Validating A Better ALS Biomarker With Coya's Fred Grossman
A conversation with Fred Grossman, DO, FAPA, president and chief medical officer, Coya Therapeutics
Neurofilament light chain (NfL) is the current most widely used biomarker for evaluating ALS drugs. Despite its proliferation, researchers are still seeking something better. Why? Because even though it can help detect ALS, it's not specific to the disease and doesn't directly correlate with disease progression.
To explain what’s happening now in ALS research and what Coya Therapeutics sees on its horizon, we spoke with the company’s president and CMO, Dr. Fred Grossman. In this interview, Dr. Grossman discusses a potential new biomarker for ALS — 4-HNE, an oxidative stress biomarker — and how it could be a more effective tool than the current standard, NfL.
Tell us about NfL and its widespread use as a biomarker for ALS. How successful has it been, and what are some of its shortcomings that prompted you to explore other options?
NfL is a scaffolding protein primarily located in myelinated axons. NfL is released at a relatively consistent level that increases with age and can be measured in cerebrospinal fluid (CSF) and blood. Neuronal damage or axonal injury results in greater release of NfL and concentrations can increase significantly. This is why NfL can be an indicator of damage in the neuro-axonal compartment.
While there is an association between high NfL levels and disease progression, there is no direct correlation between NfL levels and ALSFRS-R (ALS functional rating scale – revised) scores. Further, the observed association has been studied in ALS patients with SOD1 genetic mutations, which are associated with more rapidly progressive disease. However, ALS is a phenotypically and biologically heterogeneous disease, so NfL may not be a good predictor of disease progression in all patients. Yet despite its lack of ALS specificity, it is currently used as a marker for disease severity.
One alternative biomarker you’ve identified for further research is 4-HNE. How was this alternative biomarker identified, explored, and now pursued?
Stanley Appel, MD, distinguished chair in ALS research, Stanley H. Appel Department of Neurology, Houston Methodist, and chair of Coya’s scientific advisory board, has been studying the role of oxidative stress in promoting systemic and neuroinflammation in ALS and other neurodegenerative disorders. Data was collected from an established biobank registry at Houston Methodist, which tracks ALS patient outcomes with biomarkers. Initially, a cohort of 50 patients with ALS demonstrated that levels of the oxidative stress biomarker, 4-HNE, had strong predictive value in the rate of disease progression and survival. Specifically, 4-HNE serum levels were significantly elevated in patients with ALS vs. healthy controls and correlated with disease progression, with higher levels correlating with faster progression. Additionally, 4-HNE levels correlated with survival from diagnosis to death, meaning that the higher the levels, the shorter the survival.
Importantly, further analysis has demonstrated a sensitivity of 92% and specificity of 71% in predicting 24-month survival based on a threshold serum level of 8 ug/ml. This means that if levels are more than 8, there is a 92% chance that the survival of that patient will be less than or equal to 24 months, whereas if the level is less than 8 ug/ml, there is a 71 % chance that the patient will survive beyond 24 months. This is powerful data, and we are continuing to validate this marker using additional data from the Methodist Registry and plan to have a separate discussion with the FDA on this potential biomarker. We also plan to measure 4-HNE in addition to NfL and other biomarkers in our COYA 302 Phase 2 trial in ALS patients. COYA 302 is our combination biologic (Iow-dose IL-2 and CTLA-4 Ig). We will be submitting an IND in the first half of 2024, with the Phase 2 trial to follow.
What makes this 4-HNE biomarker a potential supplement to or preferred option to NfL?
This biomarker has the potential to be a highly sensitive and specific surrogate ALS indicator of disease progression and survival and the potential to track response to treatments. More work is underway to validate this marker, but this finding is very encouraging, and we are excited to potentially have this marker be useful to physicians and patients with ALS once validated.
We measured 4-HNE levels in a small cohort of patients with ALS given the COYA 302 combination (LD IL-2 and CTLA-4 Ig) and found that it lowered 4-HNE levels.
Before using this biomarker in clinical trials, what conversations must happen with the FDA?
We plan to have an initial meeting with the FDA, such as a Critical Path Innovation Meeting, to discuss our proposed biomarker. This discussion will start the process for our eventual Biomarker Qualification Plan submission. We will be measuring this biomarker along with other markers in our planned Phase 2 ALS trial.
How could these conversations impact Coya’s ability to seek quicker approval through one of the FDA expedited pathways, such as Fast Track and Breakthrough?
Given that there is an unmet need for effective ALS therapies — as demonstrated by recent approvals and trial results, such as the failed Relyvrio Phase 3 study — we believe that the FDA has a strong interest in working with sponsors to develop meaningful surrogate endpoints, such as biomarkers that are reasonably likely to predict clinical benefit.
To that end, Coya will apply for Fast Track designation concurrently with our initial IND submission. Pending availability and review of topline results from the Phase 2 study, Coya will apply for Breakthrough designation. Coya also will pursue conversations with other health authorities as part of our overall global regulatory strategy.
Aside from the FDA, what stakeholders must be involved in the biomarker discussion?
We will be presenting this data and submitting it for publication in peer-reviewed journals and are planning forums to discuss this with the medical community and thought leaders once we complete our analysis and regulatory discussions.
Considering trial design — as far as patient recruitment, labs, data analysis, etc. — how does a change in biomarker affect the trial design, if at all?
This will not affect trial recruitment. The planned double-blind controlled trial will be conducted in the U.S. and Canada in a randomized 1:1:1 ratio and will test two doses of COYA 302 against placebo. The primary endpoint will be the change in the ALSFRS-R after six months, with an open-label extension where all participants will be eligible to receive COYA 302. There will be a variety of additional endpoints, including respiratory function, biomarkers, and survival.
Looking ahead, how does a new biomarker such as this, if validated, change the landscape for drug development for ALS or any other neurodegenerative diseases?
It is important to do a full analysis and go through the steps to validate this potential biomarker. If the data holds up, this will add a significant tool to monitor and predict outcomes of treatment in patients with ALS.
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.