Iksuda receives US FDA IND clearance for IKS04

CA242 is a tumour-specific glycotope which is strongly expressed in a variety of GI cancers including the majority of colorectal (CRC), gastric, pancreatic and biliary tract cancers, and around half of bladder, endometrial and lung cancers, with limited expression in normal tissue.

Previous efforts to target CA242 with ADCs carrying tubulin inhibitor payloads have shown limited clinical efficacy, likely due to inherent resistance of GI cancers to this payload mechanism. In addition, there has been limited success to date with ADCs for the treatment of GI cancers such as those of the colon and stomach with topoisomerase I inhibitors, regardless of the target. There is a need for potent ADCs with differentiated cell-killing mechanisms and directed towards novel targets to enable higher efficacy and to overcome resistance.

IKS04 is a novel CA242-targeting ADC comprising an anti-CA242 humanized antibody and a highly potent pyrrolobenzodiazepine (PBD) prodrug payload. Typically, the use of potent payloads such as PBDs can limit the maximum tolerated dose of ADCs due to systemic adverse events, which in turn limits tumour tissue penetration and efficacy, particularly for high-expression targets such as CA242. This can create an antigen barrier that prevents the drug from penetrating deep into the solid tumour.

Thus, in a first for the ADC field, IKS04 will be co-administered with the unconjugated antibody to tackle the challenge of solid tumour penetration for high potency payloads. This innovative dosing approach is akin to a dosing regimen that is already used in radioimmunotherapy. 

Preclinical studies have demonstrated potent activity across a range of GI cancers alongside a favorable therapeutic index - the widest preclinical therapeutic index of any PBD-containing ADC for solid tumors. Anti-cancer activity was further enhanced in high-expressing models by co-administration of IKS04 with the anti-CA242 antibody, validating the IKS04 Regimen. 

The concept behind IKS04, including its clinical dosing regimen, is consistent with Iksuda’s general ADC-design approach: selecting the most clinically relevant combination of antibody, conjugation chemistry, linker and payload mechanism to deliver optimal therapeutic index for target and indication. IKS04, like all Iksuda’s ADC programs, incorporates pro-drug technology with tumor-selective activation and release of payload through glucuronide triggers.

This design concept, which drives improved tolerability over traditional linkers, has now been clinically validated in Iksuda’s in-clinic ADC programs IKS014, (a HER2-directed ADC containing MMAF), and IKS03, Iksuda’s CD19-directed ADC which also contains the PBD prodrug used in IKS04, and is currently in phase 1 clinical development for B-cell malignancies.

"This IND clearance for IKS04 and the IKS04 Regimen, is another important step for Iksuda and further validation of our approach to designing and developing innovative ADCs with the optimal clinical calibration for a given target and indication. IKS04 will be Iksuda’s third ADC to enter clinical development, a significant milestone for the company, with IKS014 and IKS03 both currently progressing through Phase 1 studies. This demonstrates the value of our expanding, innovative platforms, and further de-risks the clinical advancement of our novel antibodies, linkers and payloads. We look forward to progressing IKS04 into Phase 1 studies for GI cancers, an area of high unmet need with limited effective treatment options." David Simpson, CEO

"IKS04 is directed at a novel target in difficult-to-treat GI cancers. The co-administration regimen and PBD payload are a distinctive approach, and the clinical program will investigate whether they can thereby deliver a better balance of efficacy and tolerability. I am excited to see if this approach helps patients as IKS04 progresses through clinical development." Dr. Leon Pappas, Investigator, Massachusetts General Hospital

For further information please contact:

David Simpson
CEO Iksuda Therapeutics
Tel; +44 (0) 191 6031680

FTI consulting (Financial Media and IR)
Simon Conway/ Rob Winder/ Amy Byrne
Tel; +44 (0) 020 3727 1000
Iksuda@fticonsulting.com