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Designing precision therapies specifically to target the underlying cause of genomically defined diseases

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Avapritinib

Avapritinib is a potent and selective inhibitor of activated KIT and PDGFRA mutant kinases. In certain diseases, mutations in KIT and PDGFRA force protein kinases into an increasingly active state. Avapritinib is uniquely designed to bind and inhibit the active conformation of these proteins.

Activating mutations in KIT and PDGFRA are associated with gastrointestinal stromal tumors (GIST) and systemic mastocytosis (SM) and appear in lower frequency in a broad range of advanced malignancies.

Avapritinib in GIST

  • GIST is a sarcoma of the gastrointestinal tract, and is driven by the PDGFRA gene with exon 18 mutations in about 6% of patients.

  • Prior to tyrosine kinase inhibitor use in GIST, mutational testing in all patients is recommended by expert guidelines. People diagnosed with GIST should be tested for mutations to determine which type of therapy might be right for them.

  • Blueprint Medicines is developing avapritinib as a potential treatment for patients with PDGFRA exon 18 mutant GIST globally. View approved uses of avapritinib. View clinical trials of avapritinib.

Avapritinib in systemic mastocytosis

  • Systemic mastocytosis (SM) is a rare disease that results from the abnormal proliferation of mast cells; across all forms of SM, the KIT D816V mutation is the primary driver of disease.

  • SM comprises a disease spectrum ranging from indolent SM, which is predominantly characterized by severe constitutional symptoms caused by mast cell degranulation and mediator release, to advanced SM, which is characterized by organ dysfunction and reduced survival due to mast cell infiltration.

    – The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life.

    – A minority of patients have advanced SM; in addition to mast cell activation symptoms, it is associated with organ damage due to mast cell infiltration and poor overall survival.

  • Avapritinib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe indolent SM.

  • Blueprint Medicines is developing avapritinib as a potential treatment for a broad population of patients with SM globally, including advanced and non-advanced SM. View approved uses of avapritinib. View clinical trials of avapritinib.

Presentations and publications

Avapritinib in GIST

Long-term efficacy, tolerability and overall survival in patients with unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumor treated with avapritinib: NAVIGATOR phase 1 trial update. Robin L. Jones, M.D., European Society for Medical Oncology (ESMO) Virtual Congress, September 18, 2020.
Clinical Efficacy Comparison of Avapritinib With Other Tyrosine Kinase Inhibitors (TKIs) in Gastrointestinal Stromal Tumors (GIST) With PDGFRA D842V Mutation: A Retrospective Analysis of Clinical Trial and Real-World Data. Margaret von Mehren, M.D., European Society for Medical Oncology (ESMO) Virtual Congress, September 17, 2020.
Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Michael Heinrich, M.D., The Lancet Oncology, June 29, 2020.
Clinical Response to Avapritinib by RECIST and Choi Criteria in ≥ 4th Line and PDGFRA Exon 18 Gastrointestinal Stromal Tumors (GIST). Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) Annual Meeting, November 14, 2019.
Avapritinib for the Treatment of GIST: Analysis of Efficacy, Safety, and Patient Management Strategies at the Recommended Phase 2 Dose. Cissimol P. Joseph, NP-C, Connective Tissue Oncology Society (CTOS) Annual Meeting, November 14, 2019.
Clinical Activity of Avapritinib in ≥4th Line (4L+) and PDGFRA Exon 18 Gastrointestinal Stromal Tumors (GIST). Michael Heinrich, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 1, 2019.
Avapritinib is Highly Active and Well-tolerated in Patients With Advanced GIST Driven by a Diverse Variety of Oncogenic Mutations in KIT and PDGFRA. Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting, November 15, 2018.
Correlation of ctDNA and Response in Patients with PDGFRα D842 GIST Treated with Avapritinib. Suzanne George, M.D., European Society for Medical Oncology (ESMO) Congress, October 22, 2018.
An Open-label, Randomized, Phase 3 Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Metastatic or Unresectable Gastrointestinal Stromal Tumor. Sebastian Bauer, M.D., European Society for Medical Oncology (ESMO) Congress, October 22, 2018.
Clinical activity of BLU-285, a highly potent and selective KIT/PDGFRα inhibitor designed to treat gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) Annual Meeting, November 10, 2017.
Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 5, 2017.
BLU-285: A potent and highly selective inhibitor designed to target malignancies driven by KIT and PDGFRα mutations. Erica Evans, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 2, 2017.
Preliminary safety and activity in a first-in-human Phase 1 study of BLU-285, a potent, highly selective inhibitor of KIT and PDGFRα activation loop mutants in advanced gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium, December 1, 2016.

Avapritinib in systemic mastocytosis

Results from PIONEER: a randomized, double-blind, placebo-controlled, Phase 2 study of avapritinib in patients with indolent systemic mastocytosis (ISM). Cem Akin, M.D., Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress, June 12, 2020.
Avapritinib induces responses in patients with advanced systemic mastocytosis (AdvSM), regardless of prior midostaurin therapy. Jason Gotlib, M.D., Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress, June 12, 2020.
Avapritinib reduces cutaneous symptoms and mast cell burden in patients with indolent systemic mastocytosis in the PIONEER study. Karin Hartmann, M.D., European Academy of Allergy and Clinical Immunology (EAACI) 2020 Digital Congress, June 6, 2020.
PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy. Cem Akin, M.D., American Academy of Allergy, Asthma & Immunology (AAAAI) Virtual Oral Abstracts, Case Reports and Poster Sessions, March 16, 2020.
PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy. Cem Akin, M.D., American Society of Hematology (ASH) Annual Meeting, December 8, 2019.
Psychometric Evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) in patients with Advanced Systemic Mastocytosis. International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Europe Conference, November 6, 2019.
Psychometric Performance of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF). International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Europe Conference, November 6, 2019.
Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Induces Complete and Durable Responses in Patients with Advanced Systemic Mastocytosis. Deepti Radia, M.B.B.S., European Hematology Association (EHA) Annual Meeting, June 15, 2019.
Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM). Jason Gotlib, M.D., American Society of Hematology (ASH) Annual Meeting, December 2, 2018.
Avapritinib (BLU-285), a Selective KIT Inhibitor, is Associated with High Response Rate and Tolerable Safety Profile in Advanced Systemic Mastocytosis: Results of a Phase 1 Study. Michael W. Deininger, M.D., Ph.D., European Hematology Association (EHA) Annual Meeting, June 15, 2018.
Clinical activity in a Phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis. Daniel J. DeAngelo, M.D., Ph.D., American Society of Hematology (ASH) Annual Meeting, December 10, 2017.
A precision therapy against cancers driven by KIT/PDGFRA mutations. Erica K. Evans, Ph.D., et al., Science Translational Medicine, November 1, 2017.
BLU-285: A potent and highly selective inhibitor designed to target malignancies driven by KIT and PDGFRα mutations. Erica Evans, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 2, 2017.
Preliminary Safety and Activity in a Phase 1 study of BLU-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (SM). Mark Drummond, MBChB, Ph.D., American Society of Hematology (ASH) Annual Meeting, December 4, 2016.

Clinical trials

Systemic mastocytosis (SM)

Trial Phase

Trial Phase 2

Target Population

Target Population

Aggressive SM, SM with associated hematologic neoplasm, and mast cell leukemia

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT03580655

Trial Phase

Trial Phase 2

Target Population

Target Population

Indolent SM

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT03731260

Pralsetinib

Pralsetinib is a potent and selective inhibitor of oncogenic RET alterations. Across a wide range of cancers, oncogenic alterations in RET result in kinase activation, driving tumor formation and growth. The two primary mechanisms of oncogenic RET activation are fusions and mutations.

In preclinical studies, pralsetinib has achieved sub-nanomolar potency against common RET fusions and mutations. and inhibited RET at lower concentrations than other pharmacologically relevant kinases, including VEGFR2, FGFR2, and JAK2.

Oncogenic RET alterations occur in many tumor types, including 1-2% of non-small cell lung cancer (NSCLC), 90% of advanced medullary thyroid cancer (MTC), and 10-20% of papillary thyroid cancer (PTC) cases. Oncogenic RET alterations are also observed at low frequencies in colorectal, breast, pancreatic and other cancers.

Pralsetinib in non-small cell lung cancer

  • Lung cancer is the most common cancer worldwide and is the leading cause of cancer death. NSCLC is the most common form of lung cancer, making up 80-85% of cases.

  • The 5-year survival rate for NSCLC is estimated to be 18 percent.

  • RET fusions are implicated as the underlying cause of disease in about 1-2% of NSCLC cases.

  • Blueprint Medicines and Roche are developing pralsetinib globally for the treatment of patients with RET fusion-positive NSCLC. View approved uses of pralsetinib. View clinical trials of pralsetinib.

Pralsetinib in thyroid cancer

  • Thyroid cancer is the most common form of endocrine malignancy.

  • MTC comprises about 3-5% of thyroid cancer cases. RET mutations are found in nearly all cases of inherited MTC and 50% of sporadic MTC.

  • PTC comprises about 70% of thyroid cancer cases. RET fusions are found in about 10-20% of PTC cases.

  • Currently approved multi-kinase inhibitors for MTC have low tolerability, with high rates of dose reduction and discontinuation due to off-target toxicities.

  • Blueprint Medicines and Roche are developing pralsetinib globally for the treatment of patients with RET-mutant MTC and RET fusion-positive thyroid cancer. View approved uses of pralsetinib. View clinical trials of pralsetinib.

Presentations and publications

Analysis of Resistance Mechanisms to Pralsetinib (BLU-667) in Patients with RET Fusion–Positive Non-Small Cell Lung Cancer (NSCLC) from the ARROW Study. Justin Gainor, M.D., IASLC North America Conference on Lung Cancer, October 17, 2020.
Results from the registrational phase 1/2 ARROW trial of pralsetinib (BLU-667) in patients with advanced RET mutation-positive medullary thyroid cancer. Mimi I. Hu, M.D., European Society for Medical Oncology (ESMO) Virtual Congress, September 20, 2020.
Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. Vivek Subbiah, M.D., AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET Fusion+ Advanced/Metastatic Non-Small-Cell Lung Cancer (NSCLC), May 31, 2020.
AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET Fusion+ Advanced/Metastatic Non-Small-Cell Lung Cancer (NSCLC). Benjamin Besse, M.D., Ph.D., American Society of Clinical Oncology (ASCO) Virtual Scientific Program, May 29, 2020.
Registrational Dataset from the Phase 1/2 ARROW Trial of Pralsetinib (BLU-667) in Patients with Advanced RET Fusion+ Non-Small Cell Lung Cancer (NSCLC). Justin Gainor, M.D., American Society of Clinical Oncology (ASCO) Virtual Scientific Program, May 29, 2020.
Treatment With Pralsetinib (BLU-667), a Potent and Selective RET Inhibitor, Provides Rapid Clearance of ctDNA in Patients With RET-Altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer. Giuseppe Curigliano, M.D., Ph.D., European Society for Medical Oncology (ESMO) Annual Meeting, September 30, 2019.
Pralsetinib (BLU-667) demonstrates robust activity in RET-fusion-driven intracranial tumor models. Erica K. Evans, Ph.D., IASLC World Conference on Lung Cancer, September 9, 2019.
Clinical Activity and Tolerability of BLU-667, a Highly Potent and Selective RET Inhibitor, in Patients with Advanced RET-Fusion+ Non-small Cell Lung Cancer. Justin Gainor, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 3, 2019.
Activity and Tolerability of BLU-667, a Highly Potent and Selective RET Inhibitor, in Patients with Advanced RET-altered Thyroid Cancers. Matthew Taylor, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 1, 2019.
Discovery of BLU-667 for RET-driven cancers. Jason Brubaker Ph.D., American Association for Cancer Research (AACR) Annual Meeting, March 30, 2019.
Clinical activity of pralsetinib, a highly selective RET inhibitor, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study. Mimi I. Hu, M.D., American Thyroid Association (ATA) Annual Meeting, October 6, 2018.
Activity of osimertinib and the selective RET inhibitor pralsetinib in an EGFR-mutant patient with acquired RET rearrangement. Zofia Piotrowska, M.D., IASLC World Conference on Lung Cancer, September 26, 2018.
Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and PRALSETINIB (BLU-667) for acquired RET fusion. Zofia Piotrowska, M.D., et al., Cancer Discovery, September 26, 2018.
Highly potent and selective RET inhibitor, pralsetinib, achieves proof of concept in ARROW, a phase 1 study of advanced, RET-altered solid tumors. Vivek Subbiah, M.D., American Association for Cancer Research (AACR) Annual Meeting, April 15, 2018.
Precision targeted therapy with pralsetinib for RET-driven cancers. Vivek Subbiah, M.D., et al., Cancer Discovery, April 15, 2018.
Pralsetinib is a Potent and Highly Selective RET Inhibitor Being Developed for RET-Driven Cancers. Rami Rahal, Ph.D.
, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, October 29, 2017.
Pralsetinib is a potent and highly selective RET inhibitor in development for RET-driven thyroid cancers. Rami Rahal, Ph.D., 
World Congress on Thyroid Cancer, July 30, 2017.
The development of potent and selective RET inhibitors. Rami Rahal, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 18, 2016.

Clinical trials

Trial Phase

Trial Phase 1/2

Target Population

Target Population

RET-altered non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) or other solid tumors with a RET fusion or mutation

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT03037385

Trial Phase

Trial Phase 3

Target Population

Target Population

First-line RET fusion-positive, metastatic NSCLC

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT04222972

BLU-263

BLU-263 is a next-generation KIT D816V inhibitor developed based on insights from the avapritinib program.. BLU-263 was designed to potently inhibit D816V mutant KIT with minimal central nervous system penetration. These attributes may have the potential to optimize its benefit-risk profile for the treatment of broad patient populations with non-advanced systemic mastocytosis (SM).

BLU-263 in systemic mastocytosis

  • Systemic mastocytosis (SM) is a rare disease that results from the abnormal proliferation of mast cells; across all forms of SM, the KIT D816V mutation is the primary driver of disease.

  • The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life.

  • The initial focus of the BLU-263 development program is non-advanced SM. View clinical trials of BLU-263.

Presentations and publications

BLU-945, BLU-701 & BLU-451


BLU-945, BLU-701 and BLU-451 are investigational EGFR inhibitors designed to address a broad range of activating mutations and on-target resistance mechanisms in EGFR-driven non-small cell lung cancer (NSCLC), with the goal of prolonging patient benefit.

NSCLC is the most common form of lung cancer, the leading cause of cancer death worldwide. Among patients with non-small cell lung cancer, it is estimated that the EGFR mutation is present in approximately 22% of cases in the U.S., about 15% in Europe and about 40-50% in Asia.

BLU-945 and BLU-701 in EGFR-mutated NSCLC

  • For patients with NSCLC, about 80 percent of activating EGFR mutations are exon 19 deletions and L858R, combined.

  • T790M and C797S are the most common on-target resistance mutations to first-generation EGFR inhibitors and osimertinib, respectively.

  • There are currently no approved targeted therapies for osimertinib-resistant EGFR-mutated NSCLC.

  • BLU-945 and BLU-701 are selective, potent EGFR inhibitors designed to provide comprehensive coverage of common activating and on-target resistance mutations, and spare wild-type EGFR and other kinases to help limit off-target toxicities. In addition, the drug candidates were designed to prevent or treat central nervous system metastases.

  • Blueprint Medicines is developing BLU-945 and BLU-701, as monotherapies and in combination regimens, across multiple lines of therapy in EGFR-mutated NSCLC. View clinical trials of BLU-945 and BLU-701.

BLU-451 in NSCLC harboring EGFR exon 20 insertions and other uncommon EGFR activating mutations

  • Uncommon activating EGFR mutations, including exon 20 insertions, represent about 10-20 percent of EGFR-mutated NSCLC cases, varying by geography.

  • Patients with NSCLC harboring EGFR exon 20 insertion mutations have been historically associated with worse outcomes than those driven by common EGFR activating mutations.

  • BLU-451 is designed to potently target EGFR exon 20 insertion variants and other uncommon EGFR activating mutations, with marked selectivity over wild-type EGFR and off-target kinases. In addition, BLU-451 has shown central nervous system penetration in preclinical studies.

  • Blueprint Medicines is developing BLU-451 for the treatment of patients with NSCLC harboring EGFR exon 20 insertion mutations. View clinical trial of BLU-451.

Presentations and publications

BLU-222


BLU-222 is a potent and selective CDK2 inhibitor for the treatment of patients with CDK2-vulnerable cancers, including hormone receptor (HR)-positive, HER2-negative breast cancer and CCNE1 aberrant tumors. CDK2 and CCNE1 are central to regulating the cell cycle, which is involved in the process of cell growth and division. However, prior drug discovery efforts targeting CDK2 have been hindered by challenges in achieving selectivity over other CDK family members associated with toxicity.

CDK2 is believed to play an important role in tumor proliferation for patients with HR-positive, HER2-negative metastatic breast cancer. In subsets of patients with ovarian cancer and other tumor types, aberrant CCNE1 hyperactivates CDK2, resulting in cell cycle dysregulation and tumor growth. Preclinically, BLU-222 showed significant antitumor activity in a CCNE1-amplified ovarian cancer model, and BLU-222 in combination with standard of care agents led to sustained tumor regression even after treatment cessation.

BLU-222 in hormone receptor-positive metastatic breast cancer

  • Approximately 60 percent of treatment-naïve patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer receive a CDK4/6 inhibitor; however, patients ultimately become resistant to therapy over time.

  • There are limited treatment options for patients following disease progression on a CDK4/6 inhibitor.

  • Blueprint Medicines is developing BLU-222 as a monotherapy and in combination with other agents, including CDK4/6 inhibitors and ER antagonists, in HR-positive, HER2-negative breast cancer. View clinical trial of BLU-222.

BLU-222 in cyclin E aberrant cancers

  • Studies show that CCNE1 amplification across multiple tumor types is correlated with poor patient outcomes.

  • For example, approximately 10 to 20 percent of patients with high grade serous ovarian cancer, a common form of ovarian cancer, harbor CCNE1 amplifications.

  • Blueprint Medicines is developing BLU-222 as a monotherapy and in combination with other agents for the treatment of CCNE1 aberrant cancers. View clinical trial of BLU-222.

Presentations and publications

BLU-782

BLU-782 is an orally administered, potent and highly selective ALK2 inhibitor. It was designed specifically to target the underlying genetic driver of fibrodysplasia ossificans progressiva (FOP), a rare, severely disabling and ultimately life-shortening genetic disease. FOP is characterized by episodic soft tissue edema (flare-ups), and the progressive replacement of skeletal muscle, ligaments and connective tissue by heterotopic bone. FOP is caused by a gain-of-function mutation in ACVR1, which encodes activin-like kinase 2 (ALK2).

In October 2019, we entered into an exclusive, worldwide license agreement with Clementia Pharmaceuticals, a subsidiary of Ipsen, to develop and commercialize BLU-782.

BLU-782 in fibrodysplasia ossificans progressiva

  • FOP is a rare genetic disease, with an estimated prevalence of 1.36 per million.

  • In patients with FOP, mutations in the ACVR1 gene over-activate ALK2, causing disease flare-ups and heterotopic ossification (HO) or abnormal bone formation.

  • Disease flare-ups involve painful tumor-like swelling typically caused by physical trauma.

  • HO causes progressive disability and incapacitation including the locking of joints, ultimately contributing to reduced survival typically due to pulmonary insufficiency.

  • BLU-782 is designed to selectively target mutant ALK2, while sparing closely related anti-targets including ALK1, ALK3, and ALK6.

Presentations and publications

A clinical update on BLU-782, an investigational selective ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP) Alison Davis, Ph.D., American Society for Bone Mineral Research (ASBMR) Annual Meeting, September 22, 2019
BLU-782: A highly selective ALK2 inhibitor, designed specifically to target the cause of fibrodysplasia ossificans progressiva. Andy Garner, Ph.D., American Society for Bone Mineral Research (ASBMR) Annual Meeting, September 30, 2018.
Kinome illustrations reproduced courtesy of Cell Signaling Technology, Inc.

At the American Association for Cancer Research (AACR) Annual Meeting 2022, we presented new clinical and preclinical data
for multiple programs across genomically defined cancers, including lung, ovarian and breast cancers.