Radio-pharmaceuticals Light Up
The prospect of a modality that is less constrained by genetic mutations, whose mechanism of action invites combination with existing treatment categories, has Big Pharma salivating.
Radiopharmaceuticals have lit up. Strong data from Novartis’ oncology drugs Lutathera and Pluvicto, plus developers’ quest for an alternative modality with “pan-cancer” potential, has driven multibillion-dollar acquisitions, a $350 million IPO and a flurry of VC investments.
Bristol Myers Squibb’s $4.1 billion RayzeBio purchase, Eli Lilly’s POINT Biopharma buy and AstraZeneca’s $2 billion up-front deal for Fusion Pharmaceuticals, each with clinical-stage assets, catapult this Big Pharma trio into the field. Eager to stay ahead, Novartis is buying up earlier-stage assets and technology: on May 2, it announced a $1 billion deal for Mariana Oncology and its pre-clinical pipeline.
Deal
Value
Date
Novartis buys Mariana Oncology
$1bn upfront & up to $750m in m/s
May 2024
AstraZeneca buys Fusion
$2bn upfront & up to $400m contingent value rights
March 2024
Bristol Myers Squibb buys RayzeBio
$4.1bn
December 2023
Eli Lilly buys POINT Biopharma
$1.4bn
October 2023
Ariceum buys Theragnostics
$2.5m u/f; up to $41.5m m/s
June 2023
Financing
Perspective Therapeutics private placement
$87.4m
Radionetics Oncology Series A
$52.5m
January 2024
Perspective Therapeutics public & private offerings
$69m (public); $20.8 (private)
ArtBio Series A
$90m
Nucleus Radiopharma Series A
$56m
RayzeBio IPO
$358m
September 2023
Mariana Oncology Series B
$175m
Convergent Series A
May 2023
Ariceum
E22.75 ($24.7m) extension to E25m ($27m) Series A in June 2022
April 2023
Sources: Evaluate, company press releases
Radiopharmaceuticals deliver targeted radiation to cancer cells, using a cancer-targeting ligand to direct the radioactive isotope to the site of interest, with minimal damage to healthy surrounding tissue.
The appeal? Radiopharmaceuticals deliver targeted radiation to cancer cells, using a cancer-targeting ligand – such as an antibody, peptide or small molecule – to direct the radioactive isotope to the site of interest, with minimal damage to healthy surrounding tissue. They are less susceptible to typical drug resistance mechanisms, since it’s the radiation, not the ligand, that kills the cancer. Radiopharmaceuticals also offer a (literal) window onto tumour location and uptake. Their “see what you treat” quality comes thanks to the use of imaging isotopes prior to or alongside cytotoxic ones. Imaging accelerates patient selection and development times and helps optimise dosing.
As some targeted cancer meds reach sales ceilings due to ever-more-narrowly defined populations – the double-edged sword of precision medicine – the prospect of a modality that is less constrained by genetic mutations, whose mechanism of action invites combination with existing treatment categories, has Big Pharma salivating.
Targeted radiation has been around for decades: iodine was first used to zap thyroid cancers in the 1940s. Bayer’s Xofigo was approved in 2013 for prostate cancer that has spread to the bone. Lutathera and Pluvicto – which Novartis acquired from Advanced Accelerator Applications (2017) and Endocyte (2018), respectively – represent the first of a new generation of precision-engineered radiopharmaceuticals. Their strong trial data hints at what might follow, as researchers explore new radioactive isotopes, a wider range of ligands and new targets.
Lutathera cut the risk of progression or death by almost 80% in patients with advanced neuroendocrine tumors (NETs), relative to standard treatment, and last year showed similar benefits, alongside standard therapy, in another Phase 3 in patients with newly-diagnosed gastro-enteropancreatic NETs. Pluvicto significantly prolonged overall survival on top of standard of care in prostate-specific membrane antigen (PSMA)-expressing prostate cancer and more than doubled progression-free survival in a pre-chemotherapy setting. Novartis plans to file for a pre-taxane label in the second half of 2024.
By 2028 Pluvicto sales will top $3.5 billion and Lutathera will be approaching $1 billion, according to Evaluate forecasts.
Developers large and small are scurrying to buy or build better versions of Novartis’ duo and to test them across a wider range of cancers.
Developers large and small are scurrying to buy or build better versions of Novartis’ duo and to test them across a wider range of cancers. They’re testing a range of isotope-ligand-target combinations and touting clever conjugation and chelation chemistry to bind these components together. The parallels with red-hot antibody-drug-conjugates (ADCs) are many.
“We’re starting to see the data [supporting radiopharmaceuticals] emerge,” says David Hirsch, CEO of start-up Alpha9 Oncology. “But it’s still early days.”
Lutathera and Pluvicto use the isotope lutetium-177, which emits beta radiation – a mid-range, moderately powerful stream of electrons that can sever a single strand of cancer-cell DNA.
Many next-generation programs use isotopes that emit more powerful alpha radiation. This cuts through both DNA strands in target cells, leaving no room for resistance. Alpha radiation may also be more effective than beta at harnessing the immune system, scientists believe, thanks to its short, high-energy punch which generates a flurry of neo-antigens. That’s why combination trials are underway with checkpoint inhibitors.
Alpha isotopes may also win on convenience: Lutathera patients must avoid children and pregnant women for a week, due to longer range, longer-lasting radiation.
Alpha-emitting isotopes actinium-225 and lead (Pb-212) are popular.
RayzeBio (now BMS)’s most advanced candidate is an actinium-225 version of Lutathera, in Phase 3 testing for NET patients who have stopped responding to Lutathera. Fusion Pharmaceuticals (now AZ)’s lead – acquired from RadioMedix in February 2023 – also uses actinium-225, in this case to target PSMA. This alpha-flavoured Pluvicto is being positioned among patients pre-treated with Pluvicto, and among those who are radiopharmaceutical naïve.
France’s Orano Med, Perspective Therapeutics and ARTBIO are among those with clinical or close-to-clinical compounds using Pb-212. In early 2024, Orano Med and RadioMedix’s Phase 2, Pb-212-based NET program became the first targeted alpha therapy to receive US Breakthrough Therapy designation, based on promising Phase 1 and early Phase 2 safety and efficacy data.
Choosing between actinium-225 and lead-212 involves several trade-offs: actinium requires deals with specialist suppliers (think particle generators and nuclear reactors), but has a long, 11-day half-life. This means the radiation lingers, which is challenging for waste disposal. Lead-212 is more straightforward to generate, but decays faster – its half-life is just 11 hours. It packs a potent punch but needs to be made close to where it's used. Other wrinkles: actinium-225 generates “daughter isotopes” that may cause stray alpha rays and lead-212’s strong, longer-range gamma emissions that require operator shielding.
No actinium-225 or lead-212 based therapy has yet been approved.
Some companies want to minimise isotope-based risk by sticking with lutetium-177, and changing the ligand. Australia’s Telix Pharmaceuticals’ Phase II/III Pluvicto-lookalike uses antibody rosopatamab to target PSMA, rather than peptide vipivotide tetraxecan, in Novartis’ drug. (Convergent’s Phase I/II lead uses the same antibody to carry actinium-225 to PSMA receptors.)
Ligands should, to a large degree, be matched to isotope: actinium-225 and lutetium-177, with multi-day half-lives, are better suited to antibodies, which stick around. Fast-decaying Pb-212 may be more appropriate for small molecules, which tend to be more quickly washed out.
Many firms are using peptide-based ligands, which balance antibody-style target specificity with faster clearance rates. (Radiotherapies shouldn’t linger too long.) Peptides can also be tailored to the job at hand. Berlin-based 3B Pharmaceuticals has been optimising peptides for use in radiopharmaceuticals for 15 years; Novartis in 2023 licensed rights to 3B’s peptide technology targeting fibroblast activation protein (FAP), tweaking an earlier deal with Clovis Oncology. ; it also recently updated a deal with Japanese peptide discovery powerhouse PeptiDream. Mariana Oncology brings the Swiss group additional expertise in engineering “peptidic small molecules” for optimal tumour penetration and payload capacity (its programs are in development for various solid tumours).
Small molecules also have a place in the radiopharmaceuticals revolution, according to start-ups like Radionetics Oncology. It’s seeking out small molecule-isotope combos that hit G-protein coupled receptors – a category that encompasses a wide range of potential targets.
Small molecules also have a place in the radiopharmaceuticals revolution.
More creative ligand design will further broaden radiopharmaceuticals’ range of targets. New targets like FAP are popular due to its over-expression across multiple tumour types (Lilly’s POINT Biopharma also has a FAP-targeting program). Clinical candidates at AZ-owned Fusion go after insulin-like growth factor
receptor-1, EGFR-cMET and neurotensin receptor-1 (NTSR1). Orano Med and Molecular Partners are among those changing delta-like ligand 3 (DLL3).
Combination trials pair radiopharmaceuticals with cancer immunotherapies and with targeted medicines like PARP, MEK or BRAF inhibitors. Targeted “pre-radiation” may prepare the ground for other approaches.
In March 2024, Perspective signed a deal to test its Pb-212 based metastatic melanoma candidate, currently in Phase 1/ 2, with BMS’ checkpoint inhibitor
Opdivo (nivolumab). Perspective's radiopharmaceutical targets the melanocortin 1 receptor (MC1R), potentially enabling more effective checkpoint inhibition (CPI): tumour growth was slowed in pre-clinical models of CPI-resistant melanomas.
Challenges remain: isotope supply, complex manufacturing and distribution demands, administration bottlenecks (including a shortage of nuclear medicine physicians) and lingering ‘radio-phobia’. Regulators and treatment centres must also follow stringent safety protocols, for instance around how to deal with radio-active bio-waste.
New buyers Lilly, BMS and AZ know the risks. Yet they also know that if these next-wave radiopharmaceuticals do pick up where existing, multibillion dollar categories like checkpoint inhibitors (or, dare we say, antibody-drug conjugates (ADCs)) fall short, their investments will be more than justified. “This field is going to be big – potentially even bigger than ADCs,” says Orano Med CEO Julien Dodet.
This field is going to be big – potentially even bigger than ADCs.