Cardiac Drug Discovery Reignited: New Tools Unlock Genetically Defined Diseases

Valo Health is pleased to share the following white paper as a part of our library of publications through our acquisition of TARA Biosystems.


For years, cardiac drug development was epitomized by large and costly “non-inferiority” clinical trials that were designed to treat broad clinical symptoms. It wasn’t by choice: The molecular mechanisms of diseases such as coronary heart failure and various cardiomyopathies were just too complex to decipher with the available research tools. As biopharma evolved in the 1990s, research and investment moved to other indications, including new personalized frontiers in cancer medicine.

After a lull of several decades, interest in cardiac drug discovery and development is now surging. The core issues have been addressed by a range of independent technological revolutions, from affordable genomic sequencing to advances in tissue engineering and high-fidelity in vitro models. As these innovations converge, researchers can now understand and segment genetically defined subpopulations, giving rise to drug programs that address the real molecular underpinnings of cardiac diseases.


The so-called era of pre­ci­sion med­i­cine” arrived years ago. Genom­ic analy­sis is now a main­stay in the treat­ment of dif­fer­ent can­cers and the devel­op­ment of new drugs. Sophis­ti­cat­ed diag­nos­tics deter­mine if and when an indi­vid­ual is becom­ing resis­tant to an exist­ing treat­ment. Gene ther­a­pies are grad­u­al­ly gain­ing approval as func­tion­al cures for mono­genic diseases. 

It’s an excit­ing time in med­i­cine, but not all fields have ben­e­fit­ted from the same advances. Oncol­o­gy pro­grams have pro­lif­er­at­ed wild­ly, becom­ing an increas­ing­ly large share of the clin­i­cal drug devel­op­ment pipeline. At the oth­er end of the spec­trum, inter­est and invest­ment in car­diac drug dis­cov­ery has fluc­tu­at­ed – despite the vast med­ical need and mar­ket opportunity. 

Heart dis­ease remains the lead­ing cause of mor­tal­i­ty for both men and women in the Unit­ed States, dri­ving one in every four deaths and annu­al costs in excess of $200 bil­lion. The bur­den of car­diac dis­ease is also increas­ing glob­al­ly. More than three-quar­ters of deaths relat­ed to car­dio­vas­cu­lar dis­eases (a group­ing that includes heart fail­ure, car­diomy­opathies, and a range of vas­cu­lar dis­eases) now occur in low- and mid­dle-income coun­tries. The enor­mi­ty of these num­bers pro­vides a telling clue as to why these dis­eases have not been ade­quate­ly addressed. For decades, car­diac dis­eases were clas­si­fied and treat­ed based on com­mon clin­i­cal symp­toms that affect mil­lions upon mil­lions of peo­ple. Ther­a­pies were devel­oped to tar­get these symp­toms and not the under­ly­ing mech­a­nisms of the dis­ease. More nuanced pre­clin­i­cal dis­ease mod­els were typ­i­cal­ly cost- and time-pro­hib­i­tive, with results, often fail­ing to trans­late to patients. With a lack of nov­el drugs to treat the under­ly­ing cause of heart fail­ure, drugs that treat comor­bidi­ties such as high cho­les­terol and hyper­ten­sion have remained foundational. 

For decades, this has been the norm. Now, a con­ver­gence of tech­nol­o­gy break­throughs has opened the door to pre­cise mol­e­c­u­lar tar­get­ing and per­son­al­iza­tion. Some of these devel­op­ments – such as afford­able and scal­able genom­ic sequenc­ing – have ben­e­fit­ted med­i­cine as a whole. Oth­ers, such as bet­ter pre­clin­i­cal screen­ing mod­els, specif­i­cal­ly address bot­tle­necks relat­ed to study­ing and treat­ing con­di­tions of the heart. 

Below we dive into some of these devel­op­ments with a look at how they are impact­ing car­diac drug dis­cov­ery and devel­op­ment and what his­tor­i­cal bar­ri­ers they overcome. 

Chron­ic dis­ease, chron­ic failure 

In an analy­sis of clin­i­cal devel­op­ment suc­cess rates from 2006 – 2015, car­dio­vas­cu­lar pro­grams (includ­ing car­diac- spe­cif­ic pro­grams) had a 6.6% chance of pro­gress­ing from Phase 1 clin­i­cal tri­als to FDA approval.

The size and com­plex­i­ty of car­diac clin­i­cal tri­als is like­ly a con­tribut­ing fac­tor. Dis­eases that affect >1 mil­lion peo­ple in the U.S. were three times less like­ly to gain approval from Phase I com­pared to non-oncol­o­gy orphan indications.

Advances in cell biol­o­gy and 3D models 

Car­diac dis­eases span a range of com­mon and rare con­di­tions, includ­ing heart attack, heart fail­ure, arrhyth­mia, sud­den death, car­diomy­opathies, and the many diverse genet­ic dis­eases of the heart. Coro­nary heart dis­ease is both a lead­ing cause of hos­pi­tal­iza­tion among adults 65 and over and the lead­ing cause of death in the Unit­ed States. 

There is a strong case for tar­get­ing genet­i­cal­ly defined car­diac dis­eases based on their causal mech­a­nisms rather than clin­i­cal symp­toms. As not­ed in the BIO report, Improve­ments in basic sci­ence can enable bet­ter suc­cess rates. For exam­ple, more pre­dic­tive ani­mal mod­els, ear­li­er tox­i­col­o­gy eval­u­a­tion, bio­mark­er iden­ti­fi­ca­tion, and new tar­get­ed deliv­ery tech­nolo­gies may increase future suc­cess in the clinic.”

While advances in basic sci­ence have fueled the field of oncol­o­gy, cre­at­ing rel­e­vant pre­clin­i­cal mod­els for car­diac dis­eases has proven chal­leng­ing. A car­diac or myocar­dial biop­sy is incred­i­bly inva­sive and unlike tumors or organs such as the liv­er, a patient’s heart cells can­not read­i­ly be grown in vit­ro or graft­ed into a mouse. While these obsta­cles have hin­dered the field in the past, they have also encour­aged extra­or­di­nary inno­va­tion – inno­va­tion that is now com­ing to fruition. 

The lim­i­ta­tions of car­diac ani­mal models 

The ances­tors of humans and mice diverged approx­i­mate­ly 90 mil­lion years ago.2 It’s no sur­prise, then, that research in rodents often doesn’t trans­late to humans. This is par­tic­u­lar­ly true in cer­tain dis­ease areas, such as car­diac patho­phys­i­ol­o­gy, which have been his­tor­i­cal­ly held back by the lim­i­ta­tions of var­i­ous ani­mal models. 

Progress has been made in recent years. To recre­ate heart phys­i­ol­o­gy, new­er small ani­mal mod­els (includ­ing mice, rats, and guinea pigs) employ var­i­ous meth­ods from genet­ic engi­neer­ing to sur­gi­cal tech­niques to phar­ma­co­log­i­cal approaches.3 Despite this, sig­nif­i­cant gaps remain: 

Fac­tor­ing in lifestyle: Dis­eases such as heart fail­ure rep­re­sent a com­plex mix of genet­ic and envi­ron­men­tal fac­tors. Some peo­ple with genet­ic pre­dis­po­si­tions may nev­er devel­op the dis­ease. Oth­ers may be impact­ed ear­li­er in life, part­ly due to lifestyle fac­tors such as stress, diet, and smok­ing. These vari­ables all com­pli­cate the patho­phys­i­ol­o­gy of car­diac dis­eases, mak­ing them hard to recre­ate in a sin­gle exper­i­men­tal model. 

No PDx equiv­a­lent: Anoth­er dis­ad­van­tage is the lack of patient-derived xenograft (PDx) mod­els. In oncol­o­gy, human tumor cells or tis­sue may be graft­ed into an immun­od­e­fi­cient or human­ized ani­mal mod­el (usu­al­ly a mouse). As the tumor grows in its new host, it pro­vides researchers with a unique win­dow into human can­cer biol­o­gy, allow­ing them to track the nat­ur­al pro­gres­sion of the dis­ease and the impact of var­i­ous inter­ven­tions. Heart cells can­not be trans­plant­ed in this way, elim­i­nat­ing a valu­able and robust research tool. 

Mice vs. men: While rodents form the back­bone of ani­mal research, they dif­fer great­ly from humans when it comes to the anato­my, phys­i­ol­o­gy, and pathol­o­gy of the heart. Com­pound­ing this, their small­er size com­pli­cates stud­ies that require imag­ing, sur­gi­cal inter­ven­tions, and blood sam­ple col­lec­tion. Larg­er ani­mal mod­els, such as pigs and dogs, address many of these chal­lenges but require far more resources and are thus used sparingly. 

While ani­mal stud­ies are valu­able, alter­na­tive mod­els are need­ed to cre­ate an afford­able and scal­able method for gen­er­at­ing human-rel­e­vant car­diac data. There is also a desire across the indus­try to reduce reliance on ani­mal mod­els from a wel­fare and research ethics stand­point, in line with the 3Rs (replace­ment, reduc­tion, and refinement). 

Val­o’s Biowire II

Hav­ing access to repro­ducible and scal­able func­tion­ing human heart tis­sue in the lab allows researchers to ask vital ques­tions and gen­er­ate the kinds of data that haven’t been read­i­ly avail­able in the car­diac space. Nuanced heart con­di­tions are trans­formed into com­pre­hen­si­ble genet­i­cal­ly defined dis­eases. This infor­ma­tion guides short-term deci­sions and can increase the over­all prob­a­bil­i­ty of drug devel­op­ment success. 

Valo mod­els bring to light muta­tions found in car­diomy­ocytes. By repli­cat­ing this nuanced human biol­o­gy in the lab­o­ra­to­ry, we can bet­ter under­stand dis­ease. With a blend of biol­o­gy and engi­neer­ing, we can inves­ti­gate how those genet­ic changes influ­ence chem­i­cal sig­nal­ing and con­trac­til­i­ty. We can even test the effects of dif­fer­ent com­pounds. All of this helps drug devel­op­ers antic­i­pate the pos­i­tive and neg­a­tive effects of a car­diac therapy. 

This qual­i­ty of data is what drug devel­op­ers need to move inves­ti­ga­tion­al ther­a­pies into the clin­ic, as a treat­ment for a genet­i­cal­ly defined dis­ease – or even for just one per­son. Along with devel­op­ing healthy and dis­eased car­diac mod­els, Valo can also make tis­sue rep­re­sen­ta­tive of a spe­cif­ic individual’s heart. This allows sci­en­tists and clin­i­cians to under­stand, exper­i­ment, and tai­lor their care on a case-by-case basis. In oth­er words, BiowireTM II unlocks pre­ci­sion car­diac medicine. 

The March Towards Pre­ci­sion Medicine 

Tai­lor­ing treat­ments based on cer­tain patient char­ac­ter­is­tics, such as genet­ics, con­fers many ben­e­fits, from greater ther­a­peu­tic effi­ca­cy to few­er adverse events and smarter more tar­get­ed clin­i­cal tri­al designs. Finan­cial­ly, this approach can also sig­nif­i­cant­ly decrease drug devel­op­ment costs and increase the like­li­hood of reg­u­la­to­ry approvals. 

One of the cen­tral tenets of this pre­ci­sion med­i­cine approach is the use of mea­sur­able bio­log­i­cal mark­ers (bio­mark­ers) of known sig­nif­i­cance. Bio­mark­ers can inform all stages of drug devel­op­ment, from enrich­ment to strat­i­fi­ca­tion, patient selec­tion, safe­ty, and effi­ca­cy. The chal­lenge in the car­diac space is uncov­er­ing human-spe­cif­ic bio­mark­ers as those iden­ti­fied in ani­mal mod­els often don’t trans­late. This is anoth­er area where advanced in vit­ro mod­els may add val­ue, mir­ror­ing human heart phys­i­ol­o­gy in health and disease. 

While not used as broad­ly as in oncol­o­gy, car­diac bio­mark­ers have been used in var­i­ous clin­i­cal tri­als. Com­mon exam­ples include CK, CK-MB, car­diac tro­ponin T, tro­ponin I, myo­glo­bin, and car­diac enzymes. While more options could help per­son­al­ize and de-risk new car­diac medicines. 

In 2000, approx­i­mate­ly 15% of oncol­o­gy clin­i­cal tri­als includ­ed a bio­mark­er. By 2018, a major­i­ty (55%) used at least one, in line with find­ings across the indus­try that enrich­ment of patient enroll­ment at the mol­e­c­u­lar lev­el cor­re­lates strong­ly with success.

While pre­ci­sion med­i­cine often focus­es on uncov­er­ing the genet­ic deter­mi­nants of dis­ease, many dis­eases are also influ­enced by envi­ron­men­tal fac­tors and the rela­tion­ship between genes and the envi­ron­ment. One of the ways this com­plex­i­ty is being addressed is through the intro­duc­tion of phe­nomap­ping. This approach involves group­ing patients based on the man­i­fes­ta­tion of their dis­ease rather than the dis­ease itself, allow­ing sci­en­tists to tar­get their drugs, devices, and clin­i­cal tri­als more specifically.

Ulti­mate­ly, bio­mark­ers, phe­nomap­ping, and per­son­al­ized med­i­cine more broad­ly are all inex­tri­ca­bly tied to data sci­ence. Of par­tic­u­lar val­ue is machine learn­ing, a sub­set of arti­fi­cial intel­li­gence (AI) in which com­put­er pro­grams access data and use it to learn” for themselves.

Machine learn­ing is an increas­ing­ly inte­gral part of car­diac sci­ence, help­ing define and diag­nose sub­sets of the dis­ease and expe­dit­ing the dis­cov­ery of new drug tar­gets. For exam­ple, in one phe­nomap­ping study, sci­en­tists ana­lyzed a com­bi­na­tion of 67 lab­o­ra­to­ry, elec­tro­car­dio­graph­ic, and echocar­dio­graph­ic mark­ers with machine learn­ing algo­rithms to find pat­terns in 397 patients with heart fail­ure with pre­served ejec­tion frac­tion (HFpEF).6 Data of this size and com­plex­i­ty can­not be parsed manually.

A genet­i­cal­ly defined alternative

A 2012 start­up, MyoKar­dia, rep­re­sents the shift towards pre­ci­sion med­i­cine with­in car­diac drug dis­cov­ery and devel­op­ment. Instead of approach­ing heart dis­ease as a broad pop­u­la­tion, MyoKar­dia tar­gets the under­ly­ing caus­es of spe­cif­ic car­diac myopathies, iden­ti­fy­ing sub­sets of patients who share spe­cif­ic dis­ease characteristics. 

In May 2020, the com­pa­ny announced results from its Phase 3 tri­al of mava­camten for the treat­ment of patients with symp­to­matic obstruc­tive hyper­trophic car­diomy­opa­thy. Despite being a piv­otal tri­al, it enrolled just 251 par­tic­i­pants. Around 50% were ran­dom­ized to receive a place­bo, while 123 received the inves­ti­ga­tion­al drug. The study ran for 30 weeks, meet­ing its pri­ma­ry and sec­ondary endpoints.

Lat­er that same year, Bris­tol Myers Squibb announced it had acquired MyoKar­dia for $13.1 bil­lion. Suc­cess­ful car­diac tri­als and exits will no doubt encour­age more inno­va­tion and ear­ly cap­i­tal invest­ments in the space.

Expen­sive tri­als, incre­men­tal benefits 

In an analy­sis of 138 piv­otal clin­i­cal tri­als that pro­vid­ed the basis for approval of 59 new ther­a­peu­tic agents by the FDA from 2015 to 2016, the medi­an esti­mat­ed cost per tri­al was found to be $19.0 mil­lion. The car­dio­vas­cu­lar tri­als were esti­mat­ed to be more than eight times more expen­sive than the others.

The high­est esti­mat­ed tri­al cost – $346.8 mil­lion – was for a non­in­fe­ri­or­i­ty tri­al that assessed the effi­ca­cy for hos­pi­tal­iza­tion and car­dio­vas­cu­lar mor­tal­i­ty of a new com­bi­na­tion drug for chron­ic heart fail­ure, sacu­bi­tril- val­sar­tan. The tri­al enrolled 8,442 patients with an aim to demon­strate non­in­fe­ri­or­i­ty to enalapril, a proven agent in this patient population.

Drugs are more expen­sive to test when they have small­er effects that require observ­ing more patients for longer peri­ods of time,” study author Thomas J. Moore told Car​dio​vas​cu​lar​Busi​ness​.com. This applies to many car­dio­vas­cu­lar drugs because they have to be shown non-infe­ri­or to drugs we already have, or because they are intend­ed to reduce risk of future events, such as strokes or heart attacks, that may occur rarely. In con­trast, an effec­tive new antibi­ot­ic could poten­tial­ly ben­e­fit every treat­ed patient in a few weeks’ time.” 

Look­ing ahead: The future of pre­ci­sion car­dio­vas­cu­lar medicine

The shift back into the car­diac research space is hap­pen­ing quick­ly for sev­er­al rea­sons. First and fore­most, the need remains: Mil­lions of Amer­i­cans and tens of mil­lions more world­wide are at risk for or suf­fer­ing from, poten­tial­ly fatal heart dis­eases. We also have a back­log of known tar­gets that are ripe for investigation.

On the finan­cial front, emerg­ing com­pa­nies are gain­ing trac­tion and recog­ni­tion for their abil­i­ty to define and seg­ment sub­sets with­in car­diac dis­eases. In 2020 alone, Verve Ther­a­peu­tics raised $63 mil­lion in a Series A2 financ­ing round to fur­ther its gene-edit­ing ther­a­pies for heart dis­ease. A small start­up, Novo Bio­science, raised $4 mil­lion to advance its pre­clin­i­cal regen­er­a­tive med­i­cine pro­gram, which aims to repair and restore dam­aged heart mus­cle tis­sue. Pri­or to acqui­si­tion, Val­o’s TARA Biosys­tems closed on a $10 mil­lion Series A2 financ­ing round. Groups like Bridge Bio are invest­ing eager­ly, and large bio­phar­ma com­pa­nies – like Bris­tol Myers Squibb – are acquir­ing estab­lished pro­grams in ear­ly, mid-and late-stage clin­i­cal trials.

Ush­er­ing in a new era of car­diac pre­ci­sion med­i­cine will require an inter­dis­ci­pli­nary effort. Experts from data sci­ence, mol­e­c­u­lar biol­o­gy, genomics, cell, and tis­sue engi­neer­ing, and more, will all be involved from drug dis­cov­ery through clin­i­cal tri­als and com­mer­cial­iza­tion. Those experts are now com­ing togeth­er to max­i­mize new tools and avail­able capital.

In this way, Val­o’s stem cell and tis­sue engi­neer­ing plat­form stands on the shoul­ders of giants, build­ing upon the diverse tech­nol­o­gy rev­o­lu­tions out­lined above and tak­ing it one step fur­ther. It address­es one of the major remain­ing bot­tle­necks in car­diac drug devel­op­ment: the abil­i­ty to trans­late research find­ings into the clinic.

Pre­ci­sion car­diac med­i­cine won’t hap­pen overnight, but the bar­ri­ers have fall­en. That goal is now with­in reach.