4C Biomed's next-generation checkpoint inhibitors

Until quite recently, chemotherapy, radiation, surgery, and targeted therapy (small-molecule drugs and monoclonal antibodies) were the pillars of cancer therapy. Then, in 2011, a new class of drugs, immune checkpoint inhibitors, were added to the therapeutic arsenal and revolutionised cancer treatment. These drugs not only introduced a new treatment modality but, in some notable cases, delivered durable responses with less toxicity.

The first drug in this class, an anti-CTLA-4 drug, ipilimumab, was licensed in 2011, but remarkably, since then, only three other ICIs have been approved in the US (PD1, PD-L1, and LAG3). Importantly, some of these early ICIs are approaching the end of their patent lives, and the largest selling drug in this class, Keytruda, which in 2023 achieved sales of over $25bn, sees its patent end in 2028 (it accounted for 40% of Merck’s total pharma sales in 2023).

This class of therapies has become the standard of care for many malignancies. It has been especially effective in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small cell lung cancer, which have higher tumour mutational burden (TMB). However, despite these remarkable clinical results, the sad fact is that the majority of patients do not have meaningful responses to these treatments either because they undergo therapeutic failure or develop immunotherapy resistance.

In response to these challenges, the industry has looked to develop biomarkers that better predict clinical response and increase the success rates of ICI-based therapies through combination treatments. But ultimately, more and better ICIs are needed to further weaponise the fight against cancer. The large pharma companies that have benefitted from the significant success of the current approved range of ICI therapies are especially incentivised to find the next generation of checkpoint inhibitors to offset the lost sales and profits that will coincide with the loss of exclusivity when these drugs reach the end of their patent lives towards the end of this decade.

Consequently, the drive to find new, effective and safe treatments in the field of immuno-oncology has resulted in many large and small pharma companies focusing on identifying new potential checkpoints and developing drugs for these targets. This development effort has seen considerable growth in recent years, and in 2020, there were already over 4,700 immuno-oncology agents in the global clinical pipeline. However, this is not a trivial challenge. Often, these novel therapies are not potent enough to be used alone, but they can potentiate the effects of existing therapy. However, in doing so, they may result in increased incidence and severity of immune-related adverse events and new toxicities.

Clearly, more research is needed to identify novel biomarkers that can help select patients who may benefit the most from these new therapies while avoiding significant toxicities. Many potential new drugs also lack activity in “cold” tumour micro-environments and do not expand the application of these potential therapies beyond the existing treatment modalities.

One company that is helping to address this huge challenge is 4C Biomed, a biotech business Curated is currently representing. 4C has been working on this problem since it was founded in 2016. The Company has developed a platform that is uniquely able to identify critical and novel immune checkpoints on cancer cells and, in turn, has developed a bank of potential druggable candidates for drugs designed to unleash the body’s immune system to attack a range of solid cancers. These include anti-4CB1, 4C’s lead drug candidate that has shown substantial effects both alone and in combination with existing treatments across a range of common malignancies. Remarkably, anti-4CB1 has demonstrated efficacy as a monotherapy in clinical samples that did not respond to the current market-leading drug, anti-PD1 ex-vivo, and also in combination with anti-PD1 in-vivo, and with a very promising safety profile. Currently, anti-4CB1 is at the stage of completing IND-enabling studies. 4C Biomed has applied for a pre-IND meeting with the FDA and expects to enter clinical Phase I trials of ant-4CB1 by mid-2025.

We believe that 4C’s platform technology and its lead drug candidate, anti-4CB1, are highly differentiated in the field of immune checkpoint inhibitors in oncology. Of particular interest is the potential for this approach to target diseases like colorectal cancer, which is currently “cold” and not amenable to treatment with PD-1/L1 or CTLA-4 inhibitors. If so, this really would be a significant advance in the treatment of this difficult-to-treat cancer, which accounts for 10% of all cancer cases, is the third most common cancer worldwide and is the second leading cause of cancer-related deaths.

For obvious reasons, Curated expects 4C Biomed to attract a lot of attention from pharma companies in the cancer market where, as we have already highlighted, the search for new and effective ICI therapies is especially active. This search will only intensify over the next few years as we inexorably approach the significant patent expiries that many businesses in this sector confront.