Appeal type: Experimental/Investigational
Decision: Overturned

The patient is a male who was born full term with weight of 3 kilograms (kg). He was normal at birth and achieved milestones during the first few months of life. He never walked independently and began developing regression by 1 year with weight loss, weakness, vomiting and only eating pureed food. He was evaluated by a pediatric neurologist at 17 months of life and underwent an electroencephalogram (EEG) and magnetic resonance imaging (MRI) brain which showed a possible demyelinating process. Whole exome sequencing revealed homozygous NDUFV2 missense mutation diagnostic of Leigh Syndrome with a heterozygous LRPPRC mutation. The patient can cruise but not stand or walk. He has only 5 words. He eats a regular diet and sleeps through the night. His physical exam (PE) reveals mild dysmorphic features and developmental delay.
Leigh's disease is a rare inherited neurometabolic disorder that affects the central nervous system. In the U.S., it affects 1 in 40,000 newborns. There is no curative treatment at this time. Symptoms typically develop in the first year of life with progressive loss of mental and movement abilities. Death typically occurs within two to three years usually due to respiratory failure although some patients with partial deficiencies live to 6-7 years old. Some patients have survived into mid- teenage years.
Leigh's disease can occur from mutations in one of over 75 different genes. These mutations occur in mitochondrial deoxyribonucleic acid (DNA) and interfere with the energy sources and affect the brain and motor functions. Severe muscle and movement disorders result from these mutations. Many affected patients develop weakness or paralysis of the muscles that move the eyes. Some patients develop hypertrophic cardiomyopathy.
There is no curative treatment for Leigh's disease. The common treatment is thiamine or Vitamin B1. Oral sodium bicarbonate or sodium citrate may be taken to control lactic acidosis.
The request of the treating providers is to administer an oral mTOR inhibitor to this patient. What is at issue is approval for this prescription and whether there is sufficient evidence that it will be beneficial.

The health plan's determination is overturned.

Yes, the proposed health service/treatment of Afinitor (everolimus) is likely to be more beneficial than any standard treatment for the patient's threatening and disabling disease. There is no known alternative treatment for Leigh's disease other than supportive medications of thiamine (Vitamin B1). As this is a rare disease (1 in 40,000 newborns), it will be difficult to conduct a randomized clinical trial to demonstrate the benefit of mTOR inhibitors in Leigh's disease. As there are over 75 mutations in multiple genes that can cause mitochondrial disorders, it will take an extended time to determine which subtypes will respond to everolimus and other mTOR inhibitors.

There is one case report of two children with mitochondrial disorders being treated with mTOR inhibitor. The one patient with Leigh's syndrome showed clear benefit in neurological and muscular function within 6 months of taking everolimus. The second patient had a diagnosis of MELAS (Mitochondrial Encephalopathy, Lactic acidosis, and Stroke-Like episodes) and did not benefit from everolimus. It is apparent that some but not all patients with mitochondrial disorders may benefit from mTOR inhibitors. As there are over 75 possible genes involved in mitochondrial disorders, it is not surprising that not all patients may benefit. Clinical trials are needed to determine which subset of patients could benefit from everolimus or other mTOR inhibitors.

There is no curative treatment for Leigh's disease. There is no other treatment for Leigh's that provides benefit or has an impact on the natural course of this disease. mTOR inhibitors now are a class of medications for which there is strong scientific evidence of potential benefit. This is evidenced by a few case reports of benefits, by preclinical data in animal studies showing clear benefit, and by the development and initiation of a national clinical trial of nab-sirolimus.