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Published: Apr 14, 2022 By Gail Dutton
Convergent Therapeutics CEO Philip Kantoff/Courtesy of Memorial Sloan Kettering Cancer Center
Chemotherapy and radiation therapies, long the bane of cancer patients, are being replaced or augmented with a new generation of radiopharmaceutical therapies that offer greater specificity and, therefore, fewer side effects.
Philip Kantoff, CEO of Convergent Therapeutics, spoke to BioSpace before the American Association for Cancer Research (AACR) Annual Meeting on April 8-13 about CONV01-α. This is his company’s proprietary prostate-specific membrane antigen (PSMA)-targeted antibody radiolabeled with Actinium-225, 225Ac rosopatamab tetraxetan with a PSMA-targeted small molecule ligand carrying Lutetium-177 (177Lu). The data is being presented at the meeting by Scott Tagawa, M.D., from Weill Cornell Medicine.
BioSpace (BSP): Why did you target prostate cancer?
Philip Kantoff (PK): There is a great unmet need for treatments in prostate cancer. Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in men in the US. About 35,000 men die each year in the US and 375,000 worldwide. Although there have been numerous therapeutic advances in the past two decades, mortality remains very high.
BSP: Where are the unmet needs in radiopharmaceuticals?
PK: Radiopharmaceuticals are administered to cancer patients either alone or coupled to a targeting molecule of small peptides, aptamers or antibodies. Radium-223 was FDA-approved in 2013 for patients with advanced prostate cancer. It prolonged survival and reduced pain in patients. It targets areas of increased bone metabolism (which commonly occurs when tumor spreads to bone) rather than targeting the cancer. Therefore, tumor responses – including decreases in prostate-specific antigen (PSA) – were infrequent. Because of its mechanism of action, Radium-223 treatment is not applicable to patients with disease outside of the bone. Currently, about 15% of patients receive Radium-223 at some time during their course of treatment.
In March 2022, the FDA approved Pluvicto (the targeted radioligand 177Lu-PSMA-617) by Novartis for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). This was a fantastic advance, improving progression-free and overall survival. This was an important first step and clear validation of PSMA-targeted radiopharmaceuticals. While many patients benefitted, a good portion of patients either did not respond to Pluvicto® or relapsed after initially responding. So, clearly, there is the opportunity to improve upon this approach.
BSP: What is Convergent doing to advance radiopharmaceutical therapy for prostate cancer?
PK: We’re taking a unique path. While others are limited to either a small molecule radioligand or a radioantibody, we are developing therapies that enable dual-targeting of molecules – like PSMA – on the surface of tumors. By targeting two different domains of the molecule with different types of targeting molecules – radioantibodies and radioligands – we can deliver a more efficacious therapeutic dose of radiation to the tumor without additional toxicity.
More specifically, Convergent has licensed 225Ac rosopatamab tetraxetan, a PSMA-directed antibody radiolabeled with Actinium-225. Tagawa is leading a clinical trial combining it with Point Biopharma’s 177Lu-PSMA-I&T radioligand. Results from the first nine patients treated suggest the combination is safe and effective.
Actinium-225 releases alpha particles, which are bigger, more powerful and more precise than the beta particles delivered by Lutetium-177. Alpha particles cause irreparable double strand breaks within the tumor cells’ DNA. Beta particles, in contrast, cause single strand breaks in the DNA, which tumor cells can repair. In addition, beta particles from Lutetium-177 are not very effective at killing small volume, micrometastatic lesions in the range of 5mm or less. Those lesions are beyond the limits of detection by the best imaging modalities available today. Therefore, these small tumor lesions that escape radioligand-beta therapy continue to grow and become imageable recurrent cancers. These small lesions are, however, can be treated with Actinium-225.
We feel the best way to administer PSMA-directed therapy with Actinium-225 and its alpha particles is through an antibody. The antibody we chose doesn’t bind to the salivary or lacrimal glands, so patients don’t experience the severe dry mouth or dry eyes that are side effects of radioligands carrying Actinium-225.
BSP: What results is 225Ac rosopatamab tetraxetan getting?
PK: A Phase I single ascending dose escalation study with 225Ac rosopatamab tetraxetan in 31 men with heavily pre-treated, rapidly progressing mCRPC showed that most had PSA declines, and about half had PSA declines greater than 50%. Their PSA declines corresponded to PSMA PET scan responses. Some patients had quite prolonged responses.
Patients in this trial all had pre-treatment PSMA PET imaging. Unlike other trials that exclude 10-25% of patients because of low tumor PSMA uptake on scans, this trial allowed those patients to be treated. In addition, many of these patients had already failed on prior radiopharmaceutical therapy; 28% had received Radium-223 and 42% had received Pluvicto® or a radiopharmaceutical similar to it (177Lu-PSMA-I&T, Point Biopharma). Given these factors, these patients were less likely to respond and more likely to have toxicity from a radiopharmaceutical. Yet, the response rate was impressive, and the toxicity was limited with no maximum tolerated dose being reached.
Interestingly, those prostate cancer patients who previously had been treated with Pluvicto or 177Lu-PSMA-I&T responded as well as those who had not been treated with those agents. This tells us that 225Ac rosopatamab tetraxetan has a different mechanism of action than Pluvicto® or 177Lu-PSMA-I&T and that alpha particles may be more effective than beta particles. We are planning a registrational trial to assess 225Ac rosopatamab tetraxetan for treatment of mCRPC patients who have been previously treated with Pluvicto®.
BSP: What other programs are you considering?
PK: We also plan to combine alpha and beta particles as well as antibodies and ligands to develop the most effective radiotherapies. Preclinical data generated by Convergent’s founder Neil Bander, M.D., of Weill Cornell Medicine, suggests that ligands and antibodies carrying radionuclides are synergistic in their ability to kill cancer cells. Our antibody (rosopatamab tetraxetan) increases the uptake and retention of the ligand, thereby enhancing the potency of radioligand.
BSP: May these programs have applications beyond prostate cancer?
PK: PSMA is expressed in the microvasculature of many solid tumors, so we believe it is applicable to prostate cancer and other cancers that express PSMA in their vasculature. In other programs, we’re looking to apply the same concept by developing combinations of antibodies and ligands carrying alpha and beta particles targeting a variety of lineage-specific molecules that are expressed on the surface of other cancers.
BSP: How often must the 225Ac rosopatamab tetraxetan therapy be administered?
PK: 225Ac rosopatamab tetraxetan is administered intravenously, either given twice over two weeks or every six weeks. The optimal dosing and schedule are still being determined.
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