Dalantercept (ACE-041). XLRN_Dalanter… · Collaboration with Drs. Wang, Bhatt, Mier, Atkins; Beth...

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Dalantercept (ACE-041) Overview for Cancer Research UK February 2016

Transcript of Dalantercept (ACE-041). XLRN_Dalanter… · Collaboration with Drs. Wang, Bhatt, Mier, Atkins; Beth...

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Dalantercept (ACE-041) Overview for Cancer Research UK

February 2016

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TGF-β Family

30 ligands

12 receptors

10 ligand traps

in vivo Pharmacology

Internal GMP Manufacturing

Facility

Cell Biology

Protein Engineering

Luspatercept

Sotatercept

Dalantercept

ACE-083

ACE-2494

ACE-3891

Red Blood Cells

Muscle

Bone

Vasculature

TGF-β superfamily regulates the growth and repair of cells and tissues

Acceleron Drug Discovery Platform Targeting TGF-β superfamily yields robust pipeline of protein therapeutics

Acceleron has unique knowledge of how to optimally design therapeutic candidates to

regulate different cell types

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Luspatercept – MDS

Luspatercept – Thalassemia

Sotatercept – CKD

Sotatercept – Myelofibrosis

Sotatercept – Myeloma

ACE-083 – FSHD

Dalantercept – RCC

Dalantercept – HCC

Phase 1

Sotatercept – DBA

Phase 2 Phase 3

ACE-2494

ACE-3891

ACE-2798

ACE-2536

ACE-2395

Preclinical

Four internally discovered molecules in the clinic

Phase 3 studies in MDS and beta-thalassemia started in 2015

Fifth molecule expected to enter the clinic in 2016

Several molecules expected to enter the clinic shortly thereafter

ACE-1332

Building One of the Industry’s Most Robust Pipelines

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Dalantercept (ACE-041) Novel Anti-Angiogenesis Agent Targeting the Activin Receptor-Like Kinase 1 (ALK1) / BMP9 Pathway

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Dalantercept is a soluble ALK1 receptor-Fc fusion protein

Dalantercept binds BMP9 and BMP10 with high affinity, and thereby inhibits

signaling via the ALK1 receptor

Administered via SC injection q3 weeks in Phase 1 and 2 studies

Dalantercept

Soluble, Recombinant ALK1-Fc Fusion Protein

Extracellular Domain of ALK1

Fc Domain of IgG1 Antibody

Note: RAP-041 is the murine ortholog

(murine ALK1: murine Fc) of ACE-041,

that is used in studies in rodent models

Dalantercept – ALK1-Fc Fusion Protein Binds BMP9

5 Definitions: ALK1 = activin receptor-like kinase 1; BMP9 = bone morphogenetic protein 9

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R-SMAD1/5/8

SRE (Smad Responsive Element)

ALK1 Type I

Receptor P

SMAD4

BMPRII Type II

Receptor

Endoglin Accessory

Receptor

BMP9/10 Dalantercept

Id1, Id3 and others: vascular maturation

Endothelial cell

Dalantercept and ALK1 Signaling

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ALK1 is selectively expressed on vascular and lymphatic endothelial cells

In mice, homozygous deletion of ALK1 (-/-) results in severe vascular defects and

embryonic lethality

Patients with hereditary hemorrhagic telangiectasia (HHT-2) have lost expression of

a single ALK1 gene resulting in defective vasculature and a reduced ability to form a

capillary bed following injury

Dalantercept – Novel Inhibitor of the ALK1 Pathway

Vehicle Dalantercept

Loss of Capillary Beds in Murine RCC Tumor Following ALK-1 Inhibition (Dalantercept) Imaging of Vasculature with μCT Imaging of MicroFil-Perfused Tumor Samples

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Dalantercept – Combination Therapy Opportunity in RCC

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Tumor secretes pro-angiogenic

factors e.g. VEGF

VEGF induces EC proliferation

Step 1

ALK1 mediates vessel maturation

and pericyte coverage

Step 2

VEGF Receptor ALK1 Receptor Mature Vessel

Proliferation Maturation

Concept: Inhibit sequential steps in pathway to generate synergistic inhibition

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ALK1 is Required for Tumor Angiogenesis and Growth Genetic evidence in a spontaneous model of pancreatic islet cell cancer (RIP1-Tag2)

RIP1-Tag2 mice spontaneously develop highly vascularized, pancreatic islet cell tumors

ALK1 (+/-) mice crossed with RIP1-Tag2 mice develop fewer and smaller tumors with

decreased vascularity

ALK1 +/- mice have decreased tumor frequency and size

Cunha et al. J Exp Med. 2010 207(1): 85-100

ALK1 is expressed on tumor

vasculature

RIP1-Tag2 mice ALK1 wt

ALK1 podocalyxin

DAPI

RIP1-Tag2 mice ALK1 wt

ALK1 +/-

CD31

CD31 Tumors in

ALK1 +/- mice have decreased

vascularity RIP1-Tag2 mice

ALK1 wt ALK1 +/-

RIP1-Tag2 mice

ALK1 wt ALK1 +/-

RIP1-Tag2 mice

CD31

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Collaboration with Drs. Wang, Bhatt, Mier, Atkins; Beth Israel Deaconess, Boston

Sunitinib

Placebo

Dalantercept + Sunitinib

Dalantercept

Sunitinib

Dalantercept + Sunitinib

Dalantercept/Sunitinib Combination Exceeds Activity of Either Alone

(Mouse Model of Renal Cell Carcinoma (A498))

Dalantercept/Sunitinib Combination Slows Tumor Growth in a Sunitinib Resistant Model

(Mouse Model of Renal Cell Carcinoma (786O))

Sunitinib resistance

Dalantercept Enhanced Anti-Tumor Effects of VEGFR TKI in RCC

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Cunha, Pietras et al, Cancer Res (2015), 75(12):2445-56

Docetaxel

Placebo

Dalantercept + Docetaxel

Dalantercept

MMTV-PyMT Breast Cancer Adenocarcinoma

Monotherapy and combination with docetaxel

RPMI2650 Squamous Carcinoma of Head and Neck

Monotherapy and combination with cisplatin

Alimzhanov et al, AACR Annual Meeting, Cancer Res (2014), 74:1692

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Dalantercept Additive Efficacy with Chemotherapies

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Dalantercept (ACE-041) Clinical Program and Phase 1 Study Overview

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Study Phase 1 Phase 2 SCCHN

Phase 2 Endometrial (GOG/NRG-sponsored)

Phase 2 Ovarian

(GOG/NRG-sponsored)

Phase 1b HCC

Phase 2 RCC

Patients Recurrent or metastatic solid tumors

Recurrent or metastatic

Persistent or recurrent

Persistent or recurrent

Metastatic, first-line Metastatic, second-line (failed either sunitinib or pazopanib)

Treatment Dalantercept monotherapy

Dalantercept monotherapy

Dalantercept monotherapy

Dalantercept monotherapy

Sorafenib + dalantercept

Axitinib +/- dalantercept

Study Design

Dose-escalation and expansion

Open-label, two-dose cohorts

Single-arm, open-label, two-stage study

Single-arm, open-label, two-stage study

Open-label, dose escalation and expansion

Part 1: dose-escalation and expansion Part 2: randomized Ph2

Study N 37 46 28 30 21 Part 1: 29 Part 2: 130

Status Completed Completed Completed Completed Dose escalation completed, expansion ongoing

Dose escalation completed, Part 2 enrolling

Completed/Ongoing Dalantercept Phase 1 and 2 Studies

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Phase 1 Study Overview

37 patients with variety of solid tumors, refractory to standard therapies

Dalantercept at 7 dose levels from 0.1 to 4.8 mg/kg

Dose limiting toxicities of fluid overload and anemia

Non-overlapping toxicities with VEGF targeted drugs

– Hypertension, proteinuria, thrombo-embolic events, and wound-healing complications were not observed

PK: Cmax and AUC demonstrated a dose linear relationship

– T1/2 14-18 days, Tmax 4-7 days

Single agent activity observed

– 3% PR (n=1)

– 45% SD (n=13)

– Prolonged stable disease (≥12 weeks) in 8 patients

– Responses correlated with PD effect seen by FDG-PET and DCE-MRI

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Phase 1 Summary of Patients with Disease Control

Subject Diagnosis Dose

(mg/kg) Tx Period

(weeks)

RECIST

Best Response

Max % Change

Lesion

Size (CT)

FDG-PET

SUV

DCE-MRI

605 NSCLC (Sq) 3.2 to 1.6 90 SD -19.7 -29.9 N/A

807 SCCHN 1.6 33 SD -28.9 -19.3 N/A

303 SCCHN 0.4 30 PR -32.5 -44.4 N/A

702 Colorectal 4.8 to 1.6 27 SD -9.4 -2.4 N/A

302 NSCLC (Non-Sq) 0.4 24 SD -2.4 -22.7 N/A

811 Granulosa Cell 1.6 24 SD 5.2 N/A -39.9

203 Carcinoid 0.2 18 SD -3.2 -27.1 N/A

802 Small Bowel 1.6 18 SD 1.6 -52.8 -29.5

805 NSCLC (Sq) 1.6 18 SD 2.8 -40.6 -30.3

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Effect of ACE-041 Treatment is Consistent with Phenotype Observed in Genetic ALK1 Deficiency HHT

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Phase 1 Development of Telangiectasias Evidence of Target Engagement

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Dalantercept (ACE-041) Phase 2 RCC Study (DART)

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Dalantercept in Renal Cell Carcinoma (RCC)

Renal cell carcinoma is a highly angiogenic tumor

Anti-angiogenesis therapies have shown and continue to show robust efficacy in RCC

Substantial opportunity for a new drug to build upon, not compete with, large established base of numerous approved VEGF path inhibitors

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Current Approach

Physician uses preferred

VEGF path inhibitor (axitinib, bevacizumab,

pazopanib, sorafenib, sunitinib)

Dalantercept Opportunity

Physician uses preferred

VEGF path inhibitor (axitinib, bevacizumab,

pazopanib, sorafenib, sunitinib)

Dalantercept

BETTER OUTCOMES

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Phase 2 DART Study Schema – Advanced RCC

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Dose-Escalation Expansion

Part 1 Open label, dose escalation (N=29)

≥1 prior VEGFR TKI ≤3 lines of prior therapies

Part 2 Randomized, double-blind, placebo-controlled (N=130)

1 prior VEGF pathway inhibitor, may have also had 1 mTOR inhibitor and/or any prior immune therapy

Primary Endpoints: Safety, PK and RP2D Secondary Endpoints: PFS, ORR, DCR (PR+SD), biomarkers

Primary Endpoint: Progression-free survival Secondary Endpoints: ORR, DCR (PR+SD), OS, safety, PK, biomarkers

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Phase 2, Part 1 Adverse Events Regardless of Attribution As of June 3, 2015 (Presented at KCA, Nov 2015)

Preferred Term

0.6 mg/kg (N=6)

0.9 mg/kg (N=9)

1.2 mg/kg (N=14)

Overall (N=29)

Grade 1-3 n (%)

Grade 3* n (%)

Grade 1-3 n (%)

Grade 3* n (%)

Grade 1-3 n (%)

Grade 3* n (%)

Grade 1-3 n (%)

Grade 3* n (%)

Fatigue 5 (83.3) 1 (16.7) 6 (66.7) 0 10 (71.4) 0 21 (72.4) 1 (3.4)

Diarrhea 4 (66.7) 2 (33.3) 5 (55.6) 1 (11.1) 9 (64.3) 1 (7.1) 18 (62.1) 4 (13.8)

Dysphonia 4 (66.7) 0 3 (33.3) 0 6 (42.9) 0 13 (44.8) 0

Peripheral edema 0 0 4 (44.4) 0 8 (57.1) 0 12 (41.4) 0

Decreased appetite 3 (50.0) 0 2 (22.2) 0 5 (35.7) 0 10 (34.5) 0

Epistaxis 1 (16.7) 0 2 (22.2) 0 7 (50.0) 0 10 (34.5) 0

Hypertension 2 (33.3) 0 4 (44.4) 0 4 (28.6) 1 (7.1) 10 (34.5) 1 (3.4)

Nausea 2 (33.3) 0 5 (55.6) 0 3 (21.4) 0 10 (34.5) 0

Hand-foot syndrome 1 (16.7) 0 4 (44.4) 0 5 (35.7) 0 10 (34.5) 0

Arthralgia 1 (16.7) 0 4 (44.4) 0 4 (28.6) 0 9 (31.0) 0

Creatinine increase 0 0 1 (11.1) 0 8 (57.1) 0 9 (31.0) 0

Cough 1 (16.7) 0 4 (44.4) 0 4 (28.6) 0 9 (31.0) 0

Hypothyroidism 1 (16.7) 0 3 (33.3) 0 4 (28.6) 0 8 (27.6) 0

Weight decreased 2 (33.3) 0 1 (11.1) 0 5 (35.7) 1 (7.1) 8 (27.6) 1 (3.4)

Abdominal pain 1 (16.7) 0 2 (22.2) 0 4 (28.6) 1 (7.1) 7 (24.1) 1 (3.4)

Constipation 2 (33.3) 0 3 (33.3) 0 2 (14.3) 0 7 (24.1) 0

Headache 1 (16.7) 0 3 (33.3) 0 3 (21.4) 0 7 (24.1) 0

Pericardial effusion 0 0 3 (33.3) 0 4 (28.6) 0 7 (24.1) 0 * No grade 4/5 related adverse events

AEs that are common with axitinib treatment in RCC (≥30% per label)

(Note: the rates of AEs with Dalantercept + axitinib treatment were consistent with the rates in the axitinib label)

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Phase 2, Part 1 Response Rates (RECIST v1.1) As of June 3, 2015 (Presented at KCA, Nov 2015)

Endpoint 0.6 mg/kg

(N=6) 0.9 mg/kg

(N=9) 1.2 mg/kg

(N=13) Overall (N=28)

Partial Response, n (%) 2 (33.3) 3 (33.3) 2 (15.4) 7 (25.0)

Stable Disease, n (%) 2 (33.3) 6 (66.7) 9 (69.2) 17 (60.7)

Progressive Disease, n (%) 2 (33.3) 0 2 (15.4) 4 (14.3)

DCR ≥ 8 cycles (~ 6 months), n (%) 3 (50.0) 6 (66.7) 7 (53.8) 16 (57.1)

Note: 1 patient not evaluable for response based upon ineligibility

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Phase 2, Part 1 Best Overall Response (RECIST v1.1) As of June 3, 2015 (Presented at KCA, Nov 2015)

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Phase 2, Part 1 Treatment Duration As of June 3, 2015 (Presented at KCA, Nov 2015)

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Phase 2, Part 1 Survival Analyses As of June 3, 2015 (Presented at KCA, Nov 2015)

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Endpoint 0.9 mg/kg

(N=9) Overall (N=29)

Median Progression Free Survival (months) Not reached 8.3

12 month progression free survival rate* (%) 50% 39%

12 month overall survival rate* (%) 89% 75%

Analysis includes all patients who received study drugs (N=29) * Assessed by Kaplan-Meier Method

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Pro

gre

ssio

n-F

ree

Su

rviv

al

1st line

11 months for

Sunitinib(1)

2nd line 3rd line 4th line 5th line

Notes: (1) Motzer et al, NEJM, 356; Jan 11, 2007; (2) Rini et al, The Lancet, Vol 378; Dec 3, 2011; (3) Motzer et al, NEJM, 373; Nov 5, 2015 (4) Motzer et al, Lancet Oncology, 15: 286-96, Feb 17, 2014 (5) PFS rates for 3rd through 5th lines are illustrative

8.3 months for Dalantercept plus Axitinib

5 m

os.

1

0 m

os.

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4.8 mos for Axitinib(2), 4.6 mos for

Nivolumab(3)

3.6 months Sorafenib(4,5)

Phase 2, Part 1 Median PFS in RCC vs. Competition

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Median PFS vs. Competition Patients ≥ 1 Prior VEGFR TKI (2nd Line+ RCC Studies)

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0 1 2 3 4 5 6 7 8 9 10

Sorafenib (AXIS)

Everolimus (METEOR)

Everolimus (CheckMate-025)*

Nivolumab (CheckMate-025)*

Axitinib (AXIS)**

Cabozantinib (METEOR)

Dalantercept + Axitinib (DART Part 1)*

3.4

3.8

4.4

4.6

4.8

7.4

8.3

Median PFS (months)

* PFS analyses were based on investigator assessment of radiologic progression (i.e. no central read)

** PFS in patients who received prior sunitinib

Rini et al, Lancet 2011; 378: 1931–39; FDA Medical Review of axitinib NDA Jan 2011; Choueiri et al, NEJM, published on-line September 25, 2015; Motzer et al, NEJM 2015

Dalantercept plus axitinib data demonstrate proof of concept

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DART Interim Summary & Timeline to Completion

Dalantercept in combination with axitinib in Part 1 of the DART study produced clinical outcomes that exceed historical axitinib monotherapy results

Dalantercept safety profile was generally non-overlapping with VEGFR TKI and well-tolerated

Development strategy is to combine with VEGF path inhibitors to improve outcomes beyond VEGFR TKI monotherapy

Enrollment ongoing in Part 2 of the DART study (130 patient, randomized, double-blind, placebo-controlled trial)

PFS data from Part 2 of the DART study projected to be available end of 2016

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Dalantercept (ACE-041) Indications and Combination Regimens of Interest

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Combination Regimens and Indications to Consider

Dalantercept + Immune Oncology Therapies

– Dal + nivolumab in mRCC

– Dal + atezolizumab + bevacizumab in mRCC

Dalantercept + bevacizumab +/- chemotherapy

– Dal + bevacizumab + taxane in platinum-resistant ovarian

– Dal + bev + chemo in mCRC

– Dal + bev + chemo in NSCLC

– Dal + bev in GBM

– Dal + ramucirumab +/- chemo in gastric or GEJ adenocarcinoma

Dalantercept + VEGFR TKIs

– Dal + pazopanib, sunitinib or cabozantinib in mRCC

– Dal + sunitinib in pancreatic neuroendocrine tumors

– Dal + pazopanib in soft tissue sarcoma

– Dal + cabozantinib or lenvatinib in medullary thyroid cancer

– Dal + regorafenib in mCRC

Dalantercept + chemotherapy

– Dalantercept + chemo in triple-negative breast cancer

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