Five major failure clinical cases: lucky is always a few, unfortunate is each has its own misfortune

It may cost the company money, it may also affect the development of the pipeline in other indications, but the most important thing is that the patient feels "hopeless".

Often, the impact of drug failure is greatest late in the clinical phase and near the end of the trial. Although new drugs have been relatively stable at later stages, no drug can be guaranteed to pass the clinic and reach the market through safety.

A review of 640 trials published in Contemporary Clinical trials Communications found that 54% of new therapies failed in phase III trials, 57% of which were due to inadequate efficacy.

Over the past few months, disappointing trial data have been reported for products from early to late stages of development and for a range of different diseases. Here are the five most influential trial failures.

1

Astrazeneca/Oxford COVID-19 nasal spray vaccine fails

Drug developers have been actively searching for a new generation of COVID-19 vaccines to overcome some of the limitations of vaccines, and nasal sprays certainly offer new ideas. Nasal sprays not only allow the immune system to attack the virus where it enters the body, they are also more convenient to use.

At least 12 nasal spray COVID-19 vaccines are in development, with four candidates in phase III trials. Several studies have reported positive results, two of which received regulatory approval: one in China and the other in India.

But this month Astrazeneca and Oxford University said a nasal spray of their ChAdOx1 adenovirus vector-based vaccine "failed to induce a consistent mucosal antibody response or a strong systemic response" in a small phase I trial.

The study is believed to be the first to publish data on an adenovirus vector-based vaccine using a "simple nasal spray," which is easier to use than those approved in China that require a complex spray device, according to the researchers.

The vaccine was previously suspended after 24 countries reported links to rare blood clots. Still, Astrazeneca made $4 billion on COVID-related products last year, but the company expects its sales to fall by at least 20% in 2022. Astrazeneca's hopes of reviving its market position with a nasal spray vaccine are slim.

Of course, work is ongoing in the industry to develop nasal sprays using other technologies. New York-based Codagenix said the COVI-VAC nasal spray vaccine it owns could be approved as early as next year.

2

Biohaven's phase II trial of an ALS drug, Trident

On September 29, Relyvrio, an ALS drug from Amylyx Pharmaceuticals, received FDA approval. Amylyx was funded in part by the Ice Bucket Challenge, which went viral in 2014. Relyvrio is the third drug approved for ALS.

But on the same day, Biohaven's ALS drug Verdiperstat failed a phase III trial. Verdiperstat was introduced from Astrazeneca in 2018 and was being studied with multiple experimental ALS drugs at Massachusetts General Hospital. However, the drug failed to improve disease progression or survival compared with placebo.

In May, Biohaven struck a major deal with Pfizer, which bought Biohaven's migraine products for $11.6 billion. Biohaven has not disclosed whether it will continue to develop Verdiperstat for other indications, but only one is currently in phase III clinical practice, an OCD treatment, with data scheduled to be reported later this year.

Just days after the Biohaven news, Clene Nanomedicine also reported that its ALS drug failed to meet its primary and secondary endpoints in a phase II trial. Clene Nanomedicine is currently seeking strategic partners for the product to advance the efficacy trials of the drug at different doses.

3

Novartis anti-inflammatory drug 'falls' for third time in Phase III

Novartis has an ambitious goal in oncology to develop treatments that can prevent cancer in high-risk populations, and in particular to develop immune-targeted drugs that modulate inflammation. Novartis believes it could be the "next frontier" for cancer treatment.

However, its efforts to use an anti-inflammatory rare disease drug called Canakinumab for cancer treatment have failed to meet expectations. Canakinumab was previously approved for the treatment of 3 rare and unique types of periodic fever syndrome. In August, Novartis said Canakinumab had failed in its third trial against non-small-cell lung cancer (NSCLC), and the drug was recently being tested to prevent tumor recurrence after surgery. This is the third phase III trial failure of Canakinumab.

In 2018, the FDA declined to approve a new indication application for Canakinumab as a preventive treatment for certain heart conditions, and now Novartis's expansion of the drug in NSCLC also appears to be deadlocked. Analysts at Jefferies had forecast that the expanded approval could boost Canakinumab sales to $2 billion.

The company is running another trial of the drug in lung cancer, and an oncologist recently told Bloomberg that Canakinumab's anti-inflammatory properties could still make it a "good model" for cancer prevention targeting the right patient group.

4

Intercept targets NASH pipeline setback again

Nonalcoholic steatohepatitis (NASH) has been considered a "graveyard of drug development" with no significant progress for a long time. This huge market of about US $35 billion has spurred a race to develop the first approved drug.

NASH is a metabolic disorder that usually results from obesity (rather than alcohol intake) and leads to scarring, cirrhosis, and even liver failure.

Intercept Pharmaceuticals' obeticholic acid drug Ocaliva, which is being tested for several NASH-related indications, was previously approved for biliary cirrhosis. Intercept has been in communication with the FDA for more than a year to advance the approval of Ocaliva for patients with liver fibrosis due to NASH. More recently, the company's failure of a trial involving patients with compensated cirrhosis due to NASH has further complicated drug development in this field.

"Statistical significance for a histologic end point of compensated cirrhosis due to NASH is a very high bar in a clinical trial," said M. Michelle Berrey, president of research and development and chief medical officer at Intercept.

On September 30, Intercept announced that Ocaliva had failed to meet its primary endpoint in the Reverse trial. The results will not affect Ocaliva's NDA program for liver fibrosis, which had positive phase III results, the company said in a statement. Intercept plans to file the NDA by the end of the year.

Several other companies, including Novo Nordisk, Alnylam and its partners Regeneron and Akero Therapeutics, have NASH programs.

5

Relmada depression medications did not meet their primary endpoint

The field of psychedelic-based new drug development for depression has been reinvigorated in recent years, with products such as Johnson & Johnson's Spravato ketamine nasal spray and Axsome Therapeutics' Auvelity, which was approved in August as the first fast-acting oral treatment for major depression.

Relmada Therapeutics has also been working on the indications for REL-1017. The novel NMDA receptor (NMDAR) antagonist REL-1017 (dexmethadone) blocks the "hyperactive NDMAR channel". If the drug is successful, Relmada believes this "new approach" could provide another option for treating depression quickly.

However, Relmada announced this month that a phase III study of REL-1017 for major depressive disorder (MDD) failed to meet its primary endpoint after a four-week course of treatment due to a higher-than-expected placebo response. News of the trial's failure sent the company's shares plunging nearly 80 percent.

Relmada is now pinning its hopes on the performance of REL-1017, the company's only significant product, which will be tested alongside other depression drugs in two other phase III trials. Relmada said positive results from these studies may be sufficient to submit an application to the FDA. However, any failure could spell doom for Relmada, whose other development projects include "psilocybin and its derivatives" acquired through acquisitions.

The pipeline of promising drug candidates to treat depression remains small. With an analysis late last year showing only nine candidate drugs with positive phase II or III trial efficacy for depression, innovation is still needed in the field.