After a demoralizing period punctuated by the withdrawal of one of the few marketed therapies for ALS, investment in new biotechs, state-backed collaborative initiatives and buzz at BIO2025 suggest a new day in drug development for one of medicine’s most intractable diseases.
The past couple of years have been disheartening for the amyotrophic lateral sclerosis community—to say the least. With the approval of Biogen’s Qalsody shining as the one bright spot, ALS patients have otherwise been dealt one blow after another, from the market withdrawal of Amylyx’s Relyvrio to the failure of candidates from Sanofi and Denali Therapeutics. So it was especially encouraging at BIO2025 earlier this summer to learn of a budding resurgence in ALS drug development.
Approximately one-third of the companies that BioSpace sat down with at the convention highlighted the intractable neurodegenerative disease as a key focus. Boehringer Ingelheim’s BI Venture Fund is shepherding two young biotechs, Rgenta Therapeutics and Libra Therapeutics, focused on novel targets for ALS; Korro Bio has an RNA-editing candidate in the discovery stages; and GATC Health is the AI engine behind a Louisiana-backed ALS initiative aiming to mine the world’s largest ALS multiomics dataset to accelerate the discovery of new drug targets.
That the failures of the past two years have not dampened the appetite of investors or biopharma companies for ALS was not a surprise to the experts BioSpace spoke with.
“[Relyvrio is] a medicine that was approved on the basis of a single Phase II trial, and I think there was a lot of still residual uncertainty about how effective it was,” said Eric Green, CEO of Trace Neuroscience, which launched last November with $101 million in series A funds and is initially targeting ALS. “But even so, you saw a really rapid uptake, and I think it really illustrates just how strong the desire is for anything new in these patients who really have very minimal options.”
The Next Wave
Unlike Relyvrio, Biogen’s Qalsody, an antisense oligonucleotide (ASO), has been on the market for over two years—and it’s helping patients.
“We’re seeing not only slowing of disease, but in a number of patients we’re actually seeing frank reversal of disease,” said Green, whose company is also developing an ASO. “I think this has been a huge bright spot in ALS, one that I think offers a lot of lessons for how we think about discovering and developing medicines for the broader population.”
Greenlit by the FDA in April 2023, Qalsody became just the fourth treatment for ALS. While a significant accomplishment, Qalsody is approved to treat just 2% of ALS patients—those with a mutation in the superoxide dismutase 1 (SOD1) gene.
ALS, like cancer or Alzheimer’s disease, is a heterogeneous malady—one comprising myriad patient subtypes. Green believes that Trace’s eventual therapy should be broadly applicable. “I think that’s kind of our call to action here. . . . We think that this is an opportunity to bring that genomic medicine to the other 98% of people with ALS who don’t have that option today,” he said.
Trace is seeking to restore the function of UNC13A, a protein that plays an essential role in coordinating neuronal communication that studies have found to be insufficient in patients with ALS, according to the biotech’s website.
“UNC” refers to uncoordinated, Green explained, because it was discovered that when it is missing in worms, mice or flies, they become paralyzed because nerves and muscle cells cannot communicate with each other. Then, nearly five years ago, Trace’s scientific founders found that “nearly all people with ALS lose the UNC13A protein” due to the improper processing of RNA, he said. As a result, RNA is degraded, and the protein doesn’t get made.
Likewise, GATC president Rahul Gupta is hopeful that the company’s platform, which integrates genomics, transcriptomics and proteomics, can uncover novel treatments for a broad range of patients with ALS. Because of this multi-omic approach, “we are able to find those patterns across diverse patient subtypes, basically, then map those disease drivers and stratified mechanism types,” he told BioSpace.
With the Answer ALS–backed Louisiana AI Drug Development Infrastructure for ALS (LADDIA) initiative, GATC and its partners are looking to marry the power of artificial intelligence with “one of the largest ALS databases in the world” to discover novel treatments for the disease.
Gupta said the AI-powered ability to generate targets and discover treatments in a complex, combined, multiphasic way is like “going from the cart and buggy to a rocket.”
“There’s a lot more that could be found without being traditional,” he added.
Another common target across many neurodegenerative diseases is neuroinflammation. This is the focus of Houston-based Coya Therapeutics.
“I think the big focus in ALS, and [the] realization a lot of people are coming to is neuroinflammation is the way to address ALS,” CEO Arun Swaminathan told BioSpace. “I think you’re increasingly seeing investor understanding of that, the science behind why neurodegenerative diseases are driven by neuroinflammation.”
Specifically, Coya is developing therapies—including COYA 302 for ALS—to enhance the function of regulatory T cells (Tregs). “There’s a lot of publications that show that . . . the more dysfunctional [Tregs] are in ALS patients, these ALS patients tend to progress faster, meaning their disease progression is faster and also eventual death, the timelines are faster as well,” Swaminathan said.
Tregs are the “internal brakes of the immune system,” he explained. They ensure that the T cells do not spin out of control and damage healthy neurons and nerve cells, “which is kind of what happens in diseases like ALS.” Ultimately, if you can make these brakes work more efficiently, and keep them working, “then in theory, you should be able to stop the progression of neuroinflammation, therefore translating to stopping the progression of the disease.”
On Aug. 25, the FDA accepted Coya’s investigational new drug application for a Phase II trial of COYA 302 in patients with ALS, marking “a pivotal moment in [the company’s] journey,” Swaminathan said in a prepared statement.
ALS Buzz at BIO2025
Meanwhile, back at BIO2025, Korro Bio CEO Ram Aiyar revealed that the biotech’s third development program will target the DNA/RNA-binding protein TDP-43. The mislocalization of this protein from the nucleus to the cytoplasm leads to a cascade of cellular dysfunctions, including impaired RNA processing, defective axonal transport and mitochondrial issues. Korro’s strategy is to make a single protein change that keeps TDP-43 in the nucleus. It’s a “very elegant way of solving this problem,” Aiyar said.
And ALS may well be Boehringer Ingelheim’s first foray into neurodegeneration—that is if it makes a play for two companies currently under the wing of the Boehringer Ingelheim Venture Fund.
Detlev Mennerich, global head of the fund, noted that ALS is an attractive target for a small biotech because the trials are affordable. “ALS is such a progressive disease, where the motor neuron function drops so fast that you . . . can fund an affordable volume Phase II where you see a meaningful clinical endpoint with a limited amount of patients,” he told BioSpace on the sidelines of the conference.
Gupta, for one, has seen his own patients die from ALS. “I’ve seen the whole cycle,” he said, adding that he believes we’re now at a turning point. “In the area of rare and ultra rare diseases, there hasn’t been enough investment focus or adaptation of science. There just hasn’t been. And somehow, now both the administration is interested [and] there’s datasets there. There are people that are suffering that need the treatment today, not five, ten years from now. It’s a race against time.”
