Have you ever considered supply chains at the molecular level? How exactly can a cancer cell be targeted with precision, so it is destroyed and there is no collateral damage to healthy cells? What is the delivery equivalent of Amazon getting a package to the doorstep of an individual cell?
Pharma has long been interested in this question, and its attention has been tuning in to the field of targeted cancer medicine through molecular radiotherapy or targeted radionuclides.
The targeting mechanism, the way that the payload is specifically delivered to the end of its life saving supply chain, is based on the recognition that cancer cells, with their characteristically incessant dividing, typically have an overabundance of different, often mutated, proteins compared to healthy cells. This then becomes the shining beacon to drop nuclear warheads on. Novartis’s Lutathera®, for treating neuroendocrine tumors expressing the hormone receptor somatostatin receptor 2 (sst2), is the current poster child for this new form of nuclear medicine, with potential to become a $bn oncology brand, the biggest ever radionuclide therapy product. The product was developed by French company Advanced Accelerator Applications S.A. (AAA), which Novartis acquired for $3.9 billion in 2017. In 2019, Lutathera® reported sales were $414 million, with $217 million revenues in H1 2020 and analyst peak sales estimates ranging between $1 billion to $2 billion. Novartis also acquired a further radiopharmaceutical company, Endocyte, for $2.1 billion in 2018. As part of its expansion of this franchise Novartis said in July 2020 it was planning to build a second US manufacturing facility to meet demand for Lutathera® and its PSMA radionuclide therapies – which are also forecast to be blockbusters. Novartis writes here about how it is investing in this emerging form of nuclear medicine because it has the potential to become a foundational pillar of cancer therapy. Today, approximately two-thirds of all cancer patients receive some form of radiation during the course of their therapy.
Investors are also tuning into radiopharmaceuticals. Alpha Tau Medical (focused on Diffusing Alpha-emitters Radiation Therapy) closed a private Series B financing of $26m recently (raising $55 to date), while 2020 has also seen Lantheus Medical Imaging acquire Progenics Pharmaceuticals in an all-stock transaction valuing Progenics at around $380m plus contingent value rights cash payments for achieving future sales milestones with its PSMA radiopharmaceutical, and Point Biopharma (Radioligands) closed a Series A of $20m. In June 2020, the appetite for radiopharmaceuticals was extended to public investors in Fusion Pharmaceutical’s $212.5m Nasdaq debut.
The next generation in molecular radiotherapy is to deliver a radioactive payload to active PARP (Poly(ADP-ribose)-Polymerase) proteins that are attached to and repair damaged DNA in cancer cells. The payload may be commonly used Iodine-123, Iodine-131 or At-211 that most hospitals can create on-site or centrally manufacture, that when it decays within the cancer cell, releases enough nuclear energy to obliterate the bonds holding DNA together.
Payloads are categorized as to whether they release alpha particles, which give out more energy over shorter distances, or those that emit less powerful beta particles over longer millimeter ranges. Theragnostics has been investigating auger-particle emitters, which combine the best features of alpha and beta: pinpoint targeting with high energy release over a very short range on the scale of nanometers, without off-target effects. This contrasts with alpha or beta radiation emitters which can cause toxicity to the kidneys. Auger therapy has long been of interest because of this potential for reduced toxicity but also because the radiation damage caused in such a short range requires very close proximity to DNA, the targeting drugs to enable its use were not available to nuclear medicine. Targeting active PARP with PARP inhibitors to bind the payload to DNA now gives the first opportunity for a company to test an auger therapy.
What makes molecular radiotherapy such a desirable platform is that the targeted radioactive element can also be used as a precision diagnostic prior to therapeutic application with standard diagnostic isotopes such as F-18, providing a powerful ‘see it, treat it’ capability. The dream is that the dose of the payload can be personalized to the likely patient response, although current approaches are with fixed doses.
By generating an exquisitely delineated image of a tumor, effectively making it light up, a clinician can clearly see exactly which lymph nodes a cancer has spread to, and more accurately determine a patient’s staging, and adjust treatment accordingly. Future scans can help doctors determine if the medicine is working as treatment progresses.
People, and patients in particular, can get nervous about the idea of using radiation, with all its negative connotations, in medicine, but this is about precision, not explosion, and has an important quality of life role to stabilise end-stage disease where other treatments are just not working. Early clinical trials have improved outcomes for patients with otherwise untreatable prostate and thyroid cancers, as well as neuroendocrine tumours.
The cancer community is waiting keenly on the outcome, due in 2021, of Novartis’s 177Lu-PSMA-617 radionuclide therapy (acquired with Endocyte) in Phase III testing for Prostate-Specific Membrane Antigen (PSMA)-positive metastatic castration resistant prostate cancer. If that delivers a positive outcome, it will highlight Novartis’s wisdom in taking a significant position in this space. We will then be rejoicing over the airwaves that radiotherapeutics has something new in cancer medicine for the 21st Century.
Article written by Nick Stevens, Chairman of Theragnostics