The promise of targeted radiopharma

Targeted radiopharmaceuticals (TRPs)—therapies composed of a targeting molecule, linker, chelating agent and radionuclide—are the latest radiotherapy modality. In the same way that antibody drug conjugates (ADCs) aspire to replace conventional chemotherapy, TRP therapeutics aspire to replace nontargeted external or internal radiotherapy. Zevalin (2002) and Bexxar (2003) were arguably the first commercially launched examples of this modality.

More recently we’ve seen Novartis launch Lutathera (2018) and Pluvicto (2022), which have realized greater commercial success than their predecessors. TRPs can also be used as diagnostics. TRP diagnostics have developed over a similar period of time, with applications as companion diagnostics for TRP therapeutics as well as stand-alone diagnostics.

For companies evaluating entry to these modalities, it’s critical to understand the landscape, where best to direct deal-making and what unique barriers exist to maximizing outcomes for patients and commercial success.

There are several factors driving increased investment in TRPs. From a clinical improvement perspective, Lutathera and Pluvicto have each demonstrated dramatic benefit over standard of care (SOC) in GEP-NET and mCRPC, respectively. Lutathera reduced the risk of progression by 79% compared to SOC in the phase 3 NETTER-1 trial and 72% in the phase 3 NETTER-2 trial. Pluvicto reduced the risk of progression by 38% compared to SOC in the phase 3 VISION trial and doubled the progression-free survival compared to SOC in the phase 3 PSMAfore trial.

TRP diagnostics have increased the sensitivity of disease classification. Pylarify PET/CT demonstrated significantly higher specificity (97.9%) compared to conventional imaging (65.1%), which included identifying early metastatic disease in patients classified with localized disease by conventional imaging.

Lutathera has also seen rapid growth on the commercial front, hitting $605 million in sales for Novartis in 2023. Pluvicto is set to become the first TRP blockbuster, with $980 million in sales in 2023 (despite supply issues postlaunch) and is expected to grow further in 2024 with potential indication expansion. Pylarify is also closing in on blockbuster status with revenues of around $850 million in 2023, a 60% increase from 2022. The TRP market as a whole is projected to grow to approximately $6 to $9 billion by 2028, according to Evaluate Pharma and other sources such as MarketsandMarkets and Futuremarkets.

Similar to ADCs, the modularity of TRPs makes them an ideal platform to generate assets for different indications efficiently. This modularity is especially evident in how varying targeting molecules (see Table 1) and radionuclides (see Table 2) can achieve different applications.

Interestingly, while TRP therapeutics are currently developed almost exclusively in cancer, TRP diagnostics are being developed extensively both within cancer and outside of cancer (see Figure 1). As expected, TRP therapeutics are seeing heavy development in derisked tumor types like prostate cancer and neuroendocrine tumors—good starting points due to their presence of relatively ubiquitous targets, high unmet need and radiosensitivity, especially relative to sensitivity to other modalities like immunotherapy. Development is also ongoing in less-well-proven but more commercially attractive tumor types like breast cancer and lung cancer. Within cancer, TRP diagnostics are following a similar trend (often as companion diagnostics for TRP therapeutics). Outside of cancer, TRP diagnostics are seeing extensive development around identifying neurodegenerative diseases.

_{Note: Others in radio-therapeutics include adrenal cancer, carcinoid syndrome, malignant jugulotympanic paraganglioma, melanoma, multiple myeloma, esophageal cancer and thyroid cancer. Others in radio-diagnostics include acute venous thrombosis, bladder cancer, colorectal cancer, brain cancer, head and neck cancer, hepatocellular carcinoma, multiple myeloma, ovarian cancer and systemic amyloidosis.}

_{Sources: Pharmaprojects, Evaluate Pharma, Intelligencia, desk research.}

When examining TRPs by target, like indication, we see a “follow the leader” approach with development focused in PMSA and SSTR (Figure 2). We also see theranostic targets in breast (for example, GRPR) and lung cancer (for example, FAP), mirroring development by tumor type. For TRP diagnostics, we also see extensive development around targets for Alzheimer’s disease (Tau, amyloid) and Parkinson’s disease (DAT).

_{Note: Others in radio-therapeutics include Cadherin-3, CD147, CD20, CD33, CD37, CD45, EGFR and cMET, gastrin-releasing peptide receptor, human kallikrein-2 (hK2), IGF type 1 receptor, Integrin alphavbeta3/5, integrin beta-3/beta-5, melanocortin 1 receptor (MC1R), and norepinephrine transporter. Others in radio-diagnostics include activated T-cells, amorphous calcium phosphate deposits, insoluble hydroxyapatite crystals, androgen receptor expression, CD66, CD8, choline, CXCR4-expressing cancer cells, dihydrofolate reductase, FAP and integrin αvβ3, heavy chain of human myosin, HER2, integrin αvβ3, mannose-receptor, melanocortin 2 receptor (MC2R), mitochondrial complex 1 (MC-1), NCA-90, norepinephrine transporter, PARP-1, phosphatidylethanolamine (PE), Poly(ADP-ribose) polymerase 1; Poly(ADP-ribose) polymerase 2, serum calcium, sigma-1 receptors, STEAP1 protein, TAG-72, thymidine kinase-1 (TK-1) and enzyme.}

_{Sources: Pharmaprojects, as accessed on 2/22/2024; Evaluate Pharma, as accessed on 2/23/2024; Intelligencia; desk research.}

The extent to which TRP therapeutic development is concentrated in derisked tumor types and targets might beg the question: “Where is there opportunity for innovation?” Alpha-emitting radionuclides could be the answer. While there’s still extensive TRP therapeutic development around the beta-emitter Lu-177, alpha-emitters Ac-225, Th-227 and Pb-212 are emerging in preregistrational and registrational trials (Figure 3). Given the relative pros and cons of each type of radionuclide and the potential for different use cases, it’s likely that both types will coexist in the future landscape. On the diagnostic side, most radionuclides are gamma emitters; F-18 has a plurality of trials but other radionuclides like Tc-99 and Ga-68 are also seeing extensive development.

_{Note: Others in radio-therapeutics include actinium-225 + gallium-68, copper-64, copper-67, and copper-67 + copper-64. Others in radio-diagnostics include actinium-225 + gallium-68, copper-67, copper-67 + copper-64, and iodine-124.}

_{Source: Pharmaprojects, as accessed on 2/22/2024; Evaluate Pharma, as accessed on 2/23/2024; Intelligencia; desk research.}

While four deals (Lilly-POINT Biopharma at $1.4B, BMS-RayzeBio at $4.1B, AZ-Fusion Pharma at $2B and Novartis-Mariana Oncology at over $1B) have garnered headlines in the last 12 months, deal-making around TRPs has been steady over the last seven years (since the Novartis-AAA deal), with nearly 200 deals in total across therapeutics and diagnostics (Figure 4). About two-thirds of these deals have involved TRP therapeutics and about one-third have involved TRP diagnostics.

We see a plurality of TRP therapeutic deals around financing (primarily VC-backed), with roughly the same number of deals around both licensing and acquisition. This is in contrast with what we have seen historically for antibody drug conjugates, where licensing is much more common than acquisition. Licensing is more common for TRP diagnostics, followed by financing (VC-backed), acquisitions and alliances.

_{Source: Biomedtracker, as accessed on 3/20/2024.}

TRP therapeutic deals have primarily been preclinical (Figure 5), but a non-negligible 10% have involved assets in phase 3 trials. By contrast, while about half of TRP diagnostic deals have been preclinical, nearly one-third of deals involved phase 3 or approved assets (mostly out-licensing ex-U.S.), reflecting the maturity of TRP diagnostics relative to therapeutics.

_{Source: Biomedtracker, as accessed on 3/20/2024.}

While TRP development and deal activity continue to accelerate, oncology companies with TRP portfolios need to understand where to play now and where to take their portfolios in the future, as Novartis demonstrated by bringing Mariana Oncology and their alpha emitter therapies into the fold. Oncology companies that do not yet have TRP positions—or conversely, TRP biotechs—can assess the deal landscape and find matches to bring this platform to more patients. Despite the field’s promise, there are many barriers to successful commercialization. In the future, we’ll explain these barriers and how to mitigate them.