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Editors note: BioPharma Dive, as part of Emerging Biotech Weekly, is taking a closer look at competitive areas of startup activity. We aim to give an overview of the companies developing a new technology and what their goals are.When the Food and Drug Administration approved a new prostate cancer drug last year, it validated a bet made by Novartis to acquire the drugs maker, Endocyte. The decision was also another step forward for a long-studied research field that appears to finally be coming of age.The medicine, Pluvicto, is known as a radiopharmaceutical. Unlike the small molecule or biologic medicines drugmakers use to flip cellular switches on or off, radiopharmaceuticals are designed to precisely deliver radioactive material into the body. The result is a targeted punch of radiation that can knock out tumors in a way other drugs cant.However, since Pluvictos approval, Novartis has struggled to meet demand, highlighting one of the many issues that has slowed development of radiopharmaceuticals. Theyre difficult to produce, distribute and administer. The earliest examples never lived up to commercial expectations, hamstrung by manufacturing problems, competition, high costs and safety concerns. GSK stopped making one, known as Bexxar, in 2014. Another, named Zevalin and originally developed by Idec Pharmaceuticals, never became a big seller.A group of companies, from biotechnology startups to pharmaceutical giants, think theyve solved these problems. Borrowing from progress in another cancer drug field, theyre leaning on technical advancements that have enabled researchers to design medicines capable of safely delivering a radioisotope to just the right spot.Novartis is the most invested, having spent $6 billion on acquisitions of Endocyte and Advanced Accelerator Applications. Right alongside Novartis is Bayer, which has also brought a radiopharmaceutical to market and is testing others.Behind them are a handful of publicly traded companies and at least a dozen biotech startups, making radiopharmaceuticals a hotly competitive area of drug research. Heres where things stand:What are radiopharmaceuticals, and how do they work?Born shortly after the discovery of the X-ray, radiation therapy has more than a century of history in cancer treatment. Its a way of using high-energy particles or waves to damage the DNA of cancer cells, preventing division and growth.Along with surgery, radiation therapy is a mainstay of cancer care, used to treat or prevent the recurrence of tumors in more than half of people with the disease, according to the American Cancer Society.But radiation therapy is a blunt force. Rays beamed from outside the body can damage healthy tissue, while a more targeted, inside-the-body approach is costly and complex.By comparison, radiopharmaceuticals can deliver the destructive power of radiation directly into tumors. They are akin to microscopic smart bombs radioactive material guided by a molecular courier to cells with specific protein flags.With Novartis drug Pluvicto, a radioisotope known as lutetium is chemically fused to a small molecule that binds to PSMA, a protein overexpressed in most prostate cancers. Novartis other radiopharmaceutical, Lutathera, delivers radioactive lutetium to SSTR, a target found on certain neuroendocrine tumors.The drugs are complex, made of hand-picked parts. Different radioactive materials may weigh more or less, last longer or pack a bigger punch. Some radiopharmaceuticals may require a chelator, a molecule that keeps the radioactive material intact as its carried through the body.Drugmakers also have to design chemical linkers that hold their therapies together, but dont stick around too long after reaching their target. A molecular guide that seeks out malignant cells is another necessary component.Once designed, radiopharmaceuticals are tricky to produce at scale. Supplies of radioactive materials are limited, and their transport is controlled. The drugs must be made and delivered quickly, before the radioactive components decay too much.Why are radiopharmaceuticals a hot area of investment?Interest in radiopharmaceuticals mirrors the ascent of another class of targeted cancer medicines, known as antibody-drug conjugates, or ADCs.Like radiopharmaceuticals, ADCs deliver a toxic substance, usually a chemical, directly to a tumor. After years of slow progress, theyve undergone a renaissance catalyzed by technical advances, regulatory approvals and interest from large drugmakers. Venture investors are in turn backing new startups.Radiopharmaceuticals are now in the spotlight, too. Despite the poor sales of the fields first medicines, newer drugs are performing better. Studies supporting some, like Pluvicto, have shown radiopharmaceutical drugs can extend survival and, in some cases, outperform other types of treatments.Radiopharmaceutical drugs are now being recognized as an effective, safe, and economically and logistically viable treatment modality, wrote physicians from Johns Hopkins University School of Medicine and Memorial Sloan Kettering Cancer Center, in a 2020 article in Nature Reviews Drug Discovery.As is often the case, large pharma investment is sparking a chain reaction of activity. Novartis acquisitions of Advanced Accelerator and Endocyte yielded Lutathera and Pluvicto, which, despite production challenges, are seeing strong demand. Bayer reached close to $500 million in peak yearly sales with its radiopharmaceutical Xofigo; its now working on newer medicines and, in 2021, acquired two startups.Diagnostics company Lantheus Holdings bought the maker of Azedra, another radiopharmaceutical recently approved by the FDA for rare neuroendocrine tumors.Those deals, along with radiochemistry advances and a greater ability to innovate in complex therapeutic modalities, have spurred a wave of investments in new radiopharmaceutical companies, wrote Faisal Khurshid, an analyst with Leerink Partners, in a report last year.Some, like the publicly traded biotech Fusion Pharmaceuticals and startup RayzeBio, are going after the same targets as Pluvicto and Lutathera, but with different radioactive components or guiding molecules.Others are pursuing different cancer-associated proteins. The startup Abdera Therapeutics has a program in development aimed at DLL3, a long-studied target in a tough-to-treat form of lung cancer. Belgian biotech Precirix is evaluating a radiopharmaceutical for tumors driven to growth by HER2, a well-known cancer gene.Radiopharmaceutical drug startups are drawing interest from a range of biotech VC firmsCompanyTop investorsFunds raised (in millions)Rayze BioVenBio, Versant Ventures, Samsara Biocapital, Sofinnova Investments$418ITMTemasek, Blackrock, Nextech255Aktis OncologyMPM Capital, EcoR1 Capital, Vida Ventures, Merck & Co.$161Abdera TherapeuticsVenBio, Versant Ventures, Amplitude Ventures$142PrecirixForbion, Jeito Capital, INKEF Capital117Convergent TherapeuticsOrbiMed, RA Capital Management$90Alpha-9 TheranosticsLongitude Capital, BVF Partners, Nextech$86Mariana OncologyAtlas Venture, RA Capital, Access Biotechnology$75Ariceum TherapeuticsHealthcap, EQT Life Sciences48Ratio TherapeuticsDuquesne Capital, Schusterman Family Investments$40Radionetics5Am Ventures, Frazier Health Care Partners$30ArtbioF-Prime Capital, Omega Funds$23SOURCE: CompaniesWhich companies are working on it, and who is backing them?More than a dozen radiopharmaceutical startups have launched in recent years. Many have pulled in sizable funding rounds, sometimes with overlapping investor groups.In April, Abdera debuted with $142 million in funding and backers led by venBio and Versant Ventures. Those two investors also launched RayzeBio, which has raised $418 million since its start, making it one of the fields most well-funded companies.Convergent Therapeutics launched in May with $90 million from RA Capital Management and OrbiMed. RA Capital also helped incubate Mariana Oncology alongside Atlas Venture and Access Biotechnology.Aktis Oncology has secured $161 million in funding from Novartis, Merck & Co. and Bristol Myers Squibb, among others, since arriving in 2021.Precirix is backed by Forbion and Jeito Capital and has raised 117 million euros since 2018. Germany-based Isotope Technologies Munich, or ITM, in June secured 255 million euros in a large funding round for a European biotech.Artbio debuted in June with seed funding from Omega Funds and F-Prime Capital. Its run by Emanuele Ostuni, the former head of Novartis Oncologys cell and gene therapy operations in Europe, and was founded by the inventors of Xofigo.Other firms in the mix include Frances Atonco Pharma, Australias GlyTherix, China-based Ablaze Pharmaceuticals, University of Connecticut spinout Nami Therapeutics and Boston-based Ratio Therapeutics.These young companies join a handful of publicly traded biotechs, like Fusion, Plus Therapeutics and Point Biopharma, as well as initiatives started by diagnostics firms or suppliers of nuclear material.How far along are these new companies?Unlike other hotspots of startup activity, radiopharmaceutical developers are, in many cases, already deep into clinical development.Several companies are testing drugs that, like Lutathera, target tumors expressing the protein SSTR. RayzeBio began a Phase 3 trial in May, while ITM is further along in its late-stage program. Molecular Targeting Technologies, Arecium Therapeutics and Orano Med also have SSTR-targeting medicines in human trials.A group of developers are following in Pluvictos footsteps with drugs aimed at cells expressing PSMA. Curium Pharma has a Phase 3 study underway in prostate cancer. Point and partner Lantheus are expecting late-stage results later this year. Medicines from Fusion, Convergent and Advancell are in earlier stages.ArtBios lead program is also for prostate cancer and has entered human trials. It uses a radioactive isotope called Pb212 that the startup claims has an ideal clinical profile. Advancell and Orano Med use Pb212 as well.Other companies are earlier in their journeys. Aktis, for example, hasnt disclosed a lead program. But it has revealed the radioactive material, Actinium-225, it intends to deliver with drugs. Abdera plans to ask regulators next year to begin its first trial. '