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Disease Analysis: Acute Myeloid Leukemia (AML)

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Disease Analysis: Acute Myeloid Leukemia (AML)
Published: August 12, 2020 Content info: 128 Pages
Description

Definition

AML is a type of heterogeneous hematological malignancy that originates from immature white blood cells (blasts) in the bone marrow, which may be derived from either a hematopoietic stem cell or a lineage-specific progenitor cell. "Acute" means that the leukemia may progress rapidly - AML generally spreads quickly to the bloodstream and can then spread to other parts of the body including the lymph nodes, spleen, central nervous system, and testicles.

Latest key takeaways

Datamonitor Healthcare estimates that in 2018, there were 158,400 incident cases of acute myeloid leukemia (AML) worldwide, and expects that number to increase to 169,000 incident cases by 2027. Approximately 60% of newly diagnosed patients are eligible for intensive chemotherapy, such as the 7+3 regimen of cytarabine and daunorubicin.

In the last three years, there have been eight new drugs approved for AML in the US, dramatically changing the treatment landscape. Gone is the era where all front-line patients received either 7+3 chemotherapy or a hypomethylating agent (decitabine or azacitidine). Many of the new therapies target specific segments of AML or patients with specific mutations. As such, there is currently little competition between the new therapies, but that will change as therapies receive label expansions and new competitor therapies are approved.

Two FLT3 inhibitors have been approved for FLT3-mutated AML: Rydapt for front-line patients eligible for intensive chemotherapy, and Xospata for relapsed/refractory patients. Rydapt may soon face competition in the front-line FLT3 setting as quizartinib and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or bone marrow transplant. Crenolanib is also being evaluated as maintenance therapy after standard induction chemotherapy and consolidation. Approval in the lucrative maintenance setting would give these drugs a favorable long-term commercial outlook. Approximately 25-30% of AML patients have an FLT3 mutation.

Tibsovo and Idhifa are approved as oral, single-agent therapies for relapsed/refractory AML patients with IDH1 and IDH2 mutations, respectively. Tibsovo is also approved as a monotherapy for front-line patients over the age of 75 years. Both of these IDH inhibitors are now in Phase III trials in combination with standard induction (7+3) and consolidation chemotherapy in front-line AML. In addition, Tibsovo is being investigated in combination with azacitidine in a Phase III trial recruiting front-line patients. Tibsovo may face competition from FT-2102, an IDH1 inhibitor being evaluated in the relapsed/refractory setting in a pivotal single-arm Phase II trial both as monotherapy and in combination with azacitidine. IDH1 mutations are present in 6-9% of AML, while IDH2 mutations are present in approximately 12% of cases.

Mylotarg, an antibody-drug conjugate targeting CD33, is the only monoclonal antibody therapy approved for AML. Mylotarg combined with intensive chemotherapy is recommended for newly diagnosed patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy). Over 90% of AML patients are positive for CD33 expression.

Vyxeos, a liposomal formulation of the 7+3 chemotherapy regimen, was approved in the US and EU for the treatment of newly diagnosed patients with secondary AML after showing an improvement in overall survival compared to the 7+3 regimen in patients ≥60 years of age. Secondary AML accounts for approximately one third of new AML diagnoses, but most of these patients will be too frail for Vyxeos. Approximately 16% of patients eligible for intensive chemotherapy have secondary AML. Market access for Vyxeos is strengthened by positive recommendations from the US Centers for Medicare and Medicaid Services and from NICE in England and Wales.

Venclexta combined with azacitidine is the new standard of care for newly diagnosed AML patients not suited for intensive chemotherapy (approximately 40% of newly diagnosed patients). This combination demonstrated a survival advantage in a

Published on 12 August 2020 Disease Analysis : Acute myeloid leukemia (AML) 10 © Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed confirmatory Phase III trial, which should assure conversion of Venclexta's conditional FDA approval to a full approval. The Phase III trial will also be the basis for regulatory submissions to European and Japanese authorities. Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with lowdose cytarabine (LDAC) for newly diagnosed AML patients not suited for intensive chemotherapy, and will compete with Venclexta in this difficult-to-treat setting. However, in the US, hypomethylating agents are preferred over LDAC, so Venclexta may be preferred over Daurismo.

Oral Vidaza increased overall survival and relapse-free survival in a Phase III trial and is currently under regulatory review in the US and EU as a maintenance therapy following intensive chemotherapy for patients not suited for a bone marrow transplant. The maintenance setting would be a new setting for Vidaza, as intravenous/subcutaneous Vidaza is currently used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.

Chimerix's dociparstat sodium (DSTAT), a glycosaminoglycan analog of heparin designed to have reduced anticoagulant effects, targets the CXCR4 pathway which is involved in the homing and adhesion of AML cells to the bone marrow and is associated with resistance to systemic drugs. DSTAT is being developed in combination with intensive 7+3 chemotherapy for newly diagnosed AML, with the aim of improving the rate of durable response. A Phase III trial is enrolling patients with intermediate or unfavorable cytogenetic risk (74% of patients eligible for intensive chemotherapy).

While Xospata, Tibsovo, and Idhifa have been approved for the relapsed/refractory setting, they only target patients with mutations in FLT3, IDH1, or IDH2, respectively. Relapsed/refractory AML remains an area of unmet need, and new therapies are being developed. Not including FLT3 or IDH inhibitors, there are currently six late-stage therapies being evaluated for this setting (devimistat, DFP-10917, flotetuzumab, guadecitabine, Iomab-B, and uproleselan).

Key recent events include the presentation of numerical data from Venclexta's VIALE-A trial at ASCO 2020, and the Phase III failures of Helsinn's pracinostat and Roche's idasanutlin.

Key upcoming catalysts for 2020 include the expected US approval of oral azacitidine and top-line results from Phase III trials for uproleselan and CPI-613.

The overall likelihood of approval of a Phase I AML asset is 7.5%, and the average probability a drug advances from Phase III is 54.2%. AML drugs, on average, take 10.7 years from Phase I to approval, compared to 9.4 years in the overall oncology space.

Table of Contents
Product Code: DMKC0214158

TABLE OF CONTENTS

CONTENTS

OVERVIEW

  • Latest key takeaways

DISEASE BACKGROUND

  • Definition
  • Patient segmentation
  • Other risk factors
  • Symptoms
  • Diagnosis

TREATMENT

  • First-line treatment of AML consists of induction and consolidation

EPIDEMIOLOGY

MARKETED DRUGS

PIPELINE DRUGS

KEY REGULATORY EVENTS

  • Xospata Reimbursement Marks A First For AML In England
  • Keeping Track: Targeted Oncologics Take Center Stage, Led By Retevmo And Trabecta Approvals
  • CHMP Adopts a Positive Opinion for Daurismo
  • NICE Draft Guidance: Rejects Keytruda In Head & Neck Cancer, Xospata In AML
  • Daiichi Sankyo Plays Long Game With Quizartinib Outside Japan
  • Kiadis Crushed By EMA Rejection Of T-Cell Therapy

PROBABILITY OF SUCCESS

LICENSING AND ASSET ACQUISITION DEALS

  • Agios announces that it will receive $255m from Royalty Pharma
  • Gilead Calls Forty Seven Buyout Complementary To Kite, Other IO Efforts
  • Apollomics Gains China-Plus Rights To GlycoMimetics' E-Selectin Antagonists
  • Finance Watch: Forma Raises $100m In Quest To Become A Sickle Cell Leader
  • BerGenBio, Piramal Pharma Strike Deal For Bemcentinib
  • Immuno-Oncology Continues To Draw Pharma Companies To The Deal Table
  • With Celgene Acquisition Closed, Bristol Faces Major Milestones
  • Astellas Licenses Vector Cell Technology From RiKen
  • Chimerix Licenses AML Candidate From Cantex
  • Servier Deal Termination Fails To Dent MacroGenics' Flotetuzumab Optimism
  • Ono Licenses Rafael's Novel Chemo-Sensitizing Agent For Asia

CLINICAL TRIAL LANDSCAPE

  • Sponsors by status
  • Sponsors by phase
  • Recent events

DRUG ASSESSMENT MODEL

MARKET DYNAMICS

FUTURE TRENDS

  • New drug launches, including therapies for relapsed/refractory disease, will drive growth in the AML market over the forecast period
  • FLT3 inhibitors are expected to move into the first-line maintenance setting
  • IDH inhibitor combinations are expected to move into earlier stages of AML
  • Oral hypomethylating agents are under development in AML

CONSENSUS FORECASTS

RECENT EVENTS AND ANALYST OPINION

  • Pracinostat for AML (July 2, 2020)
  • Venclexta for AML (June 5, 2020)
  • Pevonedistat for AML (May 29, 2020)
  • Venclexta for AML (May 28, 2020)
  • Idasanutlin for AML (March 31, 2020)
  • Venclexta for AML (March 23, 2020)
  • Venclexta for AML (February 28, 2020)
  • Oral Azacitidine for AML (December 10, 2019)
  • Eprenetapopt for AML (December 9, 2019)
  • Flotetuzumab for AML (December 9, 2019)
  • Keytruda for AML (December 9, 2019)
  • Magrolimab for AML (December 9, 2019)
  • MBG453 for AML (December 9, 2019)
  • Vidaza for AML (December 9, 2019)
  • BST-236 for AML (December 7, 2019)
  • Cusatuzumab for AML (December 7, 2019)
  • Vosaroxin for AML (December 6, 2019)
  • Oral Azacitidine for AML (September 12, 2019)
  • Pracinostat for AML (July 31, 2019)
  • DSTAT for AML (July 31, 2019)
  • Magrolimab for AML (July 11, 2019)
  • SNDX-5613 for AML (June 25, 2019)
  • JTCR016 for AML (June 24, 2019)
  • Quizartinib for AML (June 21, 2019)
  • Tibsovo for AML (June 3, 2019)
  • DSTAT for AML (June 1, 2019)
  • Magrolimab for AML (May 15, 2019)
  • Quizartinib for AML (May 14, 2019)
  • Quizartinib for AML (May 10, 2019)
  • XmAb14045 for AML (April 30, 2019)
  • Xospata for AML (April 1, 2019)
  • Tibsovo for AML (February 25, 2019)
  • XmAb14045 for AML (February 20, 2019)
  • Beleodaq for AML (January 17, 2019)

KEY UPCOMING EVENTS

KEY OPINION LEADER INSIGHTS

UNMET NEEDS

BIBLIOGRAPHY

  • Prescription information

APPENDIX

LIST OF FIGURES

  • Figure 1: Front-line treatment regimens for patients <60 years old
  • Figure 2: Front-line treatment regimens for patients ≥60 years old
  • Figure 3: Relapse treatment regimens
  • Figure 4: Trends in incident cases of AML, 2018-27
  • Figure 5: Overview of pipeline drugs for AML in the US
  • Figure 6: Pipeline drugs for AML, by company
  • Figure 7: Pipeline drugs for AML, by drug type
  • Figure 8: Pipeline drugs for AML, by classification
  • Figure 9: Probability of success in the AML pipeline
  • Figure 10: Clinical trials in AML
  • Figure 11: Top 10 drugs for clinical trials in AML
  • Figure 12: Top 10 companies for clinical trials in AML
  • Figure 13: Trial locations in AML
  • Figure 14: AML trials status
  • Figure 15: AML trials sponsors, by phase
  • Figure 16: Datamonitor Healthcare's drug assessment summary for AML
  • Figure 17: Market dynamics in AML
  • Figure 18: Future trends in AML
  • Figure 19: Venclexta for AML (June 5, 2020): Phase III - Viale-A (w/Azacitidine, Elderly Naive)
  • Figure 20: Pevonedistat for AML (May 29, 2020): Phase II - w/Azacitidine
  • Figure 21: Venclexta for AML (May 28, 2020): Phase I/II - w/Ivosidenib (MD Anderson)
  • Figure 22: Idasanutlin for AML (March 31, 2020): Phase III - MIRROS (w/Cytarabine)
  • Figure 23: Venclexta for AML (March 23, 2020): Phase III - Viale-A (w/Azacitidine, Elderly Naive)
  • Figure 24: Venclexta for AML (February 28, 2020): Phase III - Viale-C (w/Cytarabine)
  • Figure 25: Oral Azacitidine for AML (December 10, 2019): Phase III - QUAZAR (Maintenance)
  • Figure 26: Flotetuzumab for AML (December 9, 2019): Phase I/II - MGD006-01
  • Figure 27: Keytruda for AML (December 9, 2019): Phase II - LCCC 1522
  • Figure 28: Magrolimab for AML (December 9, 2019): Phase Ib - w/Azacitidine (AML/MDS)
  • Figure 29: MBG453 for AML (December 9, 2019): Phase Ib - w/PDR001
  • Figure 30: Vidaza for AML (December 9, 2019): Phase II - w/Durvalumab
  • Figure 31: Oral Azacitidine for AML (September 12, 2019): Phase III - QUAZAR (Maintenance)
  • Figure 32: JTCR016 for AML (June 24, 2019): Phase I/II - AML/MDS/CML (Fred Hutch)
  • Figure 33: Tibsovo for AML (June 3, 2019): Phase Ib/II - w/Azacitidine
  • Figure 34: Xospata for AML (April 1, 2019): Phase III - ADMIRAL
  • Figure 35: Tibsovo for AML (February 25, 2019): Phase Ib/II - w/Azacitidine
  • Figure 36: Key upcoming events in AML

LIST OF TABLES

  • Table 1: 2016 revision of the World Health Organization classification of AML
  • Table 2: AML risk status based on cytogenetics or molecular abnormalities
  • Table 3: Incident cases of AML, 2018-27
  • Table 4: Marketed drugs for AML
  • Table 5: Pipeline drugs for AML in the US
  • Table 6: Historical global sales, by drug ($m), 2015-19
  • Table 7: Forecasted global sales, by drug ($m), 2020-24
  • Table 8: Pracinostat for AML (July 2, 2020)
  • Table 9: Venclexta for AML (June 5, 2020)
  • Table 10: Pevonedistat for AML (May 29, 2020)
  • Table 11: Venclexta for AML (May 28, 2020)
  • Table 12: Idasanutlin for AML (March 31, 2020)
  • Table 13: Venclexta for AML (March 23, 2020)
  • Table 14: Venclexta for AML (February 28, 2020)
  • Table 15: Oral Azacitidine for AML (December 10, 2019)
  • Table 16: Eprenetapopt for AML (December 9, 2019)
  • Table 17: Flotetuzumab for AML (December 9, 2019)
  • Table 18: Keytruda for AML (December 9, 2019)
  • Table 19: Magrolimab for AML (December 9, 2019)
  • Table 20: MBG453 for AML (December 9, 2019)
  • Table 21: Vidaza for AML (December 9, 2019)
  • Table 22: BST-236 for AML (December 7, 2019)
  • Table 23: Cusatuzumab for AML (December 7, 2019)
  • Table 24: Vosaroxin for AML (December 6, 2019)
  • Table 25: Oral Azacitidine for AML (September 12, 2019)
  • Table 26: Pracinostat for AML (July 31, 2019)
  • Table 27: DSTAT for AML (July 31, 2019)
  • Table 28: Magrolimab for AML (July 11, 2019)
  • Table 29: SNDX-5613 for AML (June 25, 2019)
  • Table 30: JTCR016 for AML (June 24, 2019)
  • Table 31: Quizartinib for AML (June 21, 2019)
  • Table 32: Tibsovo for AML (June 3, 2019)
  • Table 33: DSTAT for AML (June 1, 2019)
  • Table 34: Magrolimab for AML (May 15, 2019)
  • Table 35: Quizartinib for AML (May 14, 2019)
  • Table 36: Quizartinib for AML (May 10, 2019)
  • Table 37: XmAb14045 for AML (April 30, 2019)
  • Table 38: Xospata for AML (April 1, 2019)
  • Table 39: Tibsovo for AML (February 25, 2019)
  • Table 40: XmAb14045 for AML (February 20, 2019)
  • Table 41: Beleodaq for AML (January 17, 2019)
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