NOVARTIS (NVS): TWO PHASE 3 MISSES IN FOUR DAYS

It was a difficult week for Novartis’ (NVS) late-stage pipeline.

Between September 4 and September 8, the company reported that two Phase 3 programs — pelacarsen in cardiovascular disease and del-desiran in myotonic dystrophy type 1 (DM1) — failed to meet their primary endpoints.

Novartis' original acquisition presentation explicitly described del-desiran as being on track to potentially become the first approved drug for DM1, cited ~80,000 DM1 patients in the U.S. and Europe, and projected multi-billion-dollar opportunities from the acquired neuromuscular portfolio.

The pelacarsen result is also worth watching beyond Novartis because this was an unusually large 8,323-patient outcomes trial. Importantly, Novartis has so far disclosed that Lp(a) was lowered but the cardiovascular endpoint was missed; it has not yet released the full numerical outcome data, which it says will come at a medical congress.

1 | Pelacarsen: Lower Lp(a), but no reduction in cardiovascular events

The Phase 3 Lp(a)HORIZON study enrolled 8,323 patients with established cardiovascular disease and elevated lipoprotein(a), or Lp(a).

Lp(a) is an inherited cardiovascular risk factor. Approximately 20% of people worldwide have elevated Lp(a), levels are roughly 90% genetically determined, and there is currently no approved therapy specifically targeting it.

Pelacarsen is an antisense medicine designed to reduce the body's production of Lp(a).

The drug did what it was designed to do biologically: Lp(a) levels declined.

But the Phase 3 study was designed to answer a more important question:

• Did lowering Lp(a) actually result in fewer heart attacks, strokes, cardiovascular deaths and urgent coronary procedures?

In the overall trial population, the answer was no. The study did not meet its primary cardiovascular endpoint.

Novartis plans to present the full data at an upcoming medical congress.

2 | Del-desiran: A Phase 3 miss following a $12 billion acquisition

Four days later, Novartis announced another Phase 3 setback.

Del-desiran is being developed for myotonic dystrophy type 1 (DM1), a progressive genetic neuromuscular disease affecting an estimated ~80,000 patients in the U.S. and Europe. There are currently zero approved disease-modifying therapies for DM1.

The drug uses an antibody to deliver an RNA therapy directly into muscle cells, where it is designed to degrade the toxic DMPK messenger RNA responsible for the disease.

The 54-week HARBOR Phase 3 trial enrolled approximately 150 patients.

Its primary endpoint was video hand opening time (vHOT) — essentially measuring how quickly a patient can open their hand after making a grip, an important measure because DM1 can cause muscles to remain contracted and make releasing a grip difficult.

Del-desiran did not produce a statistically significant improvement versus placebo on that primary endpoint.

Novartis did report evidence of clinical activity across secondary endpoints and exploratory analyses and said safety results were generally consistent with previous studies. The company is analyzing the full dataset and plans to work with regulators to determine the program's next steps.

THE $12 BILLION CONNECTION

Del-desiran came to Novartis through its acquisition of Avidity Biosciences, completed earlier this year.

When Novartis announced the transaction, it valued Avidity at approximately $12 billion on a fully diluted basis, or roughly $11 billion in enterprise value.

At the time, Novartis highlighted three late-stage neuromuscular programs from Avidity:

• Del-desiran — DM1• Del-brax — FSHD• Del-zota — Duchenne muscular dystrophy

Novartis said the three programs could potentially launch before 2030 and described the DM1 and FSHD opportunities as having multi-billion-dollar peak-sales potential.

The other programs continue to advance. Del-zota has received FDA Priority Review, while Novartis plans to meet with the FDA regarding next steps for del-brax following positive Phase 1/2 biomarker data.

For now, two large Phase 3 studies produced two important datasets:

8,323 cardiovascular patients: Lp(a) was lowered, but cardiovascular outcomes did not improve enough to meet the primary endpoint.

~150 DM1 patients: del-desiran showed activity on some measures, but failed the study's primary functional endpoint.

Full datasets and subsequent regulatory discussions will determine what comes next for both programs.