Amgen and Cytokinetics have revealed they will press forward with their novel chronic heart failure (HF) therapy, omecamtiv mecarbil (OM). Announced on Dec 1, 2016, both companies will together launch their phase III trial, GALACTIC-HF. This study will assess the effect of OM on cardiovascular (CV) outcomes, concentrating on HF hospitalizations and CV death.

After strong results from COSMIC-HF, the preceding phase II study, there are high hopes OM will prove just as effective in GALACTIC-HF. Nevertheless, as the HF space evolves, gradual improvements in CV outcomes don’t provide enough benefit, as showcased by the modest uptake of Novartis’ Entresto. Analysts from GlobalData believe drug developers must focus on the unmet needs in the HF market while placing a greater focus on both the patient and the payer.

The phase III GALACTIC-HF study will enrol approximately 8000 HF patients with reduced ejection fraction (REF), and the estimated completion date is March 2021. In the trial, 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 patient’s reported quality of life using the Kansas City Cardiomyopathy Score, time to first HF hospitalization, 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). In COSMIC-HF, approximately 60 percent of patients were already taking these four HF medications. Thus, whether doctors will want to prescribe their patients yet another drug, particularly one that is taken twice daily, is the first issue Amgen and Cytokinetics will have to address.

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 hospitalizations, 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 percent were NYHA Class II, with less than 1 percent 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. Thus, GALACTIC-HF will need to enrol a sufficient number of patients with NYHA Class III and IV in order to avoid similar issues if OM does reach the 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; interestingly, 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, and 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 20–30ml/min/1.73m2 in order 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’s unlikely that OM will successfully penetrate the market.

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*This article first appeared on GlobalData Expert Insights on Dec 6, 2016