Setbacks still outweigh successes in heart failure

Yesterday’s failure of Trevena’s TRV027 to meet either its primary or secondary endpoints in the Phase IIb Blast-AHF study marks another disappointment for a promising project in the challenging field of heart failure.

Trevena has not yet disclosed the results from the study, which recruited 620 acute HF patients and tested three doses of TRV017 against placebo, but it seems unlikely that there will be a path forward for further development. Trevena will, however, put the data up for scrutiny this weekend at the upcoming European Society of Cardiology Heart Failure conference.

Cardiorentis data tlo follow

That same conference should also see the disclosure of the outcome of a closely-watched 2,157-patient phase III trial of Cardiorentis’ ularitide, also in acute heart failure, which completed earlier this year. This product has for some time been considered one of the most promising in the field.

However, Cardiorentis has been rather coy about the trial’s outcome, especially  when it withdrew – at the last moment – from making a formal presentation at a US cardiology conferencesinc in early March.  Although it may have had a genuine reason for doing so, the company’s silence since then seems unusual if it had a positive result. Of course, as a private entity, Cardiorentis has the luxury of deciding how and when to disclose its data. The company did not return calls from EP Vantage to discuss its upcoming data today.

Some positive news in acute HF has emerged in recent months from Vericel, which reported a positive outcome to its ixCELL-DCM phase II study. This trial, which tested the cell therapy ixmyelocel-T, met its primary endpoint of showing a reduction in the total number of all-cause deaths, cardiovascular hospitalisations, or unplanned outpatient and ER visits in the 12 months following treatment. However, the subsequent presentation of full data at the American College of Cardiology meeting last month showed a miss across multiple secondary endpoints, raising concerns about the strength of this result.   

Acute Heart failure is associated with significant morbidity and mortality and has seen little, if any, pharmaceutical innovation in recent years. Standard treatment still remains diuretics and nitrates, products which were introduced decades ago.    

Development of new products in this field is challenging for multiple reasons, but not least because of the complexity of endpoints required to show a clinically meaningful benefit. Trevena’s Blast-AHF study, for example, used as its primary endpoint a composite “z score”, calculated from five different outcomes: time to death or heart failure re-hospitalization, assessed at day 30; time to worsening heart failure or change in dyspnea VAS score, assessed at day five; and overall length of initial hospital stay.

By contrast, Cardiorentis’ study had two co-primary efficacy endpoints. One was a hierarchical clinical composite comprised of a patient global assessment of symptoms using a seven-point scale; persistent or worsening heart failure requiring an intervention; and all-cause mortality, assessed at six, 24 and 48 hours. The other was freedom from cardiovascular mortality during follow up.

The other late-stage programme in the acute HF field is Novartis serelaxin, which is in three large phase III trials that are due to read out early next year (see table). Interesting, all three studies have entirely different primary endpoints. These were selected presumably as a result of Novartis having tried, and failed, to gain US/EU approval on the back of a mortality benefit seen in the Relax-AHF trial.  

Ongoing late stage trials in heart failure
Project  Company Type Acronym  n Trial ID  Data
Phase III
Ularitide  Cardiorentis  Acute decompensated True-AHF  2,152  NCT01661634  May-16
C-Cure  Celyad  Chronic Ischemic Chart-1  240  NCT01768702  Jun-16
Serelaxin Novartis Acute Relax-AHF-2  6,800  NCT01870778  Jan-17
Acute Relax-AHF-EU  2,685  NCT02064868  Jan-17
Acute Relax-AHF-Asia  1,520  NCT02007720  Mar-17
Xarelto  J&J/Bayer HF with CAD CommanderHF  5,000  NCT01877915  May-18
Rexlemestrocel-L  Teva/Mesoblast  CHF 600 NCT02032004  Apr-18
Phase II/III
MyoCell  Bioheart CHF Marvel  170  NCT00526253  Feb-17

The lack of success to date in developing new agents for the acute condition, however, contrast with the situation in chronic heart failure, which has at least seen the introduction of one new product, Novartis’ Entresto, a twice-a-day fixed combination of sacubitril and valsartan. However, this product has had a very lacklustre commercial launch this year that has perplexed analysts.

The CHF field may soon see a new small molecule enter Phase III in the form of Amgen/Cytokinetics’ omecamtiv mecarbil, following a positive phase IIb trial in November last year. The 448-patient Cosmic-HF trial showed statistically significant improvements in several measures of cardiac function, including systolic ejection time, stroke volume and N-terminal-pro-brain natriuretic peptide at 20 weeks. Full data are expected to be disclosed at the ESC Heart Failure conference on Saturday.

The next major development in CHF may come in the form of a cell therapy, namely Celyad’s C-Cure, a bone marrow-derived mesenchymal cardiopoietic cell. The company’s Chart-1 study, which examined C-Cure against a sham control, is expected to render results in last two weeks of June.  

The primary endpoint Celyad selected for its study is a hierarchical composite outcome comprising: days to death from any cause, number of worsening of heart failure events, change in score for the Minnesota Living with Heart Failure Questionnaire, change in six-minute walk distance and change in left ventricular end systolic volume and left ventricular ejection fraction.

C-Cure is one of two cell therapies in late development for chronic CHF; the other being Mesoblast’s CEP-41750, also known as Revascor or rexlemestrocel-L. This product, an allogeneic mesenchymal precursor cell, has had a somewhat chequered development history in CHF, since being originally partnered with Cephalon and, following that company’s takeover, with Teva.

Teva started a large 1,800 person study of rexlemestrocel-L in CHF in 2014, but recruitment was slow and last year it was reduced to 600 patients, with the intention to run a second phase III in parallel.  Last week, Mesoblast disclosed the study had now recruited more than 250 patients and had passed an initial safety assessment, but added that Teva may review its ongoing participation at any time.  

It looks like there will be a volume of new data to examine next week and cardiologists, and indeed patients, must be hoping some will offer new prospects for improvements in the standards of care for heart failure.   

To contact the writer of this story email Robin Davison in London at or follow @RobinDavison2 on Twitter

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