In May 2014, GlaxoSmithKline (GSK) announced headline results of the Phase III SOLID-TIMI 52 outcomes trial that studied over 13,000 acute coronary syndrome (ACS) patients; the anti-inflammatory Lp-PLA2 inhibitor darapladib failed to significantly reduce the risk of cardiovascular death, myocardial infarction or urgent coronary revascularization for myocardial ischemia when added to standard of care. This news followed the November 2013 failure of darapladib to significantly reduce the time to first occurrence of any major adverse cardiovascular event from the composite of myocardial infarction, stroke and cardiovascular death in its Phase III STABILITY trial in over 15,000 coronary heart disease (CHD) patients.
Full results for the STABILITY trial were presented at the ACC Scientific Sessions in 2014. Despite not reducing the primary end point, there was a nominally significant reduction in the secondary end points of major and total coronary events. One explanation offered by the STABILITY investigators for the lack of effect of darapladib on the primary end point in this trial was related to a smaller than anticipated effect on vulnerable coronary plaque, as indicated in the Phase II IBIS-2 study.
With a higher risk population (ACS patients) providing for a greater number of events, we expected the small benefits seen in STABILITY to be more pronounced in SOLID-TIMI 52; however, this was not the case. Generally, the safety profile for darapladib did not show any major concerns. We expect GSK to conduct further analysis on the data from both SOLID-TIMI 52 and STABILITY to look for efficacy signals in specific subpopulations. However, as of now we do not expect any further development of darapladib. Full results from SOLID-TIMI 52 are expected later this year.
Earlier this month GSK announced the initiation of a Phase III study, LATITUDE-TIMI 60, to evaluate the effects of the anti-inflammatory p38 kinase inhibitor losmapimod in over 25,000 ACS patients. The twice daily agent losmapimod will be administered orally for a period of three months immediately after presentation with an ACS. The Phase II SOLSTICE trial evaluated the drug's safety and efficacy in 535 NSTEMI patients. Results showed no difference in the primary safety end point (assessment of all adverse events) or the primary efficacy end points (changes in high-sensitivity CRP and troponin I). In an MRI substudy, there was a nonsignificant reduction in infarct size and an improvement in left ventricular ejection fraction. Experts interviewed by Decision Resources have expressed concern about the high dropout rate seen in the trial and believed further Phase II clinical trial investigation was needed.
Will losmapimod share the same fate as darapladib?
We see a number of similarities between the darapladib and losmapimod development programs. Both agents target inflammatory processes with the goal to reduce the risk in ACS patients. As with darapladib we also view losmapimod as a high-risk project; compared to other mechanisms of action or drug targets, the roles that inflammatory pathways play in CV risk are relatively undefined. We also see a correlation between darapladib and losmapimod in terms of their course of development: inconsistent Phase II results leading to large outcomes studies.
Nonetheless, GSK appears committed to losmapimod, as demonstrated by the announcement of its large Phase III study. We believe GSK is hedging some of the risk through the large trial size; if overall the trial fails to deliver positive results, sufficient benefit may be seen in specific subpopulations to support approval of the drug (albeit for a narrower indication). We saw this sort of scenario with Merck's vorapaxar (Zontivity). Despite mixed results from vorapaxar's pivotal Phase III trials approval was granted in a narrower population than was studied; patients with a history of atherothrombotic disease but no history of stroke or transient ischemic attack or intracranial hemorrhage.
We remain positive for the development of losmapimod. Although there are limited clinical data, experts interviewed remain excited by its mechanism of action. Additionally, compared to darapladib, losmapimod use focuses on the first three months after the index event. Thought leaders have told us they believe this approach may increase the chances of success as it targets the vulnerable period when the majority of major adverse cardiovascular events (MACE) occur. We believe the high unmet need in the treatment of atherosclerosis, the targeted treatment approach and the fact that the product is likely to complement rather than replace existing treatment regimens provides GSK with a sizable commercial opportunity.
Event-driven Pharmacor: Acute Coronary Syndrome
Principle Analyst Graeme Green, M.Sc., Ph.D., and Data Analyst Stefanie Hoffart, M.Sc., are part of the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.