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Acceleron Presents Preliminary Interim Data from the SPECTRA Phase 2 Trial of Sotatercept in Pulmonary Arterial Hypertension (PAH) at the 2020 American Heart Association Scientific Sessions

– Treatment with sotatercept in first set of patients in the ongoing SPECTRA Phase 2 trial was associated with substantial improvements in hemodynamics, exercise tolerance and exercise capacity at week 24 –

– Sotatercept was generally well tolerated, consistent with the previously reported safety profile in PAH and in other diseases –

– Acceleron to host investor and analyst conference call and webcast with guest PAH key opinion leaders today, Friday, November 13, at 11:00 a.m. EST –

CAMBRIDGE, Mass.–(BUSINESS WIRE)–
Acceleron Pharma Inc. (Nasdaq: XLRN), a leading biopharmaceutical company in the discovery, development, and commercialization of TGF-beta superfamily therapeutics to treat serious and rare diseases, today presented a set of preliminary interim data from the ongoing SPECTRA Phase 2 trial of sotatercept in patients with pulmonary arterial hypertension (PAH).

Initial data from the trial, which is designed to assess resting and exercise hemodynamics and peak oxygen uptake—as recorded by invasive cardiopulmonary exercise testing (iCPET)—show that patients treated with sotatercept experienced substantial improvements in multiple hemodynamic measures as well as in exercise tolerance and exercise capacity. These early outcomes, obtained from the first 10 patients participating in the trial, were shared as part of an Invited Talk entitled, “SPECTRA and Beyond: Signs of Disease Modification?” presented virtually during the American Heart Association (AHA) 2020 Scientific Sessions.

Among the largest resting hemodynamic improvements observed were reductions in pulmonary vascular resistance (PVR; as measured in dynes-sec/cm⁵) from a mean of 576 at baseline to 369 at week 24 (35.9% reduction) and mean pulmonary arterial pressure (mPAP) as measured in mmHg from 43.4 to 30.6 (29.5% reduction).

“The SPECTRA trial’s innovative design is meant to help us better understand and detect sotatercept’s potential effects on underlying disease pathology,” said Aaron Waxman, M.D., Ph.D.*, Director, Pulmonary Vascular Disease Program at Boston’s Brigham and Women’s Hospital, who delivered the Invited Talk at the AHA. “Despite the limited number of patients evaluated to date, it’s difficult not to be encouraged by the range and extent of positive changes seen in key hemodynamic and exercise capacity measures thus far.”

In this single-arm, open-label multi-center exploratory study, a total of up to 25 patients with advanced PAH (classified as WHO functional class III) on stable combination background therapy are to be treated with an initial cycle of 0.3 mg/kg of sotatercept delivered subcutaneously, followed by subsequent cycles of 0.7 mg/kg of sotatercept through a 24-week treatment period. The protocol includes iCPET at baseline and at week 24 to assess change from in peak oxygen uptake or VO₂ max (the primary endpoint) as well as changes from baseline in a range of secondary endpoints, including mPAP and VO₂ at anaerobic threshold.

During his AHA talk, Dr. Waxman also provided an in-depth profile of the first patient treated in the SPECTRA trial: a 25-year-old woman diagnosed with idiopathic PAH nearly five years prior to enrollment. This patient, who was classified as WHO functional class III and on combination background therapy, experienced substantial hemodynamic and functional improvements. Perhaps most notably, this patient was reclassified from WHO functional class III at baseline to class I at week 24. The patient retained functional class I status in follow-up testing at 48 weeks.

Sotatercept was generally well tolerated in the trial. Adverse events observed in the study were generally consistent with previously published data on sotatercept in PAH and in other diseases.

“We’re thrilled to see such positive preliminary outcomes from the SPECTRA trial, which serves as another important exploration of sotatercept and the potential of its unique mechanism to alter the course and treatment of PAH,” said Habib Dable, President and Chief Executive Officer of Acceleron. “These results, combined with new PULSAR trial data presented at AHA and the topline PULSAR findings announced earlier this year, position us well to initiate a robust Phase 3 development program to realize our vision of sotatercept as a backbone therapy for patients with PAH across all stages of disease.”

Sotatercept is an investigational therapy that is not approved for any use in any country.

The presentation referenced above is available on the “Publications” page under the “Science & Pipeline” section of Acceleron’s website, www.acceleronpharma.com.

*Dr. Waxman is the principal investigator of the SPECTRA trial and a paid consultant to Acceleron.

About the SPECTRA Trial

The SPECTRA Phase 2 trial is a single arm, open-label, multi-center exploratory study to determine the effects of sotatercept plus standard of care in adults with WHO functional class III PAH. The primary endpoint of the trial is the change from baseline in peak oxygen uptake (VO₂ max) at 24 weeks, as recorded by invasive cardiopulmonary exercise testing (iCPET). Secondary hemodynamic endpoints as well as endpoints of exercise capacity and tolerance assessed via iCPET and right heart catheterization include change from baseline at 24 weeks in: ventilatory efficiency (VE/VCO₂ slope); cardiac index (L/min/m²); mean pulmonary artery pressure (mPAP); pulmonary vascular resistance (PVR); arteriovenous oxygen content difference (Ca-vO₂); ventilatory efficiency; “dead space” assessment (VE/VCO₂ slope); and oxygen consumption at anaerobic threshold (VO₂ at AT).

A total of up to 25 patients are to receive stable background combination PAH therapy plus sotatercept at a starting dose level of 0.3 mg/kg delivered subcutaneously for one cycle, escalating to 0.7 mg/kg at cycle 2 for the remainder of the treatment period. Following the 6-month open-label treatment period, participants in the trial are eligible to continue in the 18-month extension period, which includes iCPET conducted at 48 weeks.

Conference Call and Webcast Information

The Company will host a webcast and conference call today, November 13, 2020, at 11:00 a.m. EST, to review the presentations of sotatercept at AHA.

The webcast will be accessible under “Events & Presentations” in the Investors/Media page of the company’s website at www.acceleronpharma.com. Individuals can participate in the live conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and referring to the “AHA Sotatercept Conference Call.”

A replay of the webcast will be available on the Acceleron website approximately two hours after the event.

About Sotatercept

Sotatercept is an investigational reverse-remodeling agent designed to be a selective ligand trap for members of the TGF-beta superfamily to rebalance BMPR-II signaling, which is a key molecular driver of PAH. The PULSAR Phase 2 trial evaluating sotatercept in combination with approved PAH-specific medicines in patients with PAH achieved its primary endpoint of improvement in pulmonary vascular resistance and its key secondary endpoint of improvement in 6-minute walk distance. Sotatercept was generally well tolerated in the trial. Adverse events observed in the study were generally consistent with previously published data on sotatercept in other diseases. Following the PULSAR results, sotatercept was granted Breakthrough Therapy designation from the FDA and Priority Medicines designation from the EMA in PAH. Sotatercept is also being evaluated in the SPECTRA Phase 2 exploratory trial.

In preclinical research published in Science Translational Medicine, sotatercept exhibited consistent effects across multiple components of disease, including suppressed proliferation of pulmonary arterial smooth muscle and microvascular endothelial cells, reduced pulmonary pressures, lessened right ventricular hypertrophy, improved right ventricular function, and attenuated vascular remodeling.

The Company recently presented details of its Phase 3 development plan, including the design for the registrational STELLAR trial, which is expected to be initiated before the end of 2020. Acceleron is planning two additional Phase 3 studies in patients with PAH: the HYPERION trial, exploring early intervention with sotatercept, and the ZENITH trial assessing later-stage intervention.

Sotatercept is an investigational therapy that is not approved for any use in any country. Sotatercept is part of a licensing agreement with Bristol Myers Squibb.

About PAH

PAH is a rare and chronic, rapidly progressing disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. PAH results in significant strain on the heart, often leading to limited physical activity, heart failure, and reduced life expectancy. The 5-year survival rate for patients with PAH is approximately 57%. Available therapies generally act by promoting the dilation of pulmonary vessels without addressing the underlying cause of the disease. As a result, PAH often progresses rapidly for many patients despite standard of care treatment. A growing body of research has implicated imbalances in BMP and TGF-beta signaling as a primary driver of PAH in familial, idiopathic, and acquired forms of the disease.

About Acceleron

Acceleron is a biopharmaceutical company dedicated to the discovery, development, and commercialization of therapeutics to treat serious and rare diseases. Acceleron’s leadership in the understanding of TGF-beta superfamily biology and protein engineering generates innovative compounds that engage the body’s ability to regulate cellular growth and repair.

Acceleron focuses its commercialization, research, and development efforts in hematologic and pulmonary diseases. In hematology, REBLOZYL^® (luspatercept-aamt) is the first and only erythroid maturation agent approved in the United States, Europe, and Canada for the treatment of anemia in certain blood disorders. REBLOZYL is part of a global collaboration partnership with Bristol Myers Squibb. The Companies co-promote REBLOZYL in the United States and are also developing luspatercept for the treatment of anemia in patient populations of MDS, beta-thalassemia, and myelofibrosis. In pulmonary, Acceleron is developing sotatercept for the treatment of pulmonary arterial hypertension (PAH), having recently presented positive topline results of the PULSAR Phase 2 trial. The Company is currently planning multiple Phase 3 trials with the potential to support its long-term vision of establishing sotatercept as a backbone therapy for patients with PAH at all stages of the disease.

For more information, please visit www.acceleronpharma.com. Follow Acceleron on Social Media: @AcceleronPharma and LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements about Acceleron’s strategy, future plans and prospects, including statements regarding the development of sotatercept in PAH, the timeline for clinical development and regulatory approval of sotatercept in PAH, the expected timing for reporting of data from ongoing clinical trials, and the potential of Acceleron’s compounds as therapeutic drugs. The words “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “project,” “should,” “target,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

Actual results could differ materially from those included in the forward-looking statements due to various factors, risks and uncertainties, including, but not limited to, that preclinical testing of Acceleron’s compounds and data from clinical trials may not be predictive of the results or success of ongoing or later clinical trials, that regulatory approval of Acceleron’s compounds in one indication or country may not be predictive of approval in another indication or country, that the development of Acceleron’s compounds will take longer and/or cost more than planned, that Acceleron will be unable to successfully complete the clinical development of Acceleron’s compounds, that Acceleron may be delayed in initiating, enrolling or completing any clinical trials, that Acceleron’s compounds will not receive regulatory approval or become commercially successful products, and that Breakthrough Therapy or PRIME designation may not expedite the development or review of sotatercept. These and other risks and uncertainties are identified under the heading “Risk Factors” included in Acceleron’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q, and other filings that Acceleron has made and may make with the SEC in the future.

The forward-looking statements contained in this press release are based on management’s current views, plans, estimates, assumptions, and projections with respect to future events, and Acceleron does not undertake and specifically disclaims any obligation to update any forward-looking statements.

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Data from contemporary registry confirms that four out of five patients with heart failure with reduced ejection fraction eligible for treatment with FARXIGA

TRANSLATE-HF study establishes the potential for broad use of the only SGLT2 inhibitor indicated in patients with heart failure with reduced ejection fraction with and without diabetes

WILMINGTON, Del.–(BUSINESS WIRE)–
New data from a large, contemporary US hospitalized heart failure (HF) registry confirms that four out of five (81.1%) patients with NYHA class II-IV HF with reduced ejection fraction (HFrEF), with and without type 2 diabetes (T2D), could be considered as eligible candidates for sodium glucose co-transporter 2 (SGLT2) inhibitor FARXIGA^® (dapagliflozin). The analysis, presented today at the American Heart Association’s (AHA) Scientific Sessions 2020, evaluated records of more than 150,000 patients who were hospitalized for HFrEF at over 400 US hospital centers, leveraging data from the AHA’s Get With The Guidelines-Heart Failure (GWTG-HF) registry.

FARXIGA is the only SGLT2 inhibitor approved by the US Food and Drug Administration (FDA) to reduce the risk of cardiovascular (CV) death and hospitalization for HF (hHF) in adults with HFrEF with and without T2D. This indication is based on the positive results from the landmark Phase III DAPA-HF trial, which showed FARXIGA, in addition to standard of care, reduced the risk of the composite outcome of CV death or the risk of hHF versus placebo by 26% (absolute risk reduction [ARR] = 5% [event rate/100 patient years: 11.6 vs 15.6, respectively]; p<0.0001) in patients with HFrEF. The clinical characteristics of treatment candidates in the TRANSLATE-HF analysis were comparable to those in the DAPA-HF trial.

Muthiah Vaduganathan, MD, MPH, first author of the study, a cardiologist at Brigham and Women’s Hospital and faculty at Harvard Medical School, said: “There is a tremendous unmet need for people living with heart failure with reduced ejection fraction. While we’ve seen recent treatment innovation in this space, there remains a gap in its translation to clinical practice. These study results support the use of this treatment in a broad population of these patients and reinforce the urgent need for clinical uptake.”

Leandro Boer, MD, Vice President, US Medical Affairs, CVMD, said: “AstraZeneca is proud to work with the AHA to apply the established scientific evidence of FARXIGA in a real-world clinical setting for patients with heart failure with reduced ejection fraction. As an organization, we believe clinical practice must swiftly follow the science to ensure the most innovative treatment advancements are considered for patients. Through this analysis, we’re hopeful that more patients in need may benefit from treatment with FARXIGA.”

This analysis is the first in a series of studies under the TRANSLATE-HF research platform, developed by the AHA with support and partnership from AstraZeneca. The series focuses on evidence-based treatment for patients with HF and will utilize data from the GWTG-HF registry to address critical knowledge gaps and potential barriers to prescribing the latest, evidence-based therapies for patients diagnosed with HF. Findings will also help to identify potential areas for increasing implementation efforts that can improve quality of care delivery, and ultimately, patient outcomes. This first analysis was simultaneously published today in JAMA Cardiology.

In the US, FARXIGAis indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D and to reduce the risk of hHF in patients with T2D and established CV disease or multiple CV risk factors. In May, FARXIGAwas approved in the US to reduce the risk of CV death and hHF in adults with HFrEF, with and without T2D.

INDICATIONS AND LIMITATIONS OF USE for FARXIGA^® (dapagliflozin)

FARXIGA is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple CV risk factors
• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for FARXIGA^® (dapagliflozin) 5 mg and 10 mg tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) being treated for glycemic control without established CV disease or multiple CV risk factors
• Patients on dialysis

Warnings and Precautions

• Volume Depletion: FARXIGA can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in these patients, assess volume status and renal function. After initiating therapy, monitor for signs and symptoms of hypotension and renal function
• Ketoacidosis in Diabetes Mellitus has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters
• Lactation: FARXIGA is not recommended when breastfeeding

DOSING

• To improve glycemic control in patients with T2D, the recommended starting dose of FARXIGA is 5 mg orally once daily, taken in the morning. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily
• To reduce the risk of hospitalization for heart failure in patients with T2D and established CV disease or multiple CV risk factors, the recommended dose of FARXIGA is 10 mg orally once daily
• To reduce the risk of CV death and hospitalization for heart failure in patients with HFrEF, the recommended dose of FARXIGA is 10 mg orally once daily

Please see accompanying US Full Prescribing Information and Medication Guide for FARXIGA.

TRANSLATE-HF

TRANSLATE-HF is a contemporary US hospitalized heart failure (HF) registry study designed to evaluate the eligibility of patients hospitalized with HF with reduced ejection fraction (HFrEF), with or without type 2 diabetes, for treatment with the SGLT2 inhibitor dapagliflozin based on the US Food and Drug Administration (FDA) label (excluding eGFR<30 mL/min/1.73 m², dialysis, or type 1 DM). The study analyzed records of 154,714 patients with HFrEF hospitalized at 406 hospital centers across the US participating in the American Heart Association’s (AHA) Get With The Guidelines^®-Heart Failure (GWTG-HF) quality improvement initiative admitted between January 2014 – September 2019. The TRANSLATE-HF research platform, commissioned by the AHA with support and partnership from AstraZeneca, includes a series studies that focus on evidence-based treatment for patients with HF.

DapaCare Clinical Program

AstraZeneca is taking a holistic, patient-centric approach to disease management by addressing the underlying morbidity, mortality and organ damage associated with CV, metabolic and renal diseases. Due to the interconnectivity of these diseases, AstraZeneca has developed the DapaCare clinical program to explore the CV and renal profile of FARXIGA in people with and without T2D. The clinical program will enroll nearly 30,000 patients in randomized clinical trials and is supported by a multinational real-world evidence study. DapaCare will generate data across a spectrum of people with established CV disease, CV risk factors and varying stages of renal disease, both with and without T2D, providing healthcare providers with evidence needed to improve patient outcomes.

FARXIGA has also been explored for the treatment of chronic kidney disease (CKD) in the DAPA-CKD trial. DapaCare underscores our commitment to following the science by pursuing a holistic patient approach to address the multiple risk factors associated with CV, renal and metabolic diseases.

Heart Failure

HF is a life-threatening disease in which the heart cannot pump enough blood around the body. It affects approximately 64 million people worldwide (at least half of which have a reduced ejection fraction) and six million in the US. It is a chronic disease where half of patients will die within five years of diagnosis. There are two main categories of HF related to ejection fraction (EF), a measurement of the percentage of blood leaving the heart each time it contracts: HFrEF and heart failure with preserved ejection fraction (HFpEF). HFrEF occurs when the left ventricle (LV) muscle is not able to contract adequately and therefore, expels less oxygen-rich blood into the body. HF remains as fatal as some of the most common cancers in both men (prostate and bladder cancers) and women (breast cancer). It is the leading cause of hospitalization for those over the age of 65 and represents a significant clinical and economic burden.

DAPA-HF

DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multi-center, parallel-group, randomized, double-blinded trial in 4,744 patients with heart failure and reduced ejection fraction (LVEF ≤ 40%), with and without T2D, designed to evaluate the effect of FARXIGA10mg, compared with placebo, given once daily in addition to standard of care. The primary composite endpoint was time to the first occurrence of a worsening heart failure event (hospitalization or equivalent event; i.e. an urgent heart failure visit), or cardiovascular death. The median duration of follow-up was 18.2 months.

AstraZeneca in CV, Renal & Metabolism (CVMD)

CV, renal and metabolism together form one of AstraZeneca’s main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

US-47533 Last Updated 11/20

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