Macrophage Checkpoint Therapy: Roy Maute from Pheast Therapeutics in a Riveting Conversation with PharmaShots

Shots:

Recently Pheast Therapeutics shared the preclinical data for PHST001, an anti-CD24 macrophage checkpoint inhibitor at the 20th Annual PEGS Boston Summit

Today, at PharmaShots, we had a dialogue exchange with Roy Maute, Cofounder and CEO of Pheast Therapeutics

Pheast Therapeutics currently plans to initiate a clinical trial in H1’25

Saurabh: Can you walk me through how PHST001 works, specifically how it disrupts the CD24 shield on cancer cells? 

Roy: CD24 is a crucial inhibitor of phagocytosis, which signals through the Siglec10 receptor. This axis and its impact on macrophages is described by two of the Pheast co-founders in a 2019 publication in Nature. Siglec10 is expressed specifically by immunosuppressive, tumor-associated macrophages, and when these macrophages encounter a CD24-expressing cell, they are unable to phagocytose it. PHST001 blocks this interaction, enabling a potent immune response. Due to the complex glycosylation patterns on CD24, not all antibodies against this target are created equal. We have engineered PHST001 to interact with all glyco-variants of CD24, which enables potent activity. Once macrophages are activated by PHST001, they can directly de-bulk tumors by phagocytosing cancer cells, and this may also re-shape signaling in the tumor microenvironment to improve an anti-cancer response by other immune cells.

Saurabh: Can you elaborate on the preclinical models used to evaluate PHST001's efficacy? 

Roy: Pheast has used a variety of preclinical models to study our drug and our target. In vitro studies with macrophages derived from primary human monocytes allow us to test efficacy against a broad range of cancer cell types and conditions. Xenograft studies in immunocompromised mice, such as the NSG background, allow us to directly study our drug using human-derived cancers, including both cell lines and patient-derived xenografts. We have also performed biology and mechanism of action-focused studies against syngeneic cancers in immunocompetent mice, using a mouse-specific surrogate antibody that we’ve engineered to resemble PHST001 in key respects. Finally, we are in the process of executing multiple approaches to humanize the CD24/Siglec10 axis in mice, which will allow us to directly assess PHST001 in an immunocompetent setting.

Saurabh: While the data suggests monotherapy effectiveness, have you explored the potential benefits of combining PHST001 with other immunotherapies or chemotherapies, or are you planning to do that in future? 

Roy: We do see strong monotherapy activity in preclinical models, but establishing a well-supported combination strategy is a key part of our work to prepare for clinical development. We have demonstrated powerful combination efficacy in vitro and in vivo with multiple classes of widely-used cancer drugs, such as taxanes, cytotoxic chemotherapy, targeted therapies, and immune checkpoint drugs. We are planning additional studies with ADCs and radiation combos, which are well-supported by previous studies using macrophage checkpoint inhibitors.

Saurabh: The potential for PHST001 to eradicate tumors is promising. How would you translate this scientific advancement into a message of hope for cancer patients? 

Roy: One of the things that excites us most for PHST001 is that its target, CD24, is highly expressed in the majority of patients in some cancers with very high unmet need, including ovarian, triple negative breast, and cholangiocarcinoma, as well as in a subset of patients from many other indications, including pancreatic and colorectal cancer. These are indications where immunotherapies in particular have not lived up to their early promise. As a field we have made great strides, but there is still tremendous unmet clinical need in these indications, and a scarcity of new therapeutic approaches. We think PHST001 can have a major impact, and are eager to work with patients and physicians to test it clinically.

Saurabh: With other macrophage checkpoint inhibitors likely in development, how would you position PHST001 to stand out in the race for a breakthrough treatment? 

Roy: Among macrophage checkpoint targets, we think that CD24 is supported by a uniquely strong body of evidence, including human genetics, cancer genetics, and a very distinct expression pattern that helps to focus us on specific indications, which happen to be cancers where other macrophage checkpoints have not yet made a clinical impact. We’ve also run many preclinical experiments in which we’ve put PHST001 head-to-head with other macrophage checkpoint inhibitors, and seen much stronger efficacy with our drug. We expect to see a lot of interest in clinical development against CD24 in the coming years, but striking the right balance between safety and efficacy will be crucial to success. We think PHST001 is well-differentiated from other macrophage checkpoint inhibitors in this respect.

Saurabh: How is Pheast considering evaluating PHST001 in clinical trials? What indications are you planning to pursue? 

Roy: Given that CD24 is a new therapeutic target with relatively little clinical data, our initial focus will be to understand the safety profile of PHST001 as monotherapy. Once that is established, we plan to quickly move to testing indication-specific combination strategies in CD24-expressing cancers with high unmet need, including breast and ovarian cancer. Our research team is leveraging preclinical models to help define and support these combination strategies.

Saurabh: What’s the upcoming milestones we should watch as PHST001 advances to clinical development? 

Roy: As we complete the data package to support an investigational new drug (IND) application, we will be publicly presenting additional findings at an upcoming scientific meeting. Our major focus is preparing for our first clinical trial of PHST001, which we plan to initiate in the first half of 2025.

Image Source: Canva

About the Author:

Roy Maute

Roy is a scientist and biotechnology entrepreneur, and is a co-founder of Pheast Therapeutics. He serves as the company’s Chief Executive Officer and leads Pheast’s Research and Development teams. Prior to Pheast, he led the biomarker and translational science for the clinical anti-CD47 and anti-SIRPA programs at Forty Seven Inc. and Gilead Sciences. Roy also co-founded Ab Initio Biotherapeutics, an antibody discovery company acquired by Ligand Pharmaceuticals in 2019. He trained as a postdoctoral fellow in the laboratory of Dr. Irving Weissman at Stanford University School of Medicine and received his Ph.D. in genetics from Columbia University and a B.A. in molecular and cell biology from UC Berkeley.