2023-06-27 15:54:13
Alzheimer’s disease is now experiencing what multiple sclerosis experienced with interferons: the advent of drugs that make the disease treatable for millions of patients. Substances are on the way that can effectively eliminate the beta amyloid that causes the well-known plaques in the brain and thus sets the disease in motion. They slow down cognitive decline and thus improve the patient’s everyday life.
Alzheimer’s disease is the leading cause of dementia in the elderly, affecting over 36 million people worldwide. In Austria there are around 70,000 sufferers. Two thirds of them are women.
The author Ghazaleh Gouya-Lechner is a specialist in internal medicine, board member of the Society for Pharmaceutical Medicine and founder of the biotechnology start-up Gouya Insights.
Until June 2021, the pharmacological treatment consisted of four drugs: three cholinesterase inhibitors (donepezil, galantamine and rivastigmine) suitable for mild to moderate cases, and memantine, a so-called partial NMDA-R antagonist, which was the only drug recommended for moderate to severe cases cases is appropriate.
Positive study results
All of these drugs act symptomatically, slightly slowing the rate of cognitive decline without addressing the underlying pathology, says Maria Teresa Ferretti, an Alzheimer’s disease expert. Psychiatric symptoms such as depression occur in around 45 percent of cases in Alzheimer’s patients, but their management can be complex. Existing antipsychotic drugs can only be given off-label for severe symptoms and with careful monitoring.
The major research breakthroughs of the last 15 years, most notably the introduction of imaging techniques and biomarkers, have dramatically improved our understanding of the disease and its natural history. According to Joana Enes, neuroscientist at biotechnology start-up Gouya Insights, there is evidence that amyloid beta accumulation in the brain is the earliest pathological event in Alzheimer’s and that it is necessary but not sufficient to trigger the disease. It is only with the spread of tau pathology from the temporal lobes to the rest of the brain that the first symptoms appear.
This realization has led to intensive programs to develop new drugs, and new drugs have become available, initially on the American market, since last year. According to Ferretti, attempts to target amyloid pathology with monoclonal antibodies that were initially unsuccessful have now shown positive results, thanks in part to lessons learned from previous failed clinical trials.
Second-generation anti-amyloid antibodies effectively clear amyloid from the brain and show some evidence of cognitive effects, slowing cognitive decline and improving activities of daily living.
era of precision medicine
A disease-improving effect is hoped for, but longer studies and real-world data are needed to prove this. Two of these antibodies have now been approved by the US Food and Drug Administration (Aducanumab and Lecanemab) as part of an accelerated approval process. Data on a third drug (donanemab) is expected this summer. According to the developer, initial results indicate that all primary and secondary clinical endpoints have been successfully met.
All antibodies in this class carry a risk of a side effect called Aria (amyloid related imaging abnormalities), which can be symptomatic and serious in a small percentage of cases and needs to be monitored by regular MRI scans. Thus, the benefit-risk assessment is the crucial point at which the European Medicines Agency EMA will decide on the approval of these drugs.
The new generation of anti-amyloid drugs ushers in the era of precision medicine for Alzheimer’s, as they are administered based not only on the clinical diagnosis but also on the presence of a biomarker for brain amyloidosis.
A symptomatic, atypical antipsychotic for the treatment of agitation associated with Alzheimer’s dementia (brexpiprazole) was also approved this year. This is the first drug specifically approved by the FDA for this indication. Symptoms such as aggression or restlessness are associated with faster disease progression and placement in an assisted living facility, so such a treatment option greatly helps both sufferers and their caregivers. There are concerns about the risk of mortality associated with the drug, and the benefit and risk must be weighed when prescribing.
Abundant pipeline
The pipeline for the treatment of Alzheimer’s is rich: More than 140 different therapies are currently being tested – 36 of them in phase 2 and 87 in phase 3. The ongoing clinical studies do not only focus on amyloid, but also on a variety of pathological aspects, including tau- hyperphosphorylation and proliferation, and inflammation and vascular pathology.
While there is still no cure, it is very likely that over the next few years more and more diverse pharmacological agents will gradually appear on the market that can make the disease treatable for millions of people.
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