Oligonucleotides & RNA
20 articles
GSK wins FDA approval for its hepatitis B drug
- STAT reports that GSK has won FDA approval for its hepatitis B drug.
- The drug extended functional cures to far more patients than previous methods, according to the report.
- Details beyond the headline were not available to us; the product is understood to be the antisense bepirovirsen.
A functional-cure label in hepatitis B is a landmark for the field, and GSK gets it with an antisense oligo, not a small molecule or antibody. The commercial question is uptake: finite treatment courses mean less recurring revenue per patient, but a large, long-diagnosed population. Watch Vir, Arbutus and the Chinese siRNA players, who now have a bar to clear.
China proposes curbs on foreign acquisitions of critical biopharma technologies
- China is proposing new restrictions on foreign acquisitions of critical biopharma technologies as it seeks to keep control of its fast-growing drug development industry.
- Trade coverage of the draft (Fierce) describes it as targeting full transfers of proprietary cell and gene therapy, siRNA and pathogen gain-of-function platforms, while standard out-licensing and CRO/CDMO outsourcing appear to be exempt.
- The final text and timing are not confirmed.
If licensing really stays exempt, the draft mostly shuts the door on buying a Chinese platform company outright while leaving the license-in model that Western pharma has leaned on intact. That nudges deal structure toward options and NewCo licensing, not away from China. Buyers of cell, gene and siRNA platforms are the ones who should re-run their pipelines of targets.
STAT+: China moves to restrict foreign biotech acquisitions ↗
Merck KGaA buys Silence Therapeutics for about $1.3B after siRNA Phase 2 win
- Merck KGaA will acquire Silence in an all-cash deal at $20 per ADS, an equity value of about $1.3 billion, via a UK scheme of arrangement.
- The price is a 130% premium to the prior close, and Silence called it the outcome of a competitive sale process.
- The deal follows positive Phase 2 data for Silence's siRNA divesiran in polycythemia vera.
A 130% premium for a single mid-stage asset says Merck KGaA is paying for de-risked rare-haematology data and a validated platform, not for breadth. It needs growth after its portfolio gaps, and siRNA offers a modality it can slot in. Watch whether Silence's platform survives as a standalone engine or just feeds divesiran.
Merck KGaA buys Silence in $1.3B deal after siRNA drug's phase 2 blood cancer win ↗
mRNA-display macrocycle IMP2660 gives the first effector-free RAB27A structure
- mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660.
- IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions.
- Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.
The crystallography chaperone angle is the underrated payoff: wild-type RAB27A only crystallized with its effector, so a clean macrocycle-bound structure unlocks soak-in and fragment work. Whether IMP2660 itself is more than a tool is another matter, since permeability for a nonapeptide-sized macrocycle against an intracellular GTPase is the obvious hurdle.
A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗
Merck and Moderna say their mRNA cancer vaccine plan still needs a lot of exploring
- At the STAT Summit, Moderna's Stephen Hoge and Merck's Dean Li discussed pairing Keytruda with personalized mRNA cancer vaccines.
- Both executives framed the first positive results as a start, with much left to work out.
- This summary rests on the article's teaser, not the full text.
Pairing a personalized vaccine with Keytruda protects Merck's franchise as PD-1 exclusivity ages, so Merck has a strategic reason beyond the science. The executives' caution about what comes next is telling: the open questions are tumor types, dosing settings and manufacturing scale. Rivals with other neoantigen approaches should read it as a bar to clear.
Merck and Moderna have 'lot of exploring to do' after initial cancer vaccine success ↗
Roche licenses Rona's ALK7-targeting RNAi obesity candidate in a deal worth up to $1.16B
- Roche gets an exclusive license to Rona Therapeutics' investigational ALK7-targeting RNAi candidate for obesity.
- Terms: up to $100M in upfront and near-term milestones, plus up to $1.06B in longer-term milestones and tiered royalties.
- The program's codename and development stage were not disclosed.
ALK7 is the second hot RNAi obesity target after GSK's earlier SiranBio deal, and Roche says it wants to be a top-three obesity player, so this is portfolio-building on the cheap: small upfront, back-loaded milestones. It's also Roche's fifth deal with a Chinese drugmaker since late August, a sign that the best-priced early assets are still found there.
Roche inks $1.2B deal with China's Rona to enter emerging ALK7 obesity race ↗
mRNA-display macrocycles reveal CHD4 as an interaction hub in the NuRD complex
- mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
- The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
- Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.
One selection campaign delivering both hits and biology is a nice outcome. Macrocycles sitting on a protein–protein interface are rarely drug-like as they stand, so my question is whether the ternary structure lets us shrink them toward something cell-permeable; the second site on CHD4 gives another handle for that. I'd also want to see selectivity against related remodelers.
DNA origami carrying a barnase variant is built to cleave mutant KRAS mRNA
- Mutant KRAS variants are structurally diverse and lack druggable pockets, which has limited small-molecule inhibitors.
- The authors assemble a degrader on a six-helix-bundle DNA origami scaffold that targets the mRNA rather than the protein.
- One module pairs an engineered barnase variant with a programmable recognition strand, cutting RNA directly without relying on endogenous cellular machinery; a second module is designed for cell penetration.
If KRAS has no pocket worth chasing, going after the mRNA is a fair dodge, and a catalytic barnase gives a clean mechanism: sequence-guided cleavage, no reliance on endogenous machinery. But I would want to see the data before getting excited. How well does the recognition strand discriminate single-base mutants from wild-type KRAS, given barnase's cleavage is catalytic and unforgiving of leakage? And does it survive delivery, with real potency in cells and a sensible comparison to siRNA or ASO?
Novartis licenses Abogen's mRNA-encoded T-cell engager for autoimmune disease
- Novartis gains worldwide exclusive rights to ABO2203, an mRNA-encoded CD19xCD3 T-cell engager produced in vivo to reset B cells in autoimmune disease.
- The package is $575M upfront plus up to $7.2B in milestones (up to $7.8B in total) and royalties.
- Novartis also receives options on other Abogen RNA-based programs.
- The deal follows Novartis pausing an autoimmune CAR-T program after three deaths.
The $7.8B headline is mostly contingent; the $575M upfront is the real conviction signal. Landing this after pausing an autoimmune CAR-T program reads like Novartis hedging its B-cell reset thesis toward an in vivo, mRNA-delivered CD19xCD3 format. The options on other Abogen RNA programs suggest it is buying platform access, not just one asset.
Novartis pens $7.8B deal for Abogen's in vivo autoimmune T-cell engager ↗
Sefaxersen Hits Primary Endpoint in Phase 3 IgA Nephropathy Trial, Opening Path to Accelerated Approval
- Sefaxersen, Ionis's antisense oligonucleotide suppressing liver complement factor B, met the primary endpoint of Roche's Phase 3 IMAgINATION trial in high-risk primary IgA nephropathy.
- A prespecified interim analysis of 459 patients (1:1 randomized) showed statistically significant, clinically meaningful proteinuria reduction (24-hour UPCR) vs. placebo at week 37.
- The once-monthly, self-administered subcutaneous drug could support accelerated approval in a crowded IgAN market that already includes sparsentan.
Complement factor B suppression becomes a third distinct mechanism validated in IgA nephropathy, joining sparsentan's endothelin/AT1 blockade and the B-cell/APRIL plays from atacicept and sibeprenlimab; convergent proteinuria data across mechanisms suggests the market fragments by dosing convenience, not efficacy. Once-monthly self-injection undercuts daily oral and infused rivals on adherence, while Ionis banks another platform-licensing win validating its originate-and-out-license model.
Roche kidney drug's Phase 3 win sets up path to accelerated approval ↗
Better Linker Chemistry Lifts siRNA Antibody-Conjugate Delivery
- A new bioRxiv preprint investigates how the chemical architecture of antibody-oligonucleotide conjugates (AOCs) affects their performance as siRNA delivery vehicles.
- The work examines design variables such as linker composition, conjugation site on the antibody, and siRNA chemical modification pattern.
- Findings aim to clarify which structural choices most influence knockdown potency and delivery efficiency, informing rational AOC design.
Whether AOC chemists can transplant ADC lessons on conjugation-site control and linker stability wholesale — or oligo payloads demand their own rules — matters more than the siRNA payload itself. Locking down DAR and site-specificity is what turns AOCs into the extrahepatic answer GalNAc conjugates can't be, which is exactly why Alnylam, Avidity, and everyone else is racing to nail this chemistry first.
Enhancing the efficacy of siRNA Antibody Oligonucleotide Conjugates (AOCs) through chemical design ↗
BioNTech, Genentech Terminate Phase 2 Trial of mRNA Cancer Vaccine Autogene Cevumeran in Colorectal Cancer
- Autogene cevumeran is an individualized, tumor-specific neoantigen mRNA vaccine designed to trigger a T-cell response against a patient's unique tumor mutations.
- Phase 2 trial BNT122-01, run with Genentech, evaluated it as adjuvant monotherapy versus watchful waiting in ctDNA-positive patients with surgically resected Stage II (high-risk) or Stage III colorectal cancer, targeting roughly 327 enrollees with disease-free survival as the primary endpoint.
- BioNTech and Genentech terminated the trial on August 28, 2026, after an independent Data Safety Monitoring Board (DSMB) identified a numerical overall-survival imbalance disfavoring the vaccine arm and concluded continuation was unlikely to change the efficacy outcome; no new safety signals were found.
- A separate, unaffected Phase 2 trial (Imcode003) continues to evaluate autogene cevumeran combined with checkpoint inhibition and chemotherapy in adjuvant pancreatic ductal adenocarcinoma.
- BioNTech shares fell as much as 8% on the news.
An OS imbalance with no new safety signal is a different failure mode than a safety-driven halt — it indicts adjuvant monotherapy in CRC, not necessarily neoantigen mRNA vaccines as a modality. That distinction matters competitively: Moderna/Merck's V940 (INT) has paired its individualized vaccine with pembrolizumab from the outset rather than testing it solo against watchful waiting, and BioNTech's own still-running pancreatic trial (Imcode003) uses that same vaccine-plus-checkpoint-inhibitor-plus-chemo architecture. So the part of the platform that just failed is arguably its least mechanistically ambitious use case. The 8% single-day drop on one Phase 2 readout, though, is the bigger tell — it shows how much of BioNTech's valuation still rests on individualized-vaccine optionality rather than de-risked, validated pipeline.
BioNTech, Genentech terminate Phase 2 of personalized mRNA cancer vaccine ↗
Tuning the Linker Improves RNA-Degrading Drugs Targeting cMYC
- RIBOTACs (ribonuclease-targeting chimeras) are heterobifunctional small molecules that recruit an endogenous ribonuclease to degrade a chosen RNA, rather than inhibiting a protein directly.
- This study applies the approach to cMYC mRNA; cMYC is an oncogenic transcription factor long considered "undruggable" because no direct small-molecule inhibitors have reached clinical use.
- Researchers systematically varied the length and rigidity of the linker connecting the RNA-binding ligand to the ribonuclease-recruiting moiety.
- Linker geometry proved to be a key determinant of how efficiently the RIBOTAC promotes cMYC mRNA degradation.
- Optimized linkers translated into improved downstream modulation of cMYC protein levels in cell-based assays.
- The findings support linker engineering as a general design lever for RIBOTAC-based RNA-targeted therapeutics.
cMYC is the target every med chemist has scars from — decades of "undruggable" transcription-factor programs that went nowhere, so any credible new handle gets attention. What's genuinely useful here isn't the RIBOTAC concept itself but the linker SAR: length and rigidity dominating degradation efficiency is exactly the PROTAC linkerology lesson replaying in RNA-target space, and it's reassuring that the same design intuition transfers. That said, don't lose sight of the tractability problem — these are still bifunctional, comfortably-beyond-Ro5 molecules with the synthetic and PK baggage PROTACs never fully shook off. And the data are cell-based potency, not in vivo proof of concept; going from "degrades cMYC mRNA in a dish" to "a dosable, selective drug" is still the hard part nobody's solved for this target.
Linker Optimization of cMYC RIBOTAC for Efficient cMYC Modulation ↗
Modular H-Phosphonate Platform Opens New Route to Backbone-Modified Oligonucleotides
- Oligonucleotide backbone chemistry gets a new modular entry point: an H-phosphonate diester dinucleotide 'blockmer' platform that builds backbone-modified oligonucleotides through standard solid-phase synthesis.
- The method exploits the ambiphilic reactivity of H-phosphonate diesters, allowing diverse phosphate backbone modifications to be installed without air- or moisture-sensitive P(III) reagents or hazardous chemicals.
- Accessible backbone modifications span a wide range, from simple alkyl substitutions to sulfonamide-linked phosphate analogs, well beyond conventional phosphorothioate-type chemistries.
- Because the dinucleotide blockmers are compatible with existing solid-phase assembly workflows, they can be combined and positioned flexibly within a single oligonucleotide sequence.
- The platform is designed to enable systematic backbone structure-activity relationship studies in oligonucleotide drug discovery, providing a scalable and robust route for rapid analog generation.
H-phosphonate diesters as bench-stable P(III) surrogates is the headline: no more babysitting moisture-sensitive phosphitylating reagents under inert atmosphere just to install a novel backbone linkage. Backbone modification has been the stubborn bottleneck in oligo SAR — everyone can vary the sugar or the base, but stepping outside phosphorothioate/phosphorodiester space usually means bespoke phosphoramidite synthesis for every single analog. Pre-made dinucleotide blockmers flip that: build a small library of linkage types once, then mix-and-match them like ordinary phosphoramidites on standard solid-phase cycles, placing modifications at any position in the sequence. For a team running iterative backbone SAR, that's the difference between a multi-week custom-monomer detour and a same-week analog set. Real question is whether coupling efficiencies and diastereomer control hold up across the full modification set, not just the showcase examples.
Novartis' Avidity-Acquired DM1 Drug Del-Desiran Fails Phase 3 HARBOR Trial
- Del-desiran (delpacibart etedesiran), the antibody-oligonucleotide conjugate (AOC) Novartis picked up through its roughly $12B acquisition of Avidity Biosciences, failed to separate from placebo on the primary endpoint of the Phase 3 HARBOR trial.
- The 159-patient trial tested del-desiran against placebo in adults with myotonic dystrophy type 1 (DM1), a progressive muscle-wasting disease with no approved treatments.
- The primary endpoint, change in video hand opening time (vHOT) over 54 weeks, did not show a statistically significant improvement over placebo.
- Novartis said secondary and exploratory endpoints showed some evidence of clinical activity, and the company is reviewing the full dataset and plans to engage regulators on a path forward.
- Endpoints News framed the miss as Novartis' second major late-stage trial disappointment within days (following a setback for its Lp(a) drug pelacarsen), reporting that Novartis shares sank roughly 10% on the news.
The AOC platform itself isn't dead — secondary and exploratory signals suggest the biology worked, just not enough on this endpoint — but a primary miss on the lead asset from a $12B acquisition is about the worst possible first data readout for validating a new modality. Novartis bought Avidity for the platform, not just del-desiran, so the real question is whether this de-risks or re-risks the rest of the inherited AOC pipeline (cardiac, muscular dystrophy programs). Pair it with pelacarsen's stumble the same week and this reads less like bad luck than a pattern: aggressive, high-multiple platform bets hitting rocky Phase 3 data almost immediately. That's a harder story to sell investors than either miss alone, and it may cool appetite for the next big platform acquisition — Novartis' or anyone else's.
Updated: Novartis sinks after second disastrous trial failure, this time of Avidity-acquired drug ↗
Novartis' Lp(a)-lowering drug pelacarsen fails cardiovascular outcomes trial
- Novartis' pelacarsen missed the primary endpoint in the Phase 3 Lp(a)HORIZON cardiovascular outcomes trial, which enrolled 8,323 patients with elevated lipoprotein(a) and established cardiovascular disease.
- Pelacarsen is an antisense oligonucleotide, licensed from Ionis Pharmaceuticals, designed to suppress hepatic production of Lp(a), a lipid-protein particle linked to elevated cardiovascular risk.
- The drug achieved substantial lowering of Lp(a) levels in treated patients, but this biomarker reduction did not translate into a statistically significant drop in cardiovascular death, heart attack, stroke, or urgent revascularization versus placebo.
- The result is the first major late-stage setback for the emerging Lp(a)-lowering drug class, raising questions for rival programs from Amgen and Eli Lilly that use different modalities but showed larger Lp(a) reductions in earlier-stage studies.
- Novartis and Ionis had held global rights under a licensing and collaboration deal, with Ionis having discovered and advanced pelacarsen through early development before Novartis took it into Phase 3.
Pelacarsen just became the class's first hard-outcomes readout — and it missed, despite deep Lp(a) lowering. That's the uncomfortable part: this was the cleanest test yet of the Lp(a) causal hypothesis, and it didn't confirm it. Olpasiran (Amgen) and lepodisiran (Lilly) post larger percentage reductions in early studies, but bigger knockdown of the same biomarker doesn't guarantee outcomes benefit — their own outcomes trials now carry real doubt, not just execution risk. For Novartis, this was a marquee asset licensed from Ionis to anchor its cardiovascular pipeline; the miss removes a near-term blockbuster case and puts pressure on how the Ionis partnership economics get valued going forward. Biggest read-through: Lp(a) may need rethinking as a validated drug target, not just a biomarker to chase.
Novartis' experimental cardiovascular drug fails a pivotal study ↗
ARPA-H Bets $125M on On-Demand, Personalized RNA Manufacturing
- ARPA-H is funding automated manufacturing systems to produce personalized RNA medicines near the point of care in under a week, awarding up to $125M across five teams under its GIVE program.
- The largest award, up to $54.5M, went to Waterfall Scientific, which leads a six-company consortium building a continuous-flow, cell-free mRNA manufacturing and characterization platform (project ESCALATOR).
- Consortium partners include Ansa Biotechnologies (enzymatic DNA synthesis), Volta Labs (automated fluid handling), Polymorphic Biosciences (LNP formulation), Tensentric (hardware engineering) and Ginkgo Bioworks.
- Goal: compress custom RNA drug production timelines from months to days, enabling distributed, patient-proximate manufacturing without sacrificing quality.
ARPA-H is capitalizing infrastructure here, not a specific drug — Waterfall's $54.5M award and the government's stamp of approval become leverage for the consortium's next fundraising or partnering conversations. Non-dilutive capital validating a shared-infrastructure model lowers the barrier for N-of-1 and other personalized RNA programs smaller biotechs could never justify building dedicated GMP capacity for. For Ansa, it validates enzymatic DNA synthesis as a manufacturing input beyond its core synbio pitch; for Ginkgo, it's another foundry contract reinforcing the picks-and-shovels positioning it's leaned on since COVID-testing revenue dried up. Washington is treating rapid, decentralized genetic-medicine manufacturing as a national-capability question now, not just a therapeutic one.
GSK Advances Dual-Target mRNA Flu Vaccine to Phase 3 Trial
- GSK will start a Phase 3 trial of its mRNA seasonal flu vaccine after Phase 2 data (Flu-028, ~971 adults) showed stronger immune responses against every tested flu strain than licensed comparator vaccines, with acceptable tolerability.
- Unlike most approved flu shots, which target only hemagglutinin (HA), GSK's candidate also encodes neuraminidase (NA), the second major surface protein flu uses to spread between cells.
- Growing evidence suggests adding an NA response could improve protection, reduce illness severity, and limit transmission compared with HA-only vaccines.
- The Phase 3 trial will be the first late-stage study of a dual HA/NA mRNA flu vaccine, positioning GSK against Moderna's newly approved single-target mRNA flu shot.
- The FDA granted the candidate Fast Track designation in July 2026, and GSK expects to begin the pivotal trial this month.
GSK's bet: that the stronger immune responses seen in Phase 2 translate into real clinical benefit — fewer infections, milder illness, less transmission — which an HA-only shot like Moderna's already-approved mRNA flu vaccine can't match. This is the first real Phase 3 test of the "NA matters" thesis, not yet proven at scale. It's a platform signal as much as a product one. After lagging Pfizer/Moderna's first-generation, single-antigen mRNA vaccines, a Phase 3 win would show GSK's mRNA engine can handle more complex, multi-antigen constructs. Flu vaccines are a large but seasonal, commoditized, price-pressured market — the real payoff isn't flu revenue itself, it's flu as the proving ground before GSK extends dual/multi-antigen mRNA into RSV, combo respiratory shots, or pandemic-response platforms. If it works, expect the mRNA flu narrative to shift from "mRNA vs. egg-based" to "how many antigens can you stack" — the next competitive axis in a race that's outgrowing its first generation.
GSK catches phase 3 fever after mRNA flu vaccine beats standard shots ↗
Ultragenyx's Angelman Syndrome Drug Fails Phase 3 Trial, Shares Plunge 40%
- Ultragenyx's Phase 3 ASPIRE trial tested apazunersen (GTX-102), an antisense oligonucleotide, in children and adolescents with Angelman syndrome.
- The therapy failed to separate from sham on the primary endpoint, a Bayley-4 cognitive score change, and also missed the key secondary Multidomain Responder Index.
- No consistent efficacy signal emerged across the individual measures making up that secondary endpoint.
- Safety data lined up with earlier Phase 1/2 findings, with no new red flags reported.
- Shares of Ultragenyx sank more than 40% in after-hours trading on the news.
- The company said it will decide the program's fate and cut costs while leaning on its approved commercial products.
Angelman syndrome is genetically validated (UBE3A) but remains a graveyard for CNS translation — another reminder that hitting the target biology doesn't guarantee a measurable cognitive readout on Bayley-4. No consistent signal across the Multidomain Responder Index components rules out an easy subgroup-rescue story; this reads as a clean miss, narrowing Ultragenyx to kill-or-redesign rather than reslice-the-data. GTX-102/apazunersen was Ultragenyx's flagship CNS asset for years — the >40% drop erases a large chunk of market cap and pressures near-term capital allocation, even with a clean safety profile. The commercial portfolio (Crysvita, Dojolvi) buys runway to absorb this rather than face an existential crisis, but expect cost cuts and tighter pipeline focus. Broader signal: one more data point against intrathecal ASOs cracking cognitive endpoints in neurodevelopmental CNS disease.
Ultragenyx drug to treat Angelman syndrome, a rare disease, fails late-stage trial ↗
Alnylam Defends ATTR-CM Franchise After Rival's Wainua Trial Stumbles
- Full Phase 3 CARDIO-TTRansform results, presented at ESC Munich, showed AstraZeneca/Ionis's TTR silencer eplontersen (Wainua) failed to significantly cut cardiovascular death/events in ATTR-CM over roughly 140 weeks (rate ratio 0.89, p=0.277).
- Critically, patients already on a stabilizer (Pfizer's Vyndaqel, BridgeBio's Attruby) saw no added benefit from Wainua; only silencer-monotherapy patients showed a nominal gain.
- That subgroup split is uncomfortable for Alnylam, whose Amvuttra and pipeline candidate nucresiran are the same drug class and increasingly used alongside stabilizers.
- Alnylam shares fell nearly 5%.
- Executives countered that Amvuttra achieves deeper TTR knockdown than eplontersen and that nucresiran's larger TRITON-CM trial should avoid Wainua's pitfalls.
The subgroup data is the real story: if silencers add nothing once patients are already stabilized, the industry's drift toward stabilizer-plus-silencer combos loses its evidence base, and AZ/Ionis must reposition Wainua as monotherapy — a much smaller, harder-to-sell market. That's a strategic problem, not just a trial miss, and it makes Intellia's one-and-done knockdown pitch relatively more attractive. Alnylam's rebuttal (deeper knockdown, a bigger trial) is the self-interested defense you'd expect from a company facing guilt-by-association, resting on cross-trial comparisons Alnylam itself is asserting, not independent data — treat "deeper knockdown" as a hypothesis until TRITON-CM reads out. Nucresiran's margin for error just got narrower. Watch prescriber messaging: whoever wins the "silencer as add-on vs. backbone" argument sets ATTR-CM's standard of care.
Alnylam defends heart disease drugs after failure of AstraZeneca's Wainua ↗