In yet another setback to the treatment of Alzheimer’s disease, Axovant Sciences has announced that their latest attempt at creating a treatment – a drug known as Intepirdine (a (5-HT)6 receptor antagonist) – has failed during late stage clinical trials. Meanwhile, pharmaceutical giant Pfizer Inc has announced plans to leave the field of Alzheimer’s research.

This latest failed result means the 14 year period since the last effective Alzheimer’s treatment was released continues. Reports of the trials claim there was “essentially no difference” between the medicated group, compared to the placebo-controlled test subjects.

Studies on the potential drug since have given even worse results. These studies have indicated that the drug performed worse during trials than a placebo control. This is perhaps the worst result a potential medication could receive during a trial. Negative results compared to a control highlights not just a lack of effectiveness, but a worsening of symptoms compared to no treatment at all.

Following the news of the failed result, Axovant shares plummeted 75.59 percent. The shares hit a value of $5.92 a piece, before the result of the trial Axovant closed a trading session at $24.25. Share prices have continued to fall since the announcement, reaching low points of $2.76. Such a fall in share prices could prove fatal to the continuation of the company.

Effective Alzheimer’s drugs may start to seem impossibly difficult to devise. As previously explored by Hyderus, failure in pharmaceutical research is costly. Not only do companies invest vast sums into research which comes up fruitless, they may also see share prices dive dramatically when the failure  is a high-profile one, as can be seen in the case of Axovant.

These factors combined produce an environment financially hostile to those attempting to create any new medical treatments, particularly for condition such as Alzheimer’s. In years to come this may well lead to fewer and fewer attempts to treat the condition, as the risks of high financial penalties and reputational damage disincentivise researchers.

Axovant is not the only company to fail recently

Failed Alzheimer’s trials are abundant. The consequences of the failure are far reaching for the company involved due to the financial loss they incur. After its failure, Eli Lilly, revealed that their company would be losing 3500 employees. To what extent the failure of their Alzheimer’s drug played in this is unreported, though it did bring with it a considerable financial setback.

The picture remains bleak for other (5-HT)6 receptor drugs as well. Earlier in the year Lundbeck, along with their Japanese partner on the project Otsuka, announced the failure of their own medication. Idalopirdine. This was, their own (5-HT)6 receptor antagonist which also failed to produce any positive results during late stage clinical trials.

Repeated failures of (5-HT)6 receptor antagonists add to the growing list of Alzheimer’s medications that have not produced results in human trials. If a company were to produce an effective medication, the financial return would likely be significant. However, Alzheimer’s disease has a reported 99.6 percent failure rate of drug candidates, and a costly research process.

It may become likely that pharmaceutical companies will be put off from researching a condition that, with an aging global population, is only going to become a bigger problem in the coming years.

With the exit of Pfizer from the field of Alzheimer’s research this issue may become a reality. The company has announced the removal of 300 research positions. These positions are linked to research in both Alzheimer’s disease and Parkinson’s disease.

Pfizer also faced the failure of their potential Alzheimer’s medication bapineuzumab in 2012. Developed with their partner Johnson & Johnson, the drug failed during stage II human trials, showing no significant improvement in patients with mild to moderate Alzheimer’s disease.


Failure to translate initial results to human trials


While Axovant’s trials for Intepirdine resulted in failure, at the very least they represented a branching out into a more novel method of treating the disease.

For the last fourteen years, the primary target of Alzheimer’s drug trials has been amyloid beta. The reasoning behind this seems sound. Amyloid beta (Aβ), in its 42 amino acid form (Aβ-42), becomes chemically “sticky.” This lends it the ability to aggregate with other Aβ-42 molecules, forming an aggregate referred to as an amyloid plaque.

These aggregates cause dysfunction within the neurons of the brain, which can lead to dystrophies along the axon. This eventually results in neurons being killed off. The dystrophies can cause large areas of damage to the brain where surrounding axons will alter their structure to compensate for the area of damage, this can further impair axonal transport and therefore brain signalling.

As amyloid plaques can cause such a severe amount of dysfunction and have been marked as a leading cause of Alzheimer’s disease, they are an obvious target for therapeutic drugs. However, amyloid plaques alone do not account for the full pathology of the disease. Tauopathy has also been implicated as a leading cause, — this  involves the tau protein, a fibrillary protein, tangling within the axon, impairing axonal transport and, with it, brain signalling.

The amyloid hypothesis, in which amyloid plaques are the leading cause of Alzheimer’s disease, suffers from a major flaw. In researching drug targets, animal models are often used. In, for example, a mouse model for Alzheimer’s research such as APPswe/PSEN1dE9, genes are mutated that create a mouse which over-expresses the APP protein, a precursor of Aβ. This creates a high amyloid plaque load and a rough equivalent to human Alzheimer’s disease.

This animal model is of familial Alzheimer’s, an early onset type of the disease that only affects two to three percent of all those with Alzheimer’s disease. Sporadic Alzheimer’s disease, the more prevalent incarnation of the disease, has a wider variation of underlying causes that are not represented in the study of genetic Alzheimer’s.

This may be the reason why multiple attempts at creating drugs targeting amyloid plaques have worked well in a lab, but the results have not translated well into human trials. A number of these failed trials were noted in a previous Hyderus article, about the Merck & Co Inc. medication verubecestat as well as Eli Lilly’s potential Alzheimer’s medication solanezumab.


The mechanism of the drug


Intepirdine takes a different approach, It functions as an antagonist of the serotonin receptor 6 (5-HT)6, a largely central nervous system-specific member of the serotonin receptor subfamily. The receptor is typically found in areas of the brain associated with cognition and memory and as such is of great interest to Alzheimer’s research.

This is an entirely different approach from previous failed medications, but seems reasonable. The serotonergic neurotransmitter system is increasingly more dysfunctional throughout the course of Alzheimer’s disease. Modulating this receptor was therefore a potential way of regulating the effects of the disease.

Initial studies in rats showed a marked increase in cognition when artificially induced learning deficits occurred in the rat model. This presented a potential means of addressing the cognition and memory deficits present in Alzheimer’s cases through regulation of the serotonin receptor.


Handed over following stage II trials


Phase II clinical trials performed by GlaxoSmithKline (GSK) were initially found to be successful. In a dose dependant manner, the drug had  some  benefits to cognition in Alzheimer’s patients with  mild to moderate cases of the disease. Axovant subsequently bought the rights. In hindsight, this decision may have been an attempt by GSK to cut their losses, as following trials would quickly take the potential of the drug from a promising novel treatment to a shareholders’ nightmare.

Intepirdine was trialled in combination with previously created Alzheimer’s treatment Aricept upon being taken over by Axovant and taken to later stage trials. The addition of Intepirdine gave no further improvement than treatment using Aricept alone.

This prompted Axovant to set other criteria in which the drug performed better. If the data is interpreted in multiple different ways, there will almost always be an angle from which the results seem positive. However, this practice did not sit well with investors, who became sceptical of the drug before the eventual announcement of failure and subsequent stock crash.

Like other proposed treatments, this novel medication did not address the underlying mechanisms of Alzheimer’s disease. It is likely that a successful medication will require a combination therapy that addresses several underlying causes. This, however, is a difficult thing to achieve in a clinical setting. With companies leaving the field of Alzheimer’s research, the future prospects of Alzheimer’s research look grim.