The U.S. Food and Drug Administration (FDA) today announced its approval for a breakthrough treatment that will bring the promise of immunotherapy and new hope to thousands of patients diagnosed with mantle cell lymphoma (MCL) whose previous treatments fail to bring them lasting remissions.
There are more than 70 subtypes of lymphoma, and MCL is a particularly aggressive form of this blood cancer with a short remission from standard therapies. The median overall survival rate is between four and five years, but once a patient relapses from chemotherapy or BTK-targeting therapies such as ibrutinib or acalabrutinib, the prognosis is very poor with anticipated survival of perhaps only a year or less.
This latest approval, for brexucabtagene autoleucel, (formerly KTE-X19, now branded as Tecartus ™) is the first chimeric antigen receptor (CAR) T-cell therapy approved for patients with MCL. As we’ve described multiples times in this blog, CAR T-cell therapy is a revolutionary treatment approach that genetically engineers patients’ immune T cells and reintroduces them into the body through a one-time infusion to kill cancer cells. When the therapy works, the T cells continue to expand in the body and persist indefinitely, keeping the cancer at bay.
Tecartus is developed by Kite, A Gilead Company. LLS first partnered with Kite Pharma in 2015 through our Therapy Acceleration Program (TAP) to support its CAR-T trials. LLS’s support helped with trials for other types of lymphoma, but our funding helped lay the foundation to enable CAR-T therapies to tackle multiple types of blood cancers. Overall LLS has invested more than $50 million over two decades to advance CAR-T. . LLS continues to drive innovation for further improvements in CAR T-cell therapy through the support of many major academic medical centers including Memorial Sloan Kettering, the University of Pennsylvania, MD Anderson Cancer Center, City of Hope, Baylor College of Medicine, and the University of Colorado.
Kite previously received approval for its CAR-T, axicabtagene ciloleucel (Yescarta ™), for treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Today’s approval is based on the clinical trial (Zuma-2) in which 87 percent of the patients responded to treatment, with 62% benefiting from a complete response. These strong results offer hope that many of these patients will finally remain cancer-free for the long-term.
UPDATE: The U.S. Food and Drug Administration on August 5, 2020, approved belantamab mafodotin-blmf (Blenrep®; GlaxoSmithKline/GSK as a monotherapy treatment for adult patients with relapsed or refractory multiple myeloma, who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
News in mid-July that a special committee of the U.S. Food & Drug Administration called ODAC (Oncologic Drugs Advisory Committee) had ruled favorability on an investigational treatment for relapsed myeloma came as somewhat of a surprise. After all, some reviewers within the FDA have expressed serious concerns about toxicity of the drug affecting patients’ eyes, including blurred vision or dry eye, and even severe corneal ulcers that may require corneal transplant.
But on Tuesday July 14, the 12-member ODAC committee determined the benefits outweigh the risks, and voted unanimously to recommend the drug, belantamab mafodotin, be approved by the FDA. That FDA decision is due in August. The ODAC decision is based on a Phase 2 clinical trial that divided the patients into two cohorts, each receiving a different dose of the drug. The overall response rate (ORR) observed in the 97 patients who received the lower dose of belantamab mafodotin was 31%. For the 99 patients who received the higher dose of belantamab mafodotin, the ORR was 34%.
The reason this decision is so significant is that, if approved, belantamab mafodotin would be the first of an emerging approach to treating myeloma that has sparked intense interest and scrutiny. Belantamab mafodotin is among a growing number of experimental therapies designed to target a protein on the surface of myeloma cells called B-cell maturation antigen (BCMA). This cell surface receptor is present on virtually all multiple myeloma cells but is absent from normal B cells, making it an ideal target for therapy.
Belantamab mafodotin is an antibody-drug conjugate, meaning it is comprised of an antibody bound to a toxic molecule. The antibody homes in on the BCMA on the cell surface and the cancer-killing molecule is released into the cell and causes cell death.
Kymera Therapeutics is a biotech company pioneering an emerging approach to cancer therapy called “targeted protein degradation.” Whereas most targeted therapies inhibit or inactivate the proteins or genes that drive the cancer, targeted protein degradation harnesses the body’s natural system of ridding itself of unwanted, ‘old’ or ‘broken’ components of cells. In March 2020, LLS made a strategic investment in Kymera’s work to treat blood-based cancers through our Therapy Acceleration Program, our venture philanthropy model through which we partner with biotech companies to advance promising therapies. Here, Kymera’s Chief Medical Officer Jared Gollob, M.D., discusses some of its lead programs with LLS:
Q. What is targeted protein degradation?
A. Protein degradation is a natural mechanism or process by which our body’s cellular machinery breaks down or degrades unwanted proteins. Scientists first uncovered this mechanism in the 1980s, and Drs. Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize for the discovery in 2004. Targeted protein degradation (TPD) is a new therapeutic modality that uses a small molecule “degrader” drug to chemically co-opt this innate cellular process toward specific disease-causing proteins.
Q. Why is TPD a promising new treatment approach for cancer?
A. Cancer is often caused by mutations or the over-production of specific proteins in the body. While conventional small molecule inhibitor drugs and antibody therapeutics have had a tremendous impact on the treatment of diseases, including cancer, it is estimated these traditional approaches have only be able to effectively drug approximately 20% of the full human genome to date. We believe TPD represents an opportunity to target a wide array of proteins that previously have been considered undruggable. This is very important in blood cancer, because we already know that many of the key proteins that drive these cancers have not been druggable with conventional approaches. Furthermore, protein degrader therapies are small molecule drugs that can be administered orally, or in pill-form, making them more broadly accessible for patients.
Q. LLS has invested in Kymera as part of our TAP program. What does this partnership mean for Kymera?
A. The Leukemia & Lymphoma Society has developed a reputation for investing in the most promising new therapeutic approaches, helping to deliver breakthrough therapies for patients. We are honored and delighted to be partnering with LLS to advance what we see as truly innovative therapeutics with the potential to transform cancer treatment for patients. This collaboration will further our research efforts and ensure patients have access to clinical studies and the latest information on our approach and medicines.
Q. Can you elaborate further on Kymera’s approach and relevant therapies in development?
A. Kymera is working at the forefront of TPD to invent new medicines for difficult-to-treat cancers, as well as for immune-inflammatory diseases. Our proprietary Pegasus drug discovery platform enables us to design potent, highly selective molecules that utilize the body’s natural protein degradation pathway, involving so-called “E3 ligases” (enzymes needed to tag a protein for disposal), to target and degrade disease-causing proteins. Pegasus combines our broad understanding of the localization and expression levels of the hundreds of E3 ligases in the human body with our proprietary E3 Ligase Binders Toolbox, as well as our chemistry, biology, and computational capabilities to develop protein degraders that address significant, unmet medical needs.
At this year’s American Association of Cancer Research (AACR) meeting, which took place virtually on June 22-24, we presented the first preclinical data on our novel IRAKIMiD degraders, showing robust antitumor activity in lymphomas with the MYD88-mutation, which constitute approximately one quarter of all diffuse large B-cell lymphomas (DLBCL). Also, at AACR, we shared new findings from our highly selective STAT3 degrader program – demonstrating potent antitumor activity in a solid tumor models not responsive to approved immunotherapies. This complements our previous data showing our STAT3 degraders are capable of driving tumor regression in animal models of STAT3-dependent blood-based cancers.
Q. What can we expect to see from Kymera in the next year?
A. Kymera is rapidly advancing our IRAKIMiD and STAT3 programs toward the clinic with plans to initiate Phase 1 studies in the second half of 2021. We will also continue to expand our pipeline of protein degrader therapies to treat additional blood-based and tissue-based cancers with high unmet medical need. We look forward to our continued partnership with LLS and to advancing new, potentially breakthrough medicines for patients.