Novartis’s success in launching Entresto has, if anything, shown developers the opportunity that lies in a therapy area that has seen much disappointment. After all, the Swiss drugmaker’s main feat was combining two older products with a known effect on hypertension into a single pill that analysts reckon will pull in upwards of $5bn by 2020.
Yesterday, Bristol-Myers Squibb’s $300m down payment on Cardioxyl snapped up an asset that had mostly flown under the radar in this space, a nitroxyl donor that has shown signs that it can improve cardiac muscle function in decompensated heart failure. But that project is queued up behind 12 novel agents in phase II and III trials; some of the pivotal studies will be reading out next year (see table below).
Heart failure has proven so resistant to treatment that much of the research has turned to advanced approaches like stem cell therapy – for example, Celyad’s C-Cure. However, small molecules are holding their own, as Cytokinetics’ omecamtiv mecarbil returned positive phase II results last week (A qualified success in heart failure, October 28, 2015).
Considering that 30-day post-discharge mortality was 6.2% and one-year mortality 27% in a recent UK analysis, heart failure is a disorder with unmet needs and plenty of room for improvement under current treatment protocols.
Big readouts coming
Two signature events could define the heart failure space in the near term: the readout for Novartis’s Relax-AHF trial of serelaxin (RLX030) and Bayer and Johnson & Johnson’s Commander-HF trial of the blood-thinner Xarelto.
Serelaxin, of course, gave a tantalising view of its potential when it showed signs that it could prevent death and hospitalisations, but the FDA’s uncertainty about the robustness of the results has meant that Novartis had to re-run its pivotal trials (Upcoming events: Sirukumab and serelaxin face phase III readouts, October 30, 2015).
|Selected late-stage trials in heart failure|
|Project||Sponsors||Enrolment||Trial ID||Acronym||Primary completion|
|Phase III||RLX030||Novartis Pharmaceuticals||6,800||NCT01870778||RELAX-AHF-2||01/08/2016|
|Xarelto||Johnson & Johnson
|Rexlemestrocel-L||Teva Pharmaceutical Industries/Mesoblast||1,165||NCT02032004||-||01/07/2018|
|Phase II/III||MyoCell||Bioheart, Inc.||170||NCT00526253||MARVEL||01/02/2017|
|Phase II||JVS-100||Juventas Therapeutics, Inc.||90||NCT01643590||STOP-HF||Completed phase II trial|
|Omecamtiv mecarbil||Amgen/Cytokinetics||544||NCT01786512||COSMIC-HF||Completed phase II trial|
|BAY 1142524||Bayer||48||NCT02452515||CHIARA MIA 1||01/03/2016|
While Bristol has left its main cardiovascular drug Eliquis out of the mix and has chosen a novel pathway, Bayer is attempting to double up in heart failure on its asset from the same class, Xarelto.
Those factor Xa inhibitors have been successful in preventing pulmonary embolisms and strokes in patients with atrial fibrillation, but they have struggled to show effectiveness in other indications – witness the three unsuccessful attempts to achieve approval in acute coronary syndrome. The Commander-HF trial hopes to show that Xarelto can reduce death rates, heart attacks and strokes in heart failure patients with documented cardiovascular disease.
Biological projects have a much bigger role in phase III, and indeed, throughout the heart failure space. Ularatide is a recombinant peptide therapeutic owned by the private Swiss group (EP Vantage interview – Cardiorentis seeks heart-disease niche, March 27, 2013). Its trial completed enrolment in May, which it was able to do thanks to a €45m royalty financing with HealthCare Royalty Partners.
As for cell therapies, heart failure represents one of the disease areas where it is most advanced, as it holds the promise of regenerating damaged muscle rather than helping the remaining healthy tissue work better. Celyad’s C-Cure is a closely watched project, while Mesoblast’s long-suffering rexlemestrocel-L seems to have finally regained momentum after an uncertain time in Teva’s stable (Teva’s phase III rejig leaves some unanswered questions, August 25, 2015).
Already done, maybe ready for phase III
As with phase III, advanced therapies figure prominently in phase II, with Juventas Therapeutics’ gene therapy JVS-100 having finished a first mid-stage trial in early 2014. The group was recently granted fast-track status by the FDA, which also approved a phase IIb protocol.
That puts it a bit behind the other recent phase II completer, Cytokinetics’ omecamtiv, on which partner Amgen has to make a go/no-go decision by January.
The assets in phase II show how Bayer is asserting its presence in this space to counter Novartis, with vericiguat, due a readout any day, and the small-molecule chymase inhibitor BAY 1142524 having been optimistically profiled for its ability to aid in tissue remodelling at an R&D presentation last year.
The remaining small-molecule prospect in phase II, Trevena’s TRV027, will be an interesting business development case study. With ownership having been passed on to Allergan, now in serious negotiation for a takeout by Pfizer, TRV027’s coming readout could not come at a worse time.
Whether Pfizer would want to take on an R&D project in the heart failure space is anybody’s guess, but its history points more to slashing development projects than embracing them.
Novartis has shown that there is much to improve on in heart failure. The hope of rebuilding damaged tissue is strong, as demonstrated by the presence of so many cell and gene therapies in late-stage development, but there could be a simpler means of reducing mortality and improving patients’ quality of life.