Alzheimer’s disease: another new drug failed

Alzheimer’s disease: another new drug failed. Where is the treatment for Alzheimer’s disease?

This is a study that proves that removing Aβ protein can bring better clinical results. To a certain extent, it is the “amyloid hypothesis” that has been repeatedly questioned in recent years.

As we all know, the field of Alzheimer’s disease has always been the hardest hit area for new drug development, with a clinical failure rate as high as 99.6%. Although major pharmaceutical companies frequently sounded the clarion call about the research and development of new drugs in this field, most of them ended in failure. Recently, the clinical failure of new drugs for Alzheimer’s disease has added another member.

On January 18th, Biohaven Pharmaceuticals announced on its official website its EAAT2 inhibitor troriluzole for the treatment of mild to moderate Alzheimer’s disease phase II/III clinical study. After 48 weeks, the treatment group did not reach the primary clinical endpoint, and at the same time the hippocampal body mass It also failed to beat the placebo on key secondary indicators.

Troriluzole is a prodrug of riluzole approved for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease related to high levels of glutamate, and a feature of Alzheimer’s disease is also excessive glutamate activity. Troriluzole can increase the uptake of synaptic glutamate by increasing the expression and function of excitatory amino acid transporter (EAAT2) on glial cells, thereby reducing the synaptic level of glutamate.

The primary endpoint of this failed Phase II/III clinical study was to observe the patients on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-cog) and Clinical Dementia Rating Scale (CDR- There is no statistical difference in SB) score. The secondary endpoint is the hippocampal volume assessed by magnetic resonance imaging (MRI), but the results are not ideal.

In a subgroup analysis of 97 mild AD patients, after 48 weeks of treatment, the average change in hippocampal volume at baseline for 48 subjects in the triazole subgroup was -1.1%, compared with -1.6% in the placebo group. The p value is 0.2. The company stated that the subgroup analysis showed “no significant numerical differences in potential benefits” and “potential biological effects of trizole on patients with early disease”

In terms of safety and tolerability, the treatment with troriluzole at a dose of 280 mg once a day was relatively tolerated and showed safety consistent with previous studies of troriluzole. Biohaven plans to modify the ongoing long-term extended study of troriluzole in patients with mild AD so that it can continue treatment to collect more clinical and biomarker data.

According to data released by the Pharmaceutical Research and Manufacturers Association of the United States (PhRMA) in 2018, during 1998-2017, 146 AD drugs worldwide have failed clinically, and only 4 drugs have been successfully listed. On average, Alzheimer’s The clinical success rate of the new drug is only 2.7%. Among the failed drugs,

4% is the mechanism of tau protein, 15% is the mechanism of beta amyloid, 19% is the mechanism of neuroinflammatory,
26% are neurotransmitter mechanisms, and 36% are other mechanisms. From these data, it is not difficult to see how difficult it is to develop new drugs for Alzheimer’s disease.

Of course, to bear the risk of failure in drug research and development, and to keep on trial and error in failure is the value of drug developers. A week ago, another new drug for Alzheimer’s disease brought confidence to companies and researchers in this field.

Eli Lilly’s donanemab reached the primary clinical endpoint in a phase 2 clinical trial. Compared with placebo, donanemab can significantly slow the progression of early Alzheimer’s disease, and the composite index of cognition and daily function (iADRS) of patients has decreased significantly. The placebo slowed down by 32%.

It is worth noting that this is a study that proves that removing Aβ protein can bring better clinical results. To a certain extent, it is the “amyloid hypothesis” that has been repeatedly questioned in recent years.

(source:internet, reference only)

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