PGI2 receptor

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.”

September 27, 2024 I Cereno Scientific (Nasdaq First North: CRNO B), a pioneering biotech developing innovative treatments for rare and common cardiovascular disease, today announced positive topline results from the Phase IIa trial of CS1 in Pulmonary Arterial Hypertension (PAH). The results demonstrate that CS1 is safe, well tolerated and has positive impact on clinically relevant parameters such as risk, functional class and hemodynamics. “ I am delighted to share the topline data from the Phase IIa trial of CS1 in PAH. Key results from the study demonstrate both that the primary endpoint was met with good safety and tolerability of CS1 in patients with PAH, and, in addition, we also show a positive impact already after 12 weeks on clinical parameters meaningful to patients and regulatory authorities. These results, together with our foundation of preclinical data, strengthen our conviction that CS1 is a disease-modifying therapy for PAH. We are excited to now move forward with the next development phase with CS1. Our mission is to deliver a drug addressing the pathological remodeling which is progressing the PAH disease and to provide a valuable addition to the PAH toolbox of therapeutics ”, said Sten R. Sörensen, CEO, Cereno Scientific. Pulmonary Arterial Hypertension PAH is a debilitating and fatal disease with no spontaneous improvement. Epigenetic mechanisms through histone deacetylase (HDAC) drive disease progression and continuous deterioration. The disease pathology is defined by endothelial dysfunction, inflammation, vasoconstriction, hypertrophy and remodeling of pulmonary small arteries, leading to poor lung function, right heart failure and ultimately death. Existing treatment alternatives are insufficient and do not address the root cause of the disease. The goal of PAH treatment is to improve risk score status (measured by amongst others REVEAL risk score), symptoms and physical capacity (measured by functional class) and hemodynamics (measured by mean Pulmonary Arterial Pressure, mPAP and Pulmonary Vascular Resistance, PVR), to ultimately improve both patients’ quality of life and extend survival. “ PAH is a rare and devastating disease for patients suffering from it. Despite advances in treatment options there is still a pronounced need for effective, safe and disease-modifying therapies for these patients. The results presented today with primary endpoints met regarding safety and tolerability and supporting signs of clinical efficacy including improvement in risk score, improvement of functional class and impact on mean pulmonary pressure are promising,” said Dr. Raymond Benza, Network Director of Pulmonary Hypertension at Mount Sinai Icahn School of Medicine, New York; and Principal Investigator of the Phase IIa trial of CS1 . CS1 and the CS1-003 Phase IIa trial CS1 is an HDAC inhibitor that works through epigenetic modulation, being developed as a safe, effective and disease modifying treatment for PAH. CS1 targets the root cause of the disease, aiming to reverse the pathological vascular remodeling of the small lung arteries. CS1-003 is a Phase IIa trial evaluating the safety, tolerability, pharmacokinetics, and exploratory efficacy of CS1 on top of standard-of-care in patients with PAH. The study initially had as an objective to recruit 30 patients. In June, recruitment was stopped after the Study Clinical Steering Committee concluded that there was sufficient data for evaluating the next steps in development. The study, which was performed at 10 clinical sites in the US, randomized 25 patients to CS1 treatment, out of which 21 patients completed the treatment without protocol deviations. CS1 – Phase IIa safety data – Primary endpoint of safety and tolerability met successfully The primary endpoint of safety and tolerability was met successfully: CS1 Phase IIa – Compelling positive impact on exploratory clinical efficacy parameters Efficacy data from the three doses were pooled together due to therapeutic drug exposure (i.e. plasma concentration) also in the low dose group. CS1 showed compelling positive impact on exploratory clinical parameters already over a 12-week treatment period: “ I am very pleased with the positive outcomes we are seeing in our patients following treatment with CS1. Their improvements in health and well-being are encouraging and reflect the potential effectiveness of the therapy. The majority of my patients have expressed interest in enrolling into the Expanded Access Program. This progress reaffirms my commitment to advancing treatments that can make a meaningful difference in patients’ lives with PAH ,” said Dr. Jason Guichard , Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Division of Cardiology, Prisma Health-Upstate, Assistant Professor of Medicine, University of South Carolina School of Medicine Greenville and investigator in the Phase IIa trial of CS1 in PAH. CS1 phase II a study clinical data, together with preclinical information, is consistent with reversing pathological remodeling An in-depth analysis made on a subgroup of patients with a remarkable response showed: The data from the CS1-003 trial, together with recently announced preclinical data from our HDAC inhibitor program, directly demonstrating our HDAC-inhibitor program’s dose-dependent positive impact on reverse vascular remodeling in small lung arteries, provide a basis for assuming that CS1 may act with a disease-modifying capacity in PAH. Clear path forward to develop a disease-modifying therapy for PAH​ Cereno will be initiating discussions with regulatory bodies based on these encouraging results and will progress pursuing a pivotal trial of CS1 in PAH. A comprehensive analysis of the complete CS1-003 data will be conducted, with the findings to be presented at upcoming medical conferences and published in a reputable medical journals. “ We are excited to take the next steps in our journey to make a meaningful impact for patients with PAH. Our plans include engaging with regulatory authorities to in pursuing a pivotal trial for CS1 and to continue enrolling patients in our Expanded Access Program . 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 ” said Dr. Rahul Agrawal, CMO and Head of R&D, Cereno Scientific Webcast presentation on Monday, September 30 Cereno Scientific will host a webcast including a Q&A session where CEO Sten R. Sörensen, CMO and Head of R&D Dr. Rahul Agrawal, CSO Dr. Björn Dahlöf and Head of Preclinical Development, Nicholas Oakes, will present the CS1-003 topline results. Date and time: Monday, September 30, 2024, at 14:00 CET How to join: https://ir.financialhearings.com/cereno-scientific-2024 The webcast and presentation will be available on the Company’s website after the webinar at: https://cerenoscientific.com/events-presentations/ About the CS1-003 trial The CS1-003 trial titled “A Phase II, Prospective, Randomized, Open-label, Blinded Endpoint, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of 3 Doses of CS1 in Subjects With Pulmonary Arterial Hypertension ” (NCT05224531) randomized adult PAH patients with WHO Functional class II or III, stable on standard of care therapy for 90 days, to one of three total daily doses of CS1; 480 mg, 960 mg or 1920 mg. Subjects were enrolled for up to 22 weeks including a treatment period of 12 weeks. The trial was conducted at 10 specialist clinics in the US. 25 patients were randomized to CS1 treatment out of which 21 patients completed the treatment without protocol deviations. The study’s primary endpoint was to evaluate the safety and tolerability of CS1 treatment in patients with PAH. Other relevant standard endpoints used in previous studies of this patient group have been measured and evaluated in an exploratory fashion. A collaboration agreement with global healthcare company Abbott has allowed Cereno to use their cutting-edge technology CardioMEMS HF System in the trial, to measure mean Pulmonary Arterial Pressure (mPAP) and other hemodynamic parameters. CS1-003 is a Phase IIa trial that is not powered for statistically significant detection or exclusion of efficacy-related parameters. On June 28, 2024, Cereno announced the decision to close patient recruitment to the Phase IIa trial CS1-003 by July 1st, 2024, after the Study Clinical Steering Committee concluded that there was sufficient data for evaluating the next steps in development. About PAH Pulmonary Arterial Hypertension (PAH) is a rare disease and diagnosed with high blood pressure in the pulmonary circulation. Globally, the disease affects approximately 10 in 100,000 people. It is a severe, debilitating disease with no spontaneous improvement. The disease is characterized by a progressive narrowing of the pulmonary arterial vessels ultimately leading to right heart failure and death. Life expectancy is 2.5 years without therapy and 7.5 years on current standard of care. PAH has a major impact on quality of life and causes shortness of breath, fatigue, chest pains, reduced ability to work, unnatural swelling, fainting and heart palpitations. This has significant implications for a patient’s physical, mental, and social well-being. There is currently no cure available for PAH with the exception of lung transplantation, which patients are often too seriously ill to undergo. Current standard of care, mainly vasodilators, improves the patient’s symptoms and involves, at best, a moderate slowing of the disease progression. There is therefore a great need for safer therapies with disease-modifying capacity that address the root causes of PAH and that can give patients an increased opportunity for an improved quality of life and a longer life. About CS1 Drug candidate CS1 is an HDAC inhibitor that works through epigenetic modulation, being developed as a treatment for the rare disease PAH. CS1 holds the potential to be an effective, safe and disease-modifying drug, targeting the root cause of the disease by reverse remodeling. In preclinical cardiovascular disease models, HDAC inhibitors have shown disease-modifying potential through reverse pathological remodeling, as well as anti-fibrotic, anti-inflammatory, pulmonary pressure-reducing, and anti-thrombotic effects. CS1’s unique efficacy profile aligns well with the underlying mechanisms of PAH, positioning it to address the critical unmet need for more effective treatment options. The goal of CS1’s development is to improve quality of life and extend survival for patients with PAH. CS1 is part of Cereno’s HDACi portfolio, untapping the potential of epigenetic modulation in CVD. CS1 has been granted orphan drug status in both the US and EU. Since January 30, 2024, CS1 is approved by the FDA for Expanded Access, as an extension of the ongoing Phase IIa trial CS1-003 evaluating CS1 in PAH. The EAP gives patients that have completed the Phase IIa trial the opportunity to, after being judged suitable and to benefit from CS1 treatment by investigators, continue CS1 treatment of PAH when no comparable or satisfactory alternative therapy options are available. The EAP allows Cereno to, under a formal FDA-approved protocol, collect safety and efficacy data from long-term exposure to CS1 in patients with PAH. As such, this initiative not only supports the treatment of PAH patients but also enables Cereno to gather additional CS1 usage documentation for regulatory discussions and Phase IIb/III pivotal study design planning. On August 30, 2024, the Company announced that the first patient had been dosed under the EAP. About Cereno Scientific AB Cereno Scientific develops innovative treatments for rare and common cardiovascular disease. The lead drug candidate, CS1, is an HDAC (histone deacetylase) inhibitor that acts as an epigenetic modulator with pressure-reducing, reverse-remodeling, anti-inflammatory, anti-fibrotic and anti-thrombotic properties. A Phase IIa trial evaluating CS1’s safety, tolerability, and exploratory efficacy in patients with the rare disease pulmonary arterial hypertension (PAH) demonstrated that CS1 was safe, well-tolerated and showed a positive impact on exploratory clinical efficacy parameters. CS1 study data, together with preclinical information, is consistent with reversing pathological remodeling. A collaboration agreement with global healthcare company Abbott allowed Cereno to use their cutting-edge technology CardioMEMS HF System in the trial. Since January 2024, we are delighted that the FDA´s Expanded Access Program will enable patients with PAH, a serious life-threatening disease condition, to gain access to CS1 where no comparable alternative therapy options are available. Cereno’s pipeline comprises two additional programs in development through research collaborations with the University of Michigan CS014 is a new chemical entity with a multi-fold mechanism of action as an epigenetic modulator – regulating platelet activity, fibrinolysis, and clot stability for the prevention of thrombosis without an increased risk of bleeding as documented in preclinical trials. The drug candidate has also demonstrated a favorable profile in preclinical models of other cardiovascular diseases, such as PAH, with reverse remodeling of pulmonary arterial vessels and effects on vascular fibrosis. On 28th of June, 2024, Cereno initiated a first-in-human Phase I trial of CS014. Preclinical candidate CS585 is an oral, highly potent and selective prostacyclin (IP) receptor agonist that has demonstrated the potential to significantly improve disease mechanisms relevant to cardiovascular disease. While CS585 has not yet been assigned a specific indication for clinical development, preclinical data indicates that it could potentially be used in indications like Pulmonary Hypertension and thrombosis prevention without increased risk of bleeding. CS585 was in-licensed from the University of Michigan in 2023. The Company is headquartered in GoCo Health Innovation City, in Gothenburg, Sweden, and has a US subsidiary; Cereno Scientific Inc. Based in Kendall Square, Boston, Massachusetts, US. Cereno is listed on the Nasdaq First North (CRNO B). The Certified Adviser is Carnegie Investment Bank AB, certifiedadviser@carnegie.se. More information is on www.cerenoscientific.com. SOURCE: Cereno Scientific

Merck has earned an FDA approval for Winrevair (sotatercept) to treat patients with pulmonary arterial hypertension (PAH). Winrevair is the first disease-modifying treatment for the indication and is expected to achieve blockbuster sales. After three years, the crown jewel of Merck’s $11.5 billion acquisition of Acceleron is ready to pay dividends. With the FDA’s approval of Winrevair (sotatercept) to treat pulmonary arterial hypertension (PAH), Merck is set to launch the first disease-modifying treatment for the condition. Initially developed by Acceleron and Celgene and investigated as a treatment for disorders such as osteoporosis, anemia and multiple myeloma, sotatercept has found its place as an add-on therapy to standard of care in a small but important indication. PAH is a rare, rapidly progressing disease in which the blood vessels narrow in the lungs, increasing blood pressure and leading to heart failure. Roughly 40,000 people in the United States have the disorder. PAH strikes more women than men and most are in middle age, killing nearly half within five years of diagnosis. The condition begins as a more common disorder, pulmonary hypertension (PH), then can progress into PAH. Merck will charge $14,000 for a vial of Winrevair, which is dosed subcutaneously every three weeks, putting its annual cost at $238,000. Based on the label-recommended, weight-based target dose and data gathered from the STELLAR trial, Merck projects that roughly two-thirds of patients will use a single-vial kit with others needed a double-vial package. Two months ago, the Institute for Clinical and Economic Review (ICER) calculated a price range which matches the benefit patients are expected to receive for sotatercept at between $17,900 and $35,400 per year. "We believe the U.S. price of Winrevair represents the significant innovation this medicine can deliver as a first-in-class activin signaling inhibitor therapy and the first biologic approved by the FDA for PAH," Merck said in a statement.   Johnson & Johnson dominates the PAH market with Uptravi, a prostacyclin receptor (IP) agonist which generated sales of $1.6 billion last year on a 20% increase, and Opsumit, an endothelin receptor agonist which produced $2 billion in revenue, with its sales up 14% from 2022. Additionally, just four days ago, the FDA approved a combination tablet Opsynvi, which combines Opsumit an United Therapeutics’ Adcirca (tadalafil), which are often prescribed together for PAH. While all these therapies dilate the blood vessels to alleviate symptoms, they do little to ameliorate the disease. As a physician who treated PAH patents two decades ago, Merck’s head of global clinical development, Joerg Koglin, says that current treatments have done little to extend lives. “When you make that diagnosis, you essentially diagnose a disease that has a pretty high fatality,” Koglin said in an interview with Fierce Pharma. “What has happened over the last 20 years is while we had more and more tools to treat the symptoms of the disease—patients were able to walk a little bit longer and to deal with the disease better—but the mortality hasn’t really moved.” But that could change with Winrevair. As a first-in-class activin signaling inhibitor, Winrevair acts directly on the underlying problem that causes the disease by targeting a type of protein that promotes inflammatory processes associated with the disease. Winrevair has been shown to modulate vascular cell proliferation, reversing vascular and right ventricle remodeling. “We’ve learned that this narrowing of pulmonary vessels that leads to those increased pressures in our lungs has to do with an imbalance in signaling factors,” Koglin said. “Once you develop an imbalance, you see an increase in pulmonary pressures and resistance and then all the downstream effects.” In the phase 3 STELLAR trial, which conducted a 6-minute walk test as the primary endpoint, patients on sotatercept for 24 weeks as an add-on to standard of care improved their exercise capacity by an average distance of 41 meters. Additionally, sotatercept provided statistically significant improvements in eight of nine secondary measures, including extending the time to a clinical worsening event, such as death, hospitalization or needing substantially more therapy. “We were able to see a reduction in time to clinical worsening in those events—that’s a Kaplan-Meier analysis—by over 80%. That’s a dramatic effect size,” Koglin added. “And we saw that a substantial number of patients in our studies actually improved on the disease.” The trial also showed that 24 weeks of sotatercept significantly reduced right heart size and improved right ventricle function and haemodynamic status. After Bristol Myers Squibb bought out the drug's other developer, Celgene, in 2019, Merck will now make royalty payments to BMS. Merck is well-suited to commercialize Winrevair as it has had a PH drug on the market for a decade in Adempas, which it shares with Bayer. Analysts have estimated Winrevair's peak sales potential is at least $2 billion, with J.P. Morgan’s Chris Schott estimating it at $3 billion to $4 billion. J&J controlled half of the $7.3 billion PAH market in 2023. Prophecy Market Insights projects the market will grow by 5.5% annually, reaching $12.2 billion by 2032. Sotatercept also is under investigation in late-stage trials for PH due to left heart disease and for patients with PAH at intermediate or high risk of disease progression.