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Innovation in Heart Failure Drug Development – Is There Enough?

JAKE MATHONPrincipal Analyst, Citeline

PharmaprojectsPharma intelligence |


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Heart failure is a chronic condition that is of major concern to the healthcare community. 5.8 million Americans and 23 million people globally are estimated to have heart failure¹. 400,000 – 700,000 newly diagnosed cases of heart failure are estimated each year in the US alone2. Roughly half of these new cases will result in death within five years. Heart failure exacts a monetary toll on the country as well. The costs for care and treatment (including drugs) and missed days of work total $32 billion yearly and are expected to reach over $57 billion in just over a decade3, 4. In the past five years, just one new/novel drug has been registered with a regulatory authority for approval. That drug, Novartis’ serelaxin, was recently given a unanimous vote of no confidence by the FDA Cardiovascular and Renal Drugs Advisory Committee for an acute heart failure indication5. Three other compounds (ivabradine, bisoprolol, valsartan + hydrochlorothiazide) with previous approvals in other indications such as hypertension and angina were also registered/approved for heart failure. This paper will examine the landscape of pharmaceutical industry new drug development and clinical trial activity in heart failure.

Within Citeline’s Pharmaprojects database, there are currently 85 compounds in development (preclinical

through preregistration) by industry for heart failure. Bayer and Servier lead all companies in overall drug

development with six and five compounds respectively (see Figure 1). Pfizer is next with three, and 14

companies have two drugs. While Novartis is among those with just two drugs in the pipeline for heart

failure, both are Phase III and they recently received positive news that one, LCZ-696, significantly reduced

cardiovascular mortality versus treatment with an ace inhibitor6. This could potentially make up for the

previously mentioned setback with serelaxin.

1. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;14:30–41. doi: 0.1038/nrcardio.2010.165.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033496/#R2

2. Heart Failure Society of America http://www.hfsa.org/heart_failure_facts.asp

3. http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm

4. AHA Policy Statement -Forecasting the Future of Cardiovascular Disease in the United States; Circulation. 2011; 123: 933-944 http://circ.ahajournals.org/content/123/8/933/T2.expansion.html

5. http://www.medpagetoday.com/Cardiology/CHF/44979

6. http://www.forbes.com/sites/larryhusten/2014/04/01/a-new-novartis-heart-failure-drug-might-be-a-blockbuster/

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Figure 1. Heart Failure Drugs in Development

Source: Pharmaprojects®, Citeline April 2014


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Of the 85 drugs in development, 23 are in Phase II and 12 in Phase III (see Tables 1 and 2). 23% of these

products (three in Phase III and five in Phase II) are cellular therapies. While cell therapies have shown

some promise in heart failure, there has been some doubt cast on the true efficacy as a recent analysis has

shown that the effect on a major heart failure endpoint, left ventricular ejection fraction, has been minimal7.

A brief glance at the Phase III pipeline shows a dearth of innovation specific to heart failure. Just three of

the 12 compounds are new, non-cell therapy products. The remainder are older drugs already approved

for other indications or reformulations of drugs already approved for heart failure. Innovation looks a bit

better in Phase II as 15 of the 23 compounds are new, non-cell therapies. Included in this new research

are three targeted gene therapies from Juventas, Celladon, and Renova.

7. Nowbar AN, Mielewczik M, Karavassilis M, Dehbi HM, Shun-Shin MJ, Jones S, Howard JP, Cole GD, Francis DP Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis BMJ 2014;348:g2688 http://www.bmj.com/content/348/bmj.g2688

table 1. Phase iii Pipeline

PriMary Drug naMe coMPanies MechanisM oF action

pioglitazone hydrochloride Takeda Thiazolidinedione

levocarnitine, Sigma-Tau Sigma-TauCarnitine O-acetyltransferase stimulant

aliskiren Novartis Renin inhibitor

lixivaptanPfizer Cornerstone

Vasopressin 2 antagonist

urodilatin Cardiorentis Atrial natriuretic peptide agonist

LCZ-696 NovartisAngiotensin II 1 antagonist Membrane metallo endopeptidase inhibitor

autologous myoblast cell therapy, Bioheart

Bioheart Stem cells/cell therapy

mesenchymal precursor cells, allogenic, CV, Mesoblast

Mesoblast Teva

Stem cells/cell therapy

ivabradine MR ServierSodium channel antagonist Potassium channel antagonist HCN channel antagonist

carvedilol sulfate, Jiangsu HengRui Medicine

Jiangsu Hengrui Medicine

Beta 1 adrenoreceptor antagonistBeta 2 adrenoreceptor antagonistAlpha 1 adrenoreceptor antagonistReducing agent

carvedilol ER, InnoPharmaxInnoPharmax TSH Biopharm

Alpha 1 adrenoreceptor antagonistBeta 1 adrenoreceptor antagonistBeta 2 adrenoreceptor antagonist

bone marrow-derived cardiopoi-etic cells, Cardio3

Cardio3 BioSciences Stem cells/cell therapy


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table 2. Phase ii Pipeline

PriMary Drug naMe coMPanies MechanisM oF action

testosterone patch, female Actavis Testosterone receptor agonist

ranolazine GileadPartial fatty acid oxidation inhibitorSodium channel antagonist

tenapanorArdelyx AstraZeneca

Sodium/hydrogen exchange inhibitor

mesenchymal bone marrow-de-rived stem cells, Stemedica-1

Stemedica CardioCell


autologous muscle derived cells, Cook Medical

Cook Medical Stem cells/cell therapy

vericiguat Bayer Guanylate cyclase stimulant

TRV-120027 Trevena Angiotensin II 1 antagonist

TRC-4186 Torrent Pharmaceuticals Glycosylation inhibitor

S-38844 ServierUnidentified pharmacological activity

omecamtiv mecarbilCytokinetics Amgen

Unidentified pharmacological activity

JVS-100 Juventas TherapeuticsStromal cell-derived factor 1 agonist

JNJ-54452840 Johnson & Johnson Beta 1 adrenoreceptor antagonist

istaroxime CVie Therapeutics Na+ K+ transporting ATPase inhibitor

finerenone Bayer Aldosterone antagonist

endometrial regenerative cells, Medistem

Medistem Stem cells/cell therapy

CLP-1001 Sorbent TherapeuticsOsmosis stimulant (non-diuretic)Chelating agent

CHF gene therapy, Targeted Genetics

AmpliPhi Biosciences Celladon

ATPase stimulant

carvedilol CR, EgaletEgalet RedHill Biopharma

Beta 1 adrenoreceptor antagonistBeta 2 adrenoreceptor antagonistAlpha 1 adrenoreceptor antagonistReducing agent

BAY-1067197 Bayer Adenosine A1 receptor agonist

allogeneic CDCs (intracardiac), Capricor

Capricor Therapeutics Johnson & Johnson


aladorianArmgo PharmaServier

Calcium channel antagonist

adipose-derived stem cells, Bioheart

Bioheart Stem cells/cell therapy

Ad5.hAC6 Renova Therapeutics Adenylate cyclase 6 stimulant


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Figure 2. Heart Failure Trials by Company and Phase

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Citeline’s Trialtrove database tracks clinical trials that are disclosed in the public domain. As of May 2014,

there were 114 industry sponsored Phase I – III clinical trials for heart failure known to be taking place

globally8. A look at the ongoing industry activity indicates that Bayer again leads all companies, with

Novartis and Bioheart right behind followed by Pfizer and Servier. A closer look reveals that all of Pfizer’s

clinical trials are in Phase III. For the subset of acute heart failure, Novartis leads with four trials followed by

Otsuka with two, and Servier, and Johnson & Johnson with one each.

Source: Trialtrove®, May 2014 Citeline

8. Citeline data is obtained from over 30,000 sources in the public domain. Trial reporting rules and regulations differ among countries around the world and not all trial activity in some countries may be recorded.


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Using Citeline’s Sitetrove Investigator Prioritization feature (see Table 3), our analysis indicates that of the

nearly 800 identified investigators for active heart failure trials, industry sponsors are utilizing the most

attractive investigators that have the highest potential to perform well in clinical trials just 13% of the time.

And just 17% of the 600 currently available top tier investigators are being utilized for these trials. Nearly

40% of the active investigators for industry sponsored heart failure trials are categorized as Tier 3, or

lowest performing investigators recruiting the fewest numbers of patients. These figures indicate that

sponsors are missing the opportunity to enroll patients in trials quickly and thus are spending valuable

R & D money on poorly performing investigators.

Source: Sitetrove®, May 2014 Citeline

table 3. investigator Prioritization Matrix

tiers Matching search across entire Disease

Tier 1 102 600

Tier 2 389 5814

Tier 3 305 10406

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Figure 3. Heart Failure Trials by Phase and Location

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Source: Trialtrove®, May 2014 Citeline

The vast majority of ongoing clinical trial activity is occurring in the United States as there are just over 50

trials taking place there (see Figure 3). The remaining top 10 locations are spread somewhat evenly across

Europe, Canada, and Australia. Given the global prevalence of heart failure, it is surprising only three Asian

countries (China-20th, South Korea-22nd, and Japan-25th) make the top 30 list for locations, none with

more than nine active trials.


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More innovation, better location/investigator selection, stronger stem cell therapy trials needed

In summary, the heart failure landscape shows promise, although there appears to be more potential for

innovation in the Phase II pipeline. Cell therapies account for a large portion of the drugs in development,

but more and better run trials may be needed to convince the healthcare community of their viability.

While Bayer leads all companies in total development compounds, Novartis may be in position to be a

leader in this area if they can capitalize on two Phase III drugs as well as make any necessary modifications

to the serelaxin program. Heart failure clinical trial activity is heavily concentrated in the United States and

there are opportunities to conduct more trials globally, especially in Asia. Industry sponsors are under

utilizing the best performing investigators for heart failure trials.

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