In an interview with PharmaShots, Dr. Murat Kalayoglu, MD, Ph.D., President, and Chief Executive Officer at Cartesian Therapeutics shared his insights on the P-I/IIa study of Descartes-08 for the treatment of the chronic autoimmune disorder generalized myasthenia gravis (gMG)

Shots:

• Descartes-08 is an autologous T-cell product that is engineered with RNA to encode for CAR
• The company focuses to use RNA instead of DNA to engineer the cell target that helps to target antigen without increasing the risk of these cells proliferating out of control and causing the typical CAR-T cell toxicities
• Cartesian has currently three RNA cell therapies i.e., Descartes-08 & Descartes-11 which are being developed for multiple myeloma, high-risk patients, newly diagnosed multiple myeloma while Descartes-30 is an off-the-shelf, RNA engineered cell therapy. The company is expected to complete the P-II studies in 2022 and registration studies in 2024

Tuba: Tell our readers more about Descartes-08. 

Murat: Descartes-08 is an autologous T-cell product that is engineered with RNA to encode for a chimeric antigen receptor (CAR). That CAR binds to an antigen called B-cell maturation antigen (BCMA). The CAR is a molecule on the surface of the T-cell that redirects the T-cell towards those cells that express BCMA. Upon binding BCMA, the T-cell can then proceed to kill the BCMA-expressing cell. 

Tuba: Tell us more about Myasthenia Gravis.

Murat: Generalized myasthenia gravis is a debilitating autoimmune disease in which autoantibodies attack the neuromuscular junction. This disrupts the way that nerves can communicate with muscles, resulting in muscle weakness and fatigue. Myasthenia gravis affects over 60,000 individuals in the U.S. alone. It is a progressive disease that used to be fatal in one-third of patients before the emergence of chronic steroids. Those living with myasthenia can experience a variety of symptoms, ranging from drooping eyelids and double vision to debilitating muscle weakness and respiratory failure.

Tuba: Discuss this new approach to target an autoimmune disorder with CAR-T therapy?

Murat: Conventionally, CAR-T cells are modified permanently, at the DNA level. Every time a conventionally engineered CAR-T cell encounters its target and divides, the daughter cell looks genetically identical to the parent cell. So when a conventional CAR-T cell begins to proliferate, there is no telling when it's going to stop. It can often proliferate to toxic levels and cause the kind of toxicities that conventionally engineered CAR-T cells are now synonymous with, including cytokine release syndrome, neurotoxicity, increased risk of infection, and increased risk of transformation (i.e., becoming a cancer cell itself). While those risks are tolerable for people that have very advanced malignancies, they are not acceptable when you want to take cell therapy beyond the most advanced cancers into newly diagnosed cancer patients, or beyond oncology into autoimmune, neurological, respiratory, cardiovascular, and inflammatory diseases. You have to have a different approach. 

Our approach has been to use RNA instead of DNA to engineer the cell. The benefit of using RNA is that you're making a time-controlled change, conferring upon the cell drug-like properties with a defined half-life of its function. Armed with that control and repeat dosing, you can increase the safety of the product and also achieve the desired clinical benefit. The approach to autoimmune disease with RNA cell therapy makes a lot of sense because you can target the antigen without dramatically increasing the risk of these cells proliferating out of control and causing the typical CAR-T cell toxicities. You can have a potent yet safer cell therapy to target autoimmune diseases, including myasthenia gravis, but also other classic autoimmune diseases, as well as other diseases in neurology, respiratory and cardiovascular, and inflammatory conditions.

Tuba: What makes Descartes-08 different from current treatment options available, other than that it is a CAR-T? 

Murat: New therapies are greatly needed to be able to treat this disease. It is a classic autoimmune disease in that it is caused by pathogenic autoantibodies that attack the neuromuscular junction and lead to muscle weakness. It just so happens that these pathogenic autoantibodies are produced by aberrant plasma cell clones that are expressing BCMA. The idea is that if you eliminate the BCMA expressing cells you are targeting the disease right at its source.

Tuba: Why do you think Descartes-08 will help Myasthenia Gravis patients?

Murat: Descartes-08 is an RNA CAR-T cell therapy targeting BCMA. BCMA is expressed on aberrant long-lived plasma cell clones that produce pathogenic autoantibodies. The expectation is that once we eliminate those cells, that is going to have a meaningful impact on the disease process for autoimmune diseases in general, and myasthenia gravis in particular. Our approach targets the disease at the source and in a way that is currently not being addressed.

Tuba: What is the expected timeline for the development of Descartes-08?

Murat: We anticipate completing Phase 2 studies in 2022 and completing registration studies in 2024.

Tuba: Tell our readers about other therapeutic candidates Cartesian has in its pipeline.

Murat: Descartes-08 and Descartes-11 are CAR T-cell therapies being developed for multiple myeloma, specifically patients with high risk, newly diagnosed multiple myeloma. Descartes-30 is an off-the-shelf, RNA-engineered cell therapy product of human mesenchymal stem cells engineered with enzymes that degrade NETs (neutrophil extracellular traps) in patients with ARDS, including COVID-19 ARDS. NETs are sticky webs of DNA that are studded with inflammatory proteins that are released by neutrophils in their attempt to control inflammation. The enzymes that Descartes-30 secretes are designed to degrade NETs directly. 

Cartesian’s pipeline consists of both T-cell programs as well as mesenchymal stem cell programs. Our preclinical pipeline has a number of assets that are addressing indications beyond oncology, autoimmune disease, and respiratory disease, and are being developed for cardiovascular diseases and inflammatory diseases. Our investigational candidates stem from the RNA Armory®, our RNA cell therapy platform where we use the cell as both a factory for producing, as well as a vehicle for delivering, a combination of RNA therapeutics directly to the site of disease.

Tuba: Is Cartesian planning to assess Descartes-08 in other autoimmune disorders. 

Murat: We are certainly planning on taking Descartes-08 into other autoimmune diseases, but we haven't disclosed which indications at this time.

Tuba: How do you think Descartes-08 will improve the quality of life of patients?

Murat: We hope that Descartes-08 will be an important addition to the growing toolkit of therapies for patients with myasthenia gravis. It'll be one that can be used in combination therapy with other therapies and one we believe that will be addressing the disease at its root, i.e. at the level of the aberrant long-lived plasma cell clones.

Tuba: Can you comment on the pricing. What can payers expect for Descartes-08? 

Murat: One of the advantages of using RNA cell therapy is that it's significantly less costly relative to conventionally engineered (i.e., DNA engineered) cell therapies. We anticipate that our pricing will be comparable to other immunotherapies that are currently available for patients with myasthenia gravis.

Source: Medical News Today

About Author: Murat Kalayoglu is the President and CEO of Cartesian Therapeutics. Dr. Kalayoglu is a board-certified ophthalmologist & completed his residency and research fellowship at Harvard, MD/Ph.D. in immunology at the University of Wisconsin-Madison, and MBA from the MIT Sloan School of Management. He is the leader in RNA cell therapy with products in development for autoimmune, oncologic, and respiratory disorders

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