Document
false0001280600 0001280600 2020-06-24 2020-06-24


 
 
 
 
 

UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C.  20549
 
___________________________
 
FORM 8-K
___________________________

CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
 
Date of Report (Date of earliest event reported):  June 24, 2020
 ___________________________
 
ACCELERON PHARMA INC.
(Exact name of Registrant as specified in its charter)
 

Delaware
 
001-36065
 
27-0072226
(State or other jurisdiction
of incorporation)
 
(Commission
File Number)
 
(I.R.S. Employer
Identification Number)

128 Sidney Street
 
 
 
 
Cambridge,
MA
 
 
 
02139
(Address of principal
executive offices)
 
 
 
(Zip Code)
 

Registrant’s telephone number, including area code:  (617) 649-9200
 
Not Applicable
(Former name or former address, if changed since last report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
            Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
            Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
            Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
            Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Exchange Act:
Title of each class
Ticker Symbol(s)
Name of each exchange on which registered
Common Stock, $0.001 per share
XLRN
The Nasdaq Global Market
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company           
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.           

 
 
 
 
 





Item 7.01    Regulation FD Disclosure.

On June 24, 2020, Acceleron Pharma Inc. (the "Company") issued a press release titled "Acceleron Presents Topline Results of the PULSAR Phase 2 Trial of Sotatercept in Patients with Pulmonary Arterial Hypertension" announcing data presented during the “Breaking News: Clinical Trials in Pulmonary Medicine” session of the American Thoracic Society (ATS) 2020 Virtual Conference. A copy of the press release is attached as Exhibit 99.1 to this Current Report on Form 8-K.

The information contained in Item 7.01 of this Current Report on Form 8-K and Exhibit 99.1 hereto are being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or for any other purpose, and shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, regardless of any general incorporation language in any such filing, except as expressly set forth by specific reference in such a filing.

Item 8.01    Other Events.

On June 24, 2020, the Company will host a previously announced conference call and webcast to review the topline results of the PULSAR Phase 2 trial presented at the ATS 2020 Virtual Conference. A copy of the slide presentation to be presented during this conference call and webcast is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.

Item 9.01    Financial Statements and Exhibits.
 
(d)    Exhibits.
        
Exhibit Number
 
Description of Exhibit
99.1
 
99.2
 
104
 
Cover Page Interactive Data File (embedded within the Inline XBRL document)





SIGNATURES
 
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
 

 
ACCELERON PHARMA INC.
 
 
 
 
 
By:
/s/ Adam M. Veness, Esq.
 
 
Adam M. Veness, Esq.
 
 
Senior Vice President, General Counsel and Secretary
 
 
 
Date: June 24, 2020
 
 


3
Exhibit
Exhibit 99.1
https://cdn.kscope.io/f1c264aac7cb47e2526119b2e4607eef-xlrn20200624exhibit99_image2.gif




Acceleron Presents Topline Results of the PULSAR Phase 2 Trial of Sotatercept in Patients with Pulmonary Arterial Hypertension

- Data presented during ‘Breaking News’ Session of the American Thoracic Society 2020 Virtual Conference (ATS 2020 Virtual) show the PULSAR trial achieved its primary endpoint: a statistically significant mean reduction in pulmonary vascular resistance (PVR) -

- Patients on stable background therapy who were treated with 0.3 mg/kg or 0.7 mg/kg of sotatercept experienced mean PVR reductions of approximately 21% and 34%, respectively -

- The trial also achieved a statistically significant all-dose mean improvement from baseline of 54 meters in the key secondary endpoint of six-minute walk distance (6MWD) and a placebo corrected improvement of 25 meters (all doses combined) -

- Sotatercept was generally well tolerated; adverse events were consistent with previously published data on sotatercept in clinical trials in other patient populations -

- Company-hosted investor and analyst conference call and webcast with guest PAH key opinion leaders to be held today, Wednesday, June 24th at 4:30 p.m. EDT -

Cambridge, Mass. – June 24, 2020 – Acceleron Pharma Inc. (NASDAQ:XLRN), a biopharmaceutical company dedicated to the discovery, development, and commercialization of TGF-beta superfamily therapeutics to treat serious and rare diseases, today presented topline results of the PULSAR Phase 2 trial of sotatercept in patients with pulmonary arterial hypertension (PAH).

During the “Breaking News: Clinical Trials in Pulmonary Medicine” session of ATS 2020 Virtual, study investigators reported that patients on stable background PAH-specific therapies treated with sotatercept experienced a statistically significant reduction in pulmonary vascular resistance (PVR), the trial’s primary endpoint, at week 24 versus placebo.

“We’re thrilled to report the impressive magnitude of the positive effects that sotatercept, in combination with current therapies, was able to achieve in patients with PAH,” said Habib Dable, President and Chief Executive Officer of Acceleron. “Although the introduction over the past two decades of more than a dozen treatments for PAH has driven the development of today’s combination-therapy strategies, the substantial morbidity still associated with PAH clearly signals the need for a new approach. As we work now with health authorities to move sotatercept into Phase 3 testing, we are increasingly encouraged that we will be able to deliver a truly innovative therapy to patients with this debilitating disease.”

In this Phase 2 double-blind, placebo-controlled study, 106 patients were randomized to receive placebo, 0.3 mg/kg of sotatercept, or 0.7 mg/kg of sotatercept subcutaneously every 21 days in combination with stable background PAH-specific therapies, including mono, double, and triple therapy over a 24-week treatment period. Of the 106 patients participating in the trial, 35% were receiving double background PAH-specific therapies and 56% were receiving triple background PAH-specific therapies. The trial achieved its primary endpoint, key secondary endpoint, and showed concordance of results across multiple additional endpoints and regardless of baseline characteristics.





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Primary Endpoint:

Treatment*
% Reduction in PVR
P-Value
Sotatercept 0.3 mg/kg (n=32)
20.5%
0.0027
Sotatercept 0.7 mg/kg (n=42)
33.9%
<0.0001
Placebo (n=32)
2.1%
 
*All cohorts include stable background PAH-specific therapies

The trial also achieved the protocol-defined improvement in the key secondary endpoint of 6MWD at 24 weeks. Both sotatercept dose groups achieved at least a 50-meter (LS mean) increase from baseline, as demonstrated in the 0.3 mg/kg group (58 meters) and the 0.7 mg/kg group (50 meters), allowing for a pre-specified pooled analysis. Overall, treatment with sotatercept (pooled analysis) achieved a 54-meter (LS mean) change from baseline and a placebo-corrected (LS mean) difference of 25 meters (nominal p=0.03).

“These results, seen on top of existing therapies in heavily pretreated patients, are consistent with sotatercept exerting its effects through a mechanism distinct from currently approved agents,” said Dr. David Badesch, Professor of Medicine and Clinical Director of the Pulmonary Hypertension Center at the University of Colorado.

Badesch, who presented the PULSAR trial data during today’s ATS 2020 Virtual session, continued: “By selectively binding ligands of the TGF-beta superfamily, sotatercept is designed to rebalance key signaling pathways whose disruption has been shown to be important in PAH biology. If sotatercept’s efficacy and safety are confirmed in the next phase of clinical development, I believe it has the potential to substantially alter the way we treat patients with PAH.”

Treatment with sotatercept also demonstrated improvement across multiple exploratory study endpoints at week 24, including a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and 20% reduction in mean pulmonary arterial pressure. In addition, 23% of subjects improved their World Health Organization (WHO) functional class.

Sotatercept was generally well tolerated in the trial. Adverse events observed in the study were generally consistent with previously published data on sotatercept in clinical trials in other patient populations. Serious treatment-emergent adverse events (TEAEs) were reported in 6% (2/32) of patients receiving 0.3 mg/kg of sotatercept plus background therapy, 24% (10/42) of patients receiving 0.7 mg/kg of sotatercept plus background therapy, and in 9% (3/32) of patients receiving placebo plus background therapy.

Hemoglobin increase was reported in one patient (3%) in the 0.3 mg/kg sotatercept dose group and in 6 patients (14%) in the 0.7 mg/kg sotatercept dose group. No patient in the placebo group experienced an increase in hemoglobin. Two patients (6%) in the 0.3 mg/kg sotatercept dose group and 5 patients (12%) in the 0.7 mg/kg sotatercept dose group experienced thrombocytopenia. TEAEs occurring in 10% or more of all patients in any arm were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.

As of June 22, 2020, 94 of 97 patients who opted to participate in the 18-month extension period of the trial were still enrolled; 64 patients have now been treated with sotatercept for at least 12 months.

Dr. Badesch’s presentation from ATS 2020 Virtual is available in the Publications section under “Science & Pipeline” on the Company’s website at acceleronpharma.com.

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

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Dr. Badesch is the principal investigator of the PULSAR trial and a paid consultant to Acceleron.

About the PULSAR Trial

The PULSAR Phase 2 trial is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of sotatercept in PAH patients. The primary endpoint of the trial is the change from baseline in pulmonary vascular resistance (PVR) over a 24-week treatment period. PVR, as measured by right heart catheterization, is the resistance that the heart must overcome to pump blood through the pulmonary circulatory system. The key secondary endpoint was six-minute walk distance (6MWD); a measure of functional capacity/endurance. Other exploratory analyses included change in amino-terminal brain natriuretic propeptide (NT-proBNP), a hormone secreted by cardiac muscle cells in response to stretching caused by increased blood volume in the heart; mean pulmonary arterial pressure, a hemodynamic measure of average pressure in the main pulmonary arteries, which is elevated in PAH patients; and WHO functional class. A total of 106 patients were randomized in a 3:3:4 ratio to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg subcutaneously every 21 days with standard-of-care therapies in combination. The trial was powered to detect an 18% reduction in the primary endpoint of PVR and a 24-meter improvement in the secondary endpoint of 6MWD.

Following the 6-month double-blind treatment period, participants in the trial were eligible to continue in the 18-month extension period.

Conference Call and Webcast
The Company will host a webcast and conference call to discuss the topline results from the PULSAR Phase 2 trial on June 24, 2020, at 4:30 p.m. EDT.
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 conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and referring to the “Acceleron ATS 2020 Conference Call.”
The archived webcast will be available for replay on the Acceleron website approximately two hours after the event.

About Sotatercept

Sotatercept is an investigational 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. In preclinical research recently 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. Sotatercept, which is part of a licensing agreement with Bristol Myers Squibb, is also being evaluated in the exploratory, open-label SPECTRA Phase 2 trial in patients with PAH. For more information, please visit www.clinicaltrials.gov.

Sotatercept, which has been granted Breakthrough Therapy designation from the U.S. Food and Drug Administration and Priority Medicine (PRIME) designation from the European Medicines Agency in PAH, is an investigational therapy that is not approved for any use in any country.

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

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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, Acceleron and its global collaboration partner, Bristol Myers Squibb, are co-promoting REBLOZYL® (luspatercept-aamt), the first and only approved erythroid maturation agent, in the United States for the treatment of anemia in certain blood disorders. The Companies 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.

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 may take longer and/or cost more than planned, that Acceleron may 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 may 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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Source: Acceleron Pharma

CONTACT:
Acceleron Pharma Inc.

Investors:
Jamie Bernard, IRC, 617-649-9650
Associate Director, Investor Relations


Media:
Matt Fearer, 617-301-9557
Director, Corporate Communications

###





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xlrn20200624exhibit992
Exhibit 99.2 ATS 2020 Virtual: PULSAR Phase 2 Trial Results of Sotatercept in PAH June 24, 2020 1 Sotatercept is an investigational therapy that is not approved for any use in any country.


 
Acceleron Forward-Looking Statements THIS PRESENTATION CONTAINS FORWARD-LOOKING STATEMENTS ABOUT THE COMPANY’S STRATEGY, FUTURE PLANS AND PROSPECTS, including statements regarding the development and commercialization of sotatercept in pulmonary arterial hypertension (“PAH”) and of the Company's other compounds, the timeline for clinical development and regulatory approval of sotatercept in PAH and of the Company’s other compounds and the expected timing for reporting of data from ongoing clinical trials, and the potential of the Company’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 the Company'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 the Company’s compounds in one indication or country may not be predictive of approval in another indication or country, that the development of the Company's compounds may take longer and/or cost more than planned, that the Company may be unable to successfully complete the clinical development of the Company’s compounds, that the Company may be delayed in initiating, enrolling or completing any clinical trials, that the Company's compounds may not receive regulatory approval or become commercially successful products, and that Breakthrough Therapy or Priority Medicines (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 the Company's most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q, and other filings that the Company has made and may make with the SEC in the future. THE FORWARD-LOOKING STATEMENTS CONTAINED IN THIS PRESENTATION ARE BASED ON MANAGEMENT’S CURRENT VIEWS, PLANS, estimates, assumptions and projections with respect to future events, and the Company does not undertake and specifically disclaims any obligation to update any forward-looking statements. 2 This presentation is for investor relations purposes only – Not for product promotional purposes.


 
Introduction Habib Dable Chief Executive Officer


 
Significant Program Execution in Hematology and Pulmonary HEMATOLOGY1 PULMONARY REBLOZYL FDA approval in 1st indication PULSAR trial positive topline results US Commercial launch PULSAR presentation at Virtual ATS 2020 ASH 2019: 6 clinical presentations FDA Breakthrough Therapy designation in PAH Phase 3 trial planned in MF EMA PRIME designation in PAH NEJM MEDALIST Trial Publication Preclinical PAH results published in STM NEJM BELIEVE Trial Publication FDA Orphan Drug Designation granted in PAH REBLOZYL FDA approval in 2nd indication Pulmonary research deal with Fulcrum CHMP positive opinion on REBLOZYL ACE-1334 FDA Fast Track Designation 1. All REBLOZYL (luspatercept-aamt) activities are in collaboration with Bristol Myers Squibb 4 Sotatercept is part of the licensing agreement with Bristol Myers Squibb whereby Acceleron has the worldwide exclusive rights to This presentation is for investor relations purposes only – develop and commercialize sotatercept in the PH field, while BMS has an exclusive license to sotatercept outside of the PH field. Not for product promotional purposes.


 
Jay T. Backstrom, MD, MPH Executive Vice President, Head of R&D


 
Sotatercept Granted BTD and PRIME Designations First program to receive either designation in PAH PRIME – PRIORITY MEDICINES BREAKTHROUGH THERAPY DESIGNATION Sotatercept is an investigational therapy that is not approved for any use in any country. 6 Sotatercept is part of the licensing agreement with Bristol Myers Squibb whereby Acceleron has the worldwide exclusive rights to This presentation is for investor relations purposes only – develop and commercialize sotatercept in the PH field, while BMS has an exclusive license to sotatercept outside of the PH field. Not for product promotional purposes.


 
B12. Breaking News: Clinical Trial Results in Pulmonary Medicine Sotatercept for the Treatment of Pulmonary Arterial Hypertension David B. Badesch, M.D. 7


 
Guest Speakers to Present PULSAR Results *Drs. McLaughlin and Humbert are investigators in the PULSAR trial and are paid consultants to Acceleron. 8 This presentation is for investor relations purposes only – Not for product promotional purposes.


 
Sotatercept for the Treatment of Pulmonary Arterial Hypertension David B. Badesch1, Vallerie McLaughlin2, Simon Gibbs3, Mardi Gomberg-Maitland4, Marius M. Hoeper5, Ioana Preston6, Rogerio Souza7, Aaron Waxman8, Musa Mutyaba9, Solaiappan Manimaran9, Jennifer Barnes9, Janethe de Oliveira Pena9, and Marc Humbert10, on behalf of the PULSAR Study Investigators 1University of Colorado, Denver, CO; 2University of Michigan, Ann Arbor, MI; 3National Heart & Lung Institute, Imperial College London, London, England; 4George Washington University, Washington, DC; 5Department of Respiratory Medicine, Hannover Medical School and German Center of Lung Research, Hannover, Germany; 6Tufts Medical Center, Boston, MA; 7University of São Paulo, Brazil; 8Brigham and Women’s Hospital, Boston, MA; 9Acceleron Pharma, Cambridge, MA; 10University of Paris – Sud, Assistance Publique Hopitaux de Paris, Inserm U999, Le Kremlin-Bicêtre, France Welcome to


 
Pulmonary Arterial Hypertension: A Disease of Cellular Proliferation and Vascular Remodeling • Cause: progressive structural remodeling of the small pulmonary arteries • Consequence: right heart failure and death Normal PAH Galiè N et al. Eur Heart J 2016;37:67–119; Galiè N et al. Eur Respir J 2015;46:903–75 PAH: pulmonary arterial hypertension


 
Current Treatments Act Via Three Main Pathways: Prostacyclin, Endothelin-1 and Nitric Oxide Humbert M et al. Circulation 2014;130:2189–208; Lau EMT et al. Nat Rev Cardiol 2017;14:603–14 cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; ERA: endothelin 1 receptor antagonist; ET: endothelin; GMP: guanosine monophosphate; GTP: guanosine triphosphate; IPR: prostaglandin I2 receptor; PDE5: phosphodiesterase type 5; sGC: soluble guanylate cyclase


 
Targeting Novel Pathways in PAH Inflammation • Pulmonary artery endothelial cell Mitochondrial Growth dysfunction is a major abnormality metabolism factors identified in PAH • Strong translational research has Dysregulated BMPR-II/TGF-β identified a large number of novel angiogenesis superfamily targets in recent years signaling • A major challenge will be to prioritize drug discovery and development Extracellular Calcium matrix signaling Neurohormonal Vasoactive activation peptides Adapted from: Humbert M et al. Circulation 2014;130:2189–208 BMPR-II: bone morphogenetic protein receptor type 2; PAH: pulmonary arterial hypertension; TGF: transforming growth factor


 
Identifying the Role of BMPR2 in Pulmonary Hypertension • The BMP signaling pathway is defective in patients with familial primary pulmonary hypertension1 • Familial primary PH is caused by mutations in BMPR2 • The TGF-β superfamily and Smad signaling are important for the maintenance of blood vessel integrity2 • Additional evidence of the role of BMP signaling pathway in PH, demonstrating reduced BMPR-II expression in primary pulmonary hypertension3 1. Deng Z et al. Am J Hum Genet 2000;67:737–44; 2. International PPH Consortium. Nat Genet 2000;26:81–4; 3. Atkinson C et al. Circulaion 2002;105:1672–78. BMPR2: bone morphogenetic protein receptor 2 gene; BMPR-II: bone morphogenetic protein type 2 receptor; PH: pulmonary hypertension; TGF: transforming growth factor


 
Preclinical Sotatercept Research • Treatment with sotatercept in preclinical experiments improved: – Hemodynamics – Right ventricular (RV) hypertrophy – RV function – Arteriolar remodeling • Sotatercept has been demonstrated preclinically to act via a mechanism linked to rebalancing pro-proliferative and anti-proliferative signaling pathways Yung L et al. Sci Trans Med 2020;12(543):eaaz5660 RV: right ventricular


 
Sotatercept • Sotatercept is a novel, first-in-class fusion protein comprising the extracellular domain of human activin receptor type IIA linked to the Fc domain of human immunoglobulin G1 • Sotatercept is proposed to act by rebalancing signaling between pro- and anti-proliferative pathways, thereby reversing the characteristic vascular remodeling seen in PAH PAH Sotatercept Pro-proliferative Anti-proliferative Pro-proliferative Anti-proliferative Activins/GD BMPs BMPs Fs ALK ALK 1/2/3/6 ALK4/5/ ALK4/5/ 1/2/3/6 X 7 BMPR- 7 BMPR- II II ACTRIIA/B ACTRIIA/B X pSmad1/5/8 Gremlin- Gremlin- 1 1 Noggin Noggin ACTRIIA: activin receptor type 2A; ALK: activin receptor-like kinase; BMP: bone morphogenetic protein; GDF: growth differentiation factor; PAH: pulmonary arterial hypertension; pSmad; phosphorylated Smad


 
PULSAR Study Design • A phase 2 randomized, double-blind, placebo-controlled study to compare the efficacy and safety of sotatercept versus placebo when added to standard of care (SOC) for the treatment of PAH in 106 patients Inclusion Criteria • WHO Group 1 PAH • WHO Functional Class II or III • Baseline right heart catheterization with PVR ≥5 Wood units • Baseline 6-minute walk distance 150–550 m • Stable treatment with SOC therapies including mono, double, and triple Stratified by therapies: baseline – An endothelin-receptor WHO FC antagonist, a phosphodiesterase 5 inhibitor, a soluble guanylate cyclase stimulator, and/or a Trial currently in open-label prostacyclin (including IV) extension phase FC: functional class; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; SOC: standard of care; WHO: World Health Organization


 
PULSAR Study Sites • The PULSAR study enrolled 106 patients at 43 sites in 8 countries


 
PULSAR Study: Endpoints • Endpoints measured as change from baseline to 24 weeks versus placebo Primary endpoint: • Change in pulmonary vascular resistance Key secondary endpoint: • Change in 6-minute walk distance Additional endpoints and analyses included: • Change in NT-proBNP • Change in WHO functional class • Change in hemodynamics • Proportion achieving multi-component improvement (WHO FC, NT-proBNP, 6MWD) • Time to clinical worsening* * Too few events to be analyzed at the data cut-off date 6MWD: 6-minute walk distance; FC: functional class; NT-proBNP: amino-terminal brain natriuretic propeptide; PVR: pulmonary vascular resistance; WHO: World Health Organization


 
PULSAR Study: Statistical Methods Statistical Analysis Populations: • Intention to Treat: All randomized subjects • Safety Set: All randomized subjects who received at least one dose of study drug Statistical Methods: Efficacy: • Change from baseline measurements of PVR and 6MWD were analyzed using ANCOVA with randomization stratification factor and baseline value as covariates • If data were similar from both sotatercept groups, data were combined for comparison with the placebo group • All p values are two-sided; p values are nominal except for the primary endpoint (PVR) • Multiple imputation method was used for missing data handling • Other endpoints were summarized with descriptive statistics and tested using ANCOVA where appropriate Safety: • All safety analyses were performed on the Safety Population (same as Intention to Treat in this study) ANCOVA: analysis of covariance; 6MWD: 6-minute walk distance; PVR: pulmonary vascular resistance; TEAE: treatment-emergent adverse event


 
PULSAR Study: Baseline Characteristics (1) Sotatercept Sotatercept Placebo Total 0.3 mg/kg 0.7 mg/kg n=32 N=106 n=32 n=42 Female, n (%) 26 (81) 29 (91) 37 (88) 92 (87) Age, mean (range), years 46 (21–71) 48.5 (23–80) 48.5 (19–77) 48 (19–80) Time since diagnosis, mean (range), 7.2 (0.3–22) 7.6 (0.7–26) 6.2 (0.8–24) 7.4 (0.3–26) years PAH classification, n (%) Idiopathic 19 (59) 13 (41) 29 (69) 61 (58) Heritable 7 (22) 5 (16) 5 (12) 17 (16) Associated with 3 (9) 9 (28) 6 (14) 18 (17) connective-tissue disease Drug or toxin-induced 1 (3) 4 (13) 2 (5) 7 (7) Associated with corrected 2 (6) 1 (3) 0 (0) 3 (3) congenital shunts Primary analysis data cut-off date 14 January 2020 PAH: pulmonary arterial hypertension


 
PULSAR Study: Baseline Characteristics (2) Sotatercept Sotatercept Placebo Total 0.3 mg/kg 0.7 mg/kg n=32 N=106 n=32 n=42 WHO functional class, n (%) II 17 (53) 15 (47) 24 (57) 56 (53) III 15 (47) 17 (53) 18 (43) 50 (47) Standard-of-care PAH therapy, n (%) Parenteral prostacyclin 10 (31) 11 (34) 18 (43) 39 (37) Monotherapy 3 (9) 3 (9) 4 (10) 10 (9) Double therapy 12 (38) 11 (34) 14 (33) 37 (35) Triple therapy 17 (53) 18 (56) 24 (57) 59 (56) Pulmonary vascular resistance, 797 ± 57.0 789 ± 50.8 756 ± 63.5 779 ± 33.9 dyn· s/cm5 6-minute walk distance, m 409 ± 11.3 386 ± 15.7 398 ± 14.1 398 ± 8.1 NT-proBNP, pg/mL 870 ± 214.5 999 ± 227.6 871 ± 248.2 908 ± 135.4 Primary analysis data cut-off date 14 January 2020 Mean ± SE unless otherwise noted NT-proBNP: amino-terminal brain natriuretic propeptide; PAH: pulmonary arterial hypertension; WHO: World Health Organization


 
PULSAR Study: Primary Endpoint – Pulmonary Vascular Resistance (1) • Change from baseline to end of placebo-controlled treatment period (week 24) in PVR Primary analysis data cut-off date 14 January 2020 Mean ± SE PVR: pulmonary vascular resistance; SE: standard error; SOC: standard of care


 
PULSAR Study: Primary Endpoint – Pulmonary Vascular Resistance (2) • Sotatercept 0.7 mg/kg - subgroup analysis generally favors sotatercept at week 24 LS Mean (SE) Sotatercept 0.7 mg/kg Placebo + SOC Difference [95% CI] + SOC, n n Overall -240 (45.8) [-329, -150] 42 32 Sex Male -79 (94.8) [-265, -107] 5 6 Female -279 (51.5) [-380, -178] 37 26 PAH Diagnostic Group iPAH -253 (63.9) [-379, -129] 29 19 hPAH -175 (83.3) [-357, 6.3] 5 7 CTD -77 (119.6) [-335, 182] 6 3 Other -428 (172.7) [-872, 15.5] 2 3 SOC Combination Therapy Mono/Double -281 (80.5) [-439, -123] 18 15 Triple -207 (55.3) [-315, -99] 24 17 Prostacyclin Infusion Therapy Yes -188 (67.5) [-320, -55] 18 10 No -257 (63.6) [-382, -133] 24 22 WHO Functional Class II -207 (58.6) [-321, -92] 24 17 III -254 (79.3) [-410, -99] 18 15 Baseline PVR (dyn·s/cm5) ≤800 -207 (39.6) [-284, -129] 30 21 >800 -263 (115.6) [-490, -36] 12 11 Primary analysis data cut-off date 14 January 2020 CI: confidence interval; LS: least squares; CTD: connective tissue disease; hPAH: heritable pulmonary arterial hypertension; iPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; SE: standard error; SOC: standard of care; WHO: World Health Organization


 
PULSAR Study: Primary Endpoint – Pulmonary Vascular Resistance (3) • Sotatercept 0.3 mg/kg - subgroup analysis generally favors sotatercept at week 24 LS Mean (SE) Sotatercept 0.3 mg/kg Placebo + SOC Difference [95% CI] + SOC, n n Overall -146 (48.6) [-241, -51] 32 32 Sex Male 53 (96.0) [-135, 241] 3 6 Female -188 (53.9) [-294, -83] 29 26 PAH Diagnostic Group iPAH -156 (76.5) [-306, -5.6] 13 19 hPAH -165 (84.5) [-349, 19] 5 7 CTD -114 (122.6) [-151, 379] 9 3 Other -198 (122.6) [-513, 117] 5 3 SOC Combination Therapy Mono/Double -157 (83.5) [-320, 6.9] 14 15 Triple -135 (58.1) [-249, -21] 18 17 Prostacyclin Infusion Therapy Yes -125 (71.6) [-266, 15] 11 10 No -138 (65.8) [-267, -9] 21 22 WHO Functional Class II -92 (64.5) [-219, 34] 15 17 III -178 (79.9) [-335, -21] 17 15 Baseline PVR (dyn·s/cm5) ≤800 -63 (43.4) [-148, 22] 19 21 >800 -211(125) [-457, 35] 13 11 Primary analysis data cut-off date 14 January 2020 CI: confidence interval; LS: least squares; CTD: connective tissue disease; hPAH: heritable pulmonary arterial hypertension; iPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; SE: standard error; SOC: standard of care; WHO: World Health Organization


 
PULSAR Study: Key Secondary Endpoint – 6MWD • Mean change from baseline to Week 24 in 6-minute walk distance by visit Sotatercept + SOC Placebo + SOC 0.3 mg/kg 0.7 mg/kg All dose 6MWD, m n=32 n=32 n=42 n=74 LS Mean (SE) 29 (9.3) 58 (9.2) 50 (8.2) 54 (6.1) Placebo-corrected – 29 (13.1) 21 (12.4) 25 (11.1) LS Mean (SE) Difference P value* – 0.02 0.08 0.03 Primary analysis data cut-off date 14 January 2020 * nominal 6MWD: 6-minute walk distance; LS: least squares; SE: standard error; SOC: standard of care


 
PULSAR Study: 6MWD in Patients on Background Triple Therapy • Mean change from baseline in 6-minute walk distance in patients on triple therapy Sotatercept + SOC Placebo + SOC 0.3 mg/kg 0.7 mg/kg All dose 6MWD, m n=17 n=18 n=24 n=42 LS Mean (SE) 9 (12.1) 49 (11.8) 44 (10.5) 46 (7.7) Placebo-corrected – 40 (16.9) 35 (16.1) 37 (14.4) LS Mean (SE) Difference P value* – 0.02 0.03 0.01 Primary analysis data cut-off date 14 January 2020 * nominal and exploratory 6MWD: 6-minute walk distance; LS: least squares; SE: standard error; SOC: standard of care


 
PULSAR Study: Exploratory Analyses • Results were concordant across multiple exploratory endpoints at week 24 Sotatercept + SOC, All Dose n=74 Endpoint, Placebo + SOC change from baseline n=32 Absolute Change Percent Change† P Value* NT-proBNP, pg/mL +310.4 -462.4 -51% 0.0001 Right atrial pressure, mmHg +0.6 -1.4 -12% 0.03 Pulmonary arterial pressure, +0.5 -10.5 -20% 0.0001 mmHg Cardiac output, L/min +0.3 +0.1 2% 0.29 Endpoint, Placebo + SOC Sotatercept + SOC, proportion of subjects n=32 All Dose n=74 P Value* WHO FC improvement 12.5% 23% 0.20 Multi-component improvement^ 3% 38% 0.0002 † Percent change = (absolute change / mean baseline)· 100 ^ Multi-component improvement defined as meeting all three criteria: WHO FC improvement or maintenance of FC II or better, ≥30% improvement in NT- proBNP, ≥30m improvement in 6MWD Primary analysis data cut-off date 14 January 2020 * nominal 6MWD: 6-minute walk distance; FC: WHO functional class; NT-proBNP: amino-terminal brain natriuretic propeptide; PVR: pulmonary vascular resistance; SOC: standard of care


 
PULSAR Study: Safety (1) Sotatercept Sotatercept Placebo + SOC 0.3 mg/kg + SOC 0.7 mg/kg + SOC n (%) n=32 n=32 n=42 Treatment-emergent adverse events (TEAE) 28 (88) 29 (91) 34 (81) Serious TEAEs 3 (9) 2 (6) 10 (24)* Serious related TEAEs 1 (3) 0 (0) 2 (5) TEAEs leading to treatment discontinuation 1 (3) 2 (6) 3 (7) TEAEs leading to death 0 (0) 0 (0) 1 (2)^ * These 10 patients experienced SAEs of: leukopenia, neutropenia, pericardial effusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, RBC increase ^ This patient died due to a cardiac arrest deemed unrelated to study treatment and had many pre-existing risk factors Primary analysis data cut-off date 14 January 2020 RBC: red blood cell; SAE: serious adverse event; SOC: standard of care TEAE: treatment-emergent adverse event


 
PULSAR Study: Safety (2) Sotatercept Sotatercept Placebo + SOC 0.3 mg/kg + SOC 0.7 mg/kg + SOC n=32 n=32 n=42 TEAEs of special interest, n (%)* 0 (0) 3 (9) 6 (14) Leukopenia 0 (0) 1 (3) 1 (2) Neutropenia 0 (0) 0 (0) 1 (2) Thrombocytopenia^ 0 (0) 2 (6) 5 (12) Hemoglobin increase, n(%) 0 (0) 1 (3) 6 (14) Hematology variables, mean ± SD n=30 n=31 n=36 Hemoglobin, g/dL, week 24 13.8 ± 1.6 13.9 ± 1.7 15.0 ± 1.7 Change from baseline to week 24 0.0 ± 1.1 1.2 ± 1.2 1.5 ± 1.1 Platelet count, ×109/L, week 24 199 ± 75.9 218 ± 68.7 196 ± 64.2 Change from baseline to week 24 -6.3 ± 29.1 (n=29) 12.1 ± 47.7 -12.1 ± 49.8 * These events identified as events of special interest at health authority request from the previous sotatercept studies in 350 patients ^ Most patients had existing thrombocytopenia at study start and all were on concomitant prostacyclin infusion therapy; no patients had grade 3 or associated bleeding events Primary analysis data cut-off date 14 January 2020 RBC: red blood cell; SD: standard deviation; SOC: standard of care TEAE: treatment-emergent adverse event


 
PULSAR Study: All TEAEs in ≥10% of Patients TEAEs in ≥10% of all patients in any arm (all grades) Sotatercept Sotatercept Placebo + SOC 0.3 mg/kg + SOC 0.7 mg/kg + SOC Preferred Term, n (%) n=32 n=32 n=42 Headache 5 (16) 8 (25) 6 (14) Diarrhea 4 (13) 7 (22) 6 (14) Peripheral edema 5 (16) 3 (9) 5 (12) Dizziness 3 (9) 5 (16) 4 (10) Fatigue 6 (19) 2 (6) 4 (10) Hypokalemia 4 (13) 3 (9) 5 (12) Nausea 4 (13) 3 (9) 5 (12) Primary analysis data cut-off date 14 January 2020 SOC: standard of care; TEAE: treatment-emergent adverse event


 
PULSAR Study: Conclusions • The PULSAR study achieved the objectives of demonstrating improvement in PVR and in 6MWD at week 24 vs placebo • Subgroup analyses favored sotatercept at both dose levels and in patients receiving mono, double, or triple therapy • Concordance of results was seen across multiple study endpoints • Sotatercept was generally well tolerated in subjects with PAH, with a safety profile consistent with that observed in other patient populations • Sotatercept has a novel proposed MoA, rebalancing pro- and anti-proliferative signaling through a pathway distinct from the approved PAH therapies • Proof of concept has been demonstrated and a phase 3 program is planned 6MWD: 6-minute walk distance; MoA: mechanism of action; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance


 
PULSAR Study: Acknowledgements • We thank all the patients, their families, and all the PULSAR study investigators who participated in the trial – PULSAR study investigators: Y. Adir, M. Andrade-Lima, J. Arakaki, R. Argula, D. Baratz, J. Barberá, A. Bar-Shai, C. Berastagui, L. Bertoletti, D. Blanco, A. Bourdin, F. Campos, C. Church, J. Cifrian Martinez, J. Coghlan, T. Demarco, S. Eisenmann, P. Engel, P. Escribano- Subias, J. Feenstra, J. Feldman, M. Halank, L. Howard, A. Keogh, M. Kramer, T. Lange, G. Meyer, D. Montani, K. Olsson, C. Pison, G. Reeves, F. Rischard, Z. Safdar, R. Saggar, M. Segel, J. Segovia Cubero, L. Spikes, D. Shitrit, J. Wheatley, H. Wirtz • The study was sponsored by Acceleron Pharma, Cambridge, MA, USA – Acceleron personnel: A. Atanasov, C. Barron, B. Budda, E. Davis, K. de Jong, R. Gerber, S. Harrison, J. Lu, J. Reynolds, J. Oram, C. Sanmarco, M. Troy • The authors received editorial assistance from InterComm LTD, supported by Acceleron Pharma


 
KOL View on PULSAR Topline Results *Drs. McLaughlin and Humbert are investigators in the PULSAR trial and are paid consultants to Acceleron. 33 This presentation is for investor relations purposes only – Not for product promotional purposes.


 
Closing Remarks Habib Dable Chief Executive Officer


 
Priorities for Sotatercept Program in PAH ▪ Conclude end of Phase 2 interactions with global health authorities by mid- year 2020 ▪ Announce final Phase 3 trial plans in PAH expected in 2H 2020 ▪ Initiate Phase 3 trial in PAH expected by year-end 2020 ▪ Plan additional trials of sotatercept in PAH ▪ Evaluate development of sotatercept in broader PH indications ▪ Present preliminary results from SPECTRA trial expected in 1H 2021 Sotatercept is an investigational therapy that is not approved for any use in any country. 35 Sotatercept is part of the licensing agreement with Bristol Myers Squibb whereby Acceleron has the worldwide exclusive rights to This presentation is for investor relations purposes only – develop and commercialize sotatercept in the PH field, while BMS has an exclusive license to sotatercept outside of the PH field. Not for product promotional purposes.


 
Question & Answer Session Habib Dable President and Chief Executive Officer Jay T. Backstrom, MD, MPH Executive Vice President, Head of R&D Marc Humbert, MD, PhD* Professor of Respiratory Medicine at the Université Paris-Saclay Vallerie McLaughlin, MD* Professor of Cardiovascular Medicine at the University of Michigan Janethe Pena, MD, PhD Vice President, Medical Research, Pulmonary​ Sujay Kango Executive Vice President and Chief Commercial Officer Todd James Senior Vice President, Corporate Affairs and Investor Relations *Drs. McLaughlin and Humbert are investigators in the PULSAR trial and are paid consultants to Acceleron. 36 This presentation is for investor relations purposes only – Not for product promotional purposes.