AS-M801 targeting glial TLR2
On June 7th 2021, the Food and Drug Administration (FDA) granted the accelerated approval of aducanumab (amyloid beta-targeted, disease-modifying IgG monoclonal antibody) to be marketed for the treatment of Alzheimer’s disease (AD), in spite of the controversy surrounding the incongruent correlation between amyloid reduction and symptomatic benefit, along with the safety data in terms of Amyloid‐Related Imaging Abnormalities (ARIA).
However, aducanumab does not seem to have been fully resurrected because the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) voted against the highly controversial aducanumab in its November meeting and it is very dubious that the drug will be recommended for approval at its coming December meeting.
Anyway, the FDA’s approval of aducanumab seems to have significantly lowered the barriers for other anti-amyloid drugs to enter the market. Lecanemab (formerly known as BAN2401) and donanemab are following the same path and had applied to the FDA in September and in October respectively. Gantenerumab was granted the Breakthrough Therapy Designation by the FDA in October.
Besides the above-mentioned drugs, there are plenty of other drugs aiming at amyloid. Accordingly, the competition is very savage. But just as all anti-amyloid drugs have different names, their mechanisms of action are somewhat different from one another, leading to different efficacy and safety.
There are various forms of amyloids; monomers, oligomers, soluble protofibrils, insoluble fibrils, and plaques. The different binding preference of each drug may influence its clinical results. Because the removal of amyloid plaques is associated with ARIA-E, drugs targeting oligomers can avoid the ARIA-E. Lilly’s solanezumab targets primarily monomers. Biogen/Eisai’s lecanemab clears protofibrils than fibrils (but does not bind monomers or oligomers), producing less ARIA edema than its rivals; Biogen/Eisai’s aducanumab, Roche’s gantenerumab, and Lilly donanemab bind fibrils and plaques.
Acumen’s ACU193, Alzheon’s AZL-801, and Cognition Therapeutics’ Elayta (CT1812) target also oligomers like lecanemab, rather than monomers or plaques. However, donanemab recognizes a unique form of amyloid, called pyroglutamated form truncated at the N-terminus. Roche/AC Immune’s crenezumab targets various forms of amyloids including oligomers.
There is another company that has recently joined this fierce competition, under the straight-out name called ‘Amyloid Solution’. If so, as the company name implies, what has ‘Amyloid Solution’ been solving for AD?
Amyloid Solution, headquartered in Seongnam, South Korea, is a biotechnology company with a mission “Erasing Alzheimer's Disease”, focusing on everything about AD to develop the effective, safe, and diverse therapeutic solutions for the treatment of AD.
The company is developing its proprietary lead candidate, AS-S701, a small molecule that can directly disaggregate all toxic forms of amyloids including oligomers and plagues into non-toxic monomers. In this respect, AS-S701 is similar to crenezumab. However, AS-S701 has not reached the clinical stage yet, it is currently at non-clinical IND-enabling stage to evaluate its safety and efficacy.
In parallel with the development of AS-S701, the company is also developing another novel candidate drug, AS-M801, with a different mechanism of action other than directly targeting amyloids.
Toll-like Receptor 2 (TLS2) is up-regulated in the brains of neurodegenerative diseases such as AD and PD (Parkinson’s disease). TLR2 on microglia is activated by the ligands like amyloid-beta and alpha synuclein.
AS-M801, a monoclonal antibody against TLR2, can suppress inflammatory response through the inactivation of TLR2, maintaining homeostasis in the immune system. It is also currently at the IND-enabling stage.
In the meantime, Amyloid Solution successfully raised $15 million in Series B funding led by the Korea Development Bank (KDB) with the Yuhan Corporation in April 2020, which was followed by additional $1.67 million in June 2020. Previously, the company secured $12.1 million through the Series A in 2019.
In November 2020, Amyloid Solution incorporated Deargen as its subsidiary. Deargen is a biotech company developing new drugs using its advanced artificial intelligence (AI) platform technology.
Although it seems that Amyloid Solution has to go a long way before it can solve the AD meaningfully, the funding secured and the joining of Deargen will help the company expedite the development of AS-S701 and AS-M801 and enter into its global clinical trials soon.