Next-Generation Conditioning: Crucial to Delivering Cures with Hematopoietic Stem Cell Therapy

By Ronald Martell, President and Chief Executive Officer of Jasper Therapeutics

Cell and gene therapies are amongst the most exciting frontiers in medicine. They have the potential to be curative for many diseases, but unfortunately are not widely accessible to patients today. This is true for people with certain genetic conditions including sickle cell disease (SCD) and beta thalassemia, in which transplanting healthy donor stem cells or gene-corrected cells are potentially curative options.

The multi-step transplantation process requires “conditioning,” a preparative step to open space in the bone marrow, which currently comes with safety risks that limit its use. Chief among these risks is the toxicity of chemotherapy used in conditioning regimens, which often rely on akylating agents like busulfan or melphalan which damage DNA. These agents have concerning safety risks (e.g., short-term toxicities like mucositis or veno-occlusive disease and long-term oncogenic risk) for transplant patients.

At Jasper Therapeutics, our lead candidate, briquilimab, is a monoclonal antibody that targets a receptor called c-Kit (CD117) expressed on stem cells and mast cells. It is being developed as a next-generation conditioning agent in a variety of indications and patient types to potentially help address the challenges associated with existing regimens to prepare people for receiving hematopoietic stem cell therapy (HSCT). There is a growing body of clinical and scientific evidence showing that briquilimab has an attractive tolerability profile and may provide clinically meaningful stem cell engraftment for transplant patients. It is also being evaluated for use as a standalone therapy for chronic conditions such as lower-risk myelodysplastic syndromes (MDS) and chronic urticaria (hives). Briquilimab’s differentiated mechanism and therapeutic profile have the potential to overcome current challenges in the cell and gene therapy landscape, with the ultimate goal of enabling broader patient access to curative and novel therapies.

Promising data in people with sickle cell disease and beta thalassemia

Sickle Cell Disease (SCD) is a group of inherited, red blood cell disorders that affect hemoglobin, the protein that carries oxygen through the body. While the condition affects more than 100,000 people in the United States and 20 million worldwide, there has been limited investment in therapies and health resources for this community.¹ Currently, bone marrow transplants and gene therapy are the only potential cures, but, as discussed above, safety issues from the conditioning regimens for these procedures remain a concern for patients and physicians. Similarly, beta thalassemia is a genetic blood disorder involving reduced production of hemoglobin, which leads individuals to suffer from reduced oxygen levels. People with this disorder may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness or headaches.² These individuals are treated by regular blood transfusions, but improvement in treatment in beta thalassemia is an ongoing opportunity.

We recently announced the first data from a Phase 1/2 clinical trial being led by Dr. John F. Tisdale, Director of Cellular and Molecular Therapeutics Laboratory, National Heart, Lung, and Blood Institute (NHLBI), which is evaluating the addition of briquilimab to an existing nonmyeloablative bone marrow transplantation regimen in individuals with SCD and beta thalassemia considered at high risk for complications from or ineligible for standard myeloablative hematopoietic stem cell transplant. The addition of briquilimab is being studied as a way to achieve a higher percent production of healthy donor stem cell engraftment (donor chimerism) without increased toxicity. The specific goal is to boost the proportion of patients with donor myeloid chimerism ≥98% a year after transplant. Improving chimerism is crucial in leading to a sufficient proportion of healthy donor stem cells that produce healthy red blood cells and reverse the sickle cell phenotype. If successful, this would directly address conditioning toxicity as a barrier limiting more patients from accessing curative HSCT or gene therapy for SCD and beta thalassemia.

The initial clinical data is highly encouraging. All three of the first study patients (all with SCD) treated with briquilimab successfully engrafted, showing no briquilimab-related severe adverse events. The first patient achieved neutrophil engraftment at 12 days after transplant and platelet engraftment at 17 days after transplant. The second achieved the same at 12 days and at 10 days, respectively, and the third achieved the same at 16 days and at 8 days, respectively. Both of the first two participants with peripheral blood chimerism showed 100% donor myeloid chimerism at 60 days post-transplant.

Importantly as it relates to severity SCD is with lower hemoglobin levels, the first patient treated with briquilimab saw an increase in total hemoglobin from 8-9 g/dL at baseline to 13.3g/dL at five months post-transplant. This is a restoration of hemoglobin to the normal physiologic range, and such an increase is often accompanied by reduced disease burden (e.g., fewer pain episodes, less fatigue), particularly if the results remain steady over time. While the study is ongoing and there are more data to be collected, the initial data illustrates that briquilimab appears to be working: the transplanted stem cells have engrafted and are generating the desired healthy red blood cells.

Broad development program in chronic and rare diseases

Briquilimab is undergoing a broad development program, with evaluation as both a standalone therapy and a next-generation conditioning agent for cell and gene therapies. So far, it has an attractive efficacy and safety profile in 130 dosed subjects and healthy volunteers across all five transplant indications: severe combined immunodeficiency (SCID), acute myeloid leukemia, MDS, Fanconi anemia and SCD. In the near-term, we plan to initiate clinical studies of briquilimab as a primary therapeutic in lower-risk MDS patients and in chronic urticaria where we already have supportive clinical data.

Briquilimab is being evaluated for use in people of a wide range of ages, including in an elderly, frail population. This has personal significance to me, as I lost my father to MDS after doctors said that, at age 68, he was too old to receive a transplant due to the conditioning regimen required for a successful procedure. Briquilimab has been used safety as a conditioning agent for transplants in patients up to age 79; furthermore, it has also been used in children with SCID as young as 3 months.

In the near-term, our development program will consist of rapid movement into a clinical trial in chronic spontaneous urticaria and the initiation of our chronic lower to intermediate risk MDS study, with continued recruitment in the SCID, Fanconi anemia and SCD transplant studies to focus on the rare disease opportunities with the clearest and potentially fastest pathway to approval for patients and their families. Additionally, we are encouraged by the continued promise of briquilimab in AML/MDS and will continue to work with the FDA and potential partners to be ready for a registrational Phase 3 study in the future. Jasper will continue to explore the full potential of briquilimab to broaden access to curative transplant and disease-modifying treatment options.

For more information, please visit www.jaspertherapeutics.com

About the Author:

Ronald Martell is a veteran biopharmaceutical executive and serial entrepreneur, having founded five companies and served on the boards of directors of several others. In February 2022, Ronald became the CEO of Jasper Therapeutics, a biotechnology company focused on hematopoietic cell transplant therapies.

Prior to joining Jasper, Ronald served as the President and CEO of MorphImmune, Inc., a private platform company advancing a highly specific targeting technology that uses a ligand-linked payload to reprogram the immune system. Previously, he was President and CEO of Nuvelution Pharma. He was also Co-Founder and Executive Chairman of Indapta, Orca Bio and Co-Founder and CEO of Achieve Life Sciences, where he led the merger of the company with Oncogenex. Ronald has served as the CEO of three public biopharmaceutical companies, including Sevion and NeurogesX, and has overseen billions of dollars in industry transactions.

Earlier in his career, Ronald served as Senior Vice President of Commercial Operations at ImClone Systems, where he was instrumental in deals with Bristol-Myers Squibb and Merck KGaA and built ImClone Systems’ worldwide operations to market and commercialize Erbitux®. He also served in various leadership positions with Genentech where, as Group Manager, Oncology, he was responsible for building the company’s oncology franchise, including the launch of Herceptin® and Rituxan®.

Ronald is passionate about leading public biopharmaceutical companies in all phases of development and maximizing their potential across the healthcare industry.