UPDATED: Merck's DPP-4 newcomer Marizev trails Januvia in safety: Report

Januvia box

Merck ($MRK) intended its new weekly diabetes treatment, Marizev, to build on the success of its blockbuster DPP-4 inhibitor Januvia. But at least when it comes to safety, Marizev is lagging behind, a new report finds.

Healthcare analytics firm Advera Health Analytics compared the drugs' head-to-head trial data and found that Marizev had more serious side effects than Januvia in two studies. Marizev, approved by Japanese regulators in September but not cleared for sale in the U.S., turned up higher rates of prostate cancer and cardiovascular and hepatobiliary issues, or problems with the liver, pancreas or digestive system.

And Marizev did not reduce glycosylated hemoglobin, a key indicator of long-term diabetes, as well as Januvia did. The drug was also "less impressive" in improving fasting blood sugar levels, according to Advera's report.

Merck is standing by Marizev, though. "Results of double-blind, randomized, placebo- and active-controlled studies have demonstrated an overall balance in adverse events (AEs), including serious adverse events, in patients taking (Marizev)," the company told FiercePharma in an email. "Merck believes that the labeling in Japan accurately reflects the overall benefit-risk profile of our once-weekly DPP-4 inhibitor."

Last Friday, Merck said it did not plan to seek approval for Marizev in the U.S. or Europe, but will continue to sell the drug in Japan. The company said it's shifting its diabetes development focus and Marizev no longer fits the bill. It didn't drop the drug for efficacy or safety reasons, Merck's statement said.

But that's not to say that Marizev is riskier on the whole, Advera's chief product officer, Bob Kyle, told FiercePharma. Januvia already has a long-term cardiovascular study demonstrating its heart safety, Kyle said. Results from Marizev's long-term cardiovascular safety study haven't been reported out yet, so it's hard to tell how the drug will shape up, Kyle added. 

Nor is Marizev without its advantages, Kyle said. It is a weekly treatment, while Januvia is taken once a day. "That's a major benefit that might outweigh some of the potential risks that show up with Marizev," he said. 

Merck is quick to tak up both meds' safety. Results of a Phase III head-to-head study that pitted once-a-week Marizev against once-a-day Januvia showed that "the incidences of serious adverse events, drug-related adverse events and discontinuations were similar across both treatment groups," company spokeswoman Kristen Drake told FiercePharma in an email. The company reported the results at the EASD Annual Meeting in September.

The company's decision to drop Marizev in the U.S. and Europe "did not result from concerns about the efficacy or safety" of the drug, Merck said in a statement last week. The company has instead "decided to focus its development resources on a promising pipeline of late-stage compounds and, in early development, new approaches to diabetes control, while continuing to emphasize its existing portfolio," which includes Januvia, it said. Merck "remains committed" to marketing Marizev in Japan, the company said.  

Marizev competes in a crowded DPP-4 class that includes AstraZeneca's ($AZN) Onglyza and metformin combo drug Kombiglyze; Eli Lilly ($LLY) and Boehringer Ingelheim's Tradjenta and related combo meds Glyxambi and Jentadueto; and Takeda's Nesina and two combo pills, Kazano and Oseni.

Plus, the class faces a laundry list of safety issues. DPP-4 meds come with warnings about the risk of pancreatitis and allergic reactions, not to mention hypoglycemia when used in combination with other diabetes meds.

In August, the FDA issued a serious warning that the drugs might cause "severe and disabling joint pain," delivering another blow to the class. Last week, the agency flagged increased risks of heart failure with Onglyza and Nesina. Onglyza had already come under fire for its links to heart issues in patients.

Merck has fared better with Januvia in terms of safety. Last year, the company enjoyed a bright point after study results showed that the drug did not come with an increased risk of heart failure.

"It's reassuring to be able to present data from a large study over a number of years that provides more information about the safety profile," Peter Stein, Merck's VP of clinical research in diabetes and endocrinology and a member of the executive committee for the TECOS trial, told FiercePharma at the time. " ... I think that's very important in helping (physicians) to feel comfortable about the tools they're using to get their patients to glycemic goals."

That information is also important in helping Merck keep patients on Januvia and away from SGLT2 meds like Lilly and Boehringer Ingelheim's Jardiance. Last year, Jardiance became the first diabetes treatment to show that it could lower the risk of heart attack, stroke and death from cardiovascular issues.

Even though "DPP-4s are generally well-tolerated, neutral on weight and have for the most part been viewed as safe," overall they've "failed to demonstrate a CV outcomes benefit," Evercore ISI analyst Mark Schoenebaum said in a note to investors last year after the TECOS trial data was released. That, combined with Jardiance's cardiovascular benefits, could mean that "doctors will be more eager to prescribe SGLT2s in front of DPP-4s," Schoenebaum said.

- here's a link to the report
- read Merck's statement