IMPROVE-IT Go-Ahead Gives Merck Temporary Reprieve On Vytorin

Large outcomes study of Vytorin (ezetimibe/simvastatin) is allowed to carry on, reassuring investors that significant safety problems are unlikely to emerge. The development coincides with release of full results from the outcomes trial HPS2-THRIVE, in which Merck’s niacin-containing Tredaptive proved unsafe as well as ineffective.

A data safety monitoring board’s decision to allow the IMPROVE-IT outcomes study of Vytorin to carry on gives Merck & Co. Inc. some breathing room ahead of the combination drug’s patent expiration by early 2017.

On March 12, Merck said that a data safety monitoring board for the IMPROVE-IT trial of Vytorin, which combines Merck’s Zetia (ezetimibe) and its statin simvastatin (Zocor and generics), completed a planned review of study data and recommended that the study go ahead. This was the third interim analysis of the trial.

The IMPROVE-IT study compares Vytorin to Zocor for reducing cardiovascular eventsin over 18,000 patients and is due to end after about 5,000 events have been reached. In a statement, Merck said that it expects the trial will wrap up in September 2014 and that no additional interim analyses are expected.

News of the IMPROVE-IT go-ahead was well-received by investors, who took the development as good sign for the drug’s safety profile. The September 2014 date takes the drug much closer to patent expiration, giving Merck time to rack up more sales, potentially minimizing the damage of a negative outcome.In 2012, Merck reported sales of about $4.3 billion for Vytorin and Zetia, out of total sales of about $47.3 billion. But Vytorin and Zetia will face generic competition at the start of 2017, leaving little commercial life left when the results do come out, commented Bernstein Research analyst Tim Anderson in a March 12 note.

Merck has absorbed a number of pipeline setbacks recently, including a delay in filing the osteoporosis drug odanacatib and the failure of Tredaptive (long-acting niacin and laropiprant) in the HPS2-THRIVE four-year outcomes study (Also see "Merck’s CV Pipeline: A Shrinking But Strident Commitment" - Pink Sheet, 13 Aug, 2012.).

Reporting full results from the 25,000-patient strong HPS2-THRIVE study at the American College of Cardiology meeting in San Francisco on March 9, Oxford University investigators reported no significant benefit for event reduction and an unacceptably high rate of serious adverse events, most of which required hospitalization, compared to the comparator placebo arm. Furthermore, they did not identify any subgroups who would benefit from treatment.

Consequently, much has been riding on Vytorin as Merck brings in former Amgen Inc. exec Roger Perlmutter to head R&D, effective in April (Also see "A Changing Of The Guard At Merck R&D As Perlmutter Succeeds Kim" - Pink Sheet, 11 Mar, 2013.).

Bernstein’s Anderson observed that the outcome of IMPROVE-IT was most likely to be neutral or positive, and yet a “surprising number of investors” were worried about a third possibility that the drug would cause harm. Yet, in Anderson’s view, that possibility is so “highly improbable” it does not warrant serious consideration. Anderson believes that if the trial result is neutral, it is still likely to show a positive trend.

Leerink Swann analyst Seamus Fernandez similarly commented that his firm already assumed low likelihood of harm for IMPROVE-IT. Following the safety committee’s decision, this prospect seems “even more remote” and the finding of outright futility is unlikely, he wrote in a March 12 note. From here on, the biggest near-term upside opportunity for shareholders would be a major restructuring of business, Fernandez concluded.

ISI Group analyst Mark Schoenebaum made a positive comparison between the IMPROVE-IT study and the failed HPS2-THRIVE. Tredaptive, which was tested mainly as an HDL-raising drug, is very different from Zetia, which is intended for LDL-lowering, he noted. In the IMPROVE-IT study, the baseline LDL on top of lipid-lowering therapy for the first 10,000 patients enrolled (out of a total of 18,000) was much higher than the HPS2-THRIVE baseline – 97 mg/dL compared to 63 mg/dL, Schoenebaum pointed out in his March 11 note. This additional room to fall in IMPROVE-IT could theoretically translate into a higher rate of reduction in events

Implications Of HPS2-THRIVE?

Though the safety monitoring board’s decision to allow IMPROVE-IT to continue is reassuring, past experience with outcomes studies of cardiovascular drugs has been very disappointing. Abbott Laboratories Inc.’s Trilipix (fenofibric acid) was approved for reducing triglycerides and increasing HDL in combination with statins but failed to show an overall CV benefit beyond statins in the ACCORD study.

Abbott’s Niaspan (extended-release niacin) failed as an add-on therapy to reduce events in the AIM-HIGH study, though that trial’s design was heavily criticized and many clinicians viewed the results as inconclusive. Roche canceled development of its HDL-raising cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib after the drug failed in a massive outcomes trial (Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012.).

Merck itself announced in December that it was dropping U.S. development of Tredaptive after the combination drug (the laropiprant component of which was intended to minimize flushing side effects that can cause patients to stop niacin therapy) failed to show a benefit for reducing events in the HPS2-THRIVE.

A month later, the firm withdrew the product in the markets where it had been approved. At that time, few details were available, but the drug’s profile became clear with the presentation of full study results by Oxford University’s Jane Armitage at the annual ACC meeting.

HPS2-THRIVE compared the combination of 2g extended release niacin and 40 mg laropiprant to placebo in more than 25,000 patients with cardiovascular disease on intense background LDL-lowering therapy for prevention of cardiovascular events. The background lipid-lowering therapy consisted of 40 mg of simvastatin and half of the patients also received Zetia. The study’s endpoint was reduction in cardiovascular events, a composite of non-fatal heart attack or heart related death, stroke or need for angioplasty or bypass surgery

Investigators reported that the risk for events in the Tredaptive arm was 4% lower than in the placebo group (13.2% vs. 13.7%), but this result was not statistically significant. Patients on Tredaptive had significantly higher rates of bleeding (2.5% vs. 1.9%) and infections (8% vs. 6.6%), adverse events that had not been fully appreciated until now. Investigators also reported higher rates of other serious side effects that were known to be associated with niacin, such as diarrhea and risk for development of diabetes.

“This was a disappointing result, but nevertheless it is a clear and reliable result because it was a very large study with good follow-up. The role of ER niacin for prevention of cardiovascular disease needs to be reconsidered,” Armitage said during a March 9 press briefing at the meeting.

The study shows the impact of adding an HDL-raising therapy like niacin on top of very well-controlled LDL (the average baseline level in the study was 63 mg/dL). In the Tredaptive arm, on average, niacin was increased by 6 mg/dL and LDL was lowered by 10 mg/dL. Those who had greater LDL lowering benefited more from treatment with Tredaptive, though this result was not statistically significant.

“The absolute benefit in those patients was still small in comparison with the amount of harm that was caused. We were not able to identify subgroups of participants in whom the benefits outweighed the risks,” Armitage said.