Del-desiran missed on a hand-opening time that clinical experts score from video
Novartis says it saw evidence of clinical activity in secondary and exploratory analyses it has not disclosed, while the drug missed its primary endpoint, an expert-rated video timing of hand opening. Shares fell 11% in Zurich.
The Scientist · Science desk
What happened
- Novartis said del-desiran missed the primary endpoint of its Phase III HARBOR trial in myotonic dystrophy type 1: a statistically significant improvement over placebo in video Hand Opening Time through week 54.
- Shares on the SIX Swiss Exchange fell 11%, from CHF 125.46 to CHF 111.80, the company's worst one-day decline since March 2020.
- Del-desiran is one of three antibody oligonucleotide conjugates Novartis inherited when it bought Avidity Biosciences for $12 billion in a deal that completed on February 27.
- GEN counted the HARBOR result as Novartis's third clinical setback in a week, after pelacarsen's Phase III miss with Ionis and the September 2 pause of eight rap-cel trials.
Why it matters
- Who has to decide decision Novartis now chooses between running a fresh pivotal trial on a different primary endpoint and winding the program down, roughly six months after paying $12 billion for the company that brought it in.
- What it sets up precedent A frequently used myotonia measure has now failed to separate drug from placebo in a Phase III, so any sponsor picking it as a primary endpoint in DM1 has to argue against that result.
- What it limits constraint With no data released, nobody outside Novartis can test whether the antibody delivered its siRNA into muscle, which leaves the modality question open rather than answered in either direction.
- What doesn't add up contradiction STAT ties the week's failures to acquisition strategy and a patent cliff, but the three programs involved share no chemistry, so a portfolio-timing read and a modality read point in different directions.
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vHOT asks clinical experts to watch a video and time the interval between a patient's grip and the hand opening again [2]. It is a frequently used measure of hand myotonia [2], and myotonia is delayed relaxation rather than weakness [7]. The secondary measures where Novartis says it saw signs of activity are mostly instrumented or functional: grip strength and a quantitative muscle testing composite, both read off a dynamometer, plus an activity and participation scale and a 10-meter walk/run test [22]. Force and relaxation time are not the same construct, and a rater-timed interval carries measurement variance that a dynamometer does not.
None of that is checkable, because Novartis published no numbers with the topline and says it is still evaluating the full dataset [11]. A pre-specified primary endpoint carries the trial's error control; secondary and exploratory cuts examined after that endpoint misses do not, which is why a sponsor's description of "clinical activity" is a hypothesis rather than a result.
Novo Nordisk's week supplies the shape worth holding onto. Ziltivekimab lowered markers of inflammation and still failed to reduce deaths and heart attacks in ZEUS, and two further cardiovascular trials, HERMES and ATHENA, were halted after a data monitoring committee judged them unlikely to succeed [9]. Del-desiran sits one step earlier than that: the target-engagement marker itself is unreported [11].
The two listings priced the same sentence differently. CHF 125.46 to CHF 111.80 is a fall of CHF 13.66, or 10.9% [4][17]; $159.99 to $137.72 is $22.27, or 13.9% [5][18]. The three-point gap [19] lives in the exchange rate and a separate trading session, not in anything additional about HARBOR.
The other two setbacks in the same week were pelacarsen, co-developed with Ionis, missing on a composite of cardiovascular events [6], and eight trials of the CD19-directed CAR T rap-cel paused on September 2 after three patients died following immune effector cell-associated hemophagocytic syndrome [16]. Neither shares a mechanism with a transferrin receptor 1 antibody conjugated to an siRNA against toxic DMPK messenger RNA [13]. What the vHOT miss does not tell you is where that chain broke: delivery into muscle, degradation of the mRNA, or the assumption that degrading it shortens hand-opening time. Those are three different failures with three different implications for the two other antibody-oligonucleotide conjugates that came over with Avidity [15][21], and a topline separates none of them.
Novartis holds FDA Breakthrough Therapy, Fast Track and Orphan Drug designations for del-desiran, plus EMA orphan status [14], so it will not lack a hearing when it takes the dataset to regulators [11]. On the published evidence this is a result about one endpoint in one trial, and the class verdict implied by a 14% move in the American depositary shares [5] runs well ahead of it.
What to watch
- Whether Novartis publishes the vHOT distributions and DMPK knockdown data from HARBOR, or only a topline narrative and a path forward.
- What primary endpoint regulators will accept if Novartis proposes a new pivotal trial in DM1, given it says it will engage with authorities.
- Readouts from the other two antibody oligonucleotide conjugates that came with Avidity, which are the real test of the modality.
Clarity's read
What the record supports and how the coverage leans. The claims behind it follow.
Reality
- Evidence62
- Adoption
- Not scored
- Hype gap+35
- Incentives60
- Confidence60
Claim ledger
Ranked by verification strength, evidence, and original report placement.
- [1]
Del-desiran failed the Phase III HARBOR trial (NCT06411288) by missing the primary endpoint of statistically significant improvement vs. placebo in video Hand Opening Time (vHOT) through week 54, in patients with myotonic dystrophy type 1 (DM1).
- [2]
vHOT is a frequently used measure of hand myotonia, according to a 2024 study, and involves clinical experts reviewing videos to measure the time from hand grip to opening.
- [3]
Novartis disclosed the HARBOR failure on Tuesday, according to STAT.
- [4]
Novartis shares on the SIX Swiss Exchange fell 11%, from CHF 125.46 to CHF 111.80, the company's worst one-day decline since March 2020.
- [5]
On the New York Stock Exchange, Novartis' American depositary shares dropped 14%, from $159.99 to $137.72.
- [6]
Novartis and partner Ionis Pharmaceuticals acknowledged that co-developed pelacarsen failed the Phase III Lp(a)HORIZON trial by missing its primary endpoint of reducing the risk of cardiovascular events versus placebo, a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and urgent coronary revascularization requiring hospitalization.
- [7]
DM1 causes progressive muscle stiffness and weakness, and vHOT is a measure of the hand's ability to relax after squeezing.
- [8]
STAT reported that the two study flops will likely raise questions about Novartis' pipeline and its acquisition strategy as it navigates a major patent cliff, though the company did see a victory with a multiple sclerosis drug last week.
- [9]
Novo Nordisk halted the HERMES and ATHENA cardiovascular trials of ziltivekimab after a data monitoring committee found they were unlikely to succeed, following the earlier ZEUS failure in which the drug lowered markers of inflammation but did not reduce the risk of major clinical complications including deaths and heart attacks.
- [10]
GEN described del-desiran's failure as Novartis' third clinical setback in a week.
- [11]
Novartis did not disclose details of its data but said it is evaluating the full HARBOR dataset and will engage with authorities to determine the most appropriate development path for del-desiran.
- [12]
Shreeram Aradhye, president, development and chief medical officer at Novartis, said developing therapies for a complex disease like DM1 remains challenging and that setbacks are part of scientific progress, and that the company remains committed to identifying the most appropriate development path for the del-desiran program.
- [13]
Del-desiran is an antibody oligonucleotide conjugate consisting of a muscle-targeting monoclonal antibody that binds transferrin receptor 1 (TfR1), conjugated to an siRNA designed to induce degradation of disease-causing toxic DMPK messenger RNA.
- [14]
Del-desiran has received the FDA's Orphan Drug, Fast Track and Breakthrough Therapy designations, and the European Medicines Agency's Orphan Medicinal Product Designation.
- [15]
Del-desiran is one of three pipeline antibody oligonucleotide conjugates Novartis inherited when it acquired Avidity Biosciences for $12 billion in a deal completed February 27, still among this year's largest biotech acquisition transactions.
- [16]
On September 2, Novartis paused eight trials of rapcabtagene autoleucel, a personalized CD19-directed CAR T therapy, after three patients died following immune effector cell-associated hemophagocytic syndrome.
- [17]
The Swiss-listed decline was CHF 13.66 per share, or 10.9%.
- [18]
The American depositary share decline was $22.27, or 13.9%.
- [19]
The ADS decline exceeded the Swiss-listing decline by about 3.0 percentage points.
- [20]
The Phase III miss came roughly six months after the Avidity acquisition completed.
- [21]
Two antibody oligonucleotide conjugates other than del-desiran came to Novartis with the Avidity deal.
- [22]
Novartis said it saw evidence of clinical activity in exploratory analyses and secondary endpoints, which included hand grip strength and quantitative Muscle Testing composite score, both measured by dynamometer; MD1 activity and participation scale; and the 10-Meter Walk/Run Test.
- [23]
Safety findings from HARBOR were generally consistent with previously reported data, according to Novartis.
Sources
2 independent publishers whose own reporting we read for this story.
- genengnews.comNovartis Shares Slide After Neuromuscular Candidate Acquired with Avidity Fails Phase III Trial
1 article · September 8, 2026
- statnews.comSTAT+: Novo Nordisk stops two cardiovascular trials of drug aimed at lowering inflammation
5 articles · September 11, 2026
Topics and entities
Topics
- Clinical trial failures
- Pharmaceutical acquisitions
- Myotonic dystrophy type 1
- Antibody oligonucleotide conjugates
Entities
- Novartis
- Ionis Pharmaceuticals
- Avidity Biosciences
- Rapcabtagene autoleucel
- Shreeram Aradhye
- Novo Nordisk
- Video hand opening time (vHOT)