What’s New
With CAP-0121?

Since the irofulven trials,
we have made three key advances.

  • Created CAP-0121, a better, safer analog than irofulven.

  • Now understand the unique mode of action.

  • Now understand which patients will respond best.

We engineered CAP-0121 as a new analog that is better and safer than irofulven.

We screened 450 analogs of irofulven. Of these, CAP-0121 shows the best efficacy and lowest toxicity in rodents and in canine studies and is active against multi-drug resistant (MDR) cancer cells regardless of the mechanism of resistance (full details available under CDA). 

CAP-0121 demonstrated clear superiority to traditional anticancer drugs in the NCI DTP 60 cell line screening panel when true cytotoxic activity (LC50), or cancer cell killing ability, was compared to maximum tolerated dose (MTD) in rodents.

As an example of the superior cytotoxic anticancer activity, CAP-0121 produces complete tumor remissions in a multi-drug resistant xenograft model that is not responsive to over 35 traditional and experiment anti-cancer drugs.  Studies with additional drug-resistant xenografts confirmed this superiority.

Dose-ranging rodent and canine studies confirmed a favorable systemic toxicity profile (no major organ damage at high doses), as well as a favorable pharmacokinetic (PK) profile (full details available under CDA).

We understand which patients will respond best.

Illudins work by damaging DNA in a unique way compared to other drugs.  DNA damage is normally handled by the Global Genome Repair (GGR) process to prevent disruption of the TCR complex processing.  However, the DNA damage produced by CAP-0121 is unique in that it is not recognized by the GGR process (the only other type of DNA damage that remains hidden from the GGR process is that produced by short-wave UV light).  Thus, the damage caused by CAP-0121 can only be repaired by the Transcription-Coupled Repair (TCR) pathway. Cells with a normally functioning TCR pathway can survive treatment by CAP-121. As a result there is minimal toxicity towards normal diploid cells in the human body (No stomatitis, hand-foot syndrome, peripheral neuropathy, liver damage, pancreas or renal damage common with other cancer drugs).

About 20% of cancers have mutations that corrupt the TCR DNA repair process. These cancers are “TCR deficient” and can’t repair DNA damage produce by illudofulvenes. These cancers are thus 30 to 100x more sensitive to illudofulvenes like CAP-0121. We believe this is why only ~16% of irofulven patients demonstrated a dramatic response to irofulven. 

The heightened sensitivity of TCR-deficient tumors to illudofulvenes has been independently validated by multiple third parties including Memorial Sloan Kettering, Dana Farber, and a European Consortium (see Publications for details).

Califia will use a companion diagnostic to selectively treat patients with TCR-deficient cancers. (Such personalized medicine was not possible in the early 2000s when irofulven was in clinical trials).

Fresh Intellectual Property

Califia has numerous new patents granted (2021 and 2022) and pending relating to CAP-121, related compounds, and related companion diagnostics (see Patents for details).