Science2 publishers3 min readPublished
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.
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Why it matters
- 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.
- 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.
- 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.
- 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.
vHOT asks clinical experts to watch a video and time the interval between a patient's grip and the hand opening again [3]. It is a frequently used measure of hand myotonia [3], and myotonia is delayed relaxation rather than weakness [15]. 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 [4]. 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 [5]. 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 [17]. Del-desiran sits one step earlier than that: the target-engagement marker itself is unreported [5].
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% [8][1]; $159.99 to $137.72 is $22.27, or 13.9% [9][2]. The three-point gap [3] 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 [13], 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 [14]. Neither shares a mechanism with a transferrin receptor 1 antibody conjugated to an siRNA against toxic DMPK messenger RNA [10]. 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 [12][5], 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 [11], so it will not lack a hearing when it takes the dataset to regulators [5]. 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 [9] 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.