Are radiopharmaceuticals the next breakthrough in oncology?

Ben Hargreaves examines what advantages radiopharmaceuticals offer in the treatment of cancer and why there has been interest from big pharma in developing these types of therapies. The article also outlines some of the challenges remaining to be tackled.

Radiotherapy dates back more than a hundred years, yet it still remains a core part of cancer treatment today. The problem with this form of treatment is that it is not targeted and, as a result, there are a number of short- and long-term side effects which can impact patients’ lives. This is why the recent surge in development for radiopharmaceuticals is drawing attention.

Radiopharmaceutical treatments retain the advantages of radiotherapy’s ability to kill cancer cells, but are able to deliver the therapy in a more targeted manner. In addition, radiopharmaceuticals can also be used in diagnostic imaging for the detection of cancer cells.

The principal design of this type of therapy is that of a radioactive molecule combined with a targeting molecule via a linker. The compound can then be delivered through injection, infusion, inhalation, or ingestion, before making its way into the bloodstream. Once in the body, the targeting molecule can deliver the radioactive molecule to the cancer cells.

It is a similar approach to that of another form of oncology treatment that is also experiencing a surge of interest, antibody-drug conjugates (ADCs). However, there is a difference between the two: the toxic payloads of ADCs need to be absorbed into cancer cells, whereas radiopharmaceuticals can still do damage even when only bound to the cancer, and are particularly sensitive to radiation-induced DNA damage.

Investment is flowing

Big pharma has already noted its interest in the area, as seen in Novartis’  investments. Last year, the company signed two deals in quick succession, which saw it form a licensing deal worth $1.3 billion with Artios Pharma and with iTheranostics for a number of diagnostic radiopharmaceuticals.

This year, Novartis’ deal-making in the area paid off when it received US FDA approval for Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for previously-treated patients with PSMA-positive metastatic castration-resistant prostate cancer. The drug was added to Novartis’ portfolio through a $2.1 billion acquisition of Endocyte in 2018, with estimations that sales could reach $600 million in this first indication alone.

The proof of the financial viability of these types of treatment means that those companies looking to draw in early investment have managed to secure greater interest. One such company is Aktis Oncology, which announced in August that it had extended its Series A financing round and managed to add a further $84 million to the $72 million it raised last year, for an overall total of $161 million. The financing saw Merck, Bristol Myers Squibb, and Novartis all choose to invest in the biotech.

Speaking to pharmaphorum, Matthew Roden, CEO of Aktis, explained that the financing round will be used to complete two objectives: “First, Aktis is building a broad pipeline of novel, targeted radiopharmaceutical agents that are designed to address large patient populations with commonly-occurring tumour types such as lung, breast, GI, and bladder cancers […] Second, Aktis is dedicating resources to help achieve our end-to-end supply chain capabilities to deliver for patients at scale. This is an important capability because radiopharmaceuticals require just-in-time manufacture and delivery each week. Few organizations today can do that.”

Different methods

With investment and approvals beginning to flow into the area, there are a growing number of start-ups and established companies that are looking to develop radiopharmaceuticals. One such company is Clarity Pharmaceuticals, an Australian company, which is developing radiopharmaceutical-based ‘theranostics’.

The potential treatments work by finding and binding to tumour-specific receptors on cancer cells. Once the targeting molecule has found the tumour, the radioisotope can either begin emitting radiation to be registered by an imaging device or to destroy the cancer cell.

Alan Taylor, executive chairman at Clarity, told pharmaphorum how this works: “By only switching the payload from diagnostic to therapeutic, while using the same targeting molecule in the radiopharmaceutical product, the same cancers can be targeted in the body but with more powerful radiation capable of killing cancer cells.”

The treatment uses copper isotopes that are ‘held’ within a bifunctional cage (chelator), which prevents leakage into the body.

“The copper pairing provides significant supply and manufacturing advantages. The diagnostic products containing Cu-64 have a shelf-life of several days, allowing central manufacture and regional distribution, potentially reaching more treatment centres and patients,” Taylor outlined.

Clarity announced in August that its phase 1/2a trial in paediatric patients with high-risk neuroblastoma would continue recruiting across five clinical sites in the US. The treatment, 67Cu SARTATE, could be significant, as it is being tested in children where no other therapy options are available.

Aktis has taken a different approach. The biotech has developed a ‘miniprotein’ targeting system that delivers alpha-emitting isotopes. Roden outlined how the company’s approach differs, “We favour these miniprotein constructs because they have several advantages over other binder types. For instance, our miniprotein libraries have a great diversity in shape and size, which enables us to hit a wider range of tumour targets than small molecules or small peptides. Importantly, the three-dimensional shape of the miniproteins confers a high degree of specificity for the target, which improves our safety profile because, in addition to effectively getting into the tumour, it also quickly clears out of the body to minimize radiation exposure elsewhere.”

Beyond this, Roden noted that miniproteins are easy to manipulate and manufacture, so the biotech is able to advance treatment candidates quicker than traditional modalities.

Challenges remain

Manufacturing could be one of the hurdles that the industry has to face down in the wider adoption of radiopharmaceutical therapies. Even a company as large as Novartis encountered difficulties earlier this year, when it had to suspend sites in Italy and the US. The reason for the shutdown was due to potential discovery of quality issues at its plants. The company stated that there was “no indication of risk,” but it meant that the rollout and the clinical development of Pluvicto was hampered.

Another big pharma company, Bayer, encountered difficulties when its radionuclide drug, Xofigo (radium Ra 223 dichloride), was found to cause more fractures and deaths in combination with Zytiga (abiraterone acetate), in comparison to the latter treatment as a monotherapy. However, this did not stop the company from investing further into the space last year, when it acquired Noria Therapeutics and its pipeline of radionuclide drugs.

As with all developing treatment modalities, such issues are to be expected. With more work being carried out in the space, and increasing levels of investment encouraging greater numbers of clinical studies, the treatments will become more sophisticated, easier to manufacture, and safer to deliver to patients. Already, Aktis and Clarity are suggesting that they have managed to develop better manufacturing methods . With companies such as Bayer and Novartis continuing to invest, despite the setbacks, the area is one that is likely to continue to grow and attract more interest in the years to come.