Setbacks Still Outweigh Successes In Heart Failure

| About: Trevena, Inc. (TRVN)

Yesterday’s failure of Trevena’s (NASDAQ:TRVN) 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 TRV027 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 European Society of Cardiology Heart Failure conference.

Cardiorentis data to 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 the American College of Cardiology in early April. As a private entity, Cardiorentis can choose 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. 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, 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 self-reported dyspnoea score, assessed at day five; and overall length of initial hospital stay.

By contrast, Cardiorentis’ study has two co-primary efficacy endpoints. One is 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 is freedom from cardiovascular mortality during follow up.

The other late-stage program in the acute HF field is Novartis' (NYSE:NVS) serelaxin, which is in three large phase III trials that are due to read out early next year (see table). Interestingly, 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

Click to enlarge
Click to enlarge

The lack of success in the acute condition, however, contrasts with the situation in chronic heart failure, which has at least seen the introduction of one new product, Novartis’s Entresto. 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.

C-Cure is one of two cell therapies in late development for chronic HF; the other being Mesoblast’s CEP-41750, also known as Revascor or rexlemestrocel-L. The latter, 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.

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.

Trial

ID

Blast-AHF

NCT01966601

Click to enlarge
Click to enlarge