Coming Through On Precision Medicine – C4X Discovery’s IBD Test Breakthrough

UK company C4X Discovery Holdings plc has used its proprietary PatientSeek platform to identify in patients a genetic response signature that separates responders and non-responders to vedolizumab, the a4b7 antibody therapy for ulcerative colitis. Vedolizumab is a Takeda Pharmaceutical Co. Ltd. product marketed as Entyvio.

C4XD CEO Clive Dix says this is a first for immuno-inflammation precision medicine. “The data clearly demonstrate the power of PatientSeek’s analytical capabilities for patient selection based solely on genetic data,” he said.

No currently available biomarker has been robustly validated in predicting response to individual advanced therapies to guide clinical practice for inflammatory bowel disease (IBD).

Accordingly, many patients have been underserved, he continued, but that will change in the wake of C4XD’s breakthrough. Compared to clinical and “omic biomarkers,” genetic signatures do not change over time and are independent of disease progression. C4XD, now focused exclusively on immune-inflammatory indications, plans to apply PatientSeek’s capabilities widely to its drug portfolio.

The company deployed the platform after securing information on thousands of patients with ulcerative colitis and Crohn’s disease from one major IBD database ecosystem. This database holds hundreds of millions of data points accessible under licence by precision medicine researchers.

Speaking to In Vivo, Dix said: “We used our technology to analyse those patients’ genetics, and we found a very distinct genetic response signature and non-response signature to vedolizumab. With a simple blood sample and running a genetic test, we can say whether patients will or will not respond to that drug.”

At present, IBD patients are referred for courses of different treatments that might or might not work. Dix said: “Imagine if you knew this drug would work, and patients would be diagnosed in the first month rather than, say, two years later.”

Following the PatientSeek breakthrough, IBD patients will be able to get a quick test. The tool combines a unique mathematical approach to analyzing datasets containing patients’ genetic records with other information, such as electronic health records, to provide a statistically significant predictive genetic response signature.

Dix stated: “It’s a massive benefit, and it is the way medicine is going; our genetics dictate what we are. Doing things through genetics is definitive, compared to measuring markers in the blood that can change or disappear and then come back. Genetics do not change over time and are independent of disease progression.”

C4XD plans to use this twin approach of developing test response signatures at the same time as drugs for all products in its portfolio. It will utilize the data’s predictive power for use in future clinical trials for its own small molecule a4b7 integrin inhibitor, its flagship product.

“We believe this will be possible for all chronic inflammatory diseases,” Dix said, including for its TNFa and PAD4 programs. “We’ll have a stream of molecules coming out over next five years that will have a true precision medicine approach to them.”

In addition, Dix lists “four – possibly five” C4XD molecules going into the clinic, which, for a small company, “is not a bad place to be,” he said. These include a molecule targeting craving and addiction, which is going into Phase 2 in the clinic where the IP has been purchased by Indivior, following successful development under an original licensing agreement; and an NRF2 molecule being developed by AstraZeneca PLC and another molecule with Sanofi, which are both moving in the direction of the clinic.

Right Patient, Right Drug, Right Time

The PatientSeek breakthrough should lead to smaller, less expensive and more successful clinical trials targeting the right patient at the right time for the right drug, Dix said.

He is now aiming for C4XD to work with other organizations that run major patient databases. This will further support the company’s drive to analyse diseases and identify responders/non responders and the “fingerprints” – the genetic response signatures that confirm which is the right drug for a target individual.

“This is proper medicine, driven by data,” Dix said, in place of diagnosis based on clinical experience which can yield ambiguous results.

C4XD, no longer listed on AIM London and relishing the relative freedom that decision earlier this year has delivered, is funded for the next couple of years. (Also see "C4XD Delisting Highlights Funding Frustration For UK Biotechs" - Scrip, 27 Mar, 2024.)

A consultation with the UK Medicines and Healthcare products Regulatory Agency, to review regulatory strategies for a4b7, is pencilled on Dix’s to-do list. At present, Dix is mulling a phase 1 in the UK and engaging with US regulators about when to file for an IND.

The next development stages will be in partnership, said Dix, with the people who have the databases and those with the right test system to use, be it chip technology or whole genome technology – or with a partner with really good reading technology. “We’ll own the signature we’ve found and distribute it through licences, for example,” Dix said.

Payers will be very interested in C4XD’s ability to stratify patients and help prescribe the correct drug. “It could halve payers’ costs,” Dix said. Ethical pharmaceutical practice says drugs should be given only to those in whom they can be useful, he observed. “This test allows that; and I’m all for it.”