The European Medicines Agency (EMA) has turned down a conditional marketing authorization application for Blarcamesine Anavex (blarcamesine, Anavex Germany GmbH), a novel oral medication intended as an add-on treatment for early Alzheimer’s disease. In recommending refusal of the authorization, the EMA's Committee for Medicinal Products for Human Use (CHMP) said that current evidence from the main study submitted by the manufacturer failed to demonstrate the effectiveness and safety of blarcamesine in patients without mutations in the SIGMAR1 gene.

Blarcamesine works by activating the sigma-1 receptor protein encoded by the SIGMAR1 gene, which was intended to restore cellular homeostasis, including via autophagy enhancement. This aimed to improve neuronal function and protect against inflammatory damage, thereby slowing loss of cognitive function. 

The company presented results from a phase 2B/3 placebo-controlled trial involving 462 adults aged 60-85 years with early Alzheimer’s disease. It also presented results from a subgroup analysis of participants without a mutation in the SIGMAR1 gene.

Trial Failed to Meet Main Objective 

Trial results, published in the Journal of Prevention of Alzheimer's Disease in January, showed that the drug significantly slowed clinical progression by 36.3% at 48 weeks, with no associated neuroimaging adverse events. However, the CHMP said that the study had failed to meet its main objective, which was to show an improvement in both main measures of effectiveness: a reduction in cognitive decline measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and an improvement in the ability to perform daily activities measured using the Alzheimer's Disease Cooperative Study – Activities of Daily Living Scale (ADCS-ADL).

In addition, it said that the analysis had "methodological issues" that "raised concerns about the validity of the results. " During the EMA's evaluation, the company had proposed to restrict the indication to adults with mild cognitive impairment due to early Alzheimer's disease, or early-stage mild dementia due to Alzheimer's disease, in people without a mutation in the SIGMAR1 gene. 

However, given the failure of the main study and the methodological issues, and based on the analysis of the data for the subgroup of patients without SIGMAR1 mutations, it was not possible to reach a positive conclusion regarding the effectiveness of the medicine, the CHMP said. 

Safety Data Insufficient

In addition, limitations of the safety database and the way safety data were collected did not allow sufficient characterization of blarcamesine's safety profile. A high proportion of patients had stopped treatment during the main study, mainly due to central nervous system side effects, which raised concerns about how well the medicine is tolerated, the committee said. Also, based on the information provided on medicine quality, it was not possible to rule out the formation of potentially cancer-causing nitrosamine impurities.

The company had applied for a conditional marketing authorization. The CHMP acknowledged the unmet medical need for Alzheimer’s disease treatments and had taken into consideration the views of patients and healthcare professionals. However, it said that blarcamesine did not meet the criteria for granting conditional marketing authorization and therefore the agency recommended refusal.

The manufacturer has informed the agency that there are no consequences for patients receiving blarcamesine in clinical trials or in compassionate-use programs.

The company may ask for reexamination of the opinion within 15 days of receiving it.