Our understanding of the causes of Alzheimer’s disease (AD) remains incomplete, and so our treatments for AD fall short. Lacking a full understanding of AD’s multiple and interacting causes, we resort to partial solutions: treatments that address only some of the many possible disease pathways, resulting in partial or temporary improvements.
Treatments that focus on amyloid-beta (Ab) plaque, which is tightly linked to AD, represent a case in point. These treatments include aducanumab and lecanemab, which were approved in 2021 and 2023, respectively, for mild cognitive impairment and early AD. These treatments are believed to reduce plaque in the brain, but they do not bring about cures.
“There are cases in which the plaque has been completely removed, but the people are still declining, so additional therapies are needed,” says Mark Litton, PhD, president and CEO, Athira Pharma. “Unfortunately, there’s nothing yet for advanced AD that is truly disease modifying.”
Athira is working to remedy that situation. Moreover, the company is determined to distinguish itself in a space where more than 140 therapeutics are being evaluated in more than 170 interventional, industry-funded clinical trials.
Enhancing natural repair
“We’re enhancing a natural repair mechanism—hepatocyte growth factor (HGF) signaling,” Litton relates. “Essentially, we’re turning up the volume on this repair mechanism. This is a totally different approach.”
Athira’s lead candidate, fosgonimeton (ATH-1017), is designed to treat mild-to-moderate Alzheimer’s disease, an area of great unmet need. As Litton points out, “This is where patients show a dramatic drop-off in functional independence and cognition.”
Fosgonimeton, a potentially first-in-class small molecule that can cross the blood-brain barrier, appears to protect neuronal cells and extend their lives, thus improving patients’ cognition and function. The molecule is, basically, a growth factor enhancer for nerve cells. It promotes neuron growth and creates new connections. Fosgonimeton also is neuroprotective.
“We’ve shown in culture that when we give our molecule and then try to injure the cells, the molecule actually protects the cells from injury,” Litton reports. In a Phase II trial, fosgonimeton also reduced levels of biomarkers associated with inflammation.
In addition to a Phase II trial to evaluate fosgonimeton for mild-to-moderate AD was completed, a Phase II/III trial was launched. Many of the people who have been through either of these trials have continued receiving treatment in an open label extension study. According to ClinicalTrials.gov, about 450 people are enrolled. Some of them are entering their fourth year of treatment.
This molecule also was evaluated in a clinical trial for Parkinson’s disease dementia and dementia with Lewy bodies. That 28-person Phase II study measured cognitive improvement from baseline, using the Alzheimer’s Disease Assessment Scale for cognitive impairment (ADAS-Cog13). Results from five patients treated with 40-mg fosgonimeton in a modified intent-to-treat population showed a 7.2-point improvement by week 26, which suggests that fosgonimeton may be a valuable therapeutic for patients with neurodegenerative diseases.
Improved autophagy
In a preclinical study (Neurotherapeutics 2024; 21(4): e00350), Athira scientists noted that fosgonimeton “mitigated Ab-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy,” the process by which cells recycle or remove toxic materials and miscellaneous debris. “We’ve shown,” Litton maintains, “that when our molecule enhances this HGF biology, it may actually improve cells’ ability to get rid of the garbage.”
Several molecules, similar actions
In addition to fosgonimeton, Athira is developing a number of other molecules, optimizing each of them to address different diseases. The next into the clinic, ATH-1105, is designed to treat amyotrophic lateral sclerosis (ALS). In another preclinical study (Front. Neurosci. 2024:18: 1348157), Athira scientists showed that the therapeutic candidate “protects spinal motor neurons from ALS-relevant insults” and reduced biomarker levels indicative of neurodegeneration in ALS. ATH-1105 appears to distribute well throughout the body, reaching muscles and other tissues.
“About 97% of ALS patients have a misfolded protein [transactive response DNA binding protein] called TDP-43, which disrupts the cells,” Litton notes. In a TDP-43 transgenic mouse model, ATH-1105 extended survival and improved motor and nerve functions. Phase I trials in humans are expected to begin in 2024, with patient dosing starting in 2025.
Another molecule, ATH-1020, is being designed to treat neurodegenerative diseases. It has completed a Phase I clinical trial.
WSU to UW
The idea behind Athira’s approach originated at Washington State University about 25 years ago. The company formed based on that work, M3 Biotechnology, moved to an incubator across the state at the University of Washington. Its name changed to Athira Pharma in 2019.
Litton joined the company as chief operating officer a few months later, adding his expertise advancing biopharmaceutical technologies. “I loved the science,” he recalls, “and I was fascinated by the approach of enhancing this natural repair mechanism.”
The company went through a tumultuous period a few years ago when then-CEO Leen Kawas, PhD, resigned in 2021 amid allegations that she had altered images depicting her graduate work. Although Athira had not developed the same molecule that Kawas had examined in the papers at issue, Athira was one of the defendants in a class action complaint. The plaintiffs argued that Kawas’ work “laid the biological groundwork” for Athira’s approach. Xue Hua, PhD, then the vice president of clinical development, left a few months later, protesting how Athira’s board handled the situation. Last February, the company reached an agreement to settle the class action in the range of $10 million, closing that chapter in the company’s history.
Litton, who became CEO upon Kawas’ exit, is focused firmly on what he says he expects will be an exciting future for the company and for neurodegenerative therapeutics. “The business of developing therapies is a journey,” he says, “and I remind our employees how cool it is that we are part of this journey.”
Biopharma headwinds
Athira may be out of the storm, but it is, like many small companies, struggling against macroeconomic headwinds that are affecting the economy at large. “We’re trading below our cash,” Litton admits, which is not uncommon for young firms. That said, at the end of 2023, the company had approximately $147 million, which will allow it to reach certain key inflection points.
The most potentially significant of those milestones is the six-month, approximately 315-subject LIFT trial for mild-to-moderate Alzheimer’s patients. “Half will be on fosgonimeton and half on placebo,” Litton remarks. “That readout will happen later this year.”
The other major milestone will be when ATH-1105 enters the clinic later this year, with patient treatment expected to begin in 2025.
“We’re at the stage where we just need to show some promising data to reset,” Litton says. “In biotech, you need capital to keep growing. We have multiple molecules that, if we have enough capital, can be assessed across different disease settings.” Having weathered the storm, Litton is ready to turn up the volume.
