French firm Diatos has created a second generation irinotecan cancer therapy using its patented peptide-based drug delivery system, coming up with a drug that has greatly improved efficacy and safety profile compared to current irinotecan drugs such as Pfizer's Camptosar.
Diatos has used its unique Vectocell technology to create its DTS-108 drug product, connecting a Vectocell peptide to the active metabolite of irinotecan via a chemical linker. Data suggests that the new drug product can not only improve the bioavailability and biodistribution of the active metabolite, SN-38, but can also provide a much improved safety profile. Irinotecan is a widely used chemotherapy drug to treat colon cancer. It is a soluble prodrug of SN-38 (i.e. the active ingredient is not released until the irinotecan is metabolised by the body), which is an insoluble and potent inhibitor of topoisomerase, an enzyme involved in cancer cell proliferation.
In its current formulation, the rate at which irinotecan is converted to SN-38 in the liver is very low (two to eight per cent), and very variable between patients. As a result very high doses of the drug need to be administered to achieve effective results. Unfortunately, this high dosage combined with accumulation in the liver often results in very unpleasant and potentially life-threatening side-effects in patients undergoing the treatment.
Build up of high concentrations of SN-38 in the intestines can cause severe diarrhoea that requires hospitalisation and dose reduction and/or treatment interruptions, helping to relegate the treatment to a second line therapy despite good anticancer properties. By applying Diatos' Vectocell technology to SN-38, the company believes it can avoid metabolism in the liver and deliver higher doses of SN-38 to the body without eliciting the severe side effects caused by irinotecan.
DTS-108 has high water solubility, with a high proportion of the drug converted into SN-38 in the blood and tissues, instead of the liver. "Animal models have shown the amount of SN-38 within the circulation is up to 270-fold higher than observed with irinotecan at its maximum tolerated dose," John Tchélingérian, Diatos CEO told In-PharmaTechnologist.com.
"This means that significantly higher amounts of the active molecule can be delivered as DTS-108, without the toxicity issues that arise with irinotecan. This allows a significantly wider therapeutic window than is currently possible with irinotecan." Additional in vivo studies have been conducted that also demonstrate the superiority of DTS-108's anti-tumoural properties compared to irinotecan, according to Tchélingérian.
Whether the improved profile of the drug would result in less frequent or shortened treatment regimes for patients is, however, still unclear: "We are not sure as to whether treatment time would alter," Tchélingérian said.
"The compound would hit the tumour harder, with less systemic toxicity for the patient. "But clinicians would still want to dose the drug at the highest dose that the patient can withstand in order to get the maximal effect from the drug."
Diatos yesterday announced that DTS-108 would be entering pre-clinical toxicology studies, with Phase I clinical studies expected during the first half of next year. The drug is Diatos' first product based on the Vectocell technology to reach the clinic, and could conceivably challenge the likes of Pfizer's Camptosar (irinotecan), which generated sales of $715m over the first nine months of year according to results announced today.
While DTS-108 is Diatos' most advanced candidate based on the Vectocell technology, the company believes the system could also help in the development of drugs that were previously discarded as a result of toxicity concerns, or as a way of accessing new therapeutic approaches for intracellular disease targets.
The company is actively seeking partners for the DTS-108 product as well as the Vectocell platform as a whole, which it believes represents "a potential paradigm shift in drug development."