A Phase 1, Open-label, Randomized, Single-dose, 3-Period, 3-Sequence Crossover Study to Assess the Relative Bioavailability of the Intended Commercial Formulation Versus the Previous MyoKardia Formulation of Danicamtiv and to Assess the Effect of Food on the Pharmacokinetics of the Intended Commercial Formulation in Healthy Adult Participants

The purpose of this study is to assess the relative biological availability and the effect of food on the drug levels of Danicamtiv in health adults.

Start Date05 Sep 2023

Sponsor / Collaborator

Bristol Myers Squibb Co.

NCT05952089

/ CompletedPhase 1

An Open-label, Single-sequence Study to Evaluate the Effect of Coadministration of Danicamtiv on the Pharmacokinetics of Midazolam in Patients With Stable Heart Failure With Reduced Ejection Fraction

The purpose of this study is assess the effect of danicamtiv, as an inducer on the drug levels of midazolam in participants with heart failure with reduced ejection fraction (HFrEF).

Start Date17 Aug 2023

Sponsor / Collaborator

Bristol Myers Squibb Co.

NCT05806359

/ CompletedPhase 1

A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Danicamtiv in Healthy Japanese and Caucasian Participants

The purpose of this study is to assess the safety, tolerability, and single-dose pharmacokinetics of danicamtiv in healthy Japanese and Caucasian participants.

Start Date31 Mar 2023

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with Danicamtiv

100 Translational Medicine associated with Danicamtiv

100 Patents (Medical) associated with Danicamtiv

Literatures (Medical) associated with Danicamtiv

01 Jan 2025·BIOPHYSICAL JOURNAL

Bayesian estimation of muscle mechanisms and therapeutic targets using variational autoencoders

Article

Author: Daniel, Thomas ; Moussavi-Harami, Farid ; Davis, Jennifer ; Kooiker, Kristina B ; Tune, Travis

Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible damage. With advancements in genotyping, early diagnosis is now possible, potentially introducing earlier treatment. However, the intricate structure of muscle and its myriad proteins make treatment predictions challenging. Here, we approach the problem of estimating therapeutic targets for a mutation in mouse muscle using a spatially explicit half sarcomere muscle model. We selected nine rate parameters in our model linked to both small molecules and cardiomyopathy-causing mutations. We then randomly varied these rate parameters and simulated an isometric twitch for each combination to generate a large training data set. We used this data set to train a conditional variational autoencoder, a technique used in Bayesian parameter estimation. Given simulated or experimental isometric twitches, this machine learning model is able to then predict the set of rate parameters that are most likely to yield that result. We then predict the set of rate parameters associated with twitches from control mice with the cardiac troponin C (cTnC) I61Q variant and control twitches treated with the myosin activator Danicamtiv, as well as model parameters that recover the abnormal I61Q cTnC twitches.

01 Sep 2024·JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY

Danicamtiv affected isometric force and cross-bridge kinetics similarly in skinned myocardial strips from male and female rats

Article

Author: Turner, Kyrah L ; Vander Top, Blake J ; Awinda, Peter O ; Tanner, Bertrand C W

Myotropes are pharmaceuticals that have recently been developed or are under investigation for the treatment of heart diseases. Myotropes have had varied success in clinical trials. Initial research into myotropes have widely focused on animal models of cardiac dysfunction in comparison with normal animal cardiac physiology-primarily using males. In this study we examined the effect of danicamtiv, which is one type of myotrope within the class of myosin activators, on contractile function in permeabilized (skinned) myocardial strips from male and female Sprague-Dawley rats. We found that danicamtiv increased steady-state isometric force production at sub-maximal calcium levels, leading to greater Ca²⁺-sensitivity of contraction for both sexes. Danicamtiv did not affect maximal Ca²⁺-activated force for either sex. Sinusoidal length-perturbation analysis was used to assess viscoelastic myocardial stiffness and cross-bridge cycling kinetics. Data from these measurements did not vary with sex, and the data suggest that danicamtiv slows cross-bridge cycling kinetics. These findings imply that danicamtiv increases force production via increasing cross-bridge contributions to activation of contraction, especially at sub-maximal Ca²⁺-activation. The inclusion of both sexes in animal models during the formative stages of drug development could be helpful for understanding the efficacy or limitation of a drug's therapeutic impact on cardiac function.

17 Oct 2023·Journal of the American Heart Association

Effect of the Novel Myotrope Danicamtiv on Cross‐Bridge Behavior in Human Myocardium

Article

Author: Stelzer, Julian E ; Choi, Joohee ; Campbell, Kenneth S ; Holmes, Joshua B

Background:

Omecamtiv mecarbil (OM) and danicamtiv both increase myocardial force output by selectively activating myosin within the cardiac sarcomere. Enhanced force generation is presumably due to an increase in the total number of myosin heads bound to the actin filament; however, detailed comparisons of the molecular mechanisms of OM and danicamtiv are lacking.

Methods and Results:

The effect of OM and danicamtiv on Ca 2+ sensitivity of force generation was analyzed by exposing chemically skinned myocardial samples to a series of increasing Ca 2+ solutions. The results showed that OM significantly increased Ca 2+ sensitivity of force generation, whereas danicamtiv showed similar Ca 2+ sensitivity of force generation to untreated preparations. A direct comparison of OM and danicamtiv on dynamic cross‐bridge behavior was performed at a concentration that produced a similar force increase when normalized to predrug levels at submaximal force (pCa 6.1). Both OM and danicamtiv‐treated groups slowed the rates of cross‐bridge detachment from the strongly bound state and cross‐bridge recruitment into the force‐producing state. Notably, the significant OM‐induced prolongation in the time to reach force relaxation and subsequent commencement of force generation following rapid stretch was dramatically reduced in danicamtiv‐treated myocardium.

Conclusions:

This is the first study to directly compare the effects of OM and danicamtiv on cross‐bridge kinetics. At a similar level of force enhancement, danicamtiv had a less pronounced effect on the slowing of cross‐bridge kinetics and, therefore, may provide a similar improvement in systolic function as OM without excessively prolonging systolic ejection time and slowing cardiac relaxation facilitating diastolic filling at the whole‐organ level.

News (Medical) associated with Danicamtiv

07 Jan 2021

·www.biospace.com

COVID-19’s Effect on Biopharma M&As in 2020

Although they don’t necessarily agree on numbers, most reports indicate that 2020 was not a particularly good year for mergers and acquisitions in the biopharma industry. Although they don’t necessarily agree on numbers, most reports indicate that 2020 was not a particularly good year for mergers and acquisitions (M&As) in the biopharma industry. Some of that disagreement on numbers is likely related to how they are defining sectors—healthcare versus biotech and pharmaceutical, for example. But everyone agrees that the uncertainty and devastation caused by the COVID-19 pandemic had a major dampening effect on deal-making in 2020. Here’s a look. Healthcare According to Express Pharma, the healthcare industry had 103 deals in December 2020 worth $55.3 billion. This is actually significantly higher than the 12-month average from December 2019 to November 2020 of 83 deals worth $13.5 billion. Breaking that down, most of that is tied to AstraZeneca’s acquisition of Alexion Pharmaceuticals for $39 billion, which accounted for 70.5% of the total deal value in December 2020. Other deals in the same period were EQT IX Fund buying Recipharm AB, a contract development and manufacturing organization (CDMO) for about $2.1 billion; Les Laboratoires Servier SAS acquiring the oncology portfolio of Agios Pharmaceuticals for $2 billion; and Gilead Sciences takeover of MYR GmbH for $1.7 billion. Also that month, Boehringer Ingelheim acquired NBE-Therapeutics for $1.428 billion. The Express Pharma report also looked at venture capital investments, with 112 VC deals in December 2020 compared to 121 from December 2019 to November 2020. The December total was $3.8 billion compared to the 12-month average of $3 billion. The most notable for December was a $200 million investment in Tempus Labs by Baillie Gifford & Co., Franklin Templeton Investments, Novo Holdings and T Rowe Price Associates. That was followed by Matrix Partners China, RTW Investments, Beijing Konruns Pharmaceutical, C-Bridge Capital Partners, HBM Healthcare Investments and GT Fund investing $181 million in China’s Nuance Biotech. Other December VC investments were $131.2 million in Cullinan Oncology, $115 million in Neurogene, and $109 million in Neomorph. Express Pharma’s source was GlobalData. Pharmaceutical and Life Sciences PwC has a slightly different outlook and breakdown. They project 2021 will be more of a return to normal in the pharma and life sciences sector with $250 billion to $275 billion in deal activity. They found 2020 to be slow, particularly compared to 2019, largely because there were few major “transformative” deals, but also because of COVID-19, which delayed a lot of deals earlier in the pandemic. They found there to be about $150 billion in deals for the sector, one of the lowest years in more than a decade. The biggest deal in their analysis was Gilead’s acquisition of Immunomedics in September 2020 for $20.9 billion. Gilead picked up Immunomedics’ breast cancer drug Trodelvy in the deal, which is to be the cornerstone of Gilead’s cancer business. The drug is a first-in-class Trop-2 directed antibody-drug conjugate (ADC). Daniel O’Day, chairman and chief executive officer of Gilead, said in a statement at the time, “This acquisition represents significant progress in Gilead’s work to build a strong and diverse oncology portfolio. Trodelvy is an approved, transformational medicine for a form of cancer that is particularly challenging to treat.” PwC’s second notable deal is in the medical devices sector, with Siemens Healthineers acquiring Varian Medical Systems for $17.2 billion. The rest of the top deals are in the biopharma sector—PwC breaks out pharma and biotech separately, an increasingly complicated distinction. The third largest deal was Bristol Myers Squibb’s $13.1 billion takeout of MyoKardia in October. As part of the deal, Bristol Myers Squibb picked up MyoKardia’s mavacamten, a possible first-in-class cardiovascular drug for obstructive hypertrophic cardiomyopathy (HCM). HCM is a chronic heart disease with high morbidity and impact on patients’ health. They expect to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2021. MyoKardia’s pipeline also includes two clinical-stage compounds, danicamtiv and MYK-224. Danicamtiv is being developed for systolic heart failure and MYK-224 for HCM. The remaining deals in their top 10 include: • Illumina’s $8.0 billion acquisition of Grail in September 2020. • Johnson & Johnson’s $6.4 million buyout of Momenta Pharmaceuticals in August 2020. • Gilead Sciences’ $5.0 billion purchase of Forty Seven in March 2020. • Bayer AG’s acquisition of Asklepios BioPharmaceutical in October 2020 for $4.0 billion. • Sanofi’s $3.7 takeout of Principia Biopharma in August. • Merck’s acquisition of VelosBio in November for $2.8 billion. • Oscar A-Co KK (Blackstone Group’s) $2.3 billion buy of Takeda’s Japanese Consumer Healthcare Business in August 2020. Overall, PwC reported 242 deals in the Pharmaceutical and Life Sciences sector for 2020 for a value of $141 billion.

AcquisitionADCDrug ApprovalNDA

06 Jan 2021

·www.biospace.com

COVID-19's Effect on Biopharma M&As in 2020

Although they don’t necessarily agree on numbers, most reports indicate that 2020 was not a particularly good year for mergers and acquisitions (M&As) in the biopharma industry. Some of that disagreement on numbers is likely related to how they are defining sectors—healthcare versus biotech and pharmaceutical, for example. But everyone agrees that the uncertainty and devastation caused by the COVID-19 pandemic had a major dampening effect on deal-making in 2020. Here’s a look. Healthcare According to Express Pharma, the healthcare industry had 103 deals in December 2020 worth $55.3 billion. This is actually significantly higher than the 12-month average from December 2019 to November 2020 of 83 deals worth $13.5 billion. Breaking that down, most of that is tied to AstraZeneca’s acquisition of Alexion Pharmaceuticals for $39 billion, which accounted for 70.5% of the total deal value in December 2020. Other deals in the same period were EQT IX Fund buying Recipharm AB, a contract development and manufacturing organization (CDMO) for about $2.1 billion; Les Laboratoires Servier SAS acquiring the oncology portfolio of Agios Pharmaceuticals for $2 billion; and Gilead Sciences takeover of MYR GmbH for $1.7 billion. Also that month, Boehringer Ingelheim acquired NBE-Therapeutics for $1.428 billion. The Express Pharma report also looked at venture capital investments, with 112 VC deals in December 2020 compared to 121 from December 2019 to November 2020. The December total was $3.8 billion compared to the 12-month average of $3 billion. The most notable for December was a $200 million investment in Tempus Labs by Baillie Gifford & Co., Franklin Templeton Investments, Novo Holdings and T Rowe Price Associates. That was followed by Matrix Partners China, RTW Investments, Beijing Konruns Pharmaceutical, C-Bridge Capital Partners, HBM Healthcare Investments and GT Fund investing $181 million in China’s Nuance Biotech. Other December VC investments were $131.2 million in Cullinan Oncology, $115 million in Neurogene, and $109 million in Neomorph. Express Pharma’s source was GlobalData. Pharmaceutical and Life Sciences PwC has a slightly different outlook and breakdown. They project 2021 will be more of a return to normal in the pharma and life sciences sector with $250 billion to $275 billion in deal activity. They found 2020 to be slow, particularly compared to 2019, largely because there were few major “transformative” deals, but also because of COVID-19, which delayed a lot of deals earlier in the pandemic. They found there to be about $150 billion in deals for the sector, one of the lowest years in more than a decade. The biggest deal in their analysis was Gilead’s acquisition of Immunomedics in September 2020 for $20.9 billion. Gilead picked up Immunomedics’ breast cancer drug Trodelvy in the deal, which is to be the cornerstone of Gilead’s cancer business. The drug is a first-in-class Trop-2 directed antibody-drug conjugate (ADC). Daniel O’Day, chairman and chief executive officer of Gilead, said in a statement at the time, “This acquisition represents significant progress in Gilead’s work to build a strong and diverse oncology portfolio. Trodelvy is an approved, transformational medicine for a form of cancer that is particularly challenging to treat.” PwC’s second notable deal is in the medical devices sector, with Siemens Healthineers acquiring Varian Medical Systems for $17.2 billion. The rest of the top deals are in the biopharma sector—PwC breaks out pharma and biotech separately, an increasingly complicated distinction. The third largest deal was Bristol Myers Squibb’s $13.1 billion takeout of MyoKardia in October. As part of the deal, Bristol Myers Squibb picked up MyoKardia’s mavacamten, a possible first-in-class cardiovascular drug for obstructive hypertrophic cardiomyopathy (HCM). HCM is a chronic heart disease with high morbidity and impact on patients’ health. They expect to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2021. MyoKardia’s pipeline also includes two clinical-stage compounds, danicamtiv and MYK-224. Danicamtiv is being developed for systolic heart failure and MYK-224 for HCM. The remaining deals in their top 10 include: • Illumina’s $8.0 billion acquisition of Grail in September 2020. • Johnson & Johnson’s $6.4 million buyout of Momenta Pharmaceuticals in August 2020. • Gilead Sciences’ $5.0 billion purchase of Forty Seven in March 2020. • Bayer AG’s acquisition of Asklepios BioPharmaceutical in October 2020 for $4.0 billion. • Sanofi’s $3.7 takeout of Principia Biopharma in August. • Merck’s acquisition of VelosBio in November for $2.8 billion. • Oscar A-Co KK (Blackstone Group’s) $2.3 billion buy of Takeda’s Japanese Consumer Healthcare Business in August 2020. Overall, PwC reported 242 deals in the Pharmaceutical and Life Sciences sector for 2020 for a value of $141 billion. Most Read Today

AntibodyFirst in ClassADCAcquisition

16 Nov 2020

·www.colorado.edu

Bristol Myers Squibb acquires MyoKardia Inc., a biomedical company co-founded by CU professor

Global biopharmaceutical company Bristol Myers Squibb has acquired MyoKardia Inc. in an all-cash transaction for approximately $13.1 billion. MyoKardia Inc., a biomedical company founded in 2013, develops small molecule therapeutics that address key clinical needs for patients with genetic heart disease. The genetic heart diseases targeted by MyoKardia are hypertrophic cardiomyopathy and dilated cardiomyopathy, which afflict roughly 1 million people in the United States. Hypertrophic cardiomyopathy produces thickening of the heart walls and is best known as a leading cause of sudden cardiac death in young athletes. Dilated cardiomyopathy produces weakening of the heart walls and enlargement of the heart chambers. Cardiomyopathy can occur at any age, and more than 30,000 children, from newborns to 18-year-olds, suffer from some form of cardiomyopathy in the United States -- a patient population comparable to the number of people living with cystic fibrosis. CU-Boulder Professor and BioFrontiers Institute Chief Scientific Officer Leslie Leinwand is one of four MyoKardia founders who are all world leaders in the fields of muscle biology and cardiovascular genetics. In addition to Leinwand, the company’s co-founders include Professor James Spudich of Stanford University’s Department of Biochemistry, Dr. Christine Seidman of Harvard Medical School’s Department of Genetics and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital in Boston, and Professor Jonathan Seidman of Harvard Medical School’s Department of Genetics. Leinwand and Spudich have seven decades of collective experience working with the protein in cells responsible for muscle contraction, known as myosin. Jonathan and Christine Seidman are a husband-and-wife team renowned for discovering the genetic basis of hypertrophic cardiomyopathy. Before MyoKardia, no new therapeutics to treat genetic heart diseases had been brought to market in well over a decade. MyoKardia’s proprietary drug discovery platform brings together advances from the fields of cardiovascular genomics and heart muscle biology which enables its scientists to target certain heart diseases at the genetic level. This genetically targeted approach revolutionized the treatment of cardiomyopathies, and ultimately a broader spectrum of cardiovascular disease, including heart failure. Through the transaction with MyoKardia, Bristol Myers Squibb gains mavacamten, a potential first-in-class cardiovascular medicine for the treatment of obstructive hypertrophic cardiomyopathy (“HCM”), a chronic heart disease with high morbidity and patient impact. A New Drug Application (“NDA”) for mavacamten for the treatment of symptomatic obstructive HCM – based on data from the EXPLORER-HCM study – is expected to be submitted to the U.S. Food and Drug Administration in the first quarter of 2021. Bristol Myers Squibb expects to explore the full potential of mavacamten in additional indications, including non-obstructive HCM, as well as develop MyoKardia’s promising pipeline of novel compounds, including two clinical-stage therapeutics: danicamtiv (formerly MYK-491) and MYK-224, and two pre-clinical assets: ACT-1 and LUS-1. “We are excited to welcome MyoKardia colleagues to Bristol Myers Squibb. The MyoKardia team has revolutionized cardiovascular treatments to address significant unmet medical needs, and we look forward to helping more patients together,” said Giovanni Caforio, M.D., Board Chair and Chief Executive Officer of Bristol Myers Squibb. “With MyoKardia, we are bolstering our leading cardiovascular franchise and adding exceptional scientific capabilities, a potentially transformative new medicine with significant commercial potential and a promising pipeline of candidates. Cardiovascular remains an important therapeutic area for Bristol Myers Squibb with a strong legacy and a promising future.

AcquisitionNDA

100 Deals associated with Danicamtiv

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Familial Dilated Cardiomyopathy	Phase 2	United States	Bristol Myers Squibb Co.	04 Aug 2020
Familial Dilated Cardiomyopathy	Phase 2	Germany	Bristol Myers Squibb Co.	04 Aug 2020
Familial Dilated Cardiomyopathy	Phase 2	Spain	Bristol Myers Squibb Co.	04 Aug 2020
Familial Dilated Cardiomyopathy	Phase 2	United Kingdom	Bristol Myers Squibb Co.	04 Aug 2020
Cardiomyopathy, Dilated	Phase 2	France	Bristol Myers Squibb Co.	06 Feb 2018
Cardiomyopathy, Dilated	Phase 2	Netherlands	Bristol Myers Squibb Co.	06 Feb 2018
Cardiomyopathy, Dilated	Phase 2	Poland	Bristol Myers Squibb Co.	06 Feb 2018
Cardiomyopathy, Dilated	Phase 2	Sweden	Bristol Myers Squibb Co.	06 Feb 2018
Heart failure with reduced ejection fraction	Phase 2	United States	Bristol Myers Squibb Co.	06 Feb 2018
Heart failure with reduced ejection fraction	Phase 2	France	Bristol Myers Squibb Co.	06 Feb 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03447990 (Pubmed \| Eur J Heart Fail) Manual	Phase 2	Heart Failure	40	Danicamtiv	lufhthundr(jalcaegmjs) = mpkjhnlxus weanqtbqtz (obhzyswwur ) View more	Positive	01 Sep 2020
				Placebo	lufhthundr(jalcaegmjs) = jtxhkmmxnk weanqtbqtz (obhzyswwur )
ESC2020	Not Applicable	-	-	danicamtiv	gosliqvmwg(jrmxpggbbf) = essqmtnckh zspiuapgjc (ehjxajszyi ) View more	-	28 Aug 2020
				danicamtiv	gosliqvmwg(jrmxpggbbf) = ijwggqalhk zspiuapgjc (ehjxajszyi ) View more

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