Revolutionizing treatment of neurodegenerative diseases - One patient at a time

Regulatory T cells (Tregs) are a subgroup of T cells that act to suppress the immune response, maintaining homeostasis and self-tolerance. It has been shown that Tregs can inhibit T-cell proliferation and that dysregulation in Treg cell frequency or function may lead to the development of inflammatory disease. Therapeutical Treg modulation is also considered to be a promising approach to the treatment of some inflammatory disorders.

Now, Coya has developed a way to isolate a patient's dysfunctional Tregs and convert them into functional ones. What's more, these "repaired" cells can be frozen and used for future infusions as well. Interesting Engineering recently spoke to Dr. Howard Berman, the CEO of Coya Therapeutics, about this fascinating approach. 

Dr. Berman has a Bachelor's degree in Biology from the University of Michigan and a Masters and Ph.D. in Neuroscience and Pharmacology from Weill Cornell Medical School. He began his career at MD Anderson Cancer Center in the technology transfer division, responsible for ascertaining the market potential of numerous oncology-based technology platforms. He has also worked with global names such as AbbVie, Novartis Pharmaceuticals, and Eli Lilly.  

Interesting Engineering: Where did the idea come from? How long did it take to develop before you could get to trials?

Dr. Howard Berman: Dr. Stanley Appel, the “father of modern ALS” [Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease] and one of Coya’s founders, made it his mission to find groundbreaking treatments for ALS. For the past two decades, he has championed the critical role of inflammation in the decline of ALS patients. Much of that work has centered around the role of Regulatory T lymphocytes (Tregs), a protective anti-inflammatory cell type, in ALS patients. 

In the early stages of ALS, Dr. Appel discovered that the disease progression is slow, and inflammatory cell types such as microglia actually provide anti-inflammatory responses and signals that may protect the injured motor neurons.

However, during the later, more aggressive stages of the disease, microglia and other immune cells release toxic pro-inflammatory mediators that exacerbate motor neuron injury resulting in cell death. Unfortunately, this process is self-propagating, leading to the positive feedback of enhanced inflammatory signaling. The result is accelerated motor neuron and neuromuscular junction damage, resulting in faster and steady patient decline. 

We believe that targeting Tregs represents the most potent approach to address the cause of decline in many diseases, including ALS

Through a series of innovative experiments, Dr. Appel discovered that Tregs do not work properly in ALS patients. This dysfunction is one of the direct results of the runaway neuroinflammation that contributes to disease progression and patient decline. In fact, he found that the degree of Treg dysfunction in the patient’s blood correlates with the degree of the patient’s clinical status, disease progression, and patient’s survival.

Importantly, it has since been discovered by Dr. Appel’s group that the phenomenon of Treg dysfunction is prominent in other neurodegenerative diseases, such as Alzheimer’s Disease and Parkinson’s Disease. And other groups have also discovered the important role of Treg pathology in autoimmune disorders.

In healthy people, Tregs typically help suppress neuro and systemic inflammation. In contrast, in patients with ALS, as the disease progresses and the inflammatory milieu increases, the Tregs lose their suppressive function, and this loss further promotes the pro-inflammatory environment of activated immune cells, leading to damage and death of motor neurons. The dysfunctional Tregs in ALS lack the ability to suppress the pro-inflammatory cells of the innate and adaptive immune system.

With these findings, it was hypothesized that if one could convert the dysfunctional Tregs into functional Tregs, then inflammation could be mitigated, and the incessant decline of patients could be slowed or halted.

IE: How does Coya plan to achieve this? 

Coya Therapeutics, in close collaboration with Dr. Appel and the research team at Houston Methodist, is developing three therapeutic platforms to exploit and enhance the powerful immunomodulatory effects of Tregs, resulting in exciting clinical data to date.

Coya’s Treg cell therapy is outpatient with a 5-minute infusion allowing patients to go home within an hour or two.

The first platform is a Treg cell therapy (COYA 101) that works to convert dysfunctional Tregs into billions of super-functional Tregs for infusion back to the same patient [autologous infusion]. Coya has the most clinically advanced Treg cell therapy in the biotech industry. 

The second platform is a Treg exosome therapy (COYA 200 series) that isolates the “secret sauce” of the Treg cells, called exosomes, for infusion back to any patient [allogeneic infusion], meaning an off-the-shelf ready-to-use treatment. Coya has the only Treg exosome platform in the industry. The third platform is a biologic combination (COYA 301) that enhances Treg function without the need for cell therapy. 

While the cell therapy is focused on ALS, the exosomes and biologics are going to be tested in conditions that extend beyond ALS and into other inflammatory diseases which are driven by dysfunctional Tregs, such as lupus scleroderma and liver disorders.

Ultimately, enhancing Treg function in these patients works to increase the ratio of anti-inflammatory cells relative to pro-inflammatory cells and dramatically reduces systemic inflammation and oxidative stress. We believe that targeting Tregs represents the most potent approach to address the cause of the decline in many diseases, including ALS. And our clinical and biomarker data strongly suggest this. 

IE: How does the technology work?  

The Treg cell therapy (COYA 101) works as follows. Patients undergo blood draw one month before the first Treg infusion. Each patient's Tregs are separated from the rest of the white blood cells, capturing hundreds of millions of dysfunctional Tregs. Using closed system automated bioreactors, the cells are grown and expanded under appropriate conditions and converted to highly functional Tregs (super Tregs) numbering in the billions of cells.

These super Tregs now take on a new phenotype and composition that is reproducible and well-characterized by enhanced proteins that confer the anti-inflammatory and regenerative function to the Tregs. The cells are then frozen and cryopreserved to allow for shipping and storage for future infusions back to the patient, for up to a year of treatment.

Long-term maintenance dosing of ALS patients on a regular schedule is critical as the inflammatory environment of ALS is persistent, causing functional Tregs to become dysfunctional. That is why other companies developing Treg therapies as a single administration for any inflammatory-based condition may run into challenges. Patients receive either biweekly or monthly intravenous infusions of 100 million super Tregs and can continue this in perpetuity. 

IE: How is this therapy different from T cells used to treat cancer?

This therapy is different from cancer cell therapy in a number of major ways. Cancer CAR-T therapy has been a breakthrough in the treatment of lymphoma and changed the face of medicine. In cancer CAR-T Therapy, a different type of T cell is used, not the Treg. This different type of T cell is called an effector T cell that is pro-inflammatory in nature vs. the anti-inflammatory nature of Tregs.

Second, CAR-T requires genetic manipulation to target specific types of epitopes or proteins on the cancer cells. This adds additional complexity and steps to the manufacturing process as well as risks to patients. Coya’s Treg cell therapy requires no genetic manipulation as there is no one protein to target in ALS.

Third, CAR-T therapy is toxic, with the risks of cytokine storm and neurotoxicity, requiring it to be administered [using] in-patient treatment in a hospital setting. Coya’s Treg cell therapy is outpatient, with a 5-minute infusion allowing patients to go home within an hour or two, and has proven remarkably safe in phase 1 and 2a studies to date.

We are planning a first-in-human study for the Treg exosomes (COYA 201) in ALS in Q4 2022 or Q1 2023, which will be the first of its kind to be administered to patients.

Finally, leveraging automated bioreactors for Coya’s Treg cell therapy has expedited manufacturing runs to produce the requisite dose for patients in 10 days vs. up to 25-30 days for CAR-T therapies.

Treg exosomes (COYA 202 series) are harvested as a result of the manufacturing process to generate the billions of super Treg cells. The super Tregs give off, via exocytosis, their internal contents as a byproduct of the manufacturing process,  which Coya has developed patented technology to isolate and concentrate. These Treg exosomes are very unique, containing all the anti-inflammatory features of the Treg cells themselves with distinctive advantages.

First, they are not cells and cannot be ‘disabled’ in the body by inflammatory processes, unlike cells. Second, they are very small and can access sites, including the brain, much more readily than cells. Third, we can manipulate the Treg exosomes to carry specific drugs, nucleic acids, antibodies, or proteins to deliver [these] much more readily around the body as well as potential target specific epitopes or proteins on disease tissue.

Lastly, the Treg exosomes are being developed to administer in an allogeneic manner meaning we can use healthy donors to generate the exosomes for administration as an off-the-shelf product. Because they are not cells, they have a lower risk of immune reactions. Finally, the Treg exosomes are the most potent exosomes being developed to date in terms of suppressing inflammation.

In head-to-head studies, we have compared Treg exosomes to mesenchymal [bone marrow] and platelet-derived exosomes, and the differences are very profound in favor of Treg exosomes. A paper is currently in process [with] a publication documenting this. Treg exosomes represent one of the brightest opportunities to address multiple inflammatory processes across numerous disease conditions.

Finally, we have discovered, through extensive in vitro and clinical work, that combining two biologics in a specific dose and schedule (COYA 301) has the remarkable ability to enhance Tregs in vivo with the convenience of subcutaneous administration.  While this novel therapy may be useful as a stand-alone treatment in many conditions, it will likely serve as a next-generation adjuvant with Treg cell therapy or Treg exosomes to enable synergistic responses.

We believe that combination approaches, as seen in other therapeutic areas such as oncology and viral diseases, have the best chances of incrementally or exponentially enhancing positive clinical outcomes. Coya is finalizing license agreements for these combination agents, which have extensive and strong intellectual property protection. 

IE: What improvements have been seen in patients so far? 

For the Treg cell therapy (COYA 101), two clinical trials have been completed, both with encouraging results. As discussed, COYA 101 was developed to convert and expand the Tregs outside the body to become fully functional ‘Super Tregs’ and administer them back to the patients to restore the health of the immune system and stop the progression of ALS.

The Phase 1 study included three patients who underwent a process called leukapheresis, a process in which a blood sample is taken from the patient, and the dysfunctional white blood cells are separated and converted and expanded into billions of ‘Super Tregs’ with a very high level of suppressing function, after which these Tregs are administered intravenously back into the patients.

The Phase 1 study, published in the Journal Neurology in 2018, showed that improving the number and function of Tregs in ALS patients stopped or ameliorated disease progression when the cells were readministered, a tremendous feat for a disease with only a few available treatments that offer limited benefit to patients.

The Phase 2a study included eight patients who were administered Tregs over a period of a minimum of 6 months with ongoing monthly infusions. Some patients received infusions for up to 12 months. The data, currently under peer review, showed that over 50% of the patients stopped or slowed disease progression over the 6-month infusion period, confirming the promising efficacy of the Phase 1 study.

A subset of patients infused over 12 months confirmed that the responses were maintained. Furthermore, inflammatory blood biomarkers were identified that may allow for patient stratification to further identify patients with a greater chance to respond to the Tregs treatment.

We are planning a first-in-human study for the Treg exosomes (COYA 201) in ALS in Q4 2022 or Q1 2023, which will be the first of its kind to be administered to patients. We are also planning a new clinical study of COYA 301 to begin in Q1 2023.

IE: How many patients are currently undergoing trials? 

COYA 101’s phase 1 and 2a studies are complete, and a phase 2b trial is being planned for the 2023 start.  COYA 301 has just completed a Phase 1 study in 3 Alzheimer’s disease patients with dramatic results, including cognitive improvements and enhanced Treg function. An ongoing Phase 1 trial in ALS has five patients enrolled currently with exciting clinical and biomarker data seen to date. 

IE: There is no genetic engineering involved. But are you also thinking of using CRISPR and other techniques to make this treatment accessible to others? 

Treg cell therapy (COYA 101) represents only the first generation approach and the validation of exploiting the power of Tregs to treat ALS and other conditions of high unmet need. Allogeneic Treg exosomes (COYA 200 series) and biologic combination (COYA 301) represent a scalable manner to accomplish widespread use by many patients to enhance Treg function via an off-the-shelf approach.

Thus, there is no need to engineer complex genetic manipulation or CRISPR. Moreover, the ability to modify the Treg exosomes with proteins or cytokines requires no genetic manipulation and involves an ex-vivo approach.

IE: How scalable is the technology? Can therapy centers be set up at local/ national levels to get the T cell treatments? 

Treg cell therapy (COYA 101) is personalized for each patient, much like cell therapy for cancer indications. Therefore, patients will be required to travel for a leukapheresis blood draw at a site close to the manufacturing site of the cell therapy product. This can be done once per year. The manufacturing site will initially be in California but can expand to additional sites once and if the product is approved by the FDA. 

In contrast, Treg exosome allogeneic therapy (COYA 202 series) and biologics (COYA 301) will not require such a personalized approach and these off-the-shelf platforms can be delivered anywhere in the world without the logistical limitations of personalized cell therapy.