ALS Researchers Use Stratification, Diverse Endpoints To Address Heterogeneity
A conversation between Coya Therapeutics President and Chief Medical Officer Fred Grossman and Clinical Leader Executive Editor Abby Proch
Disease heterogeneity, variable rates of progression, and reliance on subjective functional endpoints can make for one heck of a challenge in designing a clinical trial. And when it’s for a treatment for amyotrophic lateral sclerosis (ALS) — one of the most complex challenges in neurology — the task is all the more critical.
What’s working for Fred Grossman, DO, FAPA, and the team at Coya Therapeutics is deep scientific connections, partnerships with regulators, and a willingness to do things a bit differently for the sake of patients and the future success of ALS trials.
In this Q&A, Grossman discusses the company’s ALSTARS Phase 2 trial of COYA 302, a dual immunomodulatory therapy designed to rebalance inflammation in ALS, and dives into its innovative design elements — such as stratification by neurofilament light chain (NfL) — and inclusion of a novel biomarker that might truly account for clinical and functional progression.
Clinical Leader: Let’s start broad. What are the most challenging factors in clinical trial design for the treatment of ALS?
Fred Grossman, DO, FAPA: To start, ALS is a heterogeneous disease that includes genotypic and phenotypic differences. The clinical endpoints are subjective, though most studies use the ALS Functional Rating Scale (ALSFRS-r). And, finally, the rates of progression are variable. If you're conducting a study with several arms and there are differing rates of progression, there could be a lot of variation in response.
How did you attempt to address those challenges when designing the ALSTARS Phase 2 trial for COYA 302?
Rate of progression can have a significant effect. We want to enroll patients when they are first diagnosed to potentially have the greatest effect on stopping or reducing progression. So, we ensure that there's a historically verified diagnosis, and the monthly progression rate is within a range of 0.5 to 1.5 change or reduction in the ALSFRS-r. These criteria allow us to remove very rapid progressors because they can be difficult to study.
Also, one of the most innovative design features we've added to this study is stratification by neurofilament light level, NfL. That's a biomarker used in neurodegenerative diseases, particularly ALS, because it’s associated with survival and decline. In our trial, we made sure there were equal participants of low, medium, and high levels of NfL to control for heterogeneity. That's a relatively new concept, and it’s important to make sure that all of the arms are equivalent with respect to NfL, thus reducing the potential for variation across groups.
The change in the ALSFRS-r is the primary endpoint, from baseline to six months. That is the endpoint that the FDA has used for approval of prior therapies in ALS. In addition, we also have a six-month blinded extension phase wherein patients remain on their therapeutic dose but the placebo group is then re-randomized into one of the two blinded therapies so all patients at that point will be offered therapy but they will not know which dose group they are in. That's going to provide a lot of information because, after six months on placebo, there would be significant progression in disease.
By re-randomizing those patients and putting them on therapy, we will generate data to determine whether the treatment not only affects progression when initially diagnosed but also when patients have progressed further. It allows all patients in the study to eventually be on this potential therapy. We measure NfL as a secondary endpoint, and we are also measuring oxidative stress markers and inflammatory cytokines, including 4-HNE.
In a 2024 interview, you discussed the 4-HNE biomarker as a possible successor to NfL. How has that stance developed over the past two years?
NfL is a generalized marker for axonal injury across neurodegenerative diseases. Because it's a measure of axonal injury, it plateaus. As ALS progresses and neurons are damaged and die, NfL goes up and then stays at a certain point because the damage has been extensive.
A study published last month by David Beers, Ph.D., and Stanley Appel, MD, studied measures of NfL, 4-HNE, and liposomal binding protein. All three were increased at diagnosis, and you'd expect that. But the 4-HNE and liposomal binding protein were significantly correlated with progression rate using the ALSFRS-r throughout the entire course of the disease whereas NfL, as expected, did not and plateaued. In our trial, we are measuring 4-HNE in the ALSTARS trial to provide even more data as a potential biomarker.
How did feedback from regulators, investigators, or other experts influence the final ALSTARS protocol?
We have a whole cadre of experts. In fact, our principal investigators are James Berry, MD, MPH, one of the foremost investigators in ALS, at Mass General. We also work closely with Dr. Appel, as an advisor at Houston Methodist.
With respect to the FDA, we're always in close contact. When we initiated this trial, we excluded patients who were on anti-hypertensives and who have autoimmune diseases at the behest of the FDA. A large percentage of people with ALS, in fact, are on antihypertensives and have some type of autoimmune disorder, such as psoriasis and hypothyroidism. So, we looked very closely at the literature and at our own data set and decided to amend the protocol and remove those two exclusions so those patients could enter the trial — with the FDA’s support. Removing that is really going to rev up recruitment and, most importantly, allow those patients, who would have been excluded, a chance at this protocol.
What was the rationale for excluding those folks in the first place?
Our therapy is a combination of low dose , IL-2 and CTLA-4 (abatacept) in a proprietary subcutaneous formulation. Both work together to enhance the functioning of Tregs, which is dysfunctional in ALS with elevated inflammation, to ultimately reduce inflammation in a sustained manner. Low dose IL-2 in anti-inflammatory whereas high dose IL-2 (Proleukin) is pro-inflammatory. In an abundance of caution, the FDA initially looked at the Proleukin label, which advises against using Proleukin with antihypertensives to avoid capillary leak syndrome characterized by hypotension and pre-existing autoimmune diseases which can be exacerbated. That is because Proleukin increases inflammation. Low dose IL-2 reduces inflammation and, in fact, has been studied in numerous clinical trials as a treatment for autoimmune diseases. The IL-2 component of Coya 302 is one-fortieth of the dose of Proleukin and it's been studied and demonstrated safety in toxicology studies and in patients with neurodegenerative diseases. Taken together including the literature of studies using low dose IL-2, the clear anti-inflammatory mechanism of action, data from toxicology studies and in patients with autoimmune diseases and neurodegenerative diseases, there is no effect on autoimmune diseases or those on antihypertensives, and there was no reason to exclude those categories of patients. We successfully provided that data to the FDA, which agreed that we can remove those restrictions from the clinical trial. That change is going to supercharge recruitment.
Looking back, what is the most important lesson Coya has learned about moving an ALS program from earlier-stage trials into Phase 2 development?
The most important lesson is to have an understanding of the mechanism of action. It is clear how this potential therapy works to reduce inflammation and rebalance the immune system.
And that allows us to target the specific populations where this can have the greatest impact, which is those patients who are diagnosed early, so we can prevent or slow that progression, which will lead to greater survival.
It's also important to study potential therapies quickly and safely into patients for proof of concept before initiating a study like this. The biologic correlates gave us a lot of confidence to move into this larger controlled trial. Additionally, it's important to have not just clinical endpoints but biologic correlates that validate the mechanism of action. It always goes back to the mechanism of action.
It sounds, then, that you have struck a balance of getting the data you need and treating the patients the way they would like to be treated.
That's exactly right. And the expression that it takes a village is absolutely true. It involves patient advocacy groups who believe in what you're doing. It involves the experts that we work with. It involves patients' willingness to put themselves forward for science, and it involves close coordination with the FDA.
Sometimes, companies look at the FDA as an obstacle, whereas we look at the FDA as a helpful group of experts where the language that's spoken is science. So, it's not a question of fighting belief systems; it's using the science to dictate the path forward.
Some reports, including data from an ACRO member survey, indicate that sponsors and CROs have noticed FDA communications delays. What has your experience been?
The FDA is clearly under a lot of pressure with reduced headcount and significant workload, and that leads to delays in response and fewer face-to-face meetings, as well as more meetings conducted either remotely or through email communications. In the past, there were clearly much more interfaced interactions in Washington.
However, people who are working at the FDA are really devoted to continuing the work and to doing the right thing. They're just working much longer now and have much more on their plate. We're definitely sensitive to that. The meetings are precious, and you have to make sure that everything and everyone is involved.
About The Expert:
Fred Grossman, DO, FAPA, is a board-certified psychiatrist and fellow of the American Psychiatric Association with over 30 years of experience in research, academia, and practice. He has held executive positions leading and building clinical development, medical affairs, and pharmacovigilance in large and small pharmaceutical companies including Eli Lilly, Johnson & Johnson, Bristol Myers Squibb, Sunovion, Glenmark, and NeuroRx. Dr. Grossman has developed and supported the launch of numerous blockbuster medications addressing significant unmet medical needs across multiple therapeutic areas including CNS, immunology, immuno-oncology, respiratory, cardiovascular/metabolics, and virology. He has close relationships with thought leaders worldwide and has negotiated directly with the FDA and global health authorities for the approval of many drugs across therapeutic areas. He has numerous publications and presentations and has held several academic appointments. Dr. Grossman was trained in psychiatry at Hahnemann University in Philadelphia and the National Institute of Mental Health in Bethesda, MD, and completed a fellowship in the section on clinical pharmacology at the NIH.