Moderna's personalized mRNA cancer vaccine, developed alongside Merck, has cleared its first Phase 3 readout—and the market reacted as if the company had won far more than a trial.

Shares of Moderna (MRNA) surged about 131% on Wednesday, more than doubling to near $148 after touching $163 intraday—a record one-day jump. Merck (MRK), the larger partner that sells Keytruda, also spiked on the news.

The companies announced that the Phase 3 INTerpath-001 trial of intismeran autogene plus Keytruda met its recurrence-free survival (RFS) and distant-metastasis-free survival (DMFS) goals in patients whose stage IIB–IV melanoma had been surgically removed. It is the first positive Phase 3 result for a personalized neoantigen therapy, and the first for an mRNA-based cancer treatment.

How the therapy works

Intismeran autogene (also called V940 or mRNA-4157) is not a mass-produced vial. Doctors sequence a patient's tumor and map its unique mutations, and the mRNA then teaches the body to manufacture neoantigens—protein fragments the immune system learns to spot and attack. Keytruda, an anti-PD-1 drug, lifts the brakes on immune cells. Together, the pairing is meant to scrub out any cancer that surgery left behind.

The combination beat Keytruda alone, the current standard of care, on both endpoints—the first time a personalized neoantigen therapy has shown a clinically meaningful edge over the blockbuster immunotherapy in the adjuvant setting, meaning treatment after surgery to prevent the disease from returning. Keytruda is a heavyweight benchmark: it generated roughly $29 billion in sales for Merck in 2024, ranking among the world's best-selling medicines. The Phase 3 result also builds on mid-stage KEYNOTE-942 data, in which the pairing cut the risk of recurrence or death by 44% versus Keytruda alone—findings that earned the regimen the FDA's Breakthrough Therapy Designation in 2023, a status intended to speed development of treatments for serious diseases.

For Moderna, which has leaned on a collapsed COVID franchise and carried one of the heaviest short bets among large caps, the readout lands at a make-or-break hour. The company has spent the post-pandemic years trying to rebuild around mRNA vaccines for flu, RSV, CMV and cancer, and the melanoma result is its first Phase 3 evidence that the technology behind its COVID shot can work in oncology. BioNTech, Moderna's COVID-era rival, is chasing the same goal with its own personalized neoantigen therapy, autogene cevumeran, developed with Genentech.

Short sellers under pressure

Traders shorting Moderna faced roughly $4.8 billion in mark-to-market losses as the stock doubled; short interest stood at 13.5% of free float.

When a heavily shorted stock rockets, borrowers scramble to buy back shares and stop the bleeding—the same short-squeeze mechanics that rattled markets during the 2021 GameStop frenzy. Crypto-linked equities recently handed short sellers $2.6 billion in losses as rallies reversed, and Moderna's move was far bigger.

"With each shorted share now down almost $100, that is exactly the kind of pressure that can trigger a squeeze," ORTEX co-founder Peter Hillerberg said in a statement.

The trial will continue to evaluate overall survival and other secondary endpoints that have not yet been reported—the test of whether the pairing extends lives rather than only delaying recurrence. Moderna and Merck have also been studying the combination in other tumor types, including lung cancer, as they work to widen the approach beyond melanoma.