Phase III Failure Sinks Drug for Rare Neurological Disorder

The Italian biotech Newron is halting the development of the experimental drug sarizotan after it failed to meet efficacy endpoints in phase III, dashing hopes for an approved drug for Rett syndrome. 

Expectations had been high that the oral drug might be able to treat breathing difficulties associated with the rare genetic disorder after promising studies in mice.

But the phase III trial found that daily sarizotan was ineffective in the primary goal of reducing the percentage of apnea episodes — or temporary pauses in breathing — while awake compared with placebo among 129 Rett syndrome patients.

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Newron CMO Ravi Anand told me that the effects of sarizotan on a mouse model of the disease had been robust and reproducible and were seen with different genetic variants, including those most frequently found in humans. 

However, these effects did not translate into clinical benefit on respiratory symptoms, even when exposures in patients exceeded the efficacious exposures in mice,” he acknowledged. 

These data indicate that changes noted in the genetic model are not predictive of effects in humans, suggesting the possibility of additional changes in patients not seen in the genetic model.”

The findings will come as a blow to individuals with Rett syndrome, who can have difficulty in controlling their muscles and eating and may have learning disabilities, respiratory issues, and fits.

People with the severe neurological disorder, who are almost exclusively female, currently have to rely on physiotherapy, speech therapy, and nutritional support to alleviate their symptoms, together with seizure medication, laxatives, and painkillers.

Sarizotan is a small molecule drug that stimulates nerve cell proteins activated by the neurotransmitters serotonin and dopamine. The compound was intended to work by compensating for some of the serotonin missing in the brain and spinal cord of individuals with Rett Syndrome.

The agent — licensed from Merck KGaA after it failed phase III trials for Parkinson’s disease — had been billed as the first therapy to become independently commercialized by Newron. Adding to the hope, animal studies had linked sarizotan with up to 85% reductions in episodes of apnea and hyperventilation, with both acute and chronic doses. 

Sarizotan is by no means the first drug to falter after promising preclinical studies. This phase III trial is one of many examples where animal studies have failed to adequately predict human disease.

Many animal models do not capture the full extent of disease physiology, genetics, and comorbidities seen in humans,” Associate Professor in Clinical Pharmacology Daniel Hackam, from Western University in Ontario, Canada, told me.   

Yale University Emeritus Professor of Epidemiology, Michael Bracken, added that only about one in ten human clinical trials support the efficacy and safety predicted from animal research. Neither Hackam nor Bracken are affiliated with Newron.

The low prediction rate seen in clinical trials could be due to inadequate animal studies that are small, poorly randomized, and had inappropriate comparison treatments and improper blinding, Bracken continued. 

Even if excellent research methodology is achieved, prediction to humans fails because the disease model, often in rodents, is wrong: biological pathways are different, drug doses are not comparable, and the assessed recovery measures do not translate from mouse to human.”

Bracken called for all animal studies to be compiled within a strict systematic review, as is required in human research. 

This should identify all the relevant studies and highlight their possible methodological inadequacies,” he said. 

There is no evidence in the published scientific literature that the sarizotan animal research was systematically reviewed before the human trial was started, which is ideally when it should be done.”

There are also many companies in Europe with the aim of reducing the use of animal models with technology such as organs-on-chips, bioprinted tissue, organoids, and in silico testing.

Newron’s stock price has reacted badly to the phase III failure, plummeting by over 50% on the SIX Swiss Exchange over the last week.


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