Despite the million-dollar funding rounds and the tremendous hype created by its charismatic founder, on 26 September 2017, Axovant Sciences announced their Phase 3 clinical trial—known as MINDSET—had failed to meet its co-primary endpoints.

The investigational drug, intepirdine, did not exhibit superior efficacy compared to placebo in improving patients’ cognition, nor did it improve physical activities of daily living. Only one secondary endpoint showed a significant difference between the intepirdine arm versus the placebo.

Alzheimer’s drug: 99% failed in clinical trial

Alzheimer's disease is fast becoming the bane of our society. In 2015, it was estimated that, there were close to 47 million people worldwide suffering from dementia and the number is likely to go up to more than 131 million by 2050. Despite the vast number of patients, there are disproportionately few drugs which were approved to treat the disease or its symptoms. Currently, there are only five approved drugs, four of which belong to the group known as cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) and the NMDA receptor AD antagonist (memantine).

The ever-growing void in effective treatment has placed a tremendous burden on the healthcare system. As the disease begins its irreversible progress, the decline in patient's mental skills will eventually impact his or her ability to think and plan daily activities.

A study published several years ago that looked that the drug development pipeline for Alzheimer's disease discovered an extremely high attrition rate: 99.6% of all clinical trials failed throughout the ten-year reporting period (2002 – 2012). In other words, only one out of 244 drug candidates successfully made it to the market. The successful compound is now known as memantine, which works to improve symptoms of Alzheimer's disease but does not cure it.

Intepirdine’s failure

In 2015, it was estimated that, there were close to 47 million people worldwide suffering from dementia – and the number is likely to go up to more than 131 million by 2050.

In 2015, it was estimated that, there were close to 47 million people worldwide suffering from dementia – and the number is likely to go up to more than 131 million by 2050.

The disappointing results from the Axovant trial had added much frustration to physicians and patients around the world. The pharmaceutical industry as a whole had spent billions of dollars seeking a cure, or at the very least, to delay the progression of Alzheimer's disease. Regrettably, all efforts seem futile as there has been no new drug introduced to the market since 2003.

“We are deeply disappointed by the results and saddened for the millions of patients and families impacted by Alzheimer's disease," lamented Dr David Hung, CEO to Axovant, following the announcement of the failure of intepirdine.

Some critics from the industry were not surprised by the negative results of MINDSET, however. Intepirdine was initially developed by the pharmaceutical giant, GlaxoSmithKline (GSK) that targeted the serotonergic neurotransmitter system. The compound showed some early success in reversing cognitive deficits in rats and was well-tolerated in healthy human volunteers.

Further early phase clinical trials conducted by GSK only showed small beneficial effects on cognition and functional outcomes. In December 2014, Axovant acquired the compound through a million-dollar agreement with GSK. Within one year of the purchase, Axovant began MINDSET, the trial that involved more than 1,000 patients with mild to moderate Alzheimer's disease.

Addressing the roadblocks in drug development

Drug development for Alzheimer's disease is plagued by a host of different problems, most notably is the slow disease progression. Symptoms of Alzheimer's may not manifest themselves years after the disease has started, making clinical trials extremely long and costly. Pharmaceutical companies must first be financially viable before a decision could be made to invest in the field. Furthermore, a company runs the risk of the patent expiring before the trial can show any meaningful results.

Secondly, our brain is well protected by the blood-brain barrier, or perhaps too well protected, that many therapeutic compounds cannot penetrate the barrier to deliver their therapeutic effect. Our limited knowledge of the disease added further difficulties to the already challenging task.

“Less is known about the biology of the condition than, say, cancer,” explained Professor Simon Lovestone of Oxford University.

The inherent heterogeneity of the disease, coupled with the requirement for long and expensive clinical trials, almost always lead to failure in any attempts to combat Alzheimer’s disease.

Despite the failure, Axovant remains optimistic in its future. A statement from Roivant, the parent company of Axovant, said “Today’s results are a setback for our company, and more importantly for patients with Alzheimer’s disease. But it is not the end of the road. Axovant remains committed to future research in this area, and we are rooting for all companies who share that commitment.” MIMS.

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