Just as the approval of Novartis’s Entresto sparked renewed interest in heart failure Amgen and Cytokinetics have scored a clinical success with a mid-stage project of their own, omecamtiv mecarbil.
However, initial Entresto revenue reported by Novartis yesterday has disappointed, suggesting that despite the excitement this therapy area will not grow explosively but rather will develop at a slow burn. And GlaxoSmithKline’s latest phase III flop, in acute coronary syndrome, shows that the cardiovascular space in general remains a tough nut to crack.
One of the problems is the huge scope of clinical trials needed to tease out a relatively small benefit, meaning that a go/no-go decision often hinges on financial rather than scientific considerations. This is one reason why Glaxo designed its failed phase III study of losmapimod as a multi-stage trial.
And progression of omecamtiv into phase III is by no means guaranteed – the positive phase II hit notwithstanding – which perhaps explains the muted 2% rise in Cytokinetics stock yesterday. Cowen analysts expect Amgen, which holds global omecamtiv rights, to make a go/no-go decision in January, and if this goes in favour of phase III initiation Cytokinetics will be due a $50m milestone.
For now Amgen and Cytokinetics can celebrate positive topline data of omecamtiv, a cardiac-specific myosin fibre activator, in the expansion phase of Cosmic-HF, a 448-patient pharmacokinetics study.
The trial showed statistically significant improvements in several key biomarkers of cardiac function, including systolic ejection time and stroke volume, and decreases in cardiac dimensions. However, the actual numbers and p values will not be revealed until the ACC meeting in April, and the clinical meaningfulness of some of the measures is not well defined.
Omecamtiv is one of several heart failure projects riding in Entresto’s slipstream (Entresto approval revives heart failure sector, July 8, 2015). However, Entresto itself has got off to a slow start, Novartis reporting third-quarter sales of $16m – short of the $20m expected by Jefferies; likewise EvaluatePharma’s sellside consensus of $147m for the year now looks like a long shot.
Medicare coverage is a stumbling block – specifically there is normally a six-month delay getting on Medicare formularies. Medicare accounts for most heart failure patients, though until October 1 no part D formulary covered Entresto. Novartis also said it needed to do more to “educate” doctors to move patients urgently from ACE inhibitors and angiotensin receptor blockers to Entresto.
Bernstein analysts concede that Entresto is likely to be slow-growing, though this does not preclude it eventually becoming a very big seller. EvaluatePharma consensus forecasts compute 2020 revenues of $5.4bn.
Meanwhile, Glaxo’s latest troubles stem from the failure of its p38 MAP kinase inhibitor losmapimod to pass an interim assessment in Latitude-Timi 60, a cardiovascular outcomes trial that had planned to enrol 25,500 acute coronary syndrome (ACS) patients.
ACS is losmapimod’s lead indication, and had earlier proved too difficult for Bayer/Johnson & Johnson’s Xarelto, which saw three US FDA rejections, as well as Glaxo’s own darapladib (Novartis gets surprise heart failure win as ACC data roll in, March 31, 2014).
The first stage of losmapimod’s trial recruited 3,503 patients. While the data do not support investment in the study’s bigger part, Glaxo will evaluate the logic of further development, presumably on the strength of losmapimod’s benefit in a subgroup of 866 patients with ST elevation myocardial infarction.
At least with losmapimod the UK company can congratulate itself on designing a trial that limited its financial damage to just a fraction of the massive study’s entire patient population.
|Losmapimod||Latitude-Timi 60||Phase III CVOT in up to 25,500 acute coronary syndrome patients||NCT02145468|
|Omecamtiv mecarbil||Cosmic-HF||Phase II trial in 448 heart failure patients||NCT01786512|