Why a drug??

This is probably the most common question we get asked when we talk about our approach to the treatment of RCDP. The natural inclination when someone hears that RCDP is caused by a deficiency of a naturally occurring lipid is “why can’t you just use diet or a supplement as a therapy?” It is a great question and the answer is really very straightforward, the dose required dictates that whatever is given should be treated as a drug. This is true regardless of whether the plasmalogen treatment is purified from a natural source or made synthetically in a lab. The clinical manifestations of RCDP are caused by severe reductions in plasmalogen levels and therefore any therapy designed to increase those levels would need to be administered at large doses for the entire life of the individual. These are NOT doses that can be found in the diet and therefore to the FDA they are either classified as “new dietary ingredients” or “new molecular entities.” Which group they fall into depends on whether the exact molecular structure is found in the food chain. Either way, the safety of the treatment is unknown and needs to be demonstrated before administration to humans.

MLD has chosen to move ahead with a synthetic plasmalogen supplement, based on years of preclinical research, but we are certainly aware of an ever-increasing number of supplements available on the market. I am sure many in the RCDP community have thought at some point, “what harm could come from trying a supplement anyways?" While we are in no position to provide personalized medical advice, we do think it is important that everyone understands there are things to consider before adding a plasmalogen supplement, or any supplement, into your diet. The fact that supplements are naturally occurring molecules makes it seem to many people that they are without risks and are by default safe. While this may be the case for many supplements on the market, it is important to understand how supplements are controlled and regulated in order to determine if they are right for you and your family. 

While the FDA is mandated with overseeing both drugs and supplements, how it performs this oversight is very different for the two categories. All new drugs need to undergo a rigorous process to demonstrate they are safe and effective before being approved. This is a lengthy and expensive process which takes years or decades and millions of dollars. The safety profile of drugs must first be thoroughly investigated in animals and healthy adult volunteers before it can even be tested in a patient. The FDA then performs a detailed review of all safety and efficacy data to determine the risk-benefit profile before they determine if they will grant marketing authorization. Even after the FDA grants approval, safety is evaluated in post-market assessments. In addition, the manufacturing of the drug is closely monitored by the FDA to ensure compliance with Good Manufacturing Practices (GMP).

The FDA’s oversight of supplements is different and is a post-market process, meaning that is it almost completely reactionary, as opposed to proactive. Their mandate is to focus on evaluating safety concerns of “Dietary ingredients”, the term used by the FDA to refer to the components of supplements. When these ingredients have a long-standing history on the market they are anticipated to be safe and therefore the only requirement of the FDA is that they are manufactured under GMP. Due to the resources of the FDA and the sheer number of facilities, supplement manufacturers are generally left to self-regulate their GMP status and are only audited when there is a suspected or reported issue. New supplements, including ingredients that have not been used in a supplement before or only used at a lower dose previously, are expected to submit to the FDA a notification that provides data illustrating that the ingredient is reasonably expected to be safe. That may sound easy to do, and if the supplement is providing a dose that can be achieved in the diet, then it may be. However, if it is a highly concentrated ingredient that is being given in doses higher than can be found in the diet, then safety should be supported by comprehensive animal studies, much like those required by new drugs. Unfortunately, it is known that many manufacturers and suppliers do not complete the necessary safety studies or the premarket notification process with the FDA. The FDA can certainly penalize companies for this and demand that production is halted, however this generally only occurs after safety concerns have been reported to the Agency. The truth is that there are just too many supplements on the market for the FDA to thoroughly monitor them all. For the consumer what this means is that there is no guarantee that the appropriate safety studies have been performed on the ingredients or final formulation of the supplement.

So, the first part of the answer to the question “why a drug?” is that the process of demonstrating safety of a high dose plasmalogen supplement should be the same regardless of the source. The second part is that the FDA considers “any articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” are by definition a drug. This means that if a plasmalogen supplement is going to be sold as a treatment for RCDP, it has to be a drug. A supplement cannot make any claims about its ability to affect the structure or function of the body. Therefore, regardless of the source of the material, a plasmalogen replenishment strategy as a treatment for RCDP would be required to undergo the standard clinical trial process and FDA approval pathway before it could be marketed for that purpose.  

Given that the route to prove safety and efficacy is the same regardless of whether we moved forward the naturally occurring structure, a synthetic modified version of a natural product, it only made sense to move forward with the structure that provided the best synthetic and storage properties. The structure of our plasmalogen drugs are a slight modification on the natural occurring plasmalogen structure, which is necessary to increase the stability of the compound. This small modification dictated that a traditional drug approach was required, but truthfully we would have undertaken the same path even if it was the naturally occurring structure.

MLD is not the only company that is moving high-dose supplement-like molecules through the traditional drug development process. For example, Medday Pharma is advancing MD1003, a high-dose pharmaceutical grade biotin supplement, as a treatment for some forms of Multiple Sclerosis. 

It is up to each family to decide if using a supplement is right for them, but MLD does ask that, should you choose to take a plasmalogen supplement and you are a part of the Natural History Study, you report this to the clinical staff. It is possible that this type of supplementation, like any supplement, can have an impact on the interpretation of the clinical data, potentially compromising the results of the study. It should also be noted that in any future interventional therapeutic trial, taking a plasmalogen supplement will be an exclusion criterion, meaning anyone on a supplement will not be eligible for the trial. This is required as taking both a supplement and another plasmalogen drug product could increase the risk profile of the treatment in a way that we can’t anticipate.  It simply isn’t possible to control for the possible interference that a supplement could cause in the trial and therefore these supplements must be excluded.