Why the delay?
There has been a lot of questions, especially from many parents, about the status of the trial and what happened in 2016 when the initial program under Phenomenome Discoveries (PDI) was put on hold.
In 2015, PDI was unable to secure further investment to keep the company running, and ultimately went bankrupt at the start of 2016. However, some of the shareholders believed there was valuable research and development and intellectual property that could be advanced, so they purchased all of Phenomenome's assets, including the plasmalogen replacement compounds and patents, through a court-appointed bidding process. The new company, called Med-Life Discoveries (MLD), won the bid and officially took ownership of the assets on November 1, 2016.
A new management team was put in place to begin rebuilding the company, followed by an extensive re-evaluation of all of the therapeutics programs. The previously proposed RCDP clinical development plan was subsequently found to have significant gaps and unrealistic timelines. There had been no consultation with the FDA, no consideration around evaluating safety, and no concrete plan for synthesizing kilogram quantities of drug under good manufacturing practice (GMP) guidelines. The program had to be redesigned, this time with close engagement of the FDA throughout the process.
Work done to date
Early in 2017, a detailed review of all the prior drug data generated at PDI was performed. The analysis led to the conclusion that ether-precursors might not be the best candidates for RCDP, and that PPI-1040, a true vinyl-ether precursor, might be preferable. Although PPI-1040 had never been evaluated for oral bioavailability, likely due to stability concerns, there was evidence in the literature suggesting that plasmalogens can be orally bioavailable. Experiments were therefore subsequently designed to determine the oral feasibility of PPI-1040.
First, a series of tests were performed exposing PPI-1040 to extremely acidic conditions, which showed that the drug stayed intact to below a pH of 3 (very acidic). Next, a specially labelled version of the drug was used to show that in a normal healthy mouse, PPI-1040 is readily absorbed fully intact with no breakdown of the vinyl-ether bond, and that it effectively augments multiple endogenous plasmalogens. Lastly, an RCDP1 mouse model was treated with PPI-1040 for a month, which showed augmentation to nearly healthy levels in the blood and normalization of behaviour with a relatively low dose. Interestingly, the ether-containing version of the molecule (that was initially proposed as the lead compound for RCDP) was not effective. Therefore, PPI-1040 was selected as the compound to advance. This was a pivotal moment in the program.
Immediately following these experiments, a top chemistry consultant with decades of experience manufacturing compounds under strict regulatory guidelines was hired. An exhaustive RFP process was performed and a vendor selected to manufacturer PPI-1040, as well as a company to formulate the drug into a patient-friendly form. This work has been actively ongoing since January of 2018, with scale up to the first 5kg batch underway as of August 2018.
A top consulting firm highly experienced in orphan drug development was also engaged to help assemble a briefing packet and request a PreIND meeting with the FDA. The meeting was granted, and in January of 2018 a PreIND meeting was held at the FDA to discuss the therapeutic development of PPI-1040 for RCDP. The meeting was very positive, with the FDA providing guidance on several aspects of the program. These recommendations have been incorporated into the current development plan, and several more interactions with the FDA are expected as the program moves forward.
Currently, the focus is on manufacturing the drug and finalizing details of the Natural History Study. As explained in detail here, the Natural History Study represents the collection of data in untreated patients over time before the drug is given, in place of a placebo-control group.
Although there is still a lot of work remaining, the entire team feels confident that the program, first and foremost, has the safety of RCDP children as a top priority. Everyone is committed to doing this the right way, by following the FDA's guidelines, and checking all the boxes along the way.
As for funding, MLD shareholders have approved several million dollars to manufacture the drug and complete all of the preclinical animal safety and toxicity studies required to file an Investigational New Drug (IND) Application to the FDA. Nevertheless, we will continue to seek both conventional and creative means of generating investment for the program. Please check back often to this site, and the MLD FaceBook page, for frequent updates.