Researchers continue to build toolbox as May recognizes ALS

Lou Gehrig / Courtesy of The Daily Beast

Many awareness months dedicated to diseases are obscure, little known to the general public. Amyotrophic lateral sclerosis (ALS), recognized in May, is not one of them. ALS, also known as Lou Gehrig’s disease for the Yankees’ “iron horse” who succumbed to the disease at the age of 37, may be attracting attention for its arbitrary nature – only 5 to 10% of cases have a hereditary component – ​​as well as its brutal path of destruction.

A progressive degenerative neuromuscular disease, the majority of people diagnosed with ALS die within 2 to 5 years of their diagnosis. In the meantime, they will become more and more paralyzed, in turn losing the ability to walk, talk, eat, swallow and finally breathe. I first learned about ALS through the film “Tuesdays with Morrie”, based on Mitch Albom’s bestselling novel, a poignant memoir chronicling Albom’s visits to a favorite teacher who was dying of the disease. Since then I have spoken to some of the bravest humans I have ever met (the patients), and doctors and researchers working hard to unlock the pathology of this relentless scourge.

This month, I spoke with a few others, including Matthew Harms, MD, head of the Muscular Dystrophy Association (MDA) medical advisory team and associate professor of neurology at Colombia University. Harms compared the complexity of understanding the nervous system to that of making the autonomous vehicles that exist today.

Matthew Harms_Columbia University“You had to have the software, the hardware, the battery life, satellites with great GPS to tell cars exactly where they are, camera technology; all these things had to converge. And to treat nervous system disorders like ALS, it’s the same,” he explained. “We’re at this exciting transition point where we’ve built some kind of software and hardware equivalents for studying ALS.”

Harms gave the examples of large DNA repositories and biofluid samples from ALS patients and the aggregation of clinical information about disease behavior over time. Another type of “software” comes from a processing space with many parallels: MDAs. MOVR Data Center (neuroMuscular ObserVational Research)which is a natural history study of people living with neuromuscular disease.

Harms explained that the MDA has been funding ALS research ever since Gehrig’s wife, Eleanor, asked the association to take the disease under her wing. MOVR, he said, follows more than 2,000 ALS patients through the clinic to learn predictors of the disease. “What are the predictors of how people respond to illness; can we predict where things go wrong and when they go wrong in order to try to avoid them? »

He also expressed his enthusiasm for whole genome sequencing and genome-wide or proteome-wide approaches, both of which are made possible by big data.

Harms called the past year “a shrinking and building of a foundation…and incremental progress in understanding the genetics of disease, understanding what’s wrong inside the cell.” He added that it was also a year of progress in finding ways to develop drugs that address these cellular problems.

Specifically, BrainStorm Cellular Therapeutics, biogenic, Ionis and Amylyx have been feeling the growing pains of this incremental progress over the past year and a half. In February 2021, the United States The Food and Drug Administration refused BrainStorm’s NurOwn, which includes autologous mesenchymal stem cells (MSCs) and neurotrophic factors (NTFs), indicating that the phase III trial did not provide the threshold of substantial evidence needed to approve the drug. And this despite the fact that the drug has elicited a robust response in a predefined subgroup patients with early stage disease.

In October 2021, Biogen and Ionis announcement that the phase III trial of tofersen, which was being studied for the treatment of SOD1-ALS, did not reach statistical significance. The companies observed “tofersen-favoring trends” on several secondary and exploratory parameters of disease and clinical function. As for Amylyx, the door is not yet closed on AMX0035, which has a PDUFA date of June 29, but in March, the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA voted against endorsing the drug by the razor-thin margin of 6-4.

Will the path be different for Therapeutic Coya? Houston-based Coya is developing a Treg cell therapy called COYA 101 for the treatment of ALS. Coya’s therapy targets Treg dysfunction, which she says is the critical ancestor of the inflammatory pathway.

Howard Berman_Coya Therapeutics2Coya CEO Dr. Howard Berman, Ph.D. explained that Coya isolated the dysfunctional Tregs found in ALS. “We were able to take hundreds of millions of dysfunctional people [tregs], cultivate them outside the body and convert them into a super-functional Treg state where they are rejuvenated. The cells are then frozen and returned to patients through monthly or bi-weekly infusions for up to one year.

“The key question in ALS is what drives the continuation of motor neuron damage and the amplification of damage,” Stanley H. Appel. MD, Peggy and Gary Edwards Distinguished Endowed Chair for the Treatment and Research of ALS, co-director of the Houston Methodist Neurological Institute, co-founder of Coya Therapeutics and member of the scientific advisory board, said. “We know that there are altered proteins in the motor neuron, but we also know that inflammation is a key driver of disease progression.”

Stanley Appel_Coya TherapeuticsWhile patient stratification based on biomarkers is an established feature in oncology trials, “it took a good number of years before anyone dared to use the term ‘biomarkers'” in ALS, Appel said. The same is true for most degenerative diseases.

In a study led by Appel and recently published in the Annals of Neurology, Coya demonstrated that COYA 101 improved the suppression of pro-inflammatory biomarkers which, in turn, were correlated with slowing disease progression in a phase I study.

The researchers found that “ferroptosis, which is iron and calcium mediated damage to mitochondria at the nerve terminal, is one of the primary ways motor neurons can die in ALS.” The new data, Coya mentioneddetails the “potential ability to select ALS patients with a greater chance of therapeutic response to Treg cell therapy (COYA 101)”.

That ALS is a heterogeneous disease for which there can be no single treatment is now well understood by those in the know.

“[ALS] is heterogeneous, and sometimes it’s really important, even when a drug doesn’t work for everyone, to see if there’s a subset that could have benefited from it,” Dr. Merit Cudkowicz, director of the Healey & AMG Center for ALS, Told NeurologyLive. This brings us back to the MOVR hub, which has another purpose: to quickly match patients with the appropriate new therapies or trials based on the data collected.

“Inflammation is the common factor to varying degrees in different patients, which we believe dictates the rate of progression in patients,” Appel said.

For patients who fall within this common denominator, the results Coya has seen so far should inspire cautious hope.

In a phase I trial, COYA-101 halted disease progression in three patients who received bi-weekly or monthly infusions. When these infusions were stopped and the patients were treated only with IL-2, the decline resumed. “This deterioration was possibly associated as a marker with a dramatic increase in oxidative stress biomarkers in the blood,” Appel explained.

Berman noted that a recently completed phase IIa trial confirmed these biological effects. Then, “Our approach is to not waste time because patients desperately need new modalities. We just don’t have the luxury of waiting too long. Therefore, Coya is aiming to start a phase IIb trial in 2023 which Berman hopes will yield a statistically significant result and a potential BLA.

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