Biogen opts into Alzheimer’s drug candidate from pact with Denali Therapeutics

By Jonathan Smith

- Last updated on GMT

Pic:getty/andrewbrookes
Pic:getty/andrewbrookes

Related tags Biogen Alzheimer's disease Us

As part of a $1 billion deal forged in 2020, Biogen has exercised the option to license a treatment candidate for Alzheimer’s disease developed by the US biotech company Denali Therapeutics. The engineered antibody drug is designed to cross into the brain and break down harmful plaques better than approved antibodies can.

Following the licensing decision, Biogen will take over the development of the candidate in addition to commercial activities and other expenses related to the program. In return, Denali will receive an undisclosed amount as a one-time option exercise payment. Denali could also receive potential development and commercial milestone payments, as well as royalties if the drug reaches the market.

Antibodies and the blood-brain barrier

Alzheimer’s disease is widely thought to be caused by the harmful buildup of a protein called amyloid-beta (Aβ) in the brain, which aggregates into plaques that damage brain cells and contribute to the dementia symptoms.

In the last few years, the US Food and Drug Administration (FDA) has given market approval to the first antibody drugs for Alzheimer’s disease that are designed to slow the disease by clearing away amyloid plaques. The first was Biogen’s Aduhelm, which was controversially given accelerated approval​ in June 2021 with limited evidence of providing clinical benefit. The second, Leqembi, was developed by Biogen and Eisai, and greenlit in January 2023 with more evidence backing its clinical efficacy.

Current antibody drugs for Alzheimer’s disease have a major limitation, however: they cannot easily cross the filter between blood vessels and the brain, known as the blood-brain barrier (BBB). This means they need to be given in large doses​ to allow enough of the drug to reach the brain. However, this large dose can also lead to headaches and bleeds in the brain in an effect called amyloid-related imaging abnormalities (ARIA).

The development of a more efficient delivery system for bypassing the BBB could allow Alzheimer’s treatments to be given in smaller doses. This would mean there is less risk of ARIA and other side effects.

Getting past the BBB by harnessing transferring receptors

Denali specializes in the development of molecules that can bypass the BBB. One part of its pipeline includes antibody drugs that are fused to proteins that activate proteins at the BBB called transferrin receptors. When the engineered proteins bind to transferrin receptors, cells in the BBB transport the drug into the brain tissue. According to Denali, antibodies modified with this so-called Antibody Transport Vehicle (ATV) technology achieve 10- to 30-fold greater brain exposure than unmodified antibody drugs, allowing for lower doses in the bloodstream.

The Alzheimer’s candidate that Biogen snapped up from Denali consists of an anti-Aβ antibody therapeutic that is modified with ATV technology to better penetrate the brain tissue, named ATV:Aβ.

“Recent progress with Aβ-directed therapeutic antibodies enables new treatment options for people living with AD, and clinical trial data have demonstrated that clearance of aggregated Aβ is associated with benefit for patients,” said Joseph Lewcock, Chief Scientific Officer of Denali.

“Our ATV:Aβ program is designed to safely increase exposure of the therapeutic antibody in the brain and potentially lead to improved efficacy and/or safety. We are pleased with Biogen’s decision to license ATV:Aβ and we are hopeful this will foster the development of next-generation anti-Aβ therapeutics.”  

Other projects in the pipeline

In addition to Alzheimer’s disease, Denali has other programs in development that harness its BBB expertise. The original 2020 agreement with Biogen included a small molecule candidate for the treatment of Parkinson’s disease, which the partners entered into late-stage clinical testing in late 2022.

Another treatment that Denali has in late-stage clinical development is a modified recombinant enzyme for treating the rare disease Hunter Syndrome. The company is also developing a small molecule drug in partnership with Sanofi for the treatment of another central nervous system (CNS) condition: amyotrophic lateral sclerosis.

In early-stage clinical development, meanwhile, Denali is working with Takeda to develop a modified protein drug that could treat Alzheimer’s disease by restoring inflammation in the brain to a healthy level.

Other attempts to navigate the BBB

The targeting of transferrin receptors has been studied for decades​ as a mechanism to unlock the BBB to CNS drugs by many academic groups as well as biotech companies such as Genentech. However, many attempts have met variable success so far.

There are also many different approaches in development to pass therapeutics through the BBB, with examples including encapsulation of drugs into nanoparticles or liposomes, and even specially designed viral vectors.

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