2.9. Ironwood’s woes or why a stock craters after a ‘successful’ phase 3 trial

03/15/24 • 29 min

A 40% share price drop after an investigational drug hits the primary endpoint of a phase 3 trial is not typical. But that’s what happened to Ironwood Pharmaceuticals when it reported data from a trial of apraglutide in patients with intestinal failure due to short bowel syndrome (SBS-IF).

The condition arises from the loss of gut function following surgical removal of a large portion of the small intestine due to conditions such as severe inflammatory bowel disease or cancer in adults or congenital problems or necrotizing enterocolitis in infants. Because patients are then unable to absorb sufficient nutrients or water, they rely on parenteral nutrition and fluid delivered directly to the bloodstream by a catheter. It’s far from ideal. Complications and infections can occur, and patients’ quality of life is severely affected. The goal of therapy is to reduce the volume of parenteral support needed. A secondary goal is to reduce the number of days per week when it needs to be administered.
Apraglutide mimics the effects of a natural peptide hormone, GLP-2, which is normally released in response to food intake. It aids nutrient absorption by slowing the passage of food through the intestine and promoting the regrowth of intestinal tissue. It is rapidly broken down and cleared from the system, however. Therapeutic analogues have been developed to resist degradation and act over longer timescales.
Ironwood reported that apraglutide reduced patients need for parenteral support by 25.5% from baseline levels – the reduction in those on placebo was 12.5%, so the net treatment effect appears modest but real. Some 43% of patients on apraglutide were able to do without parenteral support for at least one additional day per week, as compared with 27.5% of those in the placebo arm. Ironwood’s problem is that it pitting apraglutide against a long-established competitor, Takeda’s Gattex (teduglutide), another GLP-2 analogue. Generic competition cannot be too far away, as Gattex, a notoriously expensive drug, is about to lose patent protection. Apraglutide has one key advantage – it is dosed on a weekly basis, whereas Gattex requires daily administration. Whether that is enough to make it a successful product is not clear at this point. But some investors clearly think it isn’t.

Companies mentioned in this episode:
9Meters Biopharma, Hanmi Pharmaceutical, Ironwood Pharmaceuticals, Merck KGaA, NPS Pharmaceuticals, Serono, Shire, Takeda, VectivBio, Zealand Pharmaceuticals

Send us a text

Suggestion box (Suggestions on future episodes, points for clarification, comments, etc.)

Subscribe (Get notified when new episodes are available. NO marketing!)

Disclaimer
Ready to create your own impactful podcast series?
Contact us at elearningbytes.co.uk to get started!

Companies mentioned in this episode:
9Meters Biopharma, Hanmi Pharmaceutical, Ironwood Pharmaceuticals, Merck KGaA, NPS Pharmaceuticals, Serono, Shire, Takeda, VectivBio, Zealand Pharmaceuticals

Send us a text

Suggestion box (Suggestions on future episodes, points for clarification, comments, etc.)

Subscribe (Get notified when new episodes are available. NO marketing!)

Disclaimer
Ready to create your own impactful podcast series?
Contact us at elearningbytes.co.uk to get started!

Previous Episode

2.8. Alnylam’s big bet in amyloidosis

By late June or early July we’ll know whether Alnylam’s decision to alter the design of its phase 3 ‘Healios B’ study of Amvuttra (vutrisiran) in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) was a good one. The short-interfering RNA (siRNA) drug is already approved in ATTR with polyneuropathy (ATTR-PN), a debilitating, fatal condition in which misfolded transthyretin proteins clump together and create damaging deposits in the peripheral nerves.

But about ten times as many patients develop ATTR-CM, in which protein deposition occurs in cardiac tissue and gives rise to a form of heart failure. Alnylam is, therefore, attempting to establish Amvuttra in this category as well.

An earlier drug from the same stable, Onpattro (patisiran), failed to deliver in ATTR-CM, but the company argues that it needed a longer, larger trial to detect the survival signals it is now seeking with Amvuttra in the Healios B study. Pfizer is the current category leader in this space with its Vyndaqel (tafadamis) product family.

Alnylam maintains that extending the duration of the follow-up on Healios B will improve the study’s statistical power and strengthen its hand when commercializing the product. But as Alnylam’s leadership knows, changing the goalposts mid-trial can be a risky move. It’s a big play from CEO Yvonne Greenstreet and chief medical officer Pushkal Garg.

Companies mentioned in this episode:
Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Athena Neurosciences, AstraZeneca, Eidos Therapeutics, FoldRx, Ionis Pharmaceuticals, Pfizer, Neurimmune, Novo Nordisk, Prothena Biosciences

Send us a text

Suggestion box (Suggestions on future episodes, points for clarification, comments, etc.)

Subscribe (Get notified when new episodes are available. NO marketing!)

Disclaimer
Ready to create your own impactful podcast series?
Contact us at elearningbytes.co.uk to get started!

Next Episode

2.10 Relyvrio’s setback in ALS is a clinical and a regulatory failure

The failure of Relyvrio in a post-approval phase 3 study in amyotrophic lateral sclerosis (ALS) means its days as a commercial drug are probably numbered. It initially gained approval in Canada in June 2022 (where it is, confusingly, known as Albrioza) and secured FDA approval the following September.
Both approvals rested on the 24-week phase 2 ‘Centaur’ trial, in which the drug showed modest effects as compared with placebo in slowing patients’ decline in physical functions. Those data were published in the New England Journal of Medicine (Paganoni et al., 3 Sep. 2020). A follow-up analysis, published in the Annals of Clinical and Translational Neurology (Paganoni et al., 9 Oct. 2023) even suggested it could have a survival benefit. But the Phoenix trial recruited almost five times as many patients (664 vs. 137) and was twice as long, which means it is a far more rigorous test of the drug’s effects. The setback has raised questions about the FDA’s apparent leniency in approving a drug that its own expert advisory panel initially rejected.
Its approval followed a second such hearing, which, in the absence of new data, is highly irregular. If nothing else, the episode highlights the difficulty of developing effective therapies for highly varied and complex conditions whose disease biology is still not fully understood. Relyvrio’s mechanism was not a settled matter either. The drug, a fixed-dose combination of sodium phenylbutyrate and taurursodiol, ameliorates endoplasmic reticulum stress and mitochondrial dysfunction, according to its developer.
According to the FDA product label, its mechanism in ALS patients is unknown. There is an urgent need for effective therapies in ALS. Insights from genetic forms of the condition (which account for about 10% of cases) are helping scientists to unpick some of its molecular underpinnings. In time, these may help to form the basis of therapies that could help patients with either form of the condition. But for patients living with the condition at present, therapeutic options are still tragically limited.
Companies mentioned in this episode:
Amylyx Pharmaceuticals, Biogen, Ionis Pharmaceuticals, QurAlis, Sarepta Therapeutics

Send us a text

Suggestion box (Suggestions on future episodes, points for clarification, comments, etc.)

Subscribe (Get notified when new episodes are available. NO marketing!)

Disclaimer
Ready to create your own impactful podcast series?
Contact us at elearningbytes.co.uk to get started!