In December, Amgen and Cytokinetics announced that they will be moving forward with their novel chronic heart failure (HF) therapy omecamtiv mecarbil (OM) with the launch of their Phase III study GALACTIC-HF.
This trial will assess the effect of OM on cardiovascular (CV) outcomes, focusing on CV death and HF hospitalisations. Based on positive results from the Phase II COSMIC-HF study, it is likely that OM will continue to prove efficacious in GALACTIC-HF. However, in the evolving HF space, incremental improvements in CV outcomes no longer provide enough benefit, as exemplified by the modest uptake of Novartis’ Entresto.
GlobalData believes that drug developers need to start focusing on unmet needs in the HF market and place a stronger focus on both the patient and the payer.
The Phase III GALACTIC-HF study will enrol approximately 8,000 HF patients with reduced ejection fraction (REF).
The estimated completion date is March 2021. Patients will be followed for four years, with the primary outcome being onset of death or an HF event.
Secondary outcomes include time to CV death, changes in reported quality of life using the Kansas City Cardiomyopathy Score, time to first HF hospitalisation, and time to all-cause death. OM or placebo will be given twice daily, added on top of standard of care, which in most patients includes an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), beta blocker, diuretic, and a mineralocorticoid receptor antagonist (MRA).
The standard of care for HF-REF has remained unchanged and unchallenged until recently, with the launch of Novartis’ Entresto. Although results from the pivotal Phase III study of Entresto were reported as revolutionary, as they showed significant reductions in CV death and HF hospitalisations, the uptake of the drug has been extremely disappointing.
Novartis has struggled to overcome the many barriers of the HF-REF market, which have included pricing and access, as well as physician familiarity. Although detrimental for Novartis, this could prove beneficial for Amgen and Cytokinetics, as they are now in a unique position where they can learn from the failures and successes of Entresto. Despite this, based on the clear similarities between the design of Entresto’s Phase III study and OM’s GALACTIC-HF study, Amgen and Cytokinetics do not seem to be taking advantage of the situation.
A major limitation of the PARADIGM-HF study was the disconnect between the broad inclusion criteria of New York Heart Association (NYHA) Classes II–IV and the patients who were actually enrolled; approximately 70% were NYHA Class II, with less than 1% Class IV. This resulted in limited uptake of Entresto in real world HF-REF patients NYHA Class III or IV, as physicians were cautious to prescribe the drug since there are limited data demonstrating efficacy in these patients.
GALACTIC-HF will need to enrol a sufficient number of patients with NYHA Class III and IV to avoid similar issues if OM does reach the market.
An overcrowded market?
One way forward that could lead to success for Amgen and Cytokinetics is for the companies to focus on particular HF-REF subgroups. Although GALACTIC-HF will assess the drug in a broad patient cohort, subgroup analysis from the study may highlight some areas of opportunity, such as HF-REF patients with severe kidney impairment.
An intriguing feature of the study is the glomerular filtration rate (GFR) cut-off of 20ml / min / 1.73m2, differing from the common cut-off of 30ml /min / 1.73m2 that was used in PARADIGM-HF. The same cut-off used in PARADIGM-HF was also used in the Phase II COSMIC-HF study.
Lowering the cut-off to 20ml / min / 1.73m2 would allow the inclusion of patients with severely reduced kidney function. If a positive signal is seen in this subgroup, then targeting patients with kidney impairment could be one way that OM could break into the HF space. To achieve this, however, the trial will first need to enrol a sufficient number of patients with GFRs between 20ml / min / 1.73m² and 30ml / min / 1.73m2 to see a positive trend, which will need to be followed up in further large scale studies.
As with a number of other CV diseases, the chronic HF-REF space is overcrowded with cheap, generic, and efficacious treatments, and the development pipeline seems to be populated by 'me-too' drugs, with a severe lack of innovative therapies that address unmet needs.
Although OM boasts a novel mechanism of action, at this point in time there is nothing novel about the drug’s development strategy. GlobalData does anticipate positive results from the GALACTIC-HF study, but unless the drug addresses a particular unmet need in the HF space, it is unlikely that OM will successfully penetrate the market.