Clinical trials for disease-modifying therapy for Alzheimer’s disease are underway.
Biogen’s Aduhelm received accelerated approval from the FDA despite medical controversy in 2021, with the FDA overruling an advisory committee of experts who voted almost unanimously against approval. (Three members of the FDA advisory panel subsequently resigned.) Though the director of the FDA claimed that the benefits of the medication outweighed the risks, the phase 3 research results show that about one-third of the patient population developed amyloid-related imaging abnormalities (ARIA), specifically with edema. Of those patients who developed ARIA with edema, 40% also developed microhemorrhaging. Along with patient safety concerns, Aduhelm clinical trials also show conflicting or limited efficacy.
Researchers are still searching for a medication that will prove clinically effective while producing fewer undesirable side effects.
Posiphen’s Discover Study
Aimed at reducing the production of amyloid precursor proteins (APP), the medication Posiphen is currently entering its second phase of clinical trials. The first phase, called the Discover study, has produced some promising results. Instead of binding to amyloid aggregates in the manner of Aduhelm, Posiphen inhibits the formation of APP. During preliminary research, there were no reports of ARIA or adverse events that indicate ARIA.
“We hoped to determine the safety and tolerability of Posiphen across increasing dosing groups — 60 mg once daily, 60 mg twice daily, and 60 mg thrice daily,” according to Archana Balasubramanian, PhD, Project Manager of the Alzheimer’s Disease Cooperative Study at University of California, San Diego, and Doug Galasko, MD, Professor in Residence, Department of Neurosciences at University of California, San Diego. “In addition to determining the safety and tolerability of Posiphen, the intent of the Discover study was also to examine the pharmacodynamic and pharmacokinetic effects of Posiphen on blood (plasma) and cerebral spinal fluid [CSF] analytes such as Aβ 38 and 40, sAPPα, sAPPβ, and T-tau protein (T).”
Discover study patients were required to receive CSF catheter placement and undergo CSF and blood sampling every two hours during their 36-hour visits. The researchers found that, so far, Posiphen is associated with a reduction in soluble APP, Aβ, tau, p-tau and αSYN.
“Posiphen’s mechanism of action is thought to be at the level of translation: it binds to the 5’UTR of the APP mRNA, which may lower APP and Aβ protein levels in animal models, and lead to decreased sAPP and Aβ protein levels in human CSF,” say Balasubramanian and Dr. Galasko. “The field is making progress towards finding disease-modifying therapies for Alzheimer’s in the near future.”
A phase 2 study is investigating the effects of Posiphen on patients with Alzheimer’s and Parkinson’s diseases, with the aim of determining optimal dosing and identifying whether the drug modifies disease-related biomarkers. Changes in cognitive status will also be noted for participants with Alzheimer’s disease.