Landmark Plasmalogen Precursor Paper Published
MLD is thrilled to announce its publication showing, for the first time, the behavioral effect of an oral vinyl-ether plasmalogen precursor in an animal model of Rhizomelic Chondrodysplasia Punctata (RCDP) in the journal Disease Models and Mechanisms. The paper presents critical results showing that vinyl-ether plasmalogen precursor PPI-1040 is orally bioavailable and that the vinyl-ether bond remains fully intact during absorption and digestion, after which it effectively augments numerous target endogenous plasmalogens. This was demonstrated using carbon-13 labelled PPI-1040 in healthy animals, as well as unlabelled PPI-1040 in severely plasmalogen-deficient mice.
In the plasmalogen-deficient animals, PPI-1040 was orally administered 20 daily doses at 50 mg/kg over a 28-day period. No overt toxicity was observed. Circulating plasmalogen levels were normalized, and uptake into select peripheral tissues, including liver, small intestine and skeletal muscle was beginning to occur. Of major relevance to the field, the same dose with an ether-based precursor was not nearly as effective as PPI-1040 in augmenting plasmalogen levels.
Severely plasmalogen-deficient mice do not exhibit most of the severe symptoms of RCDP, but rather hyperactivity as assessed by increased time and distance travelled within an open space. PPI-1040 treatment completely normalized this behavior, while an equivalent dose of an ether-based precursor had no effect. The findings support a hypothesis that in at least some situations where plasmalogen deficiency is severe, that augmentation with a vinyl-ether might be more effective. This could be explained by the fact that enzymes and mechanisms present in the endoplasmic reticulum, which are required for converting ether-based precursors to endogenous vinyl-ether plasmalogens, are compromised in states of severe plasmalogen deficiency. Futher studies will be need to be performed to tease apart these effects.
These findings prove that not all plasmalogen precursors are created equal. In situations such as RCDP, where plasmalogen deficiency is severe, it appears that vinyl-ethers could be the best option since it is not known whether all patients will be able to metabolically convert the ether to a vinyl-ether plasmalogen. Although ether-based precursors, including MLD’s lead ether-based compound PPI-1011, have shown to increase plasmalogen levels in various systems and and functionally prevent L-DOPA induced dyskinesias in a primate model of Parkinson’s disease, these are generally otherwise healthy animals. The ability to stably formulate an orally bioavailable and highly concentrated vinyl-ether plasmalogen precursor sets PPI-1040 apart from ether-based precursors that require endogenous metabolism, such as batyl and chimyl alcohol, alkyl acyl glycerols, and alkyl diacyl glycerols.
“These results are revolutionary for the field,” says MLD’s CEO and Chief Scientific Officer Dr. Shawn Ritchie, “Although MLD believes that ether-based precursors could have utility in diseases of aging such as Alzheimer’s and Parkinson’s, the fact that a vinyl-ether precursor showed superior pharmacokinetic and pharmacodynamic functional effects in a highly deficient RCDP animal model brings into question whether vinyl-ethers might be more suitable for other plasmalogen-deficiency related disorders, regardless of the level of plasmalogen reduction. We will be addressing these questions in future studies.”
Dr. Tara Smith, VP of Therapeutics at MLD and co-first author of the paper, is excited about the ongoing work happening at MLD to further investigate plasmalogen precursor activity. “First we’d like to thank Dr. Nancy Braverman and Wedad Fallatah for all of their work performing the studies and working with us on this program. The fact that PPI-1040 showed an improvement over the ether precursor gives us confidence that we have selected the best possible candidate for clinical development in RCDP. However, this is also a finding that warrants further investigation. As part of our ongoing plasmalogen basic research initiative, we are now investing in the creation of new plasmalogen deficient model systems that will be used to test multiple classes of precursors.”
About PPI-1040:
PPI-1040 is a synthetically produced preclinical compound currently undergoing mandatory FDA IND-enabling safety toxicity studies for the treatment of RCDP.
About MLD:
MLD is a biopharma company in Saskatoon, SK, Canada leading the clinical development of several novel plasmalogen precursors for conditions associated with plasmalogen deficiency including RCDP, Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis and other Peroxisomal Biogenesis Disorders.