Leqembi, developed by Japan's Eisai and the U.S. company Biogen, along with 'donanemab' from Eli Lilly, is leading the global Alzheimer's treatment market as latecomers prepare to challenge and enter the fray.
Alzheimer's disease occurs when amyloid beta (Aβ) and tau proteins in the brain exceed their normal boundaries and become abnormally tangled. Leqembi and donanemab are antibody therapies that eliminate amyloid beta and have been approved by the U.S. Food and Drug Administration (FDA) for market release. Although amyloid beta is originally meant to protect nerve cells, it can destroy them when it breaks away and aggregates outside of brain cells.
The issue is side effects. Latecomers are developing new drugs by supplementing existing treatment strategies or creating new therapeutic approaches, as severe side effects such as brain edema and bleeding have appeared in previously released medications.
Swiss pharmaceutical company Roche announced its plans for a Phase 3 clinical trial of its Alzheimer's drug candidate, tonatinib, during its first-quarter earnings announcement on the 24th (local time). Tonatinib works by crossing the blood-brain barrier to remove aggregates of amyloid beta.
The blood-brain barrier acts as a protective shield that typically prevents foreign substances from entering the brain. Its dense and thick tissues create a significant barrier for medications to reach the brain. Roche has combined a technology for penetrating the blood-brain barrier with gantenerumab, which previously failed in Phase 3 trials.
Existing Alzheimer's treatments such as Leqembi and donanemab are made of polymer substances that do not easily penetrate the blood-brain barrier. They attack amyloid beta aggregates that accumulate around brain blood vessels by increasing the drug concentration, which can lead to serious side effects like bleeding or edema by damaging the vessel walls. In contrast, tonatinib is expected to efficiently penetrate the blood-brain barrier, reaching deep brain tissue with smaller doses than existing medications. This is anticipated to lower the risk of side effects.
British company GlaxoSmithKline (GSK) has also taken a different approach from existing treatments. The immunoregulation-based antibody treatment, AL101, currently in Phase 2 clinical trials, is developed for patients with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. AL101 increases the level of progranulin (PGRN), a protein related to immune response in the brain.
Earlier studies indicated that low levels of PGRN increase the risk of developing Alzheimer's and Parkinson's diseases. GSK confirmed the preventive effects against dementia when PGRN levels increased in preclinical trials of AL101. Recently, GSK also received the transfer of 'Grabody-B', a blood-brain barrier penetration technology from the domestic company ABL Bio.
Domestic companies have also begun to take on the challenge. The most advanced in development in Korea, Aribio, is conducting a global Phase 3 clinical trial of its oral Alzheimer's treatment, AR1001. The trial involves 1,150 Alzheimer's patients across 13 countries, including the U.S., Canada, Korea, China, the U.K., and the European Union (EU), in over 200 clinical institutions. The goal is to finish administering the last patient doses in the first half of next year and publicly share the analysis of results and key evaluation indicators.
AR1001 is a phosphodiesterase-5 (PDE5) inhibitor candidate substance that was introduced from SK Chemicals. PDE5 inhibitors improve cerebral blood flow and activate nerve cell signaling pathways to prevent damage to nerve cells.
Applying cell technology that removes toxic proteins, it also has the efficacy of removing tau proteins, which are considered to be one of the causes of Alzheimer's disease, along with amyloid beta. Tau is a protein that acts as a scaffolding for maintaining the structure of nerve cells, but it is known to cause cognitive dysfunction when it detaches from its original location and accumulates within cells.
Gemvex & KL is developing an Alzheimer's drug candidate called 'GV1001' that suppresses brain inflammation. It plans to announce the final results by the end of the year after completing the global Phase 2 clinical trial.
Adel, a biotech venture founded by Professor Yoon Seung-yong of the Brain Science Department at Asan Medical Center, is jointly developing an antibody treatment targeting tau proteins with Oscotec. Currently, a global Phase 1 clinical trial is underway in the U.S.