One missed hand-opening endpoint costs Novartis 2.5 times the Avidity purchase price
Artisan Partners' David Samra is telling Novartis's chairman to rebuild the team that does its deals, after a week of three Phase III setbacks in which one of the drugs actually met its primary endpoint.
The Scientist · Science desk
What happened
- Novartis shares fell 11 percent in a single day, wiping nearly $30 billion off market value and erasing every gain the stock had made since the start of the year.
- The drug came into Novartis through a $12 billion buyout of Avidity that brought three late-stage programs in a class the companies call Antibody Oligonucleotide Conjugates.
- On September 4, Novartis and Ionis said their co-developed pelacarsen missed the primary endpoint of the Phase III Lp(a)HORIZON trial, one of three Novartis setbacks inside a week.
Why it matters
- Who's exposed exposure Samra aimed at a person. The chairman personally owns the answer on how Novartis approves acquisitions, and whatever he says becomes the standard other holders measure him against.
- What it limits constraint The two remaining late-stage AOC candidates now carry the case for muscle-targeted siRNA delivery by themselves, and a second miss would be read as a verdict on the delivery approach.
- What doesn't add up contradiction One of the deals Samra criticised produced a trial that hit its primary endpoint, so the pelabresib grievance is about the regulatory path Novartis chose after the data, not a failed study.
- What it sets up precedent A named large-cap holder demanding changes to an M&A team gives other pharma shareholders a script to reuse, and these accounts describe eight investors at one company acting on it.
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Nearly $30 billion of market value against a $12 billion purchase price puts the one-day loss at about 2.5 times what Novartis paid for Avidity [21]. Neither account says how many patients HARBOR enrolled or how far del-desiran fell short on video Hand Opening Time [20]. The same one-day fall implies a market capitalisation close to $273 billion before it [22].
The three setbacks inside one week [4] went wrong at three different points. The distinction matters for the claim that one deals team made one repeated mistake. Del-desiran missed a functional measure: clinical experts watch video and time the interval from hand grip to hand opening, a standard read on myotonia [6], and the drug produced no statistically significant separation from placebo through week 54 [5]. Pelacarsen, co-developed with Ionis, missed a clinical outcome, the reduction of cardiovascular risk against placebo [18]. Pelabresib hit its endpoint. In MANIFEST-2, 65.9 percent of 214 patients given pelabresib plus ruxolitinib reached at least a 35 percent reduction in spleen volume at 24 weeks, against 35.2 percent of 216 patients on placebo plus ruxolitinib [16], a difference of 30.7 percentage points [23]. Novartis then dropped its plan to file in mid-2024 and said it needed more time to settle a regulatory path using the 48-week data [15].
So Novartis did not rest on its own 24-week surrogate either. A shareholder case that files the 2.7 billion euro MorphoSys deal [14] under the same heading as Avidity is arguing about which endpoint should have bought a filing.
Samra put the demand on one person. He called on Giovanni Caforio, the chairman, to strengthen the board's oversight of acquisitions [8]. "I think he needs to make changes at the board level. One of them should be on improving the team that's doing these deals because clearly they have been uninspiring at best," Samra told Reuters [9]. "If you do a $12 billion deal and it goes to zero, the management needs to be penalized for that," he said [11], while allowing that Avidity may still yield candidates that become marketable drugs [12]. Two other late-stage AOC candidates came with that deal [3].
Del-desiran's mechanism is narrow. A monoclonal antibody binds transferrin receptor 1 and carries an siRNA designed to degrade the toxic DMPK mRNA behind DM1 [7]. A miss at week 54 is compatible with too little knockdown in muscle, with adequate knockdown and no functional gain on that timescale, or with a video-timed measure too variable to resolve one. The drug held FDA Orphan Drug, Fast Track and Breakthrough Therapy designations and the EMA's Orphan Medicinal Product Designation [19] and missed anyway.
The questions are aimed at one board. Eight shareholders raised questions about the Avidity purchase and other acquisitions, Reuters reported [13]. The two accounts date that deal differently, with STAT calling it last year's purchase [13] and GEN saying it completed in February [3]. MANIFEST-3 began this year with an estimated completion date of May 2028 [17], so the pelabresib verdict arrives years after the argument over who approved the acquisition.
What to watch
- Whether Novartis publishes the full HARBOR dataset, including DMPK knockdown in muscle and the prespecified secondary endpoints.
- Whether the two remaining late-stage AOC programs from Avidity read out, and on which endpoints.
- Whether Caforio answers Artisan with named changes to the team that does Novartis's deals.
Clarity's read
What the record supports and how the coverage leans. The claims behind it follow.
Reality
- Evidence66
- Adoption22
- Hype gap+28
- Incentives68
- Confidence62
Claim ledger
Ranked by verification strength, evidence, and original report placement.
- [1]
Novartis lost roughly $30 billion in market capitalization in the week it said its neuromuscular candidate delpacibart etedesiran (del-desiran) failed a Phase III trial.
- [2]
Novartis shares slumped 11% in one day, wiping nearly $30 billion off its market value and all the gains made since the start of the year, after the del-desiran results.
- [3]
Novartis's $12 billion buyout of Avidity was completed in February with the aim of bolstering its neuroscience pipeline with three late-stage programs: del-desiran and two other candidates in a class the companies call Antibody Oligonucleotide Conjugates (AOCs).
- [4]
Del-desiran was one of three clinical setbacks for Novartis within a week.
- [5]
Novartis acknowledged that del-desiran failed the pivotal HARBOR trial (NCT06411288) by missing the primary endpoint of statistically significant improvement versus placebo in video Hand Opening Time (vHOT) through week 54.
- [6]
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.
- [7]
Del-desiran consists of a muscle-targeting monoclonal antibody that binds transferrin receptor 1 (TfR1) conjugated to a small interfering RNA designed to induce degradation of the disease-causing toxic myotonic dystrophy protein kinase (DMPK) mRNA, targeting the underlying cause of DM1.
- [8]
M. David Samra, managing director at Artisan Partners and founding partner of International Value Group, called on the Novartis board, specifically chairman Giovanni Caforio, to strengthen its oversight of the company's acquisitions.
- [9]
"I think he needs to make changes at the board level. One of them should be on improving the team that's doing these deals because clearly they have been uninspiring at best," Samra told Reuters in an interview.
- [10]
"The party is over," Samra declared, complaining that the acquisition deals lowered the value of Novartis shares, and added: "The acquisition track record is not very good."
- [11]
"If you do a $12 billion deal and it goes to zero, the management needs to be penalized for that," Samra said.
- [12]
Samra acknowledged that the Avidity acquisition may yet yield successful candidates that can be developed into marketable drugs.
- [13]
Eight shareholders said the failure of del-desiran in a late-stage study, the second major trial setback for Novartis in days, raised questions over last year's $12 billion Avidity purchase and other acquisitions, and investors are set to step up scrutiny of the company's dealmaking strategy, according to Reuters.
- [14]
Novartis's acquisition of MorphoSys for 2.7 billion euros ($3.1 billion) completed in May 2024 and was intended to bolster its oncology pipeline with the late-stage myelofibrosis candidate pelabresib and an early-stage candidate in solid tumors or lymphomas.
- [15]
Novartis delayed earlier plans to pursue mid-2024 approval filings for pelabresib and later said more time was needed to decide a regulatory path for the drug based on 48-week data from the Phase III MANIFEST-2 trial (NCT04603495).
- [16]
In MANIFEST-2, pelabresib plus ruxolitinib met the primary endpoint of at least a 35% reduction in spleen volume from baseline at 24 weeks: 65.9% of pelabresib-ruxolitinib patients (N=214) versus 35.2% of placebo-ruxolitinib patients (N=216).
- [17]
Novartis launched the Phase III MANIFEST-3 trial (NCT07357727) of pelabresib plus ruxolitinib in myelofibrosis earlier this year, with an estimated completion date of May 2028.
- [18]
On September 4, Novartis and partner Ionis Pharmaceuticals acknowledged that their co-developed pelacarsen failed the Phase III Lp(a)HORIZON trial (NCT04023552) by missing its primary endpoint of reducing cardiovascular risk compared with placebo.
- [19]
Del-desiran has received the FDA's Orphan Drug, Fast Track and Breakthrough Therapy designations, as well as the European Medicines Agency's Orphan Medicinal Product Designation.
- [20]
Neither the GEN nor the STAT account reports HARBOR's enrollment or the size of the vHOT difference between del-desiran and placebo.
- [21]
The nearly $30 billion of market value lost in the one-day fall is about 2.5 times the $12 billion Novartis paid for Avidity.
- [22]
An 11% one-day fall that removes nearly $30 billion implies a market capitalisation of roughly $273 billion immediately before the drop.
- [23]
The MANIFEST-2 spleen response difference between arms was 30.7 percentage points.
- [24]
The two reported MANIFEST-2 arms together contained 430 patients.
Sources
2 independent publishers whose own reporting we read for this story.
- genengnews.comStockWatch: Novartis Loses More than Market Value After Phase III Failure
1 article · September 13, 2026
- statnews.comSTAT+: Pharmalittle: We’re reading about anxious Novartis investors, patent expirations for biologics, and more
1 article · September 11, 2026
Topics and entities
Topics
- Shareholder Activism
- Clinical trial failures
- Pharmaceutical M&A
- Neuromuscular disease
- RNA Therapeutics