Novo-Nordisk issued a press release February 10. 2013 stating "the FDA requests additional cardiovascular data from a dedicated cardiovascular outcomes trial before the review of the New Drug Applications can be completed. Novo Nordisk is evaluating the content of the Complete Response Letter and will work closely with the FDA to provide the requested data. Novo Nordisk does not expect to be able to provide the requested data during 2013. In the letter, the FDA also states that approvals for Tresiba® and Ryzodeg® cannot be granted until the violations cited in the previously announced Warning Letter, dated 12 December 2012, have been resolved. "We are convinced that Tresiba® and Ryzodeg® offer significant benefits for people who require insulin", said Lars Rebien SÃ¸rensen, chief executive officer of Novo Nordisk. "We are surprised and disappointed to receive this letter, but we acknowledge this decision by the FDA and will work with the agency to determine the best path forward to completing the review."
If you are like me, the names for two new insulin products, Tresiba® and Ryzodeg®, are new to you, and don’t make any sense, unlike some previous insulin names that ended in "…log" (Humalog, Novolog) or "…lin" (Humulin, Novolin). But the marketers don’t seem to care that they have invented bizarre names for new insulins that don’t make any sense to physicians or patients (Apidra, Lantus, Levemir, and now Tresiba and Ryzodeg). For your information, Tresiba is the intended global brand name for a new long-acting insulin, degludec, and Ryzodeg is the intended global brand name for a combination of degludec plus a rapid-acting insulin, aspart (brand names Novolog and NovoRapid).
Nor do the marketers seem to care that Tresiba and Ryzodeg have a cardiovascular signal: FDA reviewers of Novo Nordisk’s New Drug Application have indicated that there is a "Consistent trend of CV [cardiovascular] risk increase associated with" use of these drugs in the clinical trial data that was submitted to the FDA by the manufacturer, Novo Nordisk. The FDA also said it in different words: "A CV safety signal of increased risk of MACE* has been detected in the degludec development programs. The signal appears to be credible and consistently points to the potential for harm with degludec over comparators."
*MACE (major adverse CV events) included unstable angina pectoris, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death.
So here’s a drug that may increase cardiovascular risk for people with diabetes. I needn’t remind the reader that the major risk for PWD is CV risk. It might seem totally irrational that any ethical company would continue to pursue the development of a diabetes drug that might increase CV risk, but there’s another shining example of corporate avarice in the diabetes world: GSK still sells an oral diabetes drug, Avandia (rosiglitazone) on the US market, although it’s already been forced off the market in Europe for precisely the same problem: it increases cardiovascular risk.
Well, welcome to corporate greed.
Novo Nordisk is pushing hard to have these new insulin products approved elsewhere: earlier this year they proudly boasted that they are well on their way to approval in Europe, Japan, and that "applications have been submitted for regulatory approval in Canada, Switzerland and a range of other countries."
And they hedge their problems with cardiovascular risks with a glib statement that "In November, the products received a positive vote for approval from an FDA Advisory Committee." Yes, they did get a positive vote, but Novo Nordisk fails to note a significant caveat: the company must perform a five-year cardiovascular study. The Advisory Committee unanimously recommended that a cardiovascular outcomes trial should be conducted and voted eight to four in favor of approving the products, coupled with their demand for a cardiovascular outcomes trial. The FDA may or may not agree with the AdComm’s recommendations. For instance, the FDA might insist the CV study be done before considering approval. Novo Nordisk has indicated that it expects the study to cost $256 million.
Even if the degludec study is allowed to start after FDA approval, I’d expect the US label for these drugs will include a statement of the cardiovascular risk. That’s what the FDA did for Lantus, which had shown a signal for possibly causing retinopathy during clinical trials: the FDA demanded a five-year post-approval study (which subsequently cleared Lantus of causing retinopathy). Putting the statement in the label should slow down sales; after all, degludec is a "me-too" drug with little if any advantage except to enrich the coffers of the manufacturer.
Which brings up the question: Does the diabetes world really need another product that may increase cardiovascular risk? My answer: not really. I don’t think it’s ethical to sell drugs that make the underlying risks of the disease worse, and Novo Nordisk should be forced to run their CV outcomes study before getting approval to sell the drug in the US, or if they prefer, to withdraw their application. And all other regulatory agencies should hold off on approval until the study is done: there’s no reason that people in Europe or Japan or elsewhere should be exposed to a possible additional CV risk until the study is done and analyzed and the risk thoroughly understood.
Full disclosure: The author previously was employed by Sanofi-Aventis, the manufacturer of a competing product, Lantus. He has no financial ties to Sanofi-Aventis at this time.
Physician who is living with diabetes; editor of www.D-is-for-Diabetes.com