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Drugs That Missed Key Goals In Phase III Trials

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The journey of a drug from the lab to medicine cabinet is long and uncertain.

The phase III trials, which are the longest and the most expensive trials to conduct, are said to have a success rate of 58%, according to a report from the Biotechnology Innovation Organization on "Clinical Development Success Rates over the Past Decade (2006-2015)".

In this article, we present some of the phase III clinical trial failures that made major news headlines in 2019. These were compounds on which companies had bet big, with patients and the medical community having had high hopes.

1. Selonsertib

Selonsertib, an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis, in settings of oxidative stress, was once considered a potential drug for nonalcoholic steatohepatitis (NASH).

This investigational drug from the stable of Gilead Sciences (GILD) failed in a phase III study, dubbed STELLAR-4, in January of this year, which involved patients with compensated cirrhosis (F4) due to NASH.

More bad news followed for Selonsertib when in April, the Company announced that another phase III study in patients with bridging fibrosis (F3) due to NASH had also flunked.

There is no approved drug yet for NASH. The most advanced NASH drug candidate is Intercept Pharmaceuticals Inc.'s (ICPT) Obeticholic acid, which is under FDA review, with a decision expected by March 26, 2020.

Obeticholic acid, under brand name Ocaliva, is approved in the U.S. and Europe for the treatment of primary biliary cholangitis.

2. Lartruvo

Approved in 2016 for the treatment of patients with advanced soft tissue sarcoma, under the accelerated approval program, Lartruvo failed to hit the mark in its confirmatory phase III trial, dubbed ANNOUNCE.

If a drug approved under accelerated approval pathway fails to demonstrate clinical benefit in post-market, confirmatory trials, it is withdrawn from the market.

In April of this year, Lilly announced that it is working to facilitate the withdrawal of Lartruvo from the market as the drug did not improve survival for patients in its confirmatory phase III trial.

Lartruvo was the first new therapy to be approved in over 40 years for the initial treatment of soft tissue sarcoma.

Soft tissue sarcoma (STS) is a complex disease with multiple subtypes, making it hard to diagnose and difficult to treat. According to the American Cancer Society, in 2019, an estimated 12,750 new STS cases will be diagnosed, and more than 5,000 people will not survive their disease in the U.S. alone.

3. Zuranolone

Zuranolone, a next-generation GABAA positive allosteric modulator, failed to achieve its primary endpoint in a phase III trial, dubbed MOUNTAIN, in patients with major depressive disorder, earlier this month, sending the developer Sage Therapeutics Inc.'s (SAGE) stock price down by 60%.

Also known as SAGE-217, Zuranolone is an oral follow-up to Zulresso, an IV infusion, and the Company's approved drug for postpartum depression.

In a phase III trial in women with postpartum depression, dubbed ROBIN, the results of which were reported in January, Zuranolone demonstrated a statistically significant reduction in depressive symptoms.

A phase III trial of Zuranolone on relapse prevention in adults with major depressive disorder, a phase III trial assessing the safety, tolerability, and need for re-treatment with Zuranolone in adult subjects with major depressive disorder and phase III study of Zuranolone in adult subjects with co-morbid major depressive disorder and insomnia are underway.

4. RTB101

RTB101, an oral, selective and potent inhibitor of target of rapamycin complex 1 (TORC1), failed to meet the primary endpoint in a phase III trial, wiping out as much as 88% of the manufacturer resTORbio Inc.'s (TORC) share price on the day the results were announced - on November 15, 2019.

Inhibition of TORC1 has been observed to extend lifespan and healthspan in aging preclinical species and to improve immune, cardiac and neurologic functions, suggesting potential benefits in several aging-related diseases.

RTB101, which was evaluated in clinically symptomatic respiratory illness (CSRI) in adults age 65 and older, did not meet the primary endpoint in the phase III trial, dubbed PROTECTOR 1.

The Company has stopped further development of RTB101 for the indication of clinically symptomatic respiratory illness but continues development of the compound in other aging-related diseases, including Parkinson's disease.

5. Suvodirsen

The development of Suvodirsen, a stereopure oligonucleotide, proposed for the treatment of Duchenne muscular dystrophy (DMD) in patients amenable to exon 51 skipping, has been terminated as an interim analysis of a phase I trial revealed that the drug did not increase the production of dystrophin, a protein necessary for muscle function, in the patients.

Duchenne Muscular Dystrophy, or DMD in short, is a rare genetic muscle-wasting disease caused by the absence of dystrophin, a protein necessary for muscle function. DMD usually affects boys, and its prevalence is roughly 1 in 3,500 boys worldwide.

Suvodirsen, developed by Wave Life Sciences Ltd. (WVE) was touted as a potential competitor to Sarepta Therapeutics' Exondys 51, which was approved in September 2016.

In the wake of Wave Life Sciences throwing in the towel on Suvodirsen, the phase I open-label extension study in boys with Duchenne muscular dystrophy who are amenable to exon 51 skipping, and a phase 2/3 trial in boys with Duchenne muscular dystrophy who are amenable to exon 51 skipping, dubbed DYSTANCE 51, have both been wound up.
The news sent the developer of Suvodirsen Wave Life Sciences' stock price down 55%.

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