A clinical proof-of-concept program for vitamin K2 prodrug in the treatment of calciphylaxis cutis

Due to the role of vitamin K2 role in the regulation of bone and soft tissue calcification, a drug development program for the use of vitamin K2 in the treatment of calciphylaxis cutis has now been planned. A patented pro-drug of vitamin K2 is being synthesised, formulated and will be taken through the pre-clinical toxicology program. When animal safety has been demonstrated, the drug will be undergo an accelerated phase 1 program, exposing human healthy volunteers (as well as a subgroup of patients with renal impairment) to the higher doses of vitamin K2. When the phase 1 program is completed another scientific advice meeting with the European Medicines Agency (EMA) will be conducted with the aim of obtaining protocol assistance and thus negotiate the best clinical trial design. The main backbone of the H2020 proposal is thus the pivotal phase 2 study, which in addition to providing clinical proof-of-concept (cPoC), also will be powered to suggest expected efficacy rates, and to explore whether there are any subgroups of responders. The cPoC tria is by far the main pillar of the proposal. Details will be clear only after scientific advice meetings with EMA, but the current thinking on clinical trial design and methodology is: (1) Population of patients with end-stage renal disease, on chronic hemodialysis, with CUA; (2) Randomized, double-blind, placebo-control, on top of standard-of-care, 6 months treatment; and (3) Efficacy variables include: wound healing (ulcer size, number of ulcers), pain, health-related Quality-of-Life, vascular calcification, infection rate, hospitalisations, biochemical markers. If the phase 2 results are compelling, a compassionate use program must be initiated, and it is our belief that a conditional marketing authorisation may be obtained. Therefore, regulatory affairs work to prepare such applications are included among the work packages.