RedX Pharma Cancer Trial Paused: Serious Side Effects

Redx Pharma, based in Alderley Park, UK, dosed its first patient for the Porcupine inhibitor RXC004 on February 6. The company indicates it has paused the trial after the first patient dosed had "clinically significant" adverse events.

RXC004 is a novel, oral, small molecule Porcupine inhibitor. It targets the Wnt pathway, an embryonic signaling pathway associated with cancer stem cell maintenance in multiple types of cancer.

The company and the researchers believe the adverse effects are related to the drug. Specifically, they believe their dosage was too high. "It is our current intention to propose a protocol amendment that enables dose-escalation to re-start at significantly lower dose levels," said Andrew Saunders, the company’s chief medical officer, in a statement. "This protocol amendment will be finalized with consultation with both the MHRA (Medicines and Healthcare Regulatory Agency) and principal investigators."

Although targeting Wnt has had the interests of researchers for some time, there have been significant concerns about on-target side effects. Abnormal Wnt regulation is associated with several key tumor processes, but normal Wnt pathways are involved with important and essential cellular processes, including tissue homeostasis, organ repair and skin regeneration.

Balancing the attack on the abnormal processes without harming the normal processes is difficult, as today’s report suggests. The company believed that by targeting the Porcupine enzyme, which has a central role in the WNT pathway, it would be able to avoid problems.

The dosing of the first patient apparently had surprisingly strong effects. The company is working to develop a dosing strategy that would start at a much lower dose and then escalate in a controlled fashion.

The company hopes to evaluate the drug as a monotherapy and then, if safety and efficacy issues are resolved, test in combination with checkpoint inhibitors, such as Merck & Co.’s Keytruda and Bristol-Myers Squibb’s Opdivo and Yervoy.

Labiotech notes, "It remains to be seen whether RXC004 proves effective and non-toxic at lower doses. Considering that Redx is planning to test the drug in combination with checkpoint inhibitors, which despite being effective are also known for their side effects, the company might have to stop to rethink its plan."

Any trials with checkpoint inhibitors are likely to be delayed by several months. There is, of course, also the possibility that any dosage high enough to kill tumors may be too dangerous in terms of side effects. But the company is expressing confidence.

"The Board continues to believe the overall risk/benefit assessment of RXC004 as an investigational drug is unchanged," said Iain Ross, the company’s executive chairman, in a statement. "However, in drug development, safety of patients is the first priority and it is appropriate that the Board and management has taken the decision to suspend recruitment of further patients to the trial until the company has consulted with the MHRA and agreed to a plan to move forward. While we remain confident that we can address this issue, we currently estimate that this suspension will lead to a delay of several months. The board continues to believe it has sufficient resources to continue to progress RXC004 and its broader portfolio of oncology and fibrosis assets. We intend to provide a further update in due course."

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