PPI-1040 is a synthetically-made, orally bioavailable plasmalogen precursor containing an intact vinyl-ether bond. Unlike other precursors that only contain an ether bond (such as PPI-1011 and batyl alcohol), and require metabolic conversion to the vinyl-ether by functional enzymatic pathways in the endoplasmic reticulum (a specific part of a cell), PPI-1040 does NOT require any metabolic conversion because it already contains the vinyl-ether bond. This is thought to be particularly relevant for RCDP patients.   

3D Rendering of PPI-1040

3D Rendering of PPI-1040

PPI-1040 closely mimics the endogenous plasmalogen-containing palmitic alcohol, glycerol, and DHA. However, where PPI-1040 differs from endogenous plasmalogens is that it contains a proprietary cyclic phosphoethanolamine at the third carbon of the glycerol backbone. The cyclic structure helps to stabilize the critical vinyl-ether during storage in a lipid medium. Upon oral administration and exposure to the acidic and aqueous environment of the stomach, the cyclic phosphoethanolamine opens, becoming equivalent to the naturally occurring form. It is thought that providing the vinyl-ether bond directly will decrease the dose required (compared to an ether precursor), making plasmalogen augmentation in RCDP potentially feasible.  

In both RCDP animal models and wild-type animals using a PPI-1040 tracer, the vinyl-ether bond and phosphoethanolamine were shown to remain intact during absorption and metabolism. 



Plasmalogens come in many varieties, as defined by the fatty acids/alcohols attached to the first two positions of the backbone. While PPI-1040 directly converts to a single plasmalogen species, we know that this is only one of multiple plasmalogen configurations that are synthesized endogenously in the body. Animal studies have shown that in addition to increasing the target plasmalogen, the body is able to metabolize the plasmalogen backbone into multiple different species resulting in an increase in a large percentage of the total plasmalogen pool. 


Why not a natural product?

Unfortunately, the answer is simple. There just isn't a known natural source of plasmalogens with a high enough concentration or composition to be efficacious. Although there is a natural plasmalogen extract on the market called NeuroREGAIN out of Japan, according to the packaging, each capsule contains only 0.5 mg of plasmalogen enriched extract. At this time, we believe the lowest reasonable daily dose of PPI-1040 in clinical trials will be approximately 100 mg/kg. In an RCDP patient of 7 kg (approximately 15 lbs), this translates into an average dose of 700 mg per day. In order to obtain that level of plasmalogen using a product like NeuroREGAIN, a child would need to take 1400 capsules per day!!! Obviously this is not feasible. 


why develop therapies for ultra-rare diseases? 

In addition to the obvious motivation of helping a group of children with a devastating disease, advancing a therapeutic in a rare disease has several advantages. The US government introduced the Orphan Drug Act in 1983, which is an incentive program to encourage industry to develop treatments for rare diseases, particularly those in children. This can include priority review of materials submitted to the FDA, additional interaction with the Agency throughout development of the drug, and financial incentives. While trial planning and execution can be more challenging in rare diseases, the trials are smaller simply based on the small population size. In addition, different phases of the clinical trial pathway are often combined in order to make the best use of the patient population.  

The development of PPI-1040 for RCDP stemmed out of other work evaluating the potential of augmenting plasmalogen levels as a treatment for neurodegenerative diseases including Alzheimer's and Parkinson's disease. To advance these programs, an animal model with a plasmalogen deficiency was critical, leading to the discovery and use of the Pex7 mouse model developed by Dr. Nancy Braverman. PPI-1040 was subsequently designed and tested specifically to address the severe plasmalogen deficiency in RCDP.  

RCDP belongs to a larger family of disorders known as Peroxisomal Biogenesis Disorders, which includes Zellweger Spectrum Disorder. The common tie between these disorders is compromised or absent peroxisomal function. As peroxisomal function is required for plasmalogen synthesis, individuals with other peroxisomal disorders commonly have deficient plasmalogen levels. However, while plasmalogen deficiency is central to RCDP, it is only one of a number of metabolic deficits in Zellweger Spectrum Disorders. RCDP patients have the highest potential to benefit from plasmalogen replacement therapy, but there is a possibility that this therapeutic approach could be beneficial in Zellweger patients as well. Thus, there is a potential opportunity to expand the treatment into other indications. 

Improvement in clinical outcomes by plasmalogen augmentation is also an untested hypothesis. Demonstrating that therapeutic plasmalogen replacement in RCDP is safe and efficacious will help further support a plasmalogen approach for larger indications such as Alzheimer's and Parkinson's. Ultimately, all of the safety, pharmacology, and therapeutic effectiveness learned in the RCDP trial with PPI-1040 will be beneficial for the clinical development of second-generation plasmalogen therapeutics for RCDP as well as other indications. 



The oral bioavailability of PPI-1040 and its ability to augment plasmalogen levels using various animal model systems was demonstrated in 2017. 

In one key study, a labeled version of PPI-1040 was used to show that the vinyl-ether bond stayed intact during digestion and absorption following oral administration, and augmented multiple endogenous plasmalogens in a time-dependent manner. 

A second study, performed in Dr. Nancy Braverman's lab, evaluated the ability of PPI-1040 to augment plasmalogen levels in a mouse model of RCDP1. After 4 weeks of dosing, animals that received PPI-1040 had a significant increase in plasmalogen levels in the plasma, red blood cells, liver, skeletal muscle and intestine. However, increases were not yet detectable in the kidney, lungs or brain in this study. It is expected that with a higher and longer dose, augmentation in other peripheral tissues and the brain will occur. 

In addition to increased plasmalogen levels, PPI-1040 treated animals displayed a normalization of the hyperactive phenotype characteristic of RCDP1 animals. This data shows that increasing plasmalogen levels can produce functional and behavioral changes in vivo, and is therefore highly relevant for the treatment of RCDP. 

It is important to also point out that PPI-1040 significantly outperformed ether-containing precursors in these studies, both in its ability to raise plasmalogen levels and its ability to improve behaviour. Due to its oral suitability and superiority over ether-containing precursors, PPI-1040 was selected as the lead clinical compound for the treatment of RCDP. A publication of the results of these studies is in progress.


Manufacturing and Formulation

One of the most critical parts of any drug development program is manufacturing and formulating the drug. This part of the program is often referred to as CMC, or chemistry, manufacturing and controls. It represents all of the work necessary to take the chemical synthesis of a drug from a small research and development scale, all the way up to commercial scale under strict manufacturing guidelines.

PPI-1040 is currently undergoing synthesis according to GMP (Good Manufacturing Practice) guidelines. The scale-up to synthesize 5kg batches of PPI-1040 is under way, and the first small batch of material was sent to a formulation company to test various excipients for optimal stability and shelf-life. The results of this first formulation assessment were great and we were able to overcome the requirement to store the drug at -80C and instead the formulated drug appears to be stable under standard refrigeration conditions.