PledOx® against side effects during FOLFOX treatment of colorectal cancer
In the PP-095 project, the compound PledOx® is used to reduce chemotherapy induced side-effects during cancer treatment. PledOx® has been tested in a phase IIb study and a phase III study will be initiated during 2017.
Primarily the drug is developed to reduce side effects in the treatment of colorectal cancer with the chemotherapy FOLFOX. The side-effects of chemotherapy treatment often lead to a reduction of the planned chemotherapy dose or in worst case, treatment discontinuation.
The results from the phase IIb study show that PledOx® can help prevent nerve damage in a clinically meaningful way during and after chemotherapy treatment of advanced colorectal cancer.
Phase IIb clinical trial
The randomized double-blinded study PLIANT was performed in 173 patients with advanced colorectal cancer where chemotherapy treatment was given to prolong survival and for palliative purposes.
The results indicate that the patients who received PledOx® ran a lower risk than the patients in the placebo group to suffer from nerve damage (neuropathy). The presence of the investigator reported sensory nerve damage, the primary endpoint, was after treatment 43 percent lower in the group of patients treated with PledOx® compared with the placebo group (p = 0.14). This was not statistically significant, but a difference of this magnitude is considered to be clinically relevant.
Post hoc analyzes on patient-reported neuropathy show a statistically significant reduction in the incidence and intensity of the symptoms of nerve damage in comparison with placebo. Additionally, it was noted that the investigator-reported symptoms of neuropathy occur later and disappear faster after pretreatment with PledOx®.
During the follow-up after completion of chemotherapy, the patient-reported incidence and intensity of neuropathy was statistically significantly lower in patients pretreated with PledOx®. The severity of neuropathy was 62 percent lower 12 weeks after discontinuation of treatment in the group of patients treated with PledOx® versus placebo (p <0.05) and at 24 weeks the corresponding difference between PledOx® and placebo group was 75 percent (p <0, 01). No apparent negative effect on the efficacy of the cancer treatment was observed. Median Progression-Free Survival (PFS) was 7 months and median overall survival (OS) 18 months for both PledOx® and placebo groups, which is as expected in this prognostically unfavourable patient group. Further there was a coherence between PledOx® effect on investigator-rated neuropathy and the various patient-reported evaluations made, which is valuable for future studies.
In the PLIANT abstract for the ASCO meeting in 2016 and in Company announcements, an incorrect value for objective response rate (ORR) has been reported. However, the important conclusion that there does not appear to be any negative interaction of PledOx® on the anticancer-effect of FOLFOX remains unaltered. The correct value for the placebo group should be 43% and 46% for PledOx® (p=0.6), which is in line with literature data.
Previous studies in the PP-095 project
Preclinical studies have shown that PledPharma’s substance, the PLED-derivative mangafodipir, protects healthy cells in the body without negatively affecting chemotherapy’s anti-cancer effects. There might even be a potentiation of the anti-cancer effect of the chemotherapy drugs.
Clinical phase IIa results
It has been shown that pre-treatment with the PLED-derivative mangafodipir reduces serious adverse events of chemotherapy in patients with colorectal cancer in a small clinical trial.
The study was a randomized clinical phase IIa study in 14 patients with colorectal cancer. It was designed to evaluate the reduction of side-effects in adjuvant (curative) chemotherapy with FOLFOX when patients were given the PLED-derivative mangafodipir during the three first treatment cycles of in total 12 cycles.
Four serious adverse events (grade 3) and one life-threatening adverse event (grade 4) were observed in the group that only received FOLFOX (placebo group), while no grade 3 nor grade 4 adverse events were seen in the group that was given the PLED-derivative mangafodipir. The difference between the placebo group and the group that received PLED-derivative mangafodipir was statistically significant.
Market potential PledOx®
In e.g. the USA more than 500,000 doses of chemotherapy are used in treatment of colorectal cancer. FOLFOX is used in the majority of treatments. Since every chemotherapy dose may be combined with a dose of PledOx®, the potential within colorectal cancer in the USA only is considerable. If one to this adds other chemotherapies, such as docetaxel and paclitaxel, which are the top sellers with sales of 2 million doses per year, the potential in the US will be more than 2.5 million doses per year.