UMDF | Mitochondrial Disease Education & Research



Sannie, With this, I am sending materials relevant to the legislation in Massachusetts mandating coverage of so-called mitochondrial (“mito”) cocktails, along with an article written by several physicians, including Dr. Parikh, who is Katherine’s neurologist at the Cleveland Clinic and who is considered one of the foremost experts on these conditions.I wanted to add a few of my own thoughts, which include a gap in this Massachusetts law.MITO DISEASE AND MITO COCKTAILSThe materials do a better job of discussing the diseases and cocktails than I can do, but here is my lay primer. Mitochondrial dysfunction occurs in everyone as they age, and is present in all chronic disease patients, regardless of the underlying cause of the disease. However, people with “primary mitochondrial disease” are not suffering from secondary damage to their mitochondria from a different disease, but have a genetic condition that directly effects how their mitochondria go about producing cellular energy (ATP), and producing or eliminating harmful reactive oxygen species (“ROS”). ROS are toxic and will lead to premature cell death unless they are eliminated. According to the United Mitochondrial Disease Foundation’s webstie () (emphasis added):Mitochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body except red blood cells. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is becoming more and more common.Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection Energy Factories and Much MoreThe conventional teaching in biology and medicine is that mitochondria function only as "energy factories" for the cell.?This over-simplification is a mistake which has slowed our progress toward understanding the biology underlying mitochondrial disease.?It takes about 3000 genes to make a mitochondrion.? Mitochondrial DNA encodes just 37 of these genes; the remaining genes are encoded in the cell nucleus and the resultant proteins are transported to the mitochondria.? Only about 3% of the genes necessary to make a mitochondrion (100 of the 3000) are allocated for making ATP. More than 95% (2900 of 3000) are involved with other functions tied to the specialized duties of the differentiated cell in which it resides.? These duties change as we develop from embryo to adult, and our tissues grow, mature, and adapt to the postnatal environment.? These other, non-ATP-related functions are intimately involved with most of the major metabolic pathways used by a cell to build, break down, and recycle its molecular building blocks.? Cells cannot even make the RNA and DNA they need to grow and function without mitochondria.? The building blocks of RNA and DNA are purines and pyrimidines.? Mitochondria contain the rate-limiting enzymes for pyrimidine biosynthesis (dihydroorotate dehydrogenase) and heme synthesis (d-amino levulinic acid synthetase) required to make hemoglobin.? In the liver, mitochondria are specialized to detoxify ammonia in the urea cycle.? Mitochondria are also required for cholesterol metabolism, for estrogen and testosterone synthesis, for neurotransmitter metabolism, and for free radical production and detoxification.? They do all this in addition to breaking down (oxidizing) the fat, protein, and carbohydrates we eat and drink.These diseases can be devastating and disproportionately affect children (unfortunately, this is because mitochondrial disease is often fatal). Often mito disease is a multi-system disease, and affects those parts of the body that need the most energy to function, such as the brain, heart, liver, and kidneys. Patients with mito disease may not produce enough energy for one or more of those systems to function or to heal from injury, or may produce too many ROS, leading to premature cell death in those systems. At times, these patients may function well for periods of time, but become compromised when the body has expanded energy needs, such as when injured or ill. Several known mito diseases are fatal in childhood. Mito cocktails are combinations of between 2 and 20 supplements that have been shown to effect the function and long-term health and viability of the body’s mitochondria. They differ in action and result, but they either help your mitochondria to produce energy in the form of ATP, or they remove ROS from your system. The effectiveness of these supplements differs from individual patient to individual patients, and the benefits are often difficult to quantify, as they help maintain the status quo over time by preventing damage from ROS or allowing production of ATP in times of need.The attached materials go into some detail about these issues.THE LAWThe first thing I wanted to say on the law is that Kentucky law arguably already mandates coverage for mito cocktails. At most, legislation would clarify or only slightly expand existing Kentucky law. Kentucky Revised Statute § 304.17A-258, specifically requires health plans to cover “therapeutic food, formulas, and supplements” for the “treatment of inborn errors of metabolism and genetic conditions” when obtained under the direction of a physician. Primary mitochondrial diseases are, by almost all medical definitions, “inborn errors of metabolism” and are primarily (if not exclusively) “genetic conditions.” Indeed, the mitochondria are the essential last stages of metabolism in the production of 90% of the body’s energy needs.While not directly applicable, a provision of the State Medicaid Program, KRS § 205.560, provides:For purposes of this paragraph, drugs shall include products for the treatment of inborn errors of metabolism or genetic conditions, consisting of therapeutic food, formulas, supplements, or low-protein modified food products that are medically indicated for therapeutic treatment and are administered under the direction of a physician, and include but are not limited to the following conditions:1. Phenylketonuria;2. Hyperphenylalaninemia;3. Tyrosinemia (types I, II, and III);4. Maple syrup urine disease;5. A-ketoacid dehydrogenase deficiency;6. Isovaleryl-CoA dehydrogenase deficiency;7. 3-methylcrotonyl-CoA carboxylase deficiency;8. 3-methylglutaconyl-CoA hydratase deficiency;9. 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency);10. B-ketothiolase deficiency;11. Homocystinuria;12. Glutaric aciduria (types I and II);13. Lysinuric protein intolerance;14. Non-ketotic hyperglycinemia;15. Propionic acidemia;16. Gyrate atrophy;17. Hyperornithinemia/hyperammonemia/homocitrullinuria syndrome;18. Carbamoyl phosphate synthetase deficiency;19. Ornithine carbamoyl transferase deficiency;20. Citrullinemia;21. Arginosuccinic aciduria;22. Methylmalonic acidemia; and23. Argininemia;This list is specifically stated to be not exclusive, but unfortunately mitochondrial disease is not listed among the named inborn errors of metabolism. This leaves open an argument by insurance companies that mito disease is not an inborn error of metabolism. In our case, our insurance policy contained coverage written virtually word for word from KRS § 304.17A-258. Anthem denied coverage of Katherine’s mito cocktail without so much as a reference to this provision. It analyzed the claim solely under a coverage provision stating that supplements and foods are only covered while the patient was at an in-patient facility. Apparently, it was just assumed that mito disease does not fall within the coverage for supplements to treat inborn errors of metabolism.While we are in a position to appeal this aspect of the denial, many mito patients are not in our position. In any event, we should not have to argue this issue, or rely on our appeal being heard by a non-medical person who may not understand the issue or who might determine that mito disease is not an inborn error of metabolism because it is not listed. Therefore, Kentucky law should be clarified to specifically state that these mito cocktails are covered, much like the attached Massachusetts law provides.THE NEED FOR COMPOUNDINGAn issue not contemplated by the Massachusetts law, is that most mito cocktails are prepared and combined by compounding pharmacies for several reasons, some of which are discussed below. In recent years, many insurance policies have started to contain “compound medication” exclusions. The bases for these exclusions in general is fairly debatable and not necessary to the issues presented. Unfortunately, their application to mito cocktails causes any coverage otherwise mandated by KRS § 304.17A-258 to be avoided – and KRS § 304.17A-258 rendered a virtual nullity – for the simple reason that most mito cocktails are compounded by necessity and efficacy. In our case, Anthem did not rely solely on the wrong coverage provision, but coverage was also denied because Katherine’s mito cocktail is compounded. That is a more difficult issue and one that needs to be addressed by this law (not just for mito patients but for any other listed or unlisted patient with an inborn error of metabolism with a need for supplements).Most of the ingredients that go into a mito cocktail are available either over the counter or by prescription. Physicians do not recommend buying the supplements over the counter except as a last resort – a last resort they are simply forced into by the insurance issues.Over the counter supplements of this sort, “nutraceuticals,” are not regulated. Recent scandals in this industry (not specifically related to mito cocktails) have shown that nutraceuticals often contain little, if any, of the advertised supplements. There is little reason to be assured, therefore, that a 100 mg bottle of CoQ10 (ubiquinol) actually contains that amount. Similarly, many nutraceuticals contain fillers, preservatives, flavorings and other additives. The health effects of these additives are not known.It is unreasonable to suggest that a physician treat his or her patients with a substance that may or may not contain the active ingredient and, if it contains it, it not reliable in amount or potency for dosage purposes, and that may contain any number of harmful additives (particularly since these supplements are taken several times per day for the patient’s lifetime). When similar supplements are ordered through a compounding pharmacy, these concerns are eliminated. While the supplements, themselves, are still not regulated as drugs by the FDA, the laboratories where a pharmacy obtains them are regulated. The powder forms of these supplements obtained by compounding pharmacies are assured of having known potencies and lack dangerous fillers. Therefore, by having a patient obtain the medication through a compounding pharmacy, the physician can know what and how much his/her patient is receiving and dosages can be adjusted as necessary.The compounding services are often necessary since a given mito cocktail can have anywhere between 2 and 20 different medications of differing dosages. The sanitary conditions and training of compounding pharmacists allow a mixture of the powdered medications to be combined in the exact dosage amounts and in sterile conditions, leaving just one liquid form of mito cocktail (thus the name “cocktail”) for the patient to take at regular intervals. The alternative is for a patient to accurately mix each of the up to 20 ingredients several times per day (or taking each separately), risking error and contamination.While some of the supplements are available in pill form, this is not a substitute for the mixed powders for several reasons. First among these is that many mito patients are children (as mentioned above). It is not realistic for a small child to swallow up to 20 pills each dose, several times per day. Even if given in powdered form, but not compounded by the expert pharmacist, it is unreasonable to expect a child to take 20 liquid medications each time, several times per day.Second, but related to the first, as is mentioned in the UMDF information highlighted above, mito diseases commonly cause motor problems, low muscle tone and difficulty in swallowing. Many have to have g-tubes installed. Asking a patient to swallow all of these pills or numerous separate doses of liquid medications several times per day, is often impossible and simply not realistic. Taking one small dose of compounded medications is a far better alternative. Third, there are not standardized doses for these supplements and each individual reacts to these supplements in different ways. The amount a given patient will take of any of these ingredients will be adjusted and re-adjusted throughout his or her life according to changes in age, weight, and health, and based on his or her reactions, good or bad, to any particular ingredient. For example, one year into Katherine’s mito cocktail regime, she has already had one ingredient added, and one ingredient adjusted as to dose. Creating the correct cocktail is not so simple as saying “take the standard 10 mg Lipitor pill and if that does not work, we’ll up it to 20 mgs next year.” There is no standardized dose, there is no standardized “pill,” and the dosages are adjusted and readjusted all of the time. Powdered forms of the medication compounded at the pharmacy suit this regime, not pills, and certainly not unregulated nutraceuticals.With all of these considerations, the ability of an insurance company to avoid mandatory coverage of a mito cocktail (arguably already Kentucky law), through a general compounded medication exclusion, will cause exclusion and non-coverage to be the rule (and the law a nullity) – or will greatly affect the ability of physicians to safely and effectively provide this treatment.COSTS AND COVERAGEThe costs of mito cocktails can be high. Right now, Katherine’s mito cocktail costs $250 per month. We are fortunate because she is only taking 4 of the 20 supplements and her small size makes the dosages relatively small. Other patients pay much more. The Massachusetts materials cover this issue.Because mito disease is relatively uncommon, the cost to cover patients under Insurance is small (pennies per policy). This also is covered in the Massachusetts materials. These cocktails are often the only treatment available to a mito patient and have proven beneficial in many cases. We have seen the benefit in Katherine. Not long after beginning the cocktail, her muscle tone started to improve and her shakiness got better. While not quantifiable or easily observable, even in those cases without a noticeable benefit, there are good reasons to believe that the cocktails are extending lives and warding off side-effects in the long run. Mito patients are in desperate need of help.CHANGES IN THE LAWArguably, coverage is already mandatory in Kentucky, but the insurance companies are just not complying. While this is a national statistic, at a mitochondrial disease conference report we attended last year, we were told that less than 10% of mito patients receive any insurance coverage for their medications.The Massachusett statute could fit within Kentucky’s existing statutes. For example, KRS § 304.17A-258 could be amended as follows (bold is new):KRS § 304.17A-258Coverage under health benefit plan for therapeutic food, formulas, supplements, and low-protein modified food products.(1) For purposes of this section:(a) "Therapeutic food, formulas, and supplements" means products intended for the dietary treatment of inborn errors of metabolism or genetic conditions, including, but not limited to, the treatment of mitochondrial disease, under the direction of a physician; and(b) "Low-protein modified food" means a product formulated to have less than one (1) gram of protein per serving and intended for the dietary treatment of inborn errors of metabolism or genetic conditions under the direction of a physician.(c) “Supplements for the treatment of mitochondrial disease” shall include, but not be limited to, the use of vitamin and nutritional supplements, such as CoEnzyme Q10, Vitamin E, Vitamin, Vitamin B1, Vitamin B2, Vitamin K1 and L-Carnitine. Coverage under this statute shall not be denied because two or more of these vitamins or nutritional supplements are compounded.(2) A health benefit plan that provides prescription drug coverage shall include in that coverage therapeutic food, formulas, supplements, and low-protein modified food products for the treatment of inborn errors of metabolism or genetic conditions, including those that are compounded, if the therapeutic food, formulas, supplements, and low-protein modified food products are obtained for the therapeutic treatment of inborn errors of metabolism or genetic conditions, including, but not limited to, the treatment of mitochondrial disease, under the direction of a physician. Coverage under this subsection may be subject, for each plan year, to a cap of twenty-five thousand dollars ($25,000) for therapeutic food, formulas, and supplements and a separate cap for each plan year of four thousand dollars ($4,000) on low-protein modified foods. Each cap shall be subject to annual inflation adjustments based on the consumer price index.(3) The requirements of this section shall apply to all health benefit plans issued or renewed on and after July 15, 2016.(4) Nothing in this section or KRS 205.560, 213.141, or 214.155 shall be construed to require a health benefit plan to provide coverage for therapeutic foods, formulas, supplements, or low-protein modified food for the treatment of lactose intolerance, protein intolerance, food allergy, food sensitivity, or any other condition or disease that is not an inborn error of metabolism or genetic condition. Subsection (1)(c), above, is taken from the Massachusetts law, with the compounding language added. It may not be necessary since the other modifications already specify that mito disease is covered and compounding exclusions will not apply.Thanks you for considering these issues. I hope we see you sometime soon.Dave Faughn ................
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