On January 29, 2013, FDA approved a mipomersen sodium injection known as Kynamro, co-developed by Isis Pharmaceuticals and marketed by Genzyme (a unit of Sanofi) for the indication of homozygous familial hypercholesterolemia (HoFH). On May 12, 2014, FDA posted an updated risk evaluation and mitigation strategy (REMS) for Kynamro. A close examination of the background of the Kynamro approval and the REMS documentation indicates that the REMS update does not go far enough toward ensuring patient safety.
Kynamro is an antisense oligonucleotide inhibitor that prevents the synthesis of apolipoprotein B-100, which is a component of low-density lipoprotein cholesterol (LDL-C). Familial hypercholesterolemia is a condition in which a propensity to synthesize cholesterol stems from an inherited genetic mutation. HoFH can be diagnosed by laboratory testing that detects two inherited mutations, either one in each of two genes or two in one gene. Prior to the approval of Kynamro and its competitor, Juxtapid (sold by Aegerion), the leading treatment for HoFH was plasmapheresis to filter excess cholesterol from the blood.
In its REMS documentation, Sanofi states that patients being prescribed Kynamro must have "a clinical or laboratory diagnosis consistent with HoFH," which leaves open the possibility that patients will be placed on Kynamro therapy without laboratory testing to confirm the presence of the requisite two mutated alleles. As Dr. Paul Ziajka explains, "Clinical diagnosis of HoFH is typically based on the presence of a positive family history of hypercholesterolemia and / or premature heart disease in both parents." Dr. Ziajka goes on to state that "many patients who have a clinical diagnosis of FH may not have a detectable causal mutation [...] Thus, a negative result from a genetic test does not necessarily indicate the absence of HoFH." Opening the door for clinical indications for Kynamro prescription in the absence of -- or even contrary to -- laboratory genetic testing renders Genzyme's estimate of 315 American patients with HoFH questionable, and may increase the size of the addressable market for the drug.
REMS documentation for Kynamro also states that "the effect of Kynamro on cardiovascular morbidity and mortality has not been determined" -- in other words, the drug has not been shown to lengthen life or improve health. Additionally, the drug carries serious side effects, including "elevations in transaminases" (at least 300 percent of the upper limit of normal) noted in 12 of the 34 patients taking Kynamro in its clinical trial and a "mean absolute increase in hepatic [liver] fat of 10 percent after 26 weeks of treatment." Although the REMS documentation states that "the long-term consequences of hepatic steatosis [non-alcoholic fatty liver disease, or NAFLD] associated with Kynamro therapy are unknown," this fact is unsurprising, given that the clinical trial for Kynamro lasted only six months. However, the long-term consequences of NAFLD in the population have been amply demonstrated and include liver cancer, other severe liver pathologies, and metabolic syndrome, and may include cognitive impairment.
Neither the malignant neoplasms nor the deaths among Kynamro patients observed during clinical trials are mentioned in the REMS documentation. Additionally, although the REMS documentation says that measurement of transaminases (AST and ALT), alkaline phosphatase, and total bilirubin should take place before the initiation of Kynamro therapy, the data from these tests are not required for completion of the Kynamro prescription authorization form. Indeed, there is no space to input this data on the prescription authorization form, nor is there any mechanism in place to verify that such tests have taken place before dispensing the prescription.
Finally, the "certification program" for doctors who wish to precribe Kynamro consists of reading the prescribing information for the drug, viewing a PowerPoint presentation about the risks of the drug, and signing a form and submitting it to the manufacturer for the REMS program. The "Learning Check" included in the REMS documentation is designed to be self-administered and self-checked by physicians and includes the advice, "If you have problems answering any of these questions, please review information from the previous slides to ensure you are able to answer these questions correctly." With Sanofi planning to add more sales representatives to the Kynamro detailing brigade, stringent prescribing regulations and rigorous prescriber education may be more important than ever.