Chemotherapy-induced neuropathy (nerve pain) is a potentially dose-limiting toxicity, which can reduce the efficacy of chemotherapy but also significantly impact the patient's quality of life. Nadunolimab has demonstrated a much lower rate of neuropathy than expected in pancreatic cancer patients treated with nab-paclitaxel and gemcitabine (CANFOUR, n=73). A dose-dependent reduction in neuropathy was also observed. In two further studies, patients treated with FOLFOX (CESTAFOUR, n=14) had a lower incidence of neuropathy with 1mg/kg nadunoliamb versus 0.5mg/kg, while there was a trend of lower neuropathy with higher nadunolimab doses in FOLFIRINOX (CAPAFOUR, n=18). New pre-clinical studies using vincristine, nab-paclitaxel, nab-paclitaxel plus gemcitabine, or ADC payloads have shown that a nadunolimab surrogate antibody (10 mg/kg) could completely abrogate neuropathy. Neuropathy was associated with the infiltration of immune cells and cytokines in dorsal root ganglia (nerve roots in the spine). Both clinical and preclinical evidence thus suggests that nadunolimab can protect against the neuro-inflammatory component driving chemotherapy- and ADC-induced neuropathy.

Cantargia constructed a new IL1RAP-targeting ADC that was tested in vitro and in vivo. A tubulin-binding chemotherapy molecule was connected to an IL1RAP antibody through a cleavable linker. Tubulin is used during cell division to separate chromosomes. The experiments showed that the molecule worked as intended, with the chemotherapy component being internalised by cells IL1RAP-expressing cells, which can be either cancer cells or cells surrounding them in the tumour micro-environment. The ADC showed IL1RAP-dependent cell killing in vitro. Furthermore, it demonstrated significant dose-dependent anti-tumor activity, with tumor regression observed in both in vivo models used. The safety profile was good with both the anti-human IL1RAP ADC and the anti-mouse IL1RAP ADC being well tolerated.

Of the two abstracts, the big novelty was the one describing a new ADC molecule that performed as intended. The abstract describing how nadunolimab protects against neuropathy contained mainly new pre-clinical information. ADCs have been hot in deal-making, having become a must-have in pharmaceutical companies' portfolios, so we have seen deals for earlier assets than is otherwise the case in oncology. The fact that Cantargia’s ADC studies were performed with ImmunoGen (now part of AbbVie) suggests some level of interest from big pharma. In order to sign a deal, however, we think the phase IIb study TRIFOUR in triple-negative breast cancer, which has a control group, will be crucial. The study was fully recruited on 10 March and a first readout of ORR is expected by mid-2025 (PFS and OS numbers will follow later). The first interim readout showed around double the response rate compared to historical numbers. While we do not necessarily expect such strong results in the final readout, a statistically significant improvement would likely be a major catalyst for the share. It should increase the interest in the IL1RAP ADC programme as well.