November 16, 2023

The need-to-know this morning

Regulators in the U.K. approved a CRISPR-based medicine to treat both sickle cell disease and beta thalassemia, making it the world's first therapy built on the revolutionary gene-editing technology and ushering in a new phase of genetic medicine. The treatment, called Casgevy, was developed by Vertex Pharmaceuticals and CRISPR Therapeutics. In granting conditional approval Thursday, the U.K.'s Medicines and Healthcare products Regulatory Agency (MHRA) jumped ahead of its counterparts in the U.S. and Europe, which are also reviewing the medicine.
The FDA approved a new treatment for people with non-small cell lung cancer that contains a specific genetic alteration called Ros1. The genetically targeted medicine, called Augtyro, will be sold by Bristol Myers Squibb.
Springworks Therapeutics said its experimental drug called mirdametinib achieved the main goal of a clinical trial by shrinking tumors in children and adults with neurofibromatosis type 1, a rare inherited disorder.
Astellas announced the acquisition of Propella Therapeutics, a privately held developer of cancer drugs, for $175 million.

Rare disease

After a tragic setback, Astellas charts a path for its gene therapy

An Astellas gene therapy study, halted when four children with a rare neuromuscular disorder died after treatment, showed enough promise to merit finding a path forward, the company concluded in an analysis of the trial.

Astellas' data, published in Lancet Neurology last night, found that all four patients who died had evidence of impaired liver function, and serious side effects were more common among older patients who received the highest dose of the therapy. Those observations suggest a path forward, according to the company, that would involve enrolling younger patients and giving them a lower dose of the gene therapy, which might minimize serious risks while preserving the treatment's positive effects.

The benefits, among patients who survived treatment, were substantial. Astellas' treatment dramatically reduced patients' dependence on ventilators, allowing many to stand on their own and walk unassisted.

Read more.

GLP-1

Novo is going head to head with Zepbound

A truism in the pharmaceutical world is that companies rarely conduct head-to-head studies against their rivals' products because the risks almost always outweigh the potential benefits. That, like the stock market and a few national health budgets, is getting upended by the dawn of GLP-1 treatments.

Novo Nordisk has embarked on a clinical trial testing whether CagriSema, an investigational combination of Wegovy and a complementary agent, can spur more weight loss than Eli Lilly's recently approved Zepbound for patients diagnosed with obesity. The study will run for 18 months, tracking percentage of weight lost, how many patients shed a quarter or more of their weight, and other related metrics.

The outcome will be interesting, but so too will be whether it ends up having any impact on either company. Novo and Lilly are competitors in the GLP-1 market, but the arbiters of success are payers and insurance companies, who have made clear that they're less interested in how much weight patients lose as they are in the long-term health benefits (and cost-effectiveness) of treatment. Novo's recent landmark study showed that Wegovy reduced cardiovascular problems, but it was hardly clear whether weight loss alone accounted for that benefit, suggesting that the 18-month difference between CagriSema and Zepbound might have little effect on how either medicine gets reimbursed.

research

How do we know Alzheimer's drugs 'work'?

For a couple decades, drug companies tried to treat Alzheimer's disease by targeting toxic brain plaques in hopes of slowing dementia, leading to results that ranged from outright failure to murky progress. Then, last year, an Eisai-invented drug called Leqembi demonstrated a modest but statistically significant benefit, and the conventional wisdom was that science finally built a marginally better mousetrap after years of iterative work.

But do the data back that up? Lon Schnieder, who treats and studies Alzheimer's at the University of Southern California, dug into the differences between Leqembi, which won FDA approval this year, and gantenerumab, an amyloid antibody from Roche whose Phase 3 trials failed. He found more similarities than differences. Both had substantial effects on amyloid, and both had cognitive effects of similar magnitude. Leqembi's met the threshold for statistical significance, while gantenerumab's did not, but the narrow difference could "support a view that the effects [of amyloid treatments] are small, unreliable, and barely distinguishable from no effect," Schnieder wrote in a New England Journal of Medicine commentary published yesterday.

That could well be true, but, as Schnieder notes, patients in the Roche trial had higher levels of amyloid at baseline than those in the Eisai study, which might have predisposed gantenerumab to failure. That suggests Leqembi may indeed be no more effective than gantenerumab, but it also suggests Eisai built a better mousetrap not by inventing a stronger drug but by designing a smarter clinical trial.

Regulatory

The FDA is getting more investigative

The FDA is in the final stages of making some sweeping changes to its inspection and investigation division, STAT has learned, shuffling its ranks to more efficiently enforce regulations.

As STAT's Sarah Owermohle reports, the agency's Office of Regulatory Affairs, which oversees compliance for all its regulated products, will become the Office of Inspections and Investigations. Among the big changes is that compliance officers, who are currently under ORA, will soon work under individual drug, device, and food centers.

The change comes after scrutiny tied to last year's baby formula shortage and the revelation that a whistleblower had warned FDA inspectors about safety issues at a key plant months before the agency took action.

Read more.

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