Before the FDA allows an experimental new drug to be administered to a human being, the drug must be proven to be safe. This involves manufacturing and formulating the drug under strict guidelines, followed by testing the drug in multiple species of animals at different doses and for extended periods of time.  

Preclinical studies are required to file what is called an Investigational New Drug application, or IND, with the FDA. The development team for PPI-1040, including scientists from Med-Life Discoveries, consultants from Cote Orphan (now IQVIA) and Impact Pharma, and Dr. Michael Bober, visited the FDA in January 2018 for a pre-IND meeting to discuss several aspects of clinical trial development plan. The meeting confirmed that PPI-1040 must undergo the same preclinical safety testing as any other drug before the FDA will accept the IND and allow the drug to be tested in humans. This means testing the compound in two species of animals with daily administration for up to a month, followed by a thorough assessment of all the tissues and organs in the animals to confirm that there were no adverse effects of treatment. While these studies take time and are costly, they are an essential component of the preclinical development of a drug to ensure that there are no surprises when it comes to the safety of the molecule. Preclinical safety studies also require the manufacturing of a large amount of drug. In fact, it will take nearly 5 kg of PPI-1040 just to complete the preclinical safety and a first in human Phase I clinical trial!



Before PPI-1040 is administered to participants with RCDP, it will be tested in a healthy adult human Phase I clinical trial. This is a short study of approximately one to two weeks, testing increasing doses of the drug to determine if there are any adverse effects of the compound in a human subject. In addition, it allows for the determination of preliminary pharmacokinetic and dosing measurements. The end goal of a Phase I study is to understand what dose of PPI-1040 is well tolerated in humans, and what potential adverse effects should be monitored closely in the next phases of clinical testing.  

In addition to completing the Phase I study, the FDA requires that PPI-1040 be tested in two species of animals for at least the same duration as the trial planned in RCDP children (6 months). This allows the FDA to assess if there are any safety concerns associated with long term exposure to the drug. One of these animal species must also be of juvenile age to assess if the drug affects the development of any tissue or organ. As with the shorter preclinical safety studies, these require a large amount of drug to be manufactured.     


Pivotal trial in RCDP Patients

The phase of the program where RCDP patients will be put on PPI-1040 treatment to evaluate efficacy is called the “Pivotal Trial”. Unlike conventional clinical development paths that require multiple treatment trials moving from Phase I through IV, only a single pivotal trial is anticipated for RCDP. This is not uncommon for ultra-rare diseases, and was suggested by the FDA at the PreIND meeting.

While there will be a single trial, it is likely that there will be phases within this trial. The first few patients in the trial are anticipated to undergo a dose escalation phase, where they will start at a low dose that is significantly less than the highest dose that was shown to be safe in the animal and Phase 1 studies. The dose will then be increased slowly over days or weeks to determine the highest safe dose in RCDP patients. These patients will then remain on the treatment at this dose for the remainder of the trial. Subsequently enrolled patients are expected to begin treatment at the dose determined in this first phase. Since PPI-1040 is practically a naturally occurring plasmalogen, and RCDP patients have a massive plasmalogen deficit, the goal with treatment will be to obtain the highest effective and safest efficacious doses possible. Biochemically, the objective will be to therapeutically augment circulating blood plasmalogen levels equal to, or excess of, that of a non-RCDP child.

Although the design of the pivotal trial will continue to evolve as the other portions of the program are finalized, it is currently set to run for six months. That is, each participant would be on PPI-1040 treatment every day for six months. Not all participants would begin at the same time, so it could take a year or more by the time all the participants enter and complete the study. The number of eligible participants has also not been finalized, but is estimated to currently be between 15 to 20. Ultimately, who is eligible will depend upon the inclusion criteria and results of data collected during the Natural History Study, in close consultation with the primary physicians involved in the study.

Ultimately, the pivotal trial is nothing more than an extension of the the Natural History Study, but with the addition of PPI-1040 treatment. However, the protocol will likely to be adjusted to ensure that all included assessments are relevant and appropriate for determining efficacy of treatment. These adjustments may included having more stringent requirements around inclusion and exclusion criteria, types of assessments carried forward from the Natural History Study, and number of subjects enrolled. The information gathered in the Natural History Study will be used to define these requirements. In addition, the assessments performed in the Natural History Study will be critically evaluated to determine if they provide reliable measurements of RCDP clinical parameters that they were designed to capture. Only assessments that are robust enough to assess the effectiveness of the treatment will be included in the pivotal trial. All of these details will be discussed with the FDA as the program moves forward to confirm that the trial design and assessments are acceptable from a regulatory perspective.

As the program moves forward and more details of the clinical trial become available, this section will be updated.