RYZ-101

iStock, Love Employee While Novartis and Bayer got there first, AstraZeneca, Bristol Myers Squibb and Eli Lilly are all vying to bring their radiopharmaceutical assets to a market projected to be worth over $13 billion by 2033. When the FDA approved a small and peculiar eight-amino acid peptide therapy in 2018, it also signed off on a field that today provides a precise and personalized approach to treating cancer. Novartis’ Lutathera belongs to a class called radiopharmaceuticals, which combines a radioactive substance and a biological agent into one therapeutic molecule. Lutathera carries lutetium-177, a beta-emitting isotope of lutetium that releases high-energy radiation as it degrades, in turn damaging a cancer cell’s DNA and ultimately leading to its death. Meanwhile, the drug’s eight-residue backbone allows it to specifically home in on subtype 2 somatostatin receptors, proteins typically highly expressed on specific types of cancer cells. This specific structure gives Lutathera—and radiotherapies more broadly—their characteristic precision. Radiopharmaceutical drugs “can generally shrink tumors effectively without causing much side effects,” Andrew Tsai, an analyst at Jefferies, told BioSpace in an email. The use of radioisotopes gives this modality its marked efficacy, Tsai continued, adding that these treatments might also lead to a more durable, longer-lasting therapy. “Lethality of radiation on cancer is robust, and there is no resistance mechanism to the modality,” he explained. Of course, the use of radioactive agents, no matter how targeted, is still bound to cause some toxicity. According to Tsai, radiotherapies can lead to the accumulation of radiation in various organs, which “could limit the dosing potential” of the modality. There is also a limit to how precise radiopharmaceuticals can get, and they still sometimes lead to unintended off-target side effects such as dry mouth and alopecia. On a more practical level, supply constraints also pose a roadblock to radiopharmaceuticals. “Having access to radioisotope[s] has been rate limiting in many instances even for clinical trials,” Tsai said. Another barrier, he continued, is that the practice has yet to penetrate sufficiently into current medical practice; both patients and physicians remain uninformed or uncomfortable about the tech, and there is a need to improve their awareness. Here, BioSpace looks at the current state of radiopharmaceuticals through five leading players—Novartis, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Bayer—including their strategic moves and key upcoming milestones in a space projected to be worth more than $13 billion by 2033. Novartis Seeks to Maintain Radiopharma Leadership Radiopharma assets: Lutathera, Pluvicto Novartis is the clear frontrunner in the radiopharmaceutical race. The Swiss drugmaker already has two commercial products on the market: Lutathera, indicated for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and Pluvicto, for metastatic castration-resistant prostate cancer (mCRPC). Compared with its competitors, Novartis has also fleshed out “industry-leading radioligand research and production sites” globally, Geoff Towle, vice president of the company’s radioligand therapy solid tumor strategy, told BioSpace in an email. Despite enjoying a comfortable lead, Novartis continues to strengthen its radiopharma portfolio. In May 2024, the company paid $1 billion to acquire Mariana Oncology and its promising pipeline, anchored by MC-339, an actinium-based therapy being studied in small cell lung cancer (SCLC). Novartis also recently launched two pivotal trials for the next-generation radiotherapy AAA817, which is under development for prostate cancer, Towle shared. Like Pluvicto, AAA817 targets the prostate-specific membrane antigen (PSMA) but instead carries an actinium-based payload, which could deliver higher potency . Aside from building out the pipeline, Novartis is also seeking to expand the indications for its current products. Pluvicto, for instance, is currently under review by the FDA for use in earlier-stage mCRPC, with a regulatory verdict expected in the first half of 2025 , Towle said. This approval, if granted, would allow the use of Pluvicto ahead of chemotherapy and would highlight the “potential for radioligand therapy to become an established pillar of cancer care,” he added. These strategic moves, according to Towle, place the company in a strong position to “realize the $10 billion business potential of our candidates in clinical trials or pre-clinical trials,” and bring radioligand therapies beyond prostate and neuroendocrine tumors to other areas of high unmet patient need, including breast and lung cancer. AstraZeneca Zeroes in on Radioconjugates Radiopharma assets: FPI-2265, AZD2068 AstraZeneca bought entry into the radiopharma market in March 2024, with the up to $2.4 billion acquisition of Fusion Pharmaceuticals. Despite being a relative newcomer to the space, AstraZeneca has set its sights high. In a company presentation last month, the pharma announced that radioconjugates are expected to be a strong driver of its business by 2030 and beyond. “Our aim is to build a substantial radioconjugate portfolio to offer treatment options for patients with a broad range of tumor types,” Puja Sapra, AstraZeneca’s senior vice president for biologics engineering and oncology target discovery, told BioSpace in an email. In particular, the pharma envisions that radioconjugates will complement existing radiation therapy and help reach other cancer types that have been difficult to treat. AstraZeneca’s radiopharma pipeline is anchored by FPI-2265—the centerpiece of the Fusion acquisition—which consists of a small molecule drug that targets PSMA and carries an actinium-225 radioisotope that can inflict irreparable damage to cancer cells. FPI-2265 is being assessed in the Phase II AlphaBreak study in patients with PSMA-positive mCRPC, with a readout expected in the second half of 2025, according to Sapra. AstraZeneca is also working on AZD2068, another radioconjugate from Fusion, designed to target cells expressing the EGFR and cMET markers. The asset is currently in a Phase I study for advanced solid tumors. Findings are expected in 2026 at the earliest, according to the pharma’s latest pipeline document. Aside from its pipeline, AstraZeneca is also working on “molecular imaging and computation pathology,” which according to Sapra would “enhance the delivery and monitoring” of radioconjugates. The end goal, she continued, is to “deliver the right treatment to the right patient.” BMS Leads the Way in Actinium-Based Radiotherapies Radiopharma assets: RYZ-101, RYZ-801 A few months ahead of AstraZeneca, Bristol Myers Squibb made a major radiopharma play in December 2023 with the acquisition of RayzeBio and its actinium-225-based platform for $4.1 billion. “RayzeBio is pioneering the use of Actinium-225,” which is an alpha-emitting radioisotope, Ben Hickey, the company’s president under BMS, told BioSpace in an email. “We believe alpha-emitting isotopes represent the next generation of therapeutic radionucleotides due to their higher potency as compared to beta-emitting isotopes.” Novartis’ Lutathera and Pluvicto carry beta-emitting lutetium-177. With the RayzeBio acquisition, BMS gained ownership of the biotech’s lead asset RYZ-101, which targets somatostatin receptor type 2, a protein commonly expressed on certain solid tumors. BMS is running three clinical trials for RYZ-101: A Phase III study for GEP-NETs and Phase I studies in unresectable metastatic breast cancer and extensive-stage SCLC. The SCLC study will read out later this year , while pivotal data for GEP-NETs are expected in 2026, according to Hickey. “If successful, we believe RYZ101 could be the first [actinium-255-based radiopharmaceutical therapy] approved In the U.S.” BMS is also advancing RYZ-801 , which consists of a proprietary peptide bound to an actinium-225 radioactive payload. RYZ-801, which targets the GPC3 protein, entered the clinic late last year for hepatocellular carcinoma, with enrollment currently ongoing, according to Hickey. Aside from these two clinical assets, the acquisition of RayzeBio gave BMS what Hickey called an “IND-generating engine” that can produce “several therapeutic candidates in the coming years.” BMS currently has several preclinical programs ongoing, he said. Beyond beefing up its radiopharma pipeline, BMS is also building up manufacturing capabilities. Hickey said the pharma’s facility in Indianapolis “is now fully operational” and can contribute to clinical supply, while BMS works to ramp up the site to support commercial-scale operations. Eli Lilly Enters Radiopharma Space With Dealmaking Flurry Radiopharma asset: PNT2001 and PNT2002 Ahead of both BMS and AstraZeneca, Lilly entered the radiopharma arena in October 2023 with $1.4 billion to acquire Point Biopharma—a transaction that formally closed in December that year. Less than a year later, in May 2024, Lilly doubled down on radiopharma with an agreement with Aktis Oncology worth up to $1.1 billion. The deal gave Lilly access to the biotech’s proprietary discovery engine to develop novel radiotherapeutic assets against certain cancer targets. But Lilly wasn’t done. In July 2024, the company entered into another strategic alliance , this time with Radionetics Oncology, for $140 million upfront. The partners will work on radiotherapies targeting small-molecule G-protein coupled receptors for the treatment of various solid tumors. Under the deal, Lilly also has the exclusive right to acquire Radionetics for $1 billion. From the Point acquisition, Lilly gained ownership of the biotech’s lead asset PNT2002, a PSMA-targeted lutetium-177-based therapy being proposed for patients with mCRPC whose disease has progressed after hormonal treatment. A Phase III readout in December 2023 for PNT2002 was disappointing : The asset reduced the risk of death or disease progression by 29% versus androgen receptor blockage—an effect that met statistical significance but fell below what analysts had hoped for. Regulatory filings for PNT2002 are “pending,” according to Jefferies’ Tsai. Lilly has other radiopharma bets in the clinic, including PNT2001, which targets the PSMA protein and carries a 225-actinium radioisotope payload. The asset is currently in Phase I development for prostate cancer. According to a Feb. 7 Jefferies note, Lilly also has a preclinical radiopharma candidate that uses 225-actinium. Another, PNT2003, delivers lutetium-177 and targets the somatostatin receptor to address GEP-NETs. Bayer Builds Radiopharma Pipeline Beyond Xofigo Radiopharma assets: Xofigo, 225Ac-Pelgifatamab, 225Ac-PSMA-Trillium Aside from Novartis, the only other company on this list with an FDA-approved radiopharma asset is Bayer. Xofigo , a radium-223 dichloride radioactive drug, was cleared by the FDA in 2013 for the treatment of castration-resistant prostate cancer with symptomatic bone metastases and with no known visceral metastatic disease. Unlike Novartis’ Lutathera and Pluvicto, however, Xofigo does not include a targeting moiety. Instead, the drug takes advantage of radium’s chemistry, which allows it to bind to bone minerals, in turn helping localize the drug to sites of high bone turnover. Xofigo’s market performance has been underwhelming, peaking at €408 million in 2017 . Bayer did not report specific sales for Xofigo last year. But the pharma is attempting to carve out a space in today’s radiopharma space, inking a strategic collaboration with Bicycle Therapeutics in May 2023. For $45 million upfront and up to $1.7 billion in milestones, Bayer gained access to Bicycle’s proprietary peptides, which it will use to develop targeted radiotherapies for several undisclosed cancer targets. As per its pipeline page , Bayer has at least two clinical-stage radiopharmaceutical therapies in development: 225Ac-Pelgifatamab and 225Ac-PSMA-Trillium, both actinium-based candidates in early-stage studies for advanced prostate cancer.

WEST CHESTER, PA, USA I December 09, 2024 I Molecular Targeting Technologies, Inc. (MTTI) published preclinical study results for their proprietary 225 Ac-EBTATE against SSTR2 NET cancers online in the European Journal of Nuclear Medicine. (“Long acting 225 Ac-EBTATE is highly efficacious against somatostatin receptor-2-positive neuroendocrine tumors” ( https://rdcu.be/d2lCG ). Professor Humphrey Fonge of the Université de Laval and lead author commented, “At just 40% of the administered dose reported for 225 Ac-DOTATATE, 225 Ac-EBTATE produces enhanced anti-tumor efficacy in Small Cell lung cancer (SCLC) and Pan-neuroendocrine tumor (NET) models as shown with complete tumor remissions. At a therapeutic dose of 2x 34 kBq, 225 Ac-EBTATE showed general safety for 28 days after blood biochemistry analysis, CBC, and histopathological examination of major organs and tissues. We demonstrated that 225 Ac-EBTATE was effective against human small-cell lung cancer (SCLC) with 80% complete remission and 100% survival in preclinical models.” MTTI has licensed commercial use rights for the patented Evans blue (EB) technology from the National Institute of Biomedical Imaging and Bioengineering (“ NIBIB ”), part of the National Institutes of Health (“ NIH ”). This platform is the basis for the best-in-class, new generation, collection of targeted radiopharmaceuticals (TRP). EB binds to serum albumin, extending in vivo circulatory half-life and tumor residence time, enhancing up to 30-fold uptake at a tumor and enabling good efficacy with significantly lower radiopharmaceutical activity and fewer dosing cycles vs. the current standard of care. Our 3-year follow up of 177 Lu-EBTATE in patients* (N=30) with metastatic neuroendocrine tumors, demonstrated good safety with no nephro- or hepatoxicity and 86% disease control rate using only 40% of the administered dose of 177 Lu-DOTATATE. Dr. Jean-Mathieu Beauregard, MD, Associate Professor of Department of Radiology of Université Laval, said, “I am encouraged to see the positive results of 225 Ac-EBTATE in treating small cell lung cancer and Pan-neuroendocrine tumor (NET) in preclinical studies. I look forward to working with MTTI and Professor Fonge to translate this into the clinic.” Dr. Chris Pak, President & CEO of MTTI commented “ 225 Ac-EBTATE effectiveness was encouraging, paralleling the clinical superiority of 177 Lu-EBTATE. We look forward to collaborating with Professors Beauregard and Fonge to drive 225 Ac-EBTATE into clinical trials in 2025.” Molecular Targeting Technologies, Inc. (MTTI) . Molecular Targeting Technologies, Inc. is a private, clinical stage biotech developing targeted radiopharmaceuticals (TRP) for rare cancers. MTTI is committed to building value by translating innovative TRP to improve human health. For more information: www.mtarget.com . *Jiang Y, Liu Q, Wang G, et al. Safety and efficacy of peptide receptor radionuclide therapy with 177 Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumors. Theranostics. 2022;12(15):6437-6445. SOURCE: Molecular Targeting Technologies Inc