The US Food and Drug Administration (FDA), just 29 days into the 2013 review calendar, has approved the year's first product intended to treat a rare disease known as homozygous familial hypercholesterolemia (HoHF).
Kynamro is the second product approved to treat HoHF in the last two months. In December 2012, FDA approved Juxtapid (lomitapide), which reduces LDL-C, total cholesterol, apolipoprotein B and non-HDL-C in HoHF patients.
HoHF is an inherited condition thought to affect one in every million people in the US. People affected with the condition are unable to remove low-density lipoprotein-cholesterol (LDL-C) from their bodies, resulting in subsequent adverse events like heart attacks and death, often at early ages.
The product, Kynamro (mipomersen sodium), is being marketed in a joint venture between Sanofi's Genzyme Corporation and Isis Pharmaceuticals. It had received a positive recommendation in October 2012 from FDA's Endocrinologic and Metabolic Drugs Advisory Committee (9-6), thoughthe same committee expressed concerns about the drug's side effects, including the potential for liver-related adverse events.
Liver toxicity signals had been noted in mice treated with Kynamro, though FDA's briefing document indicates that similar increased were not seen in rats, monkeys, or other species treated in preclinical testing. In Phase III clinical testing, at least one patient died from liver failure, and the group in general experienced an 18% increase relative to those suffered by the total population, and 32% relative to the HoFH population despite all patients being screened for pre-existing hepatic issues like Hepatitis C.
Those concerns clearly weighed on the mind of FDA's regulators. Though Kynamro was approved, it will be subject to a Risk Evaluation and Mitigation Strategies (REMS) plan with elements to assure safe use (ETASU), a Boxed Warning, and four postmarketing studies intended to help minimize its potential risks:
- the development of a sensitive assay that binds double-stranded (ds) DNA
- a study to assess the presence of antibodies to ds-DNA in patients treated with Kynamro
- a long-term registry of patients with HoFH to determine the long-term safety of Kynamro
- an enhanced pharmacovigilance program to monitor reports of malignancy, immune-mediated reactions and hepatic abnormalities in patients treated with Kynamro
The REMS plans will reportedly include certification for prescribers and dispensers of Kynamro and documentation of safe-use conditions requiring prescription authorization.
Genzyme has launched an additional REMS-like program it has dubbed the "Kynamro Cornerstone," which will include a dedicated case manager, disease education, in-person injection training, reimbursement support and coordinated shipment and delivery of the product.
For all the drug's safety issues, however, FDA noted that it was quite effective at treating HoHF. "On average," FDA wrote, "levels of LDL-C fell by about 25% during the first 26 weeks in those receiving the drug."
Genzyme, in a statement, also touted the drug's ability to avoid the majority of-or even all-drug-drug interactions (DDIs).
"Kynamro is an antisense drug and is metabolized without affecting the CYP450 pathways used in commonly prescribed drugs, and thus has potential for no drug-drug interactions," Genzyme wrote. "No clinically relevant pharmacokinetic interactions were reported between Kynamro and warfarin, or between Kynamro and simvastatin or ezetimibe."