubertis PhD and Craig Shepherd what it will take to move siRNA beyond the liver and into a much wider range of diseases.
Khvorova described the chemistry and biology that made liver delivery possible, including chemical stabilization and receptor-mediated uptake, and pointed to the unusual durability now achievable with some siRNA medicines. That raises the possibility of replacing daily pills with treatments given only once or twice a year. The next frontier is extrahepatic delivery, with work advancing in tissues including skin, muscle, heart and the central nervous system.
The financing discussion showed how different investors approach the same scientific risk at different points in development. Shepherd reflected on Blackstone's large, structured investment in Alnylam after the platform had survived major setbacks and demonstrated clinical validation. De Rubertis explained Medicxi's asset-centric model, which generally favors focused programs with a clearer path to proof of concept rather than financing broad platforms for decades.
Across science and capital, the conversation came back to de-risking. RNAi is no longer being asked to prove that gene silencing can work in humans. The challenge now is delivering the right molecule to the right tissue, showing meaningful clinical benefit and matching the financing model to the time required to get there.
Session Focus
Harris introduced the panel himself rather than having members do it, so he could use superlatives they would not use about themselves. The four participants span the full arc of siRNA: chemistry and delivery, translation and disease understanding, company creation, and financing at scale.
He disclosed his own position openly. He is a physician scientist seeing patients and running a laboratory, and an entrepreneur who has started five companies, all funded, as he noted possibly not coincidentally, by De Rubertis. One of those is Aldena Therapeutics, focused on siRNA delivery to skin, developed with Khvorova over eight or nine years and now in clinical testing of a JAK1-targeting approach for alopecia areata.
Why the Promise Took Fifteen Years
Harris framed the history from personal experience, having trained at UMass Chan Medical School across the hall from Craig Mello as RNAi was discovered, work that won the Nobel Prize in 2006.
The theoretical appeal was immediate and enormous. Antibodies target extracellular proteins. Small molecules typically target enzymatic proteins. Both carry limitations. siRNA can target anything with an mRNA, which is every protein.
Everyone expected immediate transformation. It took roughly 15 years and, in Harris’s account, Khvorova, to convert the discovery into an actual therapeutic, requiring extensive chemistry for durability, targeted tissue delivery and cellular delivery.
What Made Liver Delivery Work
Khvorova was direct that delivery is easy in 2026 and clearly was not in 2016. Two layers of innovation made the difference.
Full chemical stabilization. When siRNA reaches cells it is entrapped in endosomes and lysosomes, forming an intracellular depot that continually releases drug.
Hijacking asialoglycoprotein receptors, a natural liver mechanism that evolved for clearing misfolded protein. Her summary: understanding the biology and understanding the chemistry.
Her assessment of the clinical result was unusually strong. What is being seen in clinic exceeds anybody’s dream, and she considers it one of the major innovations in how medicine is delivered. Durability in patients from a single administration produces clinical efficacy up to a year, and longer in some cases.
She noted a consequence nobody anticipated: physicians are now saying the duration is too long, because the field does not know how to clinically develop drugs with that pharmacokinetic profile.
What Annual Dosing Would Mean
Khvorova argued the impact on human health is not yet fully appreciated. The transition is from one or several pills a day to something closer to a vaccination schedule, which she acknowledged may be an unfortunate word at present.
The key variable is compliance. Treating a disease with 100 percent compliance once a year or once every six months changes the cost profile substantially, both on the drug side and on administration.
Her projection: a future not far off in which a patient visits a doctor once or twice a year for a shot against high cholesterol, a shot against high blood pressure, and a shot to prevent the development of Alzheimer’s disease and dementia.
Beyond the Liver
Khvorova said robust delivery is now achievable to muscle, heart and skin. For the central nervous system, multiple clinical trials are underway and transvascular delivery to the CNS is emerging, with acknowledged challenges.
Her confidence was unqualified: she has zero doubt that CNS delivery will become as clinically impactful as the multiple liver indications are today.
Beyond her own work on skin, she has founded companies targeting siRNA to the brain for Huntington’s disease and to the placenta for preeclampsia.
The Anatomy of a $2 Billion Financing
Harris asked Shepherd what Alnylam had done right in the liver that justified pulling the trigger.
Shepherd described a holistic financing solution assembled in 2020 across four components.
A $1 billion investment in the inclisiran royalty, which Novartis has since turned into a blockbuster, resting on exactly the thesis Khvorova articulated: currently twice yearly, potentially once yearly, for hypercholesterolemia, a large market given the prevalence of atherosclerotic cardiovascular disease.
A structured debt facility into Alnylam’s siRNA platform.
Product financing in two parts, funding HELIOS-B for vutrisiran in ATTR cardiomyopathy, and zilebesiran, then relatively early stage, in resistant hypertension.
A $100 million equity purchase.
He was candid that the trajectory was not a straight line, with multiple generations of platform chemistry and delivery and meaningful failures along the way.
Why a Failure Inspired Confidence
Shepherd identified something counterintuitive as the strongest signal: the pivot from revusiran to vutrisiran.
Revusiran looked compelling in cardiomyopathy pharmacologically, achieving greater than 80 percent TTR knockdown. But it required a weekly injection, which anyone reasonable in the field recognized was not the way forward. In phase three there were multiple on-treatment deaths. Causation was never established and the patient population was very sick.
Alnylam turned the program off and went back to the laboratory to work out how to do it better.
That willingness to stop a pharmacologically working program and rebuild is what gave Blackstone confidence in the platform, rather than any single uninterrupted success.
Where Trials Fail
Harris raised a Novartis program treating myotonic dystrophy type 1 using an antibody-oligonucleotide conjugate against the transferrin receptor. The antibody binds the receptor, aiding internalization and delivering the oligonucleotide that knocks down DMPK. The HARBOR trial did not meet its endpoint.
The panel’s framing of the broader lesson is that there are many independent points of failure in an siRNA program. A trial can fail on design, on delivery, or on target biology, and distinguishing which one failed is itself difficult.
Key Takeaways
1. siRNA can address any protein with an mRNA, unlike antibodies or small molecules, which is why expectations ran ahead of capability for 15 years.
2. Two innovations made liver delivery work: full chemical stabilization creating an intracellular depot, and hijacking a natural clearance receptor.
3. Single administrations now produce efficacy for a year or more, to the point that clinical development methods have not caught up.
4. The real prize is compliance. Annual dosing at 100 percent compliance changes both drug and administration economics.
5. Muscle, heart and skin delivery are robust today, with CNS delivery emerging through multiple trials.
6. A $2 billion financing combined royalty, structured debt, product financing and equity rather than any single instrument.
7. Killing a working program built investor confidence. The revusiran to vutrisiran pivot signaled platform discipline.
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