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# Avidity’s Phase 3 Miss Leaves Novartis With a $12 Billion M&A Hangover
- URL: https://bioweek.com/aviditys-phase-3-miss-leaves-novartis-with-a-12-billion-m-a-hangover/
- Published: 2026-09-09T05:03:18.000Z
- Updated: 2026-09-10T05:04:06.000Z
- Description: Del-desiran missed its primary endpoint in myotonic dystrophy type 1, wiping 13% off Novartis, pulling rival Dyne down 22%, and casting doubt over TfR1 RNA delivery.
- Author: BioWeek
- Tags: Pipeline, Markets

Novartis [announced](https://www.globenewswire.com/news-release/2026/09/08/3357301/0/en/novartis-provides-update-on-delpacibart-etedesiran-del-desiran-phase-iii-harbor-study-for-the-treatment-of-myotonic-dystrophy-type-1-dm1.html?ref=bioweek.com) on September 8 that del-desiran, the Antibody Oligonucleotide Conjugate it bought Avidity Biosciences to own, missed the primary endpoint of the global Phase 3 HARBOR trial in myotonic dystrophy type 1\. Video hand opening time at 54 weeks did not improve versus placebo with statistical significance. The miss lands on an asset that Jefferies had modeled at $1.5 billion in peak annual sales, about one-third of the $12 billion all-cash [buyout](https://www.biopharmadive.com/news/novartis-rna-drug-failure-dm1-avidity-del-desiran/829778/?ref=bioweek.com) that closed in February 2026 after the October 2025 agreement.

The Swiss major still pointed to “evidence of clinical activity” on secondary measures. It did not publish p-values or effect sizes. That gap, more than the headline failure, is what the Street is now pricing.

### A functional clock that would not keep time

HARBOR (NCT06411288) enrolled roughly 150 patients, nearly 160 participants in the [study](https://clinicaltrials.gov/study/NCT06411288?ref=bioweek.com) registry, dosed every eight weeks. The primary readout was video hand opening time, vHOT, a timed functional test meant to capture myotonia, the delayed muscle relaxation that defines DM1\. Key secondaries included hand grip strength, Quantitative Muscle Testing total score, the DM1-Activ patient-reported scale, and the 10-meter walk/run test.

Cantor Fitzgerald’s Eric Schmidt [noted](https://www.biopharmadive.com/news/novartis-rna-drug-failure-dm1-avidity-del-desiran/829778/?ref=bioweek.com) that vHOT carries substantial test-retest variability, a precarious hurdle for a registration trial. Myotonia fluctuates with temperature, effort, and practice. A noisy stopwatch as the single gate for a $12 billion thesis is a design choice, not a biological verdict. Novartis can still argue that DMPK knockdown and splicing repair happened in muscle. What it cannot argue is that the trial’s chosen clock moved.

The biology remains coherent. DM1 is driven by a CTG trinucleotide repeat expansion in the 3' UTR of DMPK. The mutant transcript forms nuclear hairpin foci that sequester MBNL splicing factors and dysregulate the muscle chloride channel CLCN1, producing the myotonia vHOT was supposed to measure. Del-desiran pairs a monoclonal antibody against transferrin receptor 1 with an siRNA against toxic DMPK mRNA, using the TfR1 shuttle to get oligonucleotide into skeletal muscle. Phase 1/2 MARINA data [published](https://pubmed.ncbi.nlm.nih.gov/41707138/?ref=bioweek.com) in the New England Journal of Medicine showed 40% to 50% DMPK knockdown and molecular splicing correction in muscle biopsies. Molecular rescue without a clean functional win is now the central tension in TfR1-mediated muscle RNA delivery.

### A $12 billion thesis meets two other failures

Novartis shares [fell](https://www.biospace.com/drug-development/novartis-12b-avidity-acquisition-hits-phase-3-speedbump-as-dystrophy-drug-disappoints?ref=bioweek.com) more than 12% to 13%, trading below $139, as HARBOR stacked onto a brutal week. On September 4, pelacarsen missed in the Phase 3 Lp(a)HORIZON cardiovascular study of more than 8,300 patients. The company has also suspended trials of the CAR-T candidate rapcabtagene autoleucel after three patient deaths. Jefferies analyst Michael Leuchten said the Avidity deal will raise questions about business development discipline and the post-2030 growth story, even as Novartis reaffirmed 5% to 6% sales CAGR guidance through 2030.

That guidance is the tell. Management is treating del-desiran as a late-decade optional extra, not a 2030 pillar. Two remaining Avidity assets still sit inside the Swiss pipeline: del-zota (delpacibart zotadirsen), under priority review for Duchenne muscular dystrophy exon 44 skipping, and del-brax (delpacibart braxlosiran) in facioscapulohumeral muscular dystrophy. Those programs do not share HARBOR’s endpoint. They do share the TfR1 AOC chassis. If muscle delivery is the platform, one Phase 3 functional miss does not kill it. If the Street bought Avidity for a DM1 launch, the [acquisition](https://www.biopharmadive.com/news/novartis-rna-drug-failure-dm1-avidity-del-desiran/829778/?ref=bioweek.com) just repriced.

### Dyne’s 22% haircut and a halved probability

Dyne Therapeutics (Nasdaq: DYN) dropped 22% on the read-through. Its rival candidate, z-basivarsen (DYNE-101), is a Fab-ASO conjugate that also targets TfR1 and also measures hand opening time in the ongoing Phase 1/2 ACHIEVE study. Cantor Fitzgerald cut Dyne’s probability of success from 50% to 25%. The market is not distinguishing siRNA from antisense, or a full monoclonal from a Fab. It is marking down the entire TfR1-to-muscle RNA class against a functional endpoint that just failed to separate from placebo in a properly powered Phase 3.

That compression may overshoot. Del-desiran is an siRNA payload. DYNE-101 is an ASO. Dosing intervals, extrahepatic exposure, and splicing versus knockdown kinetics are not interchangeable. ACHIEVE is still early. Hand opening time as a shared measurement, however, is interchangeable, and that is the risk Dyne now owns. If vHOT is too noisy to register a real myotonia benefit, both companies need a different primary, or a composite that includes QMT, grip, and 10mWRT with prespecified hierarchy. If vHOT is an honest null, then biopsy knockdown of 40% to 50% is not enough clinical muscle.

Novartis has not said whether it will file, continue, or redesign. Secondary signals without numbers are a holding pattern, not a path. For RNA muscle delivery, HARBOR is the first large, placebo-controlled test of whether TfR1 conjugates convert nuclear DMPK knockdown into a timed functional gain. The conjugate got into muscle. The splicing story from MARINA still stands. The 54-week clock did not. Until someone shows a quieter endpoint, or a larger effect, the $12 billion Avidity premium is an M&A hangover, and Dyne is paying a 22% cover charge for a trial it did not run.