Drug development in the Alzheimer’s space is difficult and has been plagued by successive failures over the last 18 years. One company working in that space felt it was time to take a new and innovative approach to find a treatment for patients.
“The classical approach that has been followed by most companies over that time span did not really apply to what we needed to achieve,” says Hans Moebius, M.D., Ph.D., CMO of Athira Pharma. “We are targeting Alzheimer’s disease and mode of action aside, there are two development challenges that have faced drug developers: understanding dose and translation. Researchers must understand the doses needed in late-phase clinical trials. They should also use functional measurements or biomarkers in early-stage trials that lend insight for translating to clinical benefit. Those are two areas we knew we had to focus on.”
Athira has optimized their clinical development approach to address those challenges.
A New Approach
One functional measurement Athira has chosen to incorporate into the development process including clinical trials is quantitative electroencephalogram (qEEG). This enables Athira to measure changes in brain activity in response to treatment and optimize dose selection. The company is also making use of event-related-potential (ERP P300), a measurement that captures the speed by which the brain can process information and is a predictable measure of memory access. In all Alzheimer’s patients, the processing speed is significantly slowed.
“In our Phase 1B trial we demonstrated consistent changes in brain activity in all treated Alzheimer’s patients” says Moebius. “Our approach uses small molecules that are able to get past the blood brain barrier and activate a critical neurotrophic system that may lead to regeneration in the central nervous system. This is a major mind shift in drug development not only for Alzheimer’s Disease, but for CNS disorders in general.”
Xue Hua, Ph.D., VP of Clinical Development for Athira, notes that in the past drug development focused on a single pathway approach. Athira’s approach is specific, yet multi-pronged and agnostic to the underlying cause of the disease.
A Quicker And More Accurate Approach
Alzheimer’s disease is a huge unmet medical need for the more than 6 million Americans afflicted with the disease. Therefore, time is of the essence for Athira as it seeks to validate this investigational treatment approach.
“We wanted to figure out as quickly as possible if this drug would exhibit the outcomes we desired,” says Hua. “We wanted to increase our confidence in our drug’s effectiveness in early stages, prior to proceeding to a later stage study. That was a main reason why we opted to look at functional biomarkers like qEEG and ERP P300 to help refine the dose selection early on and facilitate translation.”
Hua states that a responsible approach to developing an Alzheimer’s treatment must recognize that trials are demanding on patients, caregivers, and the healthcare system. Traditionally, trials have been lengthy and burdensome. A failed trial can cost millions of dollars and discourage patients. Moving quickly and with increased confidence in a successful outcome is beneficial for all involved.
“In an Alzheimer’s trial we look at a large number of variables,” she states. “We are using qEEG and ERP P300 as an investigative tool and functional measure. It adds a lot of value in that it may show correlation to the mechanism of action of the compound. This is not a biomarker that is simply related to a hypothesized step of the disease process. It is directly reflecting brain activity. This is a way for us to quickly and accurately test whether the treatment may have desired effects in the brain.”
Achieving Patient Centered Trial Design
Early in the trial design process, Athira partnered with the Rush Alzheimer’s Disease Center at the Rush University Medical Center in Chicago to gain insight into the patient and caregiver experience. The purpose was to understand what was most important to them and understand what they most look forward to when participating in a clinical trial. They also hoped to discover patient and caregiver concerns. The trial and protocol were also discussed. Dr. Raj Shah at Rush has performed several clinical trials and felt many were run in an inefficient manner and did not have the needs of patients and caregivers in mind. That creates frustrations for patients, caregivers, and even site staff.
“The main thing those three groups are interested in is whether the drug is safe and will result in meaningful improvements for the patients,” says Hua. “Dr. Shah brought in people from the clinical team and the trial design team to gain their insights. Then they scheduled two sessions – one to meet with patients and caregivers and the other to meet with site staff. We were able to understand what was important to the stakeholders, address their concerns by optimizing the trial design, and become more efficient by eliminating redundancies.”
“Alzheimer’s trials are a huge burden for caregivers but also for the operational team because they often times don’t know what specifically they are looking for,” adds Hua. “They must watch over their patient’s safety in every aspect but also keep an impartial view on any cognitive changes”.
What’s important to caregivers is tangible clinical improvement in the patient, not a more theoretical slowing down of the rate of decline. Therefore, the design of trials conducted by Athira are focused on demonstrating improvement. Hua states it is not enough for someone to know the condition of their spouse will deteriorate more slowly. They want to know if that individual’s condition can be improved for daily function. Demonstrating improvement is clinically meaningful and is what Hua believes is necessary to address the unmet medical needs in treating Alzheimer’s disease.
Current Trials Focus On Improvement
Athira is currently recruiting for two trials – ACT-AD (https://www.act-adtrial.com/) and LIFT-AD (https://www.lift-adtrial.com/) – and hopes to enroll approximately 400 patients. Patients in these trials are randomized to receive a daily subcutaneous injection of ATH-1017 or placebo and are evaluated for changes in cognition, global, and functional assessments. ACT-AD will also measure quantitative electroencephalogram (qEEG), and Event-Related-Potential (ERP P300).
“Utilizing qEEG and ERP 300 to support translation and assess dose-dependent changes in brain function could be valuable to the field of Alzheimer’s drug development,” said Moebius. “Our goal with these trials is to demonstrate the ability of our investigational drug to treat Alzheimer’s disease and preserve cognitive health. We are focusing on a practical, rational trial design that attempts to address a very precise question which is tied to clinical improvement. We are seeking to evaluate treatment effects over a 6-month double-blind period and are creating a team dynamic between the patients, the caregivers, and the PI that creates a trial experience unique to the Alzheimer’s space.”