Treg cell therapy showing promise in ALS trials: Coya Therapeutics

For patients with amyotrophic lateral sclerosis (ALS), the prognosis is dire. According to National Institutes of Health statistics​, most people succumb to the neurogenerative disease within three to five years of receiving the diagnosis—and while there are therapies that may help the symptoms, to date there is no treatment for the disease itself.

Coya Therapeutics, a clinical-stage biotechnology firm that focuses on the discovery and development of treatments for neurogenerative diseases, believes it might have come upon a treatment that offers hope for ALS sufferers.

Coya Therapeutics CEO Howard Berman spoke with Outsourcing-Pharma about the company’s innovative research around regulatory T-cells (Tregs), how research has progressed, and what it might mean for patients with ALS.

OSP: Could you please share a little bit of perspective about why ALS is especially worthy of researchers’ attention?​

HB: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that attacks motor neurons in the brain and spinal cord. This results in the deterioration of muscle, loss of movement, and eventual paralysis.

There are an estimated 30,000 people living with ALS in the US at any given time. Every 90 minutes, someone is diagnosed with ALS. About 90% of all ALS cases are sporadic with no known history of the disease in a family. The remaining 10% of cases are known as familial ALS.

This is a horrendous and progressive disease that some patients describe as being buried alive, as the disease progressively destroys muscle controlling motor neurons, eventually paralyzing the individual and ultimately the muscles used to breathe. All while the patient’s mind, personality, intelligence, or memory remains intact.

There are no meaningful treatments that are available and the ones approved measure success by only slightly reducing deterioration, and the clinical trial landscape has been littered with many failures due to the complexity of the disease process and inability to control the underlying progenitor that leads to the decline of the patient, which is runaway inflammation. Our goal at Coya is to go beyond incremental improvements in care; rather, we aim to exponentially challenge the current treatment paradigm and transform the disease to a long term chronic

OSP: Please talk about the progress (or more accurately, the lack thereof) in the search for ALS treatments.​

HB: The treatment landscape is littered with many failures and this is due to a number of reasons, including misleading preclinical data in mice models, poor clinical trial design and methodological issues, phenotypic heterogeneity of ALS patients, and insensitive biomarkers to stratify patients. Moreover, we now know that inflammation drives the disease decline and prior treatments targeting inflammatory processes have focused on one immune pathway or cytokine, but we know that the immune system is complex, and single pathway blockade will be insufficient to dampen the runaway inflammation.

This is why we are so excited about our Treg cell therapy, as it introduces a highly immunosuppressive cell type that is upstream of the majority of immune pathways.

OSP: Could you please discuss the pioneering ALS research involving Tregs, and why this is especially important/promising?​

HB: We have learned a tremendous amount in the past 20 years, but the most significant is that the spread and decline of the disease is really a consequence of how cells around the nerves (macrophages and microglial cells, which are important cells of the immune system) respond to the dying motor neurons. It’s once this inflammatory process is triggered that the disease becomes debilitating and the patient’s decline starts to rapidly increase.

Much of the seminal work which mapped out the role of the immune system in ALS decline and deterioration was done in the laboratory and clinic of the head of our scientific advisory board Stan Appel. He discovered that regardless of the mutation or underlying cause of the disease, peripheral inflammation was directly tied to the patient’s survival and rate of decline and was driven by the dysfunction of a critical immune cell called the regulatory T cell or Treg.

Tregs have the ability to regulate the activity of other immune cells, such as the pro-inflammatory macrophages and microglial cells, acting as a stop sign when the system is overreactive. Because these cells can infiltrate the brain and spinal cord, they hold the potential to reduce the inflammation characteristic of ALS.

When you measure the blood of a patient with fast progressing ALS, you find increased levels of M1 pro-inflammatory macrophages, pro-inflammatory T cells, and cytokines. But the most significant finding is the decreased function and number of Tregs.

Coya has learned how to remove the dysfunctional Tregs from the patient from an apheresis and repair these cells back to a functional status as well as expand the new, highly suppressive Tregs into billions of cells for reinfusion back to the patient to stop the runaway inflammation and aim to stop ALS progression.

We have revolutionized Treg cell therapy and Treg exosome manufacturing steps with cryopreservation techniques that allow for an industrialized supply chain management process--single manufacturing run once per year produces enough patient doses or a full year’s supply that can be stored, shipped, rethawed, and infused at remote, outpatient facilities

Our Treg cell therapy platform aims to slow and halt the progression of not only ALS but other neurodegenerative diseases. These other diseases include Alzheimer’s Disease, Frontotemporal Dementia, Parkinson's Disease, various autoimmune conditions, in addition to ALS.

OSP: Your Treg cell therapy is in the final stages of its Phase IIa trial—could you please offer detail about the clinical progress to date, when data might be available, etc.?​

HB: This is an exciting time for our team at Coya. We had completed a Phase I trial and recently completed our Phase IIa trial, and the data is now in review by our team, Mass General, and other notable scientists. We are expecting to publish the data at the end of summer and look forward to sharing this with you and your readership.

We have learned a tremendous amount from our Phase I and IIa trials. Our Phase I trial showed that regulatory T cell infusions can stop progression and stabilize patients and are safe to infuse. Stopping disease progression is rarely seen in ALS trials. Our goal in our Phase IIa trial is to show that in the majority of cases, that we can replicate what we saw in our phase 1 study, specifically halting the progression of disease with maintenance monthly infusions and an excellent safety profile.

Moreover, we are taking additional steps to ensure that our next series of trials (post Phase IIa) are successful by implementing and leveraging correlative markers and biomarkers which are linked to efficacy signals. By personalizing a trial through biomarker-driven analysis, as is done regularly in Oncology, one significantly enriches for the correct patient population. Prior ALS trials have not been successful in this approach. By collecting a vast amount of proteomics data, immune-based profiling, and RNA expression correlations, we are aiming to be able to better stratify responders vs. nonresponders.

OSP: Can you talk about any challenges ALS trials might face that are unique to research centered on the condition? Please feel free to talk about challenges experienced by trial staff, as well as patients’ obstacles.​

HB: ALS trials have been limited by misleading preclinical data in mice models, poor clinical trial design and methodological issues, phenotypic heterogeneity of ALS patients, and insensitive biomarkers to stratify patients. Learning from these past failures and these limitations will enable Coya to design a trial that leverages the strength of the Treg mechanism of action for the right patient population who will benefit the most.

OSP: Then, how might this research impact other diseases (you mention Alzheimer’s and other neurodegenerative diseases)?​

HB: Our Treg cell therapy is in development aiming to treat ALS, frontotemporal dementia, scleroderma, and other neurodegenerative diseases. We strongly believe that our platform will greatly benefit patients suffering from several other neurogenerative diseases. These and multiple diseases are driven by dysfunctional Tregs and these conditions are ripe for leveraging our therapy.

Moreover, we are developing Treg-derived exosome therapeutics which have the potential to be given an allogeneic manner, which will enable a more scalable solution. We have shown that our exosomes are significantly more neuroprotective and immunosuppressive than mesenchymal and platelet-derived exosomes (that are currently the standard in other company approaches) and we plan to bring this therapy to the clinic in 2022.

OSP: Is there anything you’d like to add—about your company, this research, ALS, etc?​

HB: We recently were granted orphan drug status for ALS001 and are working to make a true impact in the ALS community. 

We are developing disruptive, first-in-class, autologous regulatory Treg and allogeneic exosome therapies - leveraging the seminal discoveries from the laboratory of Stanley Appel M.D., in which dysfunctional Tregs modulate neurodegenerative and autoimmune diseases. Dr. Appel has been a major advocate in the fight against ALS and other neurodegenerative diseases. With his knowledge, our strong management team, leading board of directors, and scientific advisory board’s expertise, we are in a position to change how the world looks at these diseases.