MLD's newest manuscript describes the metabolism and tissue distribution of PPI-1011

MLD is excited to announce the publication of its latest manuscript “Pharmacokinetics, Mass Balance, Excretion, and Tissue Distribution of Plasmalogen Precursor PPI-1011” in a special plasmalogen-focused issue of Frontiers in Cell and Developmental Biology.

PPI-1011 is a novel synthetic plasmalogen precursor being developed by MLD as a treatment for diseases associated with a chronic plasmalogen deficiency including Alzheimer’s disease, Parkinson’s disease, and RCDP. While MLD has published extensively over the years on PPI-1011’s ability to augment plasmalogen levels both in vitro and in vivo, as well as induce both biochemical and behavioral changes, we have never been able to profile its pharmacokinetics, absorption, metabolism, distribution and excretion. In fact, to our knowledge, there are no previously published reports outlining these characteristics for any administered plasmalogen-based product.

In support of our overall preclinical development program for PPI-1011, we synthesized a radioactively labeled version of PPI-1011 and administered it to rats. We were able to demonstrate that following oral administration, over 50% of PPI-1011 was absorbed from the gastrointestinal tract, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air.

Using quantitative whole-body autoradiography, we observed widespread tissue distribution following a single oral dose of PPI-1011, with the greatest uptake in intestines, liver, and adipose tissue. Following repeated daily dosing for 15 days, uptake was significantly increased across the entire body, with levels remaining high out to 96 hours post dose, at which point 75% of the initially absorbed compound-associated radioactivity was still detected.

Perhaps most importantly, this study demonstrates definitively for the first time, that PPI-1011 crosses the blood-brain barrier, a requirement for any plasmalogen precursor designed to address the deficiency in brain levels seen in neurodegenerative diseases of aging, such as Alzheimer’s disease.

“Based on our previous work, we always strongly believed that PPI-1011 was capable of crossing the blood-brain barrier. Having the ability to now visually demonstrate not only uptake, but regional distribution within the brain, provides an incredible boost to the preclinical program for PPI-1011 and our entire pipeline of plasmalogen precursors” says Dr. Tara Smith, VP, Therapeutics at MLD and lead author on the paper.

Another interesting finding was that adipose tissue levels remained particularly high throughout the study, suggesting it may act as a reserve of either plasmalogens or alkyl diacylglycerols that the body can continually pull from for plasmalogen biosynthesis.

Overall, these results strongly support the viability of an orally administered ether precursor for the treatment of plasmalogen deficiency, given the high uptake across the body, and the accumulation observed with repeated dosing.

Dr. Shawn Ritchie, MLD’s CEO and Chief Scientific Officer remarked, “Understanding the uptake, metabolism, and tissue distribution of PPI-1011 was a critical piece of our preclinical development plan. We are pleased to finally be able to share this work publicly and believe it provides strong support for the potential clinical utility of PPI-1011 moving forward.”