RECOMPENSE: Right VEntricular COMPENsation with SotatercEpt: a Prospective Single Arm Open Label Phase 4 Study to Evaluate the Effects of Sotatercept on Right Ventricular Function in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodelling resulting in elevated pressures in the pulmonary artery (PA). This elevated pressure ultimately leads to fulminant right heart failure. Current therapeutic options are limited and are centred around vasodilatory medications such as phosphodiesterase-5 inhibitors and prostacyclin. While these medications allow for the widening of blood vessels that are narrowed due to remodelling, they have no effect on the remodelling itself.
Sotatercept is a novel medication which targets the BMPR2/TGF-β pathway and restore a pro- and anti- proliferative balance to ultimately counteract vascular remodelling. Recent phase 2 and 3 trials showed that treatment with sotatercept led to lower resistance and pressure in the pulmonary vasculature and improved exercise tolerance. However, these results were not coupled with an increase in cardiac output, a change that is seen with other PAH-medications with a primarily vasodilatory effect. These results suggest that cardiac work is reduced and cardiac efficiency is improved in patients being treated with sotatercept, in contrast with conventional PAH therapies. This is a potentially beneficial effect that may result in improved disease control in the long-term. Our study aims to explore the effect of sotatercept on cardiac work and function. We hypothesize that the effects of sotatercept are more beneficial for cardiac function than that of traditional PAH medications.
All participants included in the trial will undergo a screening visit in which it will be checked that all inclusion criteria and no exclusion criteria are met. The screening visit involves a physical exam, blood draw, 6-minute walk test, right heart catheterization (RHC) and cardiac magnetic resonance imaging (cMRI) with contrast to assess fibrosis.
Upon inclusion, all participants will receive a subcutaneous injection of sotatercept starting at a dose of 0.3 mg/kg. Participants will return to the hospital every three weeks for a blood draw, physical examination and an adverse event review. If the laboratory values (specifically haemoglobin and platelet counts) stay stable after the first dose, the dosage will be escalated to 0.7 mg/kg. The dose will not be escalated beyond 0.7 mg/kg.
After 24 weeks of receiving sotatercept, there will be an end of treatment visit including a physical exam, 6-minute walk test, right heart catheterization (RHC) and cardiac magnetic resonance imaging (cMRI) with contrast material.

Start Date01 Jan 2025

Sponsor / Collaborator

Stichting Onderzoek Cancer Center Amsterdam

NCT06664801 / Not yet recruitingPhase 2

A Phase 2, Multicenter, Single-blinded, Randomized Study to Evaluate the Pharmacokinetics and Safety of Sotatercept (MK-7962) Administered Using Either a Weight-based or Weight-banded Approach in Participants With Pulmonary Arterial Hypertension (PAH) on Standard of Care

Researchers are looking for other ways to treat people with PAH. In PAH, the blood vessels in the lungs become thick and narrow, which makes it harder for blood to flow to the lungs.
The goal of the study is to learn:
* What happens to different doses of sotatercept in a person's body over time when it is given using weight-banded doses compared to weight-based doses. There may be differences in how the medicine works with the new dosing method (weight-banded dosing) being studied in this trial.
* About the safety of sotatercept and if people tolerate it

Start Date06 Dec 2024

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT06409026 / RecruitingPhase 4IIT

Effect of Sotatercept on Central Cardiopulmonary Performance and Peripheral Oxygen Transport During Exercise in Pulmonary Arterial Hypertension

The purpose of this study is to see if the drug sotatercept given for 36 weeks improves the functioning of the heart and improves quality of life.

Start Date05 Jul 2024

Sponsor / Collaborator

Mayo Clinic

100 Clinical Results associated with Sotatercept

100 Translational Medicine associated with Sotatercept

100 Patents (Medical) associated with Sotatercept

147

Literatures (Medical) associated with Sotatercept

01 Nov 2024·BioDrugs

Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept

Review

Author: Waxman, Aaron B ; Stump, Benjamin

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.

01 Nov 2024·The Journal of Heart and Lung Transplantation

Risk assessment models and survival in pulmonary arterial hypertension: a SPAHR analysis

Article

Author: Lautsch, Dominik ; Rådegran, Göran ; Björklund, Erik ; Wåhlander, Håkan ; Kjellström, Barbro ; Weiss, Tracey ; Papageorgiou, Joanna-Maria ; Söderberg, Stefan ; Thakur, Tanvee ; Hjalmarsson, Clara

BACKGROUNDMulticomponent improvement (MCI) is a novel endpoint for predicting survival in patients with pulmonary arterial hypertension (PAH), included in the sotatercept clinical program. For the first time, we investigated the prognostic value of MCI, ESC/ERS 4-strata risk (4SR) assessment, and the non-invasive French risk stratification score (FRS), for predicting survival in PAH patients in Sweden. All risk prediction models are based on three parameters: WHO-FC (World Health Organization Functional Class), NT-proBNP, and 6MWD (6-minute walk distance).METHODSData from the Swedish PAH & CTEPH Registry (SPAHR) collected 2008-2021 were used for the analyses. The association of MCI achievement, 4SR, and FRS calculated at 6 months (6M), with transplant-free (TF) survival was investigated in the whole cohort, as well as categorized by age (<65 and ≥65 years). All risk prediction models are based on three parameters: WHO-FC (World Health Organization Function Class), NT-proBNP, and 6MWD (6-minute walk distance). Kaplan-Meier estimate/Log-Rank test and Cox proportional model were used for survival analyses.RESULTSThe study included 411 patients (70% women) with a median [IQR] age of 66y.²¹ At 6M, the mean (SD) NT-proBNP decrease was 808 (603) and the mean 6MWD increase was 44 (11) meters. Median survival/follow-up time was 3.5y [1.7, 5.4]. After adjustment for sex and comorbidities, achievement of MCI independently predicted TF-survival; one MCI-criterion met (HR 0.65; CI 0.46-0.92, p=0.015); two MCI-criteria met (HR 0.45; CI 0.31-0.66, p<0.001); all three MCI-criteria met (HR 0.32; CI 0.21-0.52, p<0.001). Likewise, 4SR and FRS demonstrated a strong association with TF-survival with patients achieving lower risk scores exhibiting longer survival compared to those with higher risk scores. Patients ≥65Y more often had connective tissue disease-associated PAH, lower DLCO, more pronounced comorbidity burden, higher risk at baseline, less improvement during follow-up, and worse TF-survival then patients <65Y.CONCLUSIONAll models were found to have prognostic relevance for TF-survival. Risk prediction was incremental with the number of low-risk criteria met, while improvements in only one of 6MWD, NT-proBNP, or FC showed a modest association with survival. The risk assessment tools predicted outcome in patients across both age categories.

01 Oct 2024·The Journal of Heart and Lung Transplantation

A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension

Article

Author: Moles, Victor M. ; Sahay, Sandeep ; Cascino, Thomas M. ; McLaughlin, Vallerie V. ; Cascino, Thomas M ; Moles, Victor M ; McLaughlin, Vallerie V

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

112

News (Medical) associated with Sotatercept

30 Sep 2024

·www.fiercebiotech.com

Cereno's HDAC inhibitor reduces risks from pulmonary arterial hypertension in phase 2 trial

Two-thirds of patients saw a sustained reduction in their pulmonary arterial pressure. Cereno Scientific’s hypertension drug was shown to improve the risk score of 43% of patients in a phase 2 study.Of the 21 participants with pulmonary arterial hypertension (PAH), nine demonstrated an improved risk score—a measurement of the risk of death from the condition—after 12 weeks of treatment with Cereno’s histone deacetylase (HDAC) inhibitor, dubbed CS1.A further six patients reported a stable risk score, meaning 71% of patients saw their score either improve or hold steady, the Swedish biotech noted in a post-market release Friday.Two-thirds of patients saw a sustained reduction in their pulmonary arterial pressure, while a third reported an improved functional class, a term for symptoms and physical capacity.Cereno’s shares were trading up 25% on the Stockholm stock exchange at 8.72 Swedish krona on Monday afternoon local time compared to a Friday closing price of 7 krona.The trial was also a success on its primary endpoint of proving the safety and tolerability of CS1, with no treatment-related serious adverse events. No changes in liver lab values or clinically significant drug-related bleedings or decreases in platelet counts were recorded, Cereno said. The company is now looking at moving CS1 into a pivotal trial and said it will use Friday’s “encouraging results” as the basis for opening talks with regulators.“We are excited to take the next steps in our journey to make a meaningful impact for patients with PAH,” Cereno’s Head of R&D Rahul Agrawal said in the release.“The CS1-003 trial demonstrated compelling signs of clinical efficacy already over a 12-week treatment period and we expect to see additional positive impact of CS1 with longer use of our drug in patients with PAH,” Agrawal added.HDACs help regulate gene expression. The FDA has already improved four HDAC inhibitors to treat blood cancers, including Merck & Co.’s Zolinza. Cereno is hoping CS1 will have success against PAH by “targeting the root cause of the disease, aiming to reverse the pathological vascular remodeling of the small lung arteries.”PAH is a rare, rapidly progressing disease in which the blood vessels narrow in the lungs, increasing blood pressure and leading to heart failure. Johnson & Johnson dominates the PAH market with its prostacyclin receptor agonist Uptravi and the endothelin receptor agonist Opsumit.In March, Merck & Co. muscled in on the action with the approval of the activin signaling inhibitor Winrevair, which the pharma has touted as acting directly on the underlying problem that causes the disease.Despite the increasingly crowded space, Cereno claimed in its release that “existing treatment alternatives are insufficient and do not address the root cause of the disease.”

Clinical ResultPhase 2

04 Sep 2024

·www.biospace.com

WINREVAIR® (sotatercept) is now authorized for use in Canada for Adults with Pulmonary Arterial Hypertension

KIRKLAND, QC , Sept. 4, 2024 /CNW/ - Merck (NYSE: MRK), known as MSD outside of the United States and Canada , announced that WINREVAIR ® (sotatercept) is now authorized for use in Canada in combination with standard pulmonary arterial hypertension (PAH) therapy, for the treatment of adults with World Health Organization [WHO] Group 1 PAH and Functional Class (FC) II or III. Sotatercept is the first activin signaling inhibitor therapy for PAH in Canada . This represents a new class of therapy that works by improving the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation in PAH patients. “We understand the burden that PAH places on patients and caregivers. The approval of WINREVAIR ® represents a step forward for those grappling with this disease. Our commitment to advancing scientific research and developing solutions stands firm to address the unmet needs of Canadians,” said David D. Jones , Managing Director of Merck Canada. About STELLAR The STELLAR study (NCT04576988) was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to sotatercept (target dose 0.7 mg/kg) (n=163) or placebo (n=160) plus stable background therapy administered subcutaneously once every 3 weeks. The most common PAH etiologies were idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (CTD) (15%). Most participants were receiving either three (61%) or two (35%) background drugs for PAH, and 40% were receiving prostacyclin infusions. The mean time from PAH diagnosis was 8.8 years. Patients had a WHO FC II (49%) or III (51%) at baseline. WINREVAIR ® is the subject of a licensing agreement with Bristol Myers Squibb. About Merck At Merck, known as MSD outside of the United States and Canada , we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable, and healthy future for all people and communities. For more information about our operations in Canada , visit and connect with us on LinkedIn and X @MerckCanada. Forward-Looking Statement of Merck & Co. Inc., Rahway, NJ , USA This news release of Merck & Co., Inc., Rahway, N.J. , USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( ). ® Merck Sharp & Dohme B.V. Used under license. © 2024 Merck & Co., Inc., Rahway, NJ , USA and its affiliates. All rights reserved. SOURCE Merck Canada Inc.

License out/inDrug ApprovalClinical Result

04 Sep 2024

·www.pharmaceutical-technology.com

EC approves Merck’s Keytruda-Padcev combo for urothelial cancer

The recommendation was based on data from the initial interim analysis of the Phase III KEYNOTE-A39 clinical trial. Credit: R Photography Background/Shutterstock. Merck & Co has received European Commission (EC) approval for the use of Keytruda (pembrolizumab) along with Padcev (enfortumab vedotin-ejfv) as a first-line treatment for adults with unresectable or metastatic urothelial carcinoma, a type of bladder cancer. The authorisation follows the European Society for Medical Oncology and the European Association of Urology’s endorsement of this combination therapy as the preferred initial treatment for these patients, regardless of their eligibility for platinum-based chemotherapy. The EC’s decision is in line with the positive recommendation from the Committee for Medicinal Products for Human Use received in July 2024. The recommendation was based on the data from the initial interim analysis of the Phase III KEYNOTE-A39 clinical trial, conducted in collaboration with Pfizer and Astellas. The open-label, multicentre, randomised, active-controlled study compared KEYTRUDA plus enfortumab vedotin to platinum-based chemotherapy. See Also: FDA approves Amneal and Shilpa’s oncology product BORUZU A quick guide to transferring a commercial drug product to a new fill-finish CDMO The combination showed statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS). At a median follow-up of 17.3 months, the combination therapy reduced the risk of death by 53% and disease progression or death by 55% versus platinum-based chemotherapy. The approval enables the marketing of KEYTRUDA in combination with enfortumab vedotin for this indication across all 27 European Union member states, along with Liechtenstein, Iceland, Norway and Northern Ireland. In December 2023, the combination therapy received approval in the US to treat locally advanced or metastatic urothelial cancer in adults. Merck’s research laboratories oncology, global clinical development head and senior vice-president Dr Marjorie Green stated: “For the first time in decades, adult patients with unresectable or metastatic urothelial carcinoma have the option of a potential new first-line standard of care that may help extend their lives. “We are pleased with the European Commission’s decision, and we look forward to being able to provide KEYTRUDA as part of this novel treatment regimen for this devastating disease to patients in the European Union.” The development comes after the EC approved MSD’s Winrevair (sotatercept) to be used as a combination therapy for functional class II or III pulmonary arterial hypertension. This content was updated on 25 January 2024

Phase 3Drug ApprovalClinical Result

100 Deals associated with Sotatercept

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KEGG	Wiki	ATC	Drug Bank
D09670	-	-	DB12118

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Depressive Disorder	CA	Merck Canada, Inc.	01 Aug 2024
Pulmonary Arterial Hypertension	US	Merck Sharp & Dohme LLC	26 Mar 2024

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	NDA/BLA	AU	Merck Sharp & Dohme (Australia) Pty Ltd.	03 Oct 2023
Depressive Disorder	NDA/BLA	-	Merck Canada, Inc.	-
Anemia	Phase 3	US	Celgene Corp.	-
Anemia	Phase 2	US	Celgene Corp.	-
Primary Myelofibrosis	Phase 2	-	Indiana University	-
Primary Myelofibrosis	Phase 2	-	Celgene Corp.	-
Primary Myelofibrosis	Phase 2	-	Acceleron Pharma, Inc.	-
Thalassemia	Phase 2	-	The University of Texas MD Anderson Cancer Center	-
Thalassemia	Phase 2	-	Acceleron Pharma, Inc.	-
Thalassemia	Phase 2	-	Indiana University	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01999582 (CTgov)	Phase 2	Anemia	50	Sotatercept (Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) Injection)	fykcyvtubo(pgudjtqizl) = akalwjucvo kvtylgaakv (omdfuoqick, pfpqzjqbzj - jumkyndcbw) View more	-	24 Jun 2024
				Sotatercept (Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) Injection)	fykcyvtubo(pgudjtqizl) = pacdaboqxb kvtylgaakv (omdfuoqick, ataddqfjue - kersfnxbdm) View more
PULSAR (ATS2024)	Phase 2	Pulmonary Arterial Hypertension BMPR2 \| N-terminal pro B-type natriuretic peptide (NT-proBNP) \| BMPR2 mRNA	106	Sotatercept 0.3 mg/kg	(iwwgvidkxz) = nrqezbfoor rcpywgsaqb (iftmqbjjvr )	Positive	19 May 2024
				Sotatercept 0.7 mg/kg	(iwwgvidkxz) = evdqrlsepe rcpywgsaqb (iftmqbjjvr )
NCT03738150 (SPECTRA, Pubmed) Manual	Phase 2	Pulmonary Arterial Hypertension	21	Sotatercept	(zkqfjbdlmr) = sfhgvqaxqa hdohdvqygh (lnlhhwasvc, 27.72 - 177.76)	Positive	04 Apr 2024
NCT04576988 (STELLAR, FDA_CDER) Manual	Phase 3	Pulmonary Arterial Hypertension	323	WINREVAIR	(zkgnykatca) = nuwhbvyfpi njkzszgpue (mfvsxvjezi ) View more	Positive	26 Mar 2024
				Placebo	(ycfhdmrrjs) = vsyeaoqqej mrektoofdk (fugwnzckbs ) View more
NCT01146574 (CTgov)	Phase 2	Anemia	50	placebo (Part 1-Placebo)	rwwjrqfwlp(anebujfams) = tmkfqmjfly wtfbydypkb (pahttulhih, hjrjnzhvtz - wgcfgdgobr) View more	-	01 Mar 2024
				1-ACE-011 (Part 1-ACE-011 0.1 mg/kg)	(jjgbtneoqv) = zdmaxchuqy bcerkikvqy (fpomzfuyda, nkhnoeyokn - titfqplumu) View more
NCT04576988 (STELLAR, Pubmed \| Adv Ther)	Phase 3	Pulmonary Arterial Hypertension	-	Sotatercept plus background therapy (BGT)	ojspxixdpx(tyqdocwfml) = ifmawfjjet ljhtqkhxxm (vdsmzjdtyn ) View more	Positive	01 Jan 2024
				Placebo plus background therapy (BGT)	ojspxixdpx(tyqdocwfml) = xzwoxckxux ljhtqkhxxm (vdsmzjdtyn ) View more
NCT01190644 (CTgov)	Phase 2	Solid tumor	5	Sotatercept	oiifeortbh(kfvqsautxz) = fmefydieeu gsliyjvhrj (oshrbbzfww, hkmudefadf - zcmzkwvxmn) View more	-	29 Nov 2023
NCT01284348 (CTgov)	Phase 2	Anemia	26	Sotatercept 15 mg (Sotatercept 15 mg)	crvlzmyfsa(xigkrxdpof) = nwiesdhhch ijqgxuexky (xrgnvlcmar, xfnjdkognf - wmgbtqxxgu) View more	-	31 Oct 2023
				Sotatercept 30 mg (Sotatercept 30 mg)	crvlzmyfsa(xigkrxdpof) = vgmzarkeuk ijqgxuexky (xrgnvlcmar, cpxijvklos - bfzgfxrojk) View more
NCT00931606 (MK-7962-012 \| 7962-012, CTgov)	Phase 2	Anemia	30	Sotatercept (Sotatercept 0.1 mg/kg)	fbxkoutpwp(dtxnesknuy) = csoberazur krknppsngm (ibzfcpjfyr, akzrsmvrcz - sdostobxpa) View more	-	13 Sep 2023
				Sotatercept (Sotatercept 0.3 mg/kg)	fbxkoutpwp(dtxnesknuy) = yivhbecftl krknppsngm (ibzfcpjfyr, sjfmbysbvc - repuwrhisf) View more
STELLAR (Literature) Manual	Phase 3	Pulmonary Arterial Hypertension	-	sotatercept	eguecguhtd(xvgqdpdqqr) = rgelolcnij mskkcnvvoc (ndiydmptvp ) View more	Positive	11 Sep 2023
				placebo	-

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