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Alzheimer's Trials That Flopped In 2018

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Alzheimer's is the 6th leading cause of death in the U.S., and there is no cure yet for this neurodegenerative disease. The available medications for Alzheimer's can only alleviate symptoms temporarily, and they don't work for everyone.

The FDA-approved medications to treat the symptoms of Alzheimer's disease include:

-- Donepezil, marketed under the brand name Aricept, to treat all stages of the disease.
-- Galantamine, marketed under the brand name Razadyne, for mild-to-moderate stages.
-- Memantine, marketed under the brand name Namenda, and Memantine/Donepezil combo drug, marketed under the brand name Namzaric, to treat moderate to severe stages and
-- Rivastigmine, marketed under the brand name Exelon, for all stages of Alzheimer's.

No new Alzheimer's drug has been approved since 2003 - the year, in which Forest Labs' Namenda was approved in the U.S.

The success rate of Alzheimer's clinical trials is dismal. A U.S. study, which analyzed how the Alzheimer's clinical trials fared during the period of 2002 to 2012, revealed a failure rate of 99.6% compared to a failure rate of 81% for cancer drugs.
About 200 drug candidates have failed in Alzheimer's disease, according to Bloomberg.

All that said, how did 2018 stack up in terms of Alzheimer's trials?

There was a lot to be disappointed because 6 drugs failed in clinical testing - 4 in late-stage and 2 in mid-stage trials.

Pioglitazone:

Japanese drugs giant Takeda and U.S. partner Zinfandel Pharmaceuticals abandoned their pursuit of developing Pioglitazone in Alzheimer's disease in January of 2018.

Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPAR?). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.

The companies terminated their phase III trial evaluating Pioglitazone in delaying the onset of mild cognitive impairment (MCI) due to Alzheimer's disease, dubbed TOMORROW, as an interim futility analysis showed an inadequate treatment effect with the investigational drug.

Pioglitazone, sold under the brand-name Actos, is prescribed for the treatment of type 2 diabetes. The drug has been in the market since 1999 and had fetched annual sales of over $3 billion before losing patent protection in 2012.

BI 409306:

Boehringer Ingelheim pulled the plug on the development of BI 409306 in Alzheimer's disease last February, following the failure of two phase II trials of the investigational compound to meet their efficacy endpoints.

BI 409306 is a selective phosphodiesterase E9A (PDE9A) inhibitor that targets the glutamatergic signaling pathways in the brain to increase synaptic strength and plasticity.

Verubecestat:

Merck (MRK) discontinued its phase III study of Verubecestat (MK-8931) for the treatment of people with prodromal Alzheimer's disease in February of 2018.

Verubecestat was a small molecule inhibitor of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

The decision to stop the study, dubbed APECS, followed a recommendation by the external Data Monitoring Committee, which found that it was unlikely that positive benefit/risk could be established if the trial continued.

Azeliragon:

A phase III study evaluating vTv Therapeutics Inc.'s (VTVT) drug candidate Azeliragon in people with Alzheimer's disease failed to meet the key goals last April.

The study dubbed STEADFAST, did not demonstrate any improvement in cognitive or functional outcomes as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb).

However, with results of post-hoc subgroup analyses of the STEADFAST Study demonstrating positive benefit in a population of mild- Alzheimer's disease patients with type 2 diabetes, the Company has initiated start-up activities for an adaptive phase II/III trial to evaluate Azeliragon in this subgroup of patients.

Azeliragon is an oral, small molecule inhibitor of the Receptor for Advanced Glycation Endproducts (RAGE).

Atabecestat:

Another BACE inhibitor in the development of Alzheimer's disease to bite the dust is Johnson & Johnson's Atabecestat.

In May of 2018, Johnson & Johnson's subsidiary Janssen, stopped its phase II/III study of Atabecestat in subjects who are asymptomatic at risk for developing Alzheimer's dementia, dubbed EARLY, on safety concerns.

Elevations of liver enzymes, which were serious in nature, were observed in some study participants who received Atabecestat, which lead the Company to conclude that the benefit-risk ratio was no longer favorable to continue development of Atabecestat.

HTL0018318:

Japan-based Sosei Group Corporation and its license partner Allergan (AGN) voluntarily suspended the development of HTL0018318, a new symptomatic treatment for cognitive impairment in patients with Alzheimer's disease (AD) and other dementias, in September of 2018, after tests in an animal study involving non-human primates revealed unexpected toxicology findings.

HTL0018318 is a selective small molecule muscarinic M1 receptor agonist.

The companies have placed a hold on the phase I and phase II trials of HTL0018318.

So, how is 2019 faring in terms of Alzheimer's drug development?

Unfortunately, this year too has started out on a bad note.

Roche halted two identical phase III trials of Crenezumab in patients with prodromal to mild Alzheimer's disease, dubbed CREAD 1 and CREAD 2, in January of this year. The decision to discontinue the trials was based on an interim analysis by an independent data monitoring committee, which indicated that Crenezumab was unlikely to meet the primary endpoint of change from baseline in Clinical Dementia Rating-Sum of Boxes Score.

However, Crenezumab continues to be studied in the Alzheimer's Prevention Initiative (API) trial investigating a different study population from that of the CREAD program, namely cognitively healthy individuals in Colombia with an autosomal dominant mutation who are at risk to develop familial Alzheimer's disease (ADAD).

Crenezumab is a fully humanized IgG4 monoclonal antibody that binds all forms of misfolded Abeta proteins, but especially to Abeta oligomers, to prevent and break up Abeta aggregation and promote Abeta disaggregation.

The high-profile disappointments only go on to prove that Alzheimer's drug development is still a quagmire for pharma companies.

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