Danicamtiv: A Cardiovascular Drug Development Case Study

1. Introduction to Danicamtiv

Danicamtiv, an investigational small molecule, was developed as a therapeutic agent targeting specific cardiac conditions. It functions as a selective, allosteric activator of cardiac myosin, the motor protein responsible for heart muscle contraction.[1] The primary aim of Danicamtiv was to enhance cardiac systolic function, thereby improving the heart's pumping capability, while ideally preserving mechanical efficiency and minimizing adverse effects on diastolic relaxation or calcium homeostasis.[1]

Danicamtiv has been identified by several alternative names throughout its development, including MYK-491, BMS-986434, SAR440181, and DCM-1.[2] Its Chemical Abstracts Service (CAS) number is 1970972-74-7.[1] Chemically, it is classified as a small molecule and belongs to several chemical classes including amides, fluorinated hydrocarbons, isoxazoles, organic sulfur compounds, piperidines, and pyrazoles.[6] For clinical administration, Danicamtiv was formulated for oral delivery, available as tablets or a suspension.[5]

Table 1: Danicamtiv - Key Drug Information

Attribute	Details
Alternative Names	MYK-491, BMS-986434, SAR440181, DCM-1
CAS Number	1970972-74-7
Chemical Class	Small molecule, cardiac myosin activator; amides, fluorinated hydrocarbons, isoxazoles, organic sulfur compounds, piperidines, pyrazoles
Originator	MyoKardia, Inc.
Key Developers	MyoKardia, Inc., Sanofi (early collaboration), Bristol Myers Squibb

This table provides a foundational overview of Danicamtiv, consolidating key identifiers and information about its developmental origins, which are further elaborated in subsequent sections.

2. Development History and Sponsorship

The development trajectory of Danicamtiv involved several pharmaceutical entities, reflecting a common pattern in drug development where initial discovery by a smaller biotech company is followed by partnerships or acquisitions by larger pharmaceutical corporations.

Danicamtiv was originally discovered and developed by MyoKardia, Inc., a company specializing in targeted therapies for cardiovascular diseases.[5] Early in its development, MyoKardia entered into a partnership with Sanofi, which covered Danicamtiv (then MYK-491) along with other pipeline candidates like mavacamten and MYK-224, starting in 2014.[6] However, Sanofi discontinued this agreement in the first half of 2019. Subsequently, MyoKardia regained worldwide rights to all programs under this collaboration in January 2019 and specifically reacquired US royalty rights for mavacamten and MYK-224 in July 2019.[9] This shift marked a return of full control over Danicamtiv's development to MyoKardia prior to its subsequent acquisition.

A significant milestone in Danicamtiv's history was the acquisition of MyoKardia by Bristol Myers Squibb (BMS). This transaction, valued at approximately $13.1 billion, was announced in October 2020 and completed in November 2020.[10] Through this acquisition, Danicamtiv became part of BMS's cardiovascular pipeline. BMS continued the clinical development of Danicamtiv, sponsoring further Phase 1 and Phase 2 trials, including the notable CV028-005 study in patients with dilated cardiomyopathy (DCM).[4]

Despite the initial investment and continued clinical investigation under BMS, the development of Danicamtiv was ultimately discontinued. A key Phase 2 exploratory study (CV028-005, NCT04572893) in patients with DCM, which started in August 2020, was terminated early in February 2024.[4] The publicly stated reason for this termination was that "Business objectives have changed".[13] A Plain Language Summary of this trial, dated April 22, 2025, further confirmed the cessation of its development by stating, "There are no more ongoing studies of danicamtiv".[4] The drug is also notably absent from recent BMS pipeline updates.[14]

The decision to halt development, while officially attributed to shifting business objectives, may have been influenced by a combination of factors. The Plain Language Summary for the CV028-005 trial, though stating the tested dose levels were considered safe within the study's context, also reported that 5 out of 19 participants (26%) in Part B experienced serious adverse events, including liver injury, acute kidney injury, worsening of heart failure, and ventricular arrhythmia.[4] Such safety signals, particularly in a relatively small patient cohort and in the context of a chronic cardiovascular therapy where long-term safety is paramount, could significantly alter the benefit-risk assessment. This, coupled with potentially unsatisfactory interim efficacy data from the targeted DCM population or a strategic re-evaluation of BMS's cardiovascular portfolio, likely contributed to the discontinuation.

3. Mechanism of Action

Danicamtiv is designed as a selective, allosteric activator of cardiac myosin, the motor protein within sarcomeres responsible for generating the force of heart muscle contraction.[1] Its mechanism is intended to directly enhance systolic function by modulating the interaction between myosin and actin.

At the molecular level, Danicamtiv binds directly to cardiac myosin.[8] This interaction is believed to increase the number of myosin heads that can engage with actin filaments during the contractile cycle, effectively increasing the number of force-generating cross-bridges.[8] More detailed mechanistic studies suggest that Danicamtiv accelerates actomyosin association kinetics.[18] It also appears to alter cross-bridge cycling by decreasing the rate of adenosine diphosphate (ADP) release from myosin, which results in a prolonged interaction between actin and myosin.[16] Interestingly, some research indicates that while it increases the recruitment of myosin cross-bridges, it may reduce the size of the working stroke of individual myosin heads.[18] The net effect of these molecular alterations is an increase in the force-generating capacity of the cardiac muscle.

A key characteristic of Danicamtiv's intended mechanism was the enhancement of systolic function with minimal adverse impact on diastolic function (the heart's ability to relax and fill with blood) and without significantly altering intracellular calcium homeostasis.[1] This is a critical distinction from many traditional inotropic agents, which can impair relaxation or increase myocardial oxygen demand by altering calcium cycling, potentially leading to arrhythmias or ischemia. Danicamtiv has also been shown to increase the calcium sensitivity of cardiac myofibrils.[19]

Danicamtiv's mechanism has been compared to that of omecamtiv mecarbil, another cardiac myosin activator. While both drugs aim to enhance systolic function, differences in their molecular interactions with myosin may lead to distinct effects on cardiac mechanics. For instance, Danicamtiv has been suggested to have a smaller impact on myocardial relaxation kinetics compared to omecamtiv mecarbil, which could translate to better preservation of diastolic function.[16] The ability to improve contractility without unduly prolonging systole or impairing diastole was a central tenet of Danicamtiv's therapeutic rationale. However, some in vitro and in vivo data also suggest that at high concentrations, Danicamtiv could potentially limit diastolic performance.[23]

4. Pharmacology

The pharmacological profile of Danicamtiv has been investigated through preclinical studies and Phase 1 and Phase 2 clinical trials, focusing on its pharmacokinetics (PK) and pharmacodynamics (PD).

4.1 Pharmacokinetics

Preclinical Pharmacokinetics:

Studies in animal models provided initial insights into Danicamtiv's absorption, distribution, metabolism, and excretion (ADME) properties. In vitro metabolic pathways identified include CYP-mediated amide-cleavage, N-demethylation, and opening of the isoxazole and piperidine rings.10 Danicamtiv demonstrated high permeability and no significant efflux in Caco-2 cell assays, suggesting good potential for oral absorption. Plasma protein binding in humans was moderate, with a fraction unbound of 0.16, and the whole blood-to-plasma partitioning ratio was 0.8.10

In vivo clearance was generally low across species: 15.5 mL/min/kg in mice, 15.3 mL/min/kg in rats, 1.6 mL/min/kg in dogs, and 5.7 mL/min/kg in monkeys. The volume of distribution varied, from 0.24 L/kg in mice to 1.7 L/kg in rats. Oral bioavailability was also species-dependent, ranging from 26% in mice to 108% in dogs.10 Allometric scaling from these preclinical data predicted a human plasma clearance of 0.64 mL/min/kg, a volume of distribution of 0.98 L/kg, and a half-life of approximately 17.7 hours.10

Human Pharmacokinetics (Phase 1):

Several Phase 1 studies were conducted in healthy volunteers and patients.

A single-ascending dose (SAD) study (MYK-491-001) in healthy volunteers, with doses ranging from 3 mg to 550 mg, indicated that Danicamtiv's PK profile was amenable to once- or twice-daily dosing.27

Trial NCT05806359 was a SAD study evaluating safety, tolerability, and PK in healthy Japanese and Caucasian participants; this study has been completed, though specific PK data are not detailed in the provided materials.1

Trial NCT06027437 assessed the relative bioavailability of an intended commercial formulation versus a previous MyoKardia formulation and the effect of food on Danicamtiv PK in healthy adults. This trial is also listed as completed, but specific results regarding bioavailability or food effects are not available in the snippets.1

Drug-Drug Interactions (DDI):

Given that Danicamtiv undergoes CYP-mediated metabolism, DDI studies were important.

Trial NCT05952089 (previously CV028-009) evaluated the effect of Danicamtiv on the pharmacokinetics of midazolam (a CYP3A4 substrate) in patients with stable HFrEF. This study is reported as completed, but its results are not detailed.1

Trial NCT05162222 investigated the effect of itraconazole (a strong CYP3A inhibitor) and diltiazem (a moderate CYP3A inhibitor) on the PK of a single dose of Danicamtiv in healthy participants. This study is also listed as completed.1 While the snippets 48 discuss DDI studies involving itraconazole and diltiazem, these results pertain to a different BMS compound, milvexian (NCT02807909), and not Danicamtiv. Therefore, the specific impact of strong or moderate CYP3A inhibitors on Danicamtiv exposure remains unclarified by the provided research material. The initiation of these DDI studies underscores the recognized potential for interactions given Danicamtiv's metabolic pathways and the common polypharmacy in heart failure patients.

4.2 Pharmacodynamics

Effects on Cardiac Contractility and Systolic Function:

Pharmacodynamic assessments consistently showed that Danicamtiv enhances cardiac systolic function.

In the Phase 1a study (MYK-491-001) in healthy volunteers, Danicamtiv administration led to a 5-20% increase in cardiac contractility across various echocardiographic parameters, including left ventricular stroke volume (LVSV), ejection fraction (LVEF), and fractional shortening (LVFS), particularly at higher drug concentrations. A modest prolongation of systolic ejection time (SET) was also observed, with minimal impact on diastolic function.27

In the Phase 2a trial in patients with HFrEF (Voors et al., 2020), Danicamtiv (at plasma concentrations ≥2000 ng/mL) demonstrated statistically significant improvements [19]:

• Increased LVSV by up to +7.8 mL (P < 0.01).
• Improved global longitudinal strain (LVGLS) by up to -1.0% (P < 0.05).
• Improved global circumferential strain (LVGCS) by up to -3.3% (P < 0.01).
• Increased SET by a mean placebo-corrected 36 ms to 48 ms (P < 0.01). LVEF did not show a significant change in the multiple-dose part of this HFrEF trial, although an increase was noted in the single-dose crossover phase.[19]

Effects on Left Atrial (LA) Volume and Function:

A notable finding from the Phase 2a HFrEF trial was the positive impact of Danicamtiv on LA parameters 19:

• Decreased LA minimal volume index (LA_min_Vi) by up to -2.4 mL/m² (P < 0.01).
• Increased LA emptying fraction (LAEF) with a mean placebo-corrected increase of +3.3% to +3.6% (P < 0.05).
• Increased LA function index (LAFI) by up to +6.1 (P < 0.01). These improvements in LA structure and function were considered significant, as LA parameters are prognostic indicators in heart failure and for atrial fibrillation.[35] Preclinical data supported these clinical observations, indicating a direct effect of Danicamtiv on LA contractility.[19] This suggested a potential dual benefit on both left ventricular and atrial performance.

The consistent pharmacodynamic effects on systolic function observed in both healthy volunteers and HFrEF patients provided support for Danicamtiv's mechanism as a cardiac myosin activator. The unexpected positive effects on LA function added another dimension to its potential therapeutic profile, suggesting it might offer more comprehensive benefits in heart failure than initially anticipated.

5. Clinical Development Program

Danicamtiv underwent a series of clinical trials, progressing from Phase 1 studies in healthy volunteers to Phase 2 trials in patient populations with HFrEF and DCM. The program aimed to establish the safety, tolerability, PK/PD profile, and preliminary efficacy of the drug.

Table 2: Overview of Key Clinical Trials for Danicamtiv

Trial ID	Phase	Indication(s)	Key Objectives	Participants (N)	Status	Key Outcomes Summary (from snippets)
MYK-491-001	1a	Healthy Volunteers	Safety, tolerability, PK, PD (single ascending dose)	64	Completed	Well tolerated; increased contractility (5-20%) at higher doses; minimal diastolic impact 27
NCT03447990 (MYK-491-003)	1b/2a	Stable HFrEF	Safety, tolerability, PK, PD (single & multiple doses), preliminary efficacy	40 (30 Danicamtiv, 10 Placebo in multi-dose part)	Completed	Well tolerated; improved LVSV, LV strain, LA volume & function; no significant LVEF change (multi-dose) 19
NCT04572893 (CV028-005 / MYK-491-006)	2a	Primary DCM (MYH7/TTN variants or other causalities)	Safety, preliminary efficacy	41 (enrolled)	Terminated (Feb 2024)	Part A (N=41): 15% AEs, 0% SAEs. Part B (N=19): 90% AEs, 26% SAEs (liver/kidney injury, worsening HF, arrhythmia). Terminated due to "business objectives changed" 4
NCT06027437	1	Healthy Volunteers	Relative bioavailability (commercial vs. MyoKardia formulation), food effect	21	Completed (Nov 2023)	Results not detailed in snippets 6
NCT05806359	1	Stable HFrEF Patients	Effect of Danicamtiv on midazolam PK (DDI)	13	Completed (Apr 2024)	Results not detailed in snippets 1
NCT05162222	1	Healthy Volunteers	Effect of itraconazole or diltiazem on Danicamtiv PK (DDI)	30	Completed	Results not detailed in snippets 1
NCT03062956	1	Dilated Cardiomyopathy	Safety, PK, PD	N/A (mentioned as a Phase 1 trial in DCM)	Completed	General reference, specific results not detailed 1

Indications Investigated:

The primary indications explored for Danicamtiv were:

• Heart Failure with Reduced Ejection Fraction (HFrEF): The Phase 2a trial (NCT03447990) provided initial proof-of-concept data in this broad patient population, demonstrating improvements in several echocardiographic parameters of systolic and left atrial function.[19] These findings were published by Voors et al. in the European Journal of Heart Failure in 2020.[19]
• Dilated Cardiomyopathy (DCM): Development subsequently focused on primary DCM, particularly cases linked to genetic variants in sarcomeric proteins like MYH7 (myosin heavy chain 7) and TTN (titin).[2] The rationale was that Danicamtiv's direct action on myosin might be particularly beneficial in conditions where the underlying defect lies within the contractile machinery of the heart muscle.[8] The open-label, exploratory Phase 2 study (CV028-005 / NCT04572893) was designed to assess safety and preliminary efficacy in this targeted DCM population.[4] This trial, however, was terminated prematurely.
• Atrial Fibrillation: While not a primary indication with dedicated trials detailed in the snippets, the observed positive effects on LA volume and function in the HFrEF trial led to suggestions of potential utility in patients with atrial fibrillation, a common comorbidity in heart failure.[35]

The clinical development program for Danicamtiv did not advance to Phase 3 trials prior to its discontinuation.[16] The shift in focus from a broader HFrEF population to the more specific genetic DCM population represented a strategic effort to identify a patient group where Danicamtiv's unique mechanism of action could provide the most significant benefit. The termination of the CV028-005 trial marked the end of this clinical development effort.

6. Clinical Efficacy

The clinical efficacy of Danicamtiv was primarily assessed in Phase 2a trials for HFrEF and DCM.

Heart Failure with Reduced Ejection Fraction (HFrEF):

The Phase 2a trial (NCT03447990), results of which were published by Voors et al. (2020), showed that Danicamtiv, at plasma concentrations ≥2000 ng/mL, led to statistically significant improvements in several echocardiographic measures of cardiac function compared to placebo in patients with stable chronic HFrEF.19 These are summarized in Table 3.

Table 3: Summary of Efficacy Outcomes from Phase 2a HFrEF Trial (Voors et al., 2020; NCT03447990) at Plasma Concentrations ≥2000 ng/mL

Parameter	Placebo-Corrected Difference (Danicamtiv vs. Placebo)	P-value
LV Stroke Volume (LVSV)	Up to +7.8 mL	< 0.01
LV Global Longitudinal Strain (LVGLS)	Up to -1.0% (improvement)	< 0.05
LV Global Circumferential Strain (LVGCS)	Up to -3.3% (improvement)	< 0.01
LA Minimal Volume Index (LA_min_Vi)	Up to -2.4 mL/m²	< 0.01
LA Function Index (LAFI)	Up to +6.1	< 0.01
Systolic Ejection Time (SET)	Mean increase 36-48 ms	< 0.01

Source: [19]

Notably, LVEF did not show a statistically significant change in the multiple-dose portion of this trial, although an increase was observed in the single-dose crossover phase.[19] The study did not report on functional capacity measures such as the 6-minute walk test (6MWT) or the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the provided publication summary.

Dilated Cardiomyopathy (DCM):

The Phase 2 exploratory study in DCM (CV028-005, NCT04572893) was designed to assess safety and preliminary efficacy.4 However, this trial was terminated early in February 2024 due to "business objectives have changed".4 The Plain Language Summary for this trial, dated April 2025, focuses on the safety findings and the early termination, and does not provide specific efficacy outcomes beyond stating the study's aim to understand Danicamtiv's effect on primary DCM.4 Given the premature termination, it is unlikely that comprehensive or definitive efficacy data for DCM were generated or publicly disseminated. No efficacy data from this trial were presented at major cardiology conferences (AHA, ACC, ESC, HFSA) between 2022 and 2025, according to the available snippets.4

The positive hemodynamic findings in the HFrEF trial were initially promising and consistent with Danicamtiv's mechanism of action. The lack of robust, publicly available efficacy data from the more targeted DCM trial, which was halted, suggests that the preliminary efficacy signals in that specific patient population may not have been sufficiently compelling to warrant continued development, especially when considered alongside other factors such as safety or strategic priorities.

7. Safety and Tolerability

The safety and tolerability profile of Danicamtiv was evaluated across its clinical trial program.

Healthy Volunteers (Phase 1a, MYK-491-001):

In the single-ascending dose study involving 64 healthy volunteers, Danicamtiv was generally well-tolerated at doses up to 550 mg. No dose-limiting toxicities were observed. The most common adverse event (AE) reported was headache. Transient and spontaneously resolving arrhythmias were also noted, but there was no clear trend of increased AE frequency with higher doses.27

HFrEF Patients (Phase 2a, Voors et al., 2020):

In patients with stable chronic HFrEF, Danicamtiv was also generally well-tolerated.19

• Treatment-emergent adverse events (TEAEs) were reported in 57% of patients receiving Danicamtiv compared to 40% in the placebo group. Most TEAEs were mild.
• No TEAE led to permanent treatment discontinuation or death.
• One serious AE, hyperkalemia, occurred in a Danicamtiv-treated patient but resolved.
• The most common TEAEs in the Danicamtiv group (each reported in two patients) included increases in hepatic transaminases, contact dermatitis, fatigue, and non-sustained ventricular tachycardia (NSVT).
• A notable finding was transient, asymptomatic increases in cardiac troponin I (cTnI) or high-sensitivity troponin T (hs-TnT) in 23% of Danicamtiv-treated patients, versus none in the placebo group. One such case was assessed as a possible myocardial injury, which resolved without intervention.
• Holter monitoring showed no increase in atrial or ventricular arrhythmias, and no QTc prolongation was observed with Danicamtiv compared to placebo.

DCM Patients (Phase 2 - CV028-005):

The Plain Language Summary for this terminated trial provides insights into the safety observations 4:

• The dose levels tested were considered "safe for participants" within the context of this exploratory study.
• In Part A (41 participants, shorter exposure/dose titration), 15% experienced any side effects, with no serious side effects reported.
• In Part B (19 participants, potentially longer exposure/sustained doses), a significantly higher proportion experienced side effects: 90% reported any side effects, and 26% (5 participants) experienced serious side effects.
• The 7 serious side effects experienced by these 5 participants in Part B included: liver injury, sudden (acute) kidney injury, worsening of heart failure, urinary tract infection, and life-threatening irregular heart rhythm (ventricular arrhythmia) requiring electronic shock treatment.
• Common related side effects (affecting 1-2 participants each) were abdominal pain, upper abdominal pain, and accidental overdose.

Table 4: Summary of Reported Adverse Events in Key Danicamtiv Clinical Trials

Trial (Indication)	Adverse Event Category	Danicamtiv Group	Placebo Group	Notes
Phase 1a (Healthy Volunteers) 27	Most Common AE	Headache	N/A	Well tolerated up to 550mg. Transient arrhythmias reported.
Phase 2a (HFrEF) 19	Any TEAE	57% (17/30)	40% (4/10)	Mostly mild.
	Serious AE	3.3% (1/30) (Hyperkalemia)	0% (0/10)	Resolved.
	Common TEAEs (≥2 patients)	Increased transaminases, contact dermatitis, fatigue, NSVT	-	-
	Troponin Increase	23% (7/30)	0% (0/10)	Asymptomatic, transient. One possible myocardial injury (resolved).
CV028-005 (DCM) - Part A 4	Any Side Effects	15% (6/41)	N/A (Open-label components)	-
	Serious Side Effects	0% (0/41)	N/A	-
CV028-005 (DCM) - Part B 4	Any Side Effects	90% (17/19)	N/A	-
	Serious Side Effects	26% (5/19)	N/A	Liver injury, acute kidney injury, worsening HF, UTI, ventricular arrhythmia.

The safety profile of Danicamtiv appeared acceptable in early studies with healthy volunteers and in the HFrEF patient population, with most AEs being mild and transient. However, the emergence of several serious adverse events affecting multiple organ systems (hepatic, renal, cardiac) in a small cohort of DCM patients during Part B of the CV028-005 trial is a significant finding.[4] This escalation in SAE incidence and severity in the DCM trial, particularly involving events like liver and kidney injury and worsening heart failure or arrhythmias, would undoubtedly raise substantial safety concerns. Such findings, even if affecting a limited number of patients in an exploratory study, could heavily influence the benefit-risk assessment and contribute to a decision to halt further development, aligning with the eventual discontinuation of the program. The transient troponin elevations observed earlier in the HFrEF study, while mostly asymptomatic, might have been an early indicator of potential cardiac effects that warranted careful monitoring and could have gained more significance in light of the later SAEs in the DCM population.

8. Regulatory Status

Danicamtiv remained an investigational drug throughout its development and did not receive marketing approval from major regulatory agencies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[40]

There is no information in the provided research snippets to suggest that Danicamtiv received Orphan Drug Designation (ODD) from either the FDA or EMA for its investigated indications of DCM or HFrEF.[40] While other cardiovascular drugs, such as mavacamten for obstructive HCM and ixmyelocel-T for DCM, have received ODD [45], this was not reported for Danicamtiv. The absence of ODD could be due to various reasons, including the conditions not meeting the specific prevalence criteria for orphan diseases as defined by the regulatory agencies, or a strategic decision by the sponsor not to pursue this designation.

9. Discontinuation of Development

The clinical development of Danicamtiv was officially discontinued by Bristol Myers Squibb. The pivotal event signaling this cessation was the early termination of the Phase 2 exploratory study in primary dilated cardiomyopathy (CV028-005 / NCT04572893) in February 2024.[4] This trial, which was a cornerstone of Danicamtiv's later-stage investigation, was halted significantly ahead of its planned completion date (originally anticipated for February 2026).[13]

The sponsor, Bristol Myers Squibb, cited "Business objectives have changed" as the reason for the trial's termination.[13] This was further corroborated by a Plain Language Summary for the CV028-005 study, dated April 22, 2025, which explicitly stated: "There are no more ongoing studies of danicamtiv".[4] Consistent with this, Danicamtiv is no longer featured in Bristol Myers Squibb's current cardiovascular pipeline disclosures.[14]

While "changed business objectives" is a general corporate explanation, the underlying factors for such a decision in pharmaceutical development are often multifaceted. The emergence of serious adverse events in Part B of the CV028-005 trial, affecting 5 of the 19 participants and including liver injury, acute kidney injury, worsening heart failure, and ventricular arrhythmia, likely played a critical role in reassessing the drug's viability.[4] Although the Plain Language Summary mentioned that the tested dose levels were deemed "safe for participants" within the specific exploratory context of that study, the nature and frequency of these SAEs in a vulnerable patient population could have significantly skewed the benefit-risk profile negatively.

Furthermore, the broader therapeutic landscape for heart failure and cardiomyopathies is competitive and rapidly evolving. The FDA's earlier decision not to approve omecamtiv mecarbil, another cardiac myosin activator with a somewhat related mechanism, may also have influenced the perceived development risk and commercial prospects for Danicamtiv.[40] Ultimately, a combination of emerging clinical data (potentially including less compelling efficacy than hoped for in the DCM cohort, alongside the safety signals), strategic portfolio prioritization within BMS, and the overall challenges of developing novel cardiac therapies likely contributed to the decision to discontinue the Danicamtiv program.

10. Conclusion

Danicamtiv (MYK-491, BMS-986434) was an investigational oral small molecule designed as a selective cardiac myosin activator. Its mechanism aimed to enhance systolic function by directly modulating the actin-myosin interaction, with early indications of a potentially favorable profile regarding diastolic function and calcium homeostasis compared to older inotropes. The drug progressed through Phase 1 studies in healthy volunteers and patients, and into Phase 2a trials for heart failure with reduced ejection fraction (HFrEF) and, more specifically, primary dilated cardiomyopathy (DCM), including forms with genetic origins.

Early clinical data, particularly from the HFrEF trial, showed promising pharmacodynamic effects, including improvements in left ventricular stroke volume and left atrial function. However, the development program was discontinued by Bristol Myers Squibb following the early termination of the Phase 2 DCM trial (CV028-005) in February 2024. While the official reason cited was a change in business objectives, the emergence of serious adverse events in a cohort of the DCM trial, including hepatic, renal, and cardiac complications, likely contributed significantly to this decision by altering the perceived benefit-risk balance.

The journey of Danicamtiv from a promising novel cardiac agent through to discontinuation underscores the inherent complexities and risks in cardiovascular drug development. Even with a targeted mechanism of action and positive early physiological signals, demonstrating a clear and safe clinical benefit in chronic, complex conditions like heart failure and cardiomyopathy remains a formidable challenge. The Danicamtiv experience serves as a case study on how evolving clinical data, strategic corporate decisions, and the competitive landscape collectively shape the fate of investigational therapies.

Works cited

1. Danicamtiv (MYK-491) | Cardiac Myosin Activator - MedchemExpress.com, accessed June 3, 2025, https://www.medchemexpress.com/danicamtiv.html
2. Danicamtiv – Application in Therapy and Current Clinical Research, accessed June 3, 2025, https://clinicaltrials.eu/inn/danicamtiv/
3. Danicamtiv | CAS NO.:1970972-74-7 - GlpBio, accessed June 3, 2025, https://www.glpbio.com/danicamtiv.html
4. Plain Language Summary of Clinical Study Results - Thank You!, accessed June 3, 2025, https://www.bms.com/assets/bms/shared/plain-language-summary/cv028-005/CV028-005-pls-eng-final-update-18April2025-approved.pdf
5. Risk Adjusted Net Present Value: What is the current valuation of Bristol-Myers Squibb's Danicamtiv - Pharmaceutical Technology, accessed June 3, 2025, https://www.pharmaceutical-technology.com/data-insights/danicamtiv-bristol-myers-squibb-net-present-value/
6. Danicamtiv - MyoKardia - AdisInsight - Springer, accessed June 3, 2025, https://adisinsight.springer.com/drugs/800048829
7. Phase 2a study of danicamtiv in MYH7-DCM or TTN-DCM patients, accessed June 3, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/phase-2a-study-of-myk-491-in-myh7-dcm-patients/
8. MyoKardia Doses First Patient in Phase 2 Clinical Trial of Danicamtiv in Genetic Dilated Cardiomyopathy - FirstWord Pharma, accessed June 3, 2025, https://firstwordpharma.com/story/5102093
9. Bristol Myers Squibb Takes Heart Drug Firm MyoKardia - CHEManager Online, accessed June 3, 2025, https://chemanager-online.com/en/news/bristol-myers-squibb-takes-heart-drug-firm-myokardia
10. Danicamtiv - Wikipedia, accessed June 3, 2025, https://en.wikipedia.org/wiki/Danicamtiv
11. Bristol Myers Squibb to Acquire MyoKardia for $13.1 Billion in Cash, accessed June 3, 2025, https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-to-Acquire-MyoKardia-for-13.1-Billion-in-Cash/default.aspx
12. (a)(5)(xv) - SEC.gov, accessed June 3, 2025, https://www.sec.gov/Archives/edgar/data/14272/000114036120025760/nt10016009x4_ex99a5xv.htm
13. danicamtiv (MYK-491) News - LARVOL Sigma, accessed June 3, 2025, https://sigma.larvol.com/product.php?e1=733493&tab=newstrac
14. Pharmaceutical research and development pipeline - Bristol Myers Squibb, accessed June 3, 2025, https://www.bms.com/researchers-and-partners/in-the-pipeline.html
15. Our research in cardiovascular disease - Bristol Myers Squibb, accessed June 3, 2025, https://www.bms.com/researchers-and-partners/areas-of-focus/our-research-in-cardiovascular.html
16. Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge ..., accessed June 3, 2025, https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.322629
17. Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge ..., accessed June 3, 2025, https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.123.322629
18. Danicamtiv reduces myosin's working stroke but enhances ... - bioRxiv, accessed June 3, 2025, https://www.biorxiv.org/content/10.1101/2024.10.09.617269v1
19. Effects of danicamtiv, a novel cardiac myosin activator, in heart ..., accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/32558989/
20. Danicamtiv (MYK-491, SAR440181, CAS Number: 1970972-74-7) | Cayman Chemical, accessed June 3, 2025, https://www.caymanchem.com/product/36875
21. Effects of danicamtiv, a novel cardiac myosin activator, in heart ..., accessed June 3, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689751/
22. Effect of the Novel Myotrope Danicamtiv on Cross‐Bridge Behavior in Human Myocardium, accessed June 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10757519/
23. (PDF) The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications - ResearchGate, accessed June 3, 2025, https://www.researchgate.net/publication/366637846_The_Novel_Cardiac_Myosin_Activator_Danicamtiv_Improves_Cardiac_Systolic_Function_at_the_Expense_of_Diastolic_Dysfunction_In_Vitro_and_In_Vivo_Implications_for_Clinical_Applications
24. Danicamtiv | CAS#1970972-74-7 | Positive Inotropic Agent | MedKoo, accessed June 3, 2025, https://www.medkoo.com/products/20510
25. Preclinical in vitro and in vivo pharmacokinetic properties of ..., accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/33078965/
26. www.tandfonline.com, accessed June 3, 2025, https://www.tandfonline.com/doi/full/10.1080/00498254.2020.1839982
27. MyoKardia Presents Results from Phase 1a Clinical Trial of MYK-491 at the European Society of Cardiology Heart Failure Congress in Athens, Greece - BioSpace, accessed June 3, 2025, https://www.biospace.com/myokardia-presents-results-from-phase-1a-clinical-trial-of-myk-491-at-the-european-society-of-cardiology-heart-failure-congress-in-athens-greece
28. Danicamtiv - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 3, 2025, https://synapse.patsnap.com/drug/9e2d757e86774fd29b5b3665711b40d7
29. Danicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament - PubMed, accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/39416013/
30. Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle - PubMed, accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/37470183/
31. Danicamtiv (MYK-491) | 99.13%(HPLC) | Cardiac Myosin activator - Selleck Chemicals, accessed June 3, 2025, https://www.selleckchem.com/products/danicamtiv-myk-491.html
32. A Study to Assess the Effect of Danicamtiv on the Drug Levels of Midazolam in Participants With Stable Heart Failure - BMS Clinical Trials, accessed June 3, 2025, https://www.bmsstudyconnect.com/dk/en/clinical-trials/NCT05952089.html
33. Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial - PubMed Central, accessed June 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7689751/
34. A Study to Evaluate the Effect of Co-administration of Itraconazole or Diltiazem on the Single-dose of Danicamtiv in Healthy Participants - BMS Clinical Trials, accessed June 3, 2025, https://www.bmsstudyconnect.com/cz/en/clinical-trials/NCT05162222.html
35. MyoKardia Announces Positive Data from Phase 2a Clinical Trial of Danicamtiv Presented at ESC's HFA Discoveries with Simultaneous Publication in European Journal of Heart Failure - BioSpace, accessed June 3, 2025, https://www.biospace.com/myokardia-announces-positive-data-from-phase-2a-clinical-trial-of-danicamtiv-presented-at-esc-s-hfa-discoveries-with-simultaneous-publication-in-european-journal-of-heart-failure
36. MyoKardia Announces Positive Data from Phase 2a Clinical Trial of Danicamtiv Presented at ESC's HFA Discoveries with Simultaneous Publication in European Journal of Heart Failure - GlobeNewswire, accessed June 3, 2025, https://www.globenewswire.com/news-release/2020/06/22/2051190/37418/en/MyoKardia-Announces-Positive-Data-from-Phase-2a-Clinical-Trial-of-Danicamtiv-Presented-at-ESC-s-HFA-Discoveries-with-Simultaneous-Publication-in-European-Journal-of-Heart-Failure.html
37. PRODUCT INFORMATION - Cayman Chemical, accessed June 3, 2025, https://cdn.caymanchem.com/cdn/insert/36875.pdf
38. Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle | bioRxiv, accessed June 3, 2025, https://www.biorxiv.org/content/10.1101/2023.01.31.526380v1.full-text
39. MyoKardia Announces Positive Data from Phase 2a Clinical Trial of Danicamtiv Presented at ESC's HFA Discoveries with Simultaneous Publication in European Journal of Heart Failure - FirstWord Pharma, accessed June 3, 2025, https://firstwordpharma.com/story/5044169
40. Danicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament, accessed June 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11482770/
41. Mavacamten: First Approval, accessed June 3, 2025, https://d-nb.info/127024292X/34
42. Which of these orphan drug designations is right for you? - TMC Pharma, accessed June 3, 2025, https://tmcpharma.com/fda-vs-ema-orphan-drug-designation/
43. Applying for orphan designation | European Medicines Agency (EMA), accessed June 3, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/research-development/orphan-designation-research-development/applying-orphan-designation
44. Dilated cardiomyopathy - Orphanet, accessed June 3, 2025, https://www.orpha.net/en/disease/detail/217604
45. Dilated Cardiomyopathy (DCM) - Market Insights, Epidemiology and Market Forecast, accessed June 3, 2025, https://www.delveinsight.com/report-store/dilated-cardiomyopathy-dcm-market-insights
46. MyoKardia Doses First Patient in Phase 3 VALOR-HCM Trial of Mavacamten - ngram, accessed June 3, 2025, https://www.ngram.com/news/ed1244ebaaca2e5f5c453cde6c3c96476fc70e157d0925e540e50e6ec6771b4d714b4e4b831f10e75d109ceee7532156e2f98c306c17a3bee5ab14f33c720ad5
47. Bristol Myers Squibb to Present Data at ASCO® 2025 Highlighting Differentiated Research Platform of Oncology Treatments and Innovative Research Pipeline, accessed June 3, 2025, https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-to-Present-Data-at-ASCO-2025-Highlighting-Differentiated-Research-Platform-of-Oncology-Treatments-and-Innovative-Research-Pipeline/default.aspx
48. Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor - PubMed, accessed June 3, 2025, https://pubmed.ncbi.nlm.nih.gov/35641780/
49. Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor - PMC, accessed June 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9381674/
50. Diltiazem and itraconazole Interactions - Drugs.com, accessed June 3, 2025, https://www.drugs.com/drug-interactions/diltiazem-with-itraconazole-890-0-1406-0.html?professional=1
51. Diltiazem and itraconazole Interactions - Drugs.com, accessed June 3, 2025, https://www.drugs.com/drug-interactions/diltiazem-with-itraconazole-890-0-1406-0.html
52. (PDF) Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor - ResearchGate, accessed June 3, 2025, https://www.researchgate.net/publication/360992455_Effects_of_Itraconazole_and_Diltiazem_on_the_Pharmacokinetics_and_Pharmacodynamics_of_Milvexian_A_Factor_XIa_Inhibitor