Neurodegeneration

Lilly Lands Disarm Therapeutics and NAD+ Metabolism Drug to Fight Neurological Diseases

The addition of Disarm's promising programs for axonal degeneration expands Eli Lilly and Company’s R&D efforts in pain and neurodegeneration.

By Noemi Canditi

Neurodegeneration is a prevalent yet unaddressed symptom of a wide range of neurological illnesses that can impair many of your body’s functions, including talking, breathing, balance, movement, and heart function. However, there are currently no effective therapeutics because clinical trials for neuroprotective treatments that address neurodegenerative disorders have failed.

The pharmaceutical company Eli Lilly and Company recently declared a decisive agreement to legally obtain Disarm Therapeutics, a privately-held biotechnology company developing a new type of disease-altering therapeutics for people with axonal degeneration. Degeneration of the axon, a long cable that carries nerve impulses from one neuron to another, has been identified as a major promotor of illness and disease progression in central nervous system diseases such as Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, in addition to ocular disorders, such as glaucoma, and peripheral nervous system disorders such as chemotherapy-induced, diabetic, and inherited neuropathies.

The founders of Disarm Therapeutics, Dr. Jeffery Milbrandt and Dr. Aaron DiAntonio of Washington University School of Medicine, identified the SARM1 protein as a central moderator of axonal degeneration in response to stress and injury, making it a particular therapeutic target that could possibly lead to the treatment of various neurodegenerative disorders. Through the enzymatic activity, SARM1 mechanistically works by depleting the essential cellular metabolite nicotinamide adenine dinucleotide (NAD+) through enzymatic activity.

The balance between the survival and self-destruction of axons is tightly linked to NAD+ metabolism, and a reduction in NAD+ levels is an early indicator of age-related and disease-associated degeneration of neurons. Following injury, SARM1 launches a local elimination program that incorporates the quick breakdown of NAD+. Diminishing cellular levels of this compound by SARM1 eventually induces severe energetic problems and cell death. Therefore, inhibiting SARM1’s ability to reduce cellular NAD+ levels is crucial for halting axonal degeneration and is being investigated as an alternative or synergistic therapeutic method for the treatment of neurological diseases.

In preclinical development, Disarm Therapeutics is working on SARM1 inhibitors that are engineered to directly inhibit NAD+ depleting activity and block axon elimination, with the goal of bringing breakthrough effective therapeutics to patients suffering from peripheral neuropathy and other neurological disorders. These therapies may stop axon degeneration in chronic and acute illnesses of the central, ocular, and peripheral nervous systems by preventing the SARM1 protein from eliminating NAD+ in response to stress or injury. Thus, for a wide range of neurological disorders, the therapeutic goal is to inhibit further axonal degeneration, stabilize disease, and promote functional recovery of the nervous system.

According to the terms of agreement, Lilly will make an upfront payment of $135.0 million to purchase Disarm Therapeutics. In addition, if Lilly successfully develops and commercializes new medications as a result of this acquisition, Disarm Therapeutics equity holders may be entitled up to $1.225 billion in additional future payments for possible commercial, development, and regulatory milestones.

“Lilly continues to seek medicines to treat the debilitating pain and loss of function associated with nerve damage,” said Mark Mintun, M.D., vice president of pain and neurodegeneration research at Lilly, in a press release. “The scientific team at Disarm discovered an important and highly promising approach to combat axonal degeneration. We will move quickly to develop their SARM1 inhibitors into potential medicines for peripheral neuropathy and neurological diseases, such as ALS and multiple sclerosis.”

“Disarm’s innovative approach to treating axonal degeneration holds tremendous promise for addressing a wide spectrum of neurological diseases, and we have made significant strides toward enabling potentially transformative therapies,” said Alvin Shih, M.D., Chief Executive Officer of Disarm, in a press release. “Lilly is ideally suited to advance this exciting new approach to treating axonal degeneration, and we look forward to seeing patients benefit from the work that Disarm initiated.”

Atlas Venture, Drs. Milbrandt and DiAntonio of Washington University School of Medicine in St. Louis, in addition to Atlas Entrepreneurs-in-Residence Dr. Rajesh Devraj and Dr. Raul Krauss, co-founded Disarm Therapeutics. In addition, Atlas partnered with Lightstone Ventures and AbbVie Ventures to assist with the core development at Disarm Therapeutics.

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