Disease Analysis: Acute Myeloid Leukemia (AML)
Author: David Dahan
Publisher: Datamonitor Healthcare
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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.
CONTENTS
9 OVERVIEW
9 Latest key takeaways
11 DISEASE BACKGROUND
11 Definition
11 Patient segmentation
14 Other risk factors
15 Symptoms
15 Diagnosis
17 TREATMENT
17 First-line treatment of AML consists of induction and consolidation
21 EPIDEMIOLOGY
24 MARKETED DRUGS
28 PIPELINE DRUGS
52 KEY REGULATORY EVENTS
52 Xospata Reimbursement Marks A First For AML In England
52 Keeping Track: Targeted Oncologics Take Center Stage, Led By Retevmo And Trabecta Approvals
52 CHMP Adopts a Positive Opinion for Daurismo
52 NICE Draft Guidance: Rejects Keytruda In Head & Neck Cancer, Xospata In AML
53 Daiichi Sankyo Plays Long Game With Quizartinib Outside Japan
53 Kiadis Crushed By EMA Rejection Of T-Cell Therapy
54 PROBABILITY OF SUCCESS
55 LICENSING AND ASSET ACQUISITION DEALS
55 Agios announces that it will receive $255m from Royalty Pharma
55 Gilead Calls Forty Seven Buyout Complementary To Kite, Other IO Efforts
55 Apollomics Gains China-Plus Rights To GlycoMimetics’ E-Selectin Antagonists
55 Finance Watch: Forma Raises $100m In Quest To Become A Sickle Cell Leader
56 BerGenBio, Piramal Pharma Strike Deal For Bemcentinib
56 Immuno-Oncology Continues To Draw Pharma Companies To The Deal Table
56 With Celgene Acquisition Closed, Bristol Faces Major Milestones
56 Astellas Licenses Vector Cell Technology From RiKen
57 Chimerix Licenses AML Candidate From Cantex
57 Servier Deal Termination Fails To Dent MacroGenics’ Flotetuzumab Optimism
57 Ono Licenses Rafael’s Novel Chemo-Sensitizing Agent For Asia
58 CLINICAL TRIAL LANDSCAPE
59 Sponsors by status
60 Sponsors by phase
61 Recent events
63 DRUG ASSESSMENT MODEL
69 MARKET DYNAMICS
70 FUTURE TRENDS
70 New drug launches, including therapies for relapsed/refractory disease, will drive growth in the AML market over the forecast period
70 FLT3 inhibitors are expected to move into the first-line maintenance setting
71 IDH inhibitor combinations are expected to move into earlier stages of AML
71 Oral hypomethylating agents are under development in AML
72 CONSENSUS FORECASTS
75 RECENT EVENTS AND ANALYST OPINION
75 Pracinostat for AML (July 2, 2020)
76 Venclexta for AML (June 5, 2020)
77 Pevonedistat for AML (May 29, 2020)
79 Venclexta for AML (May 28, 2020)
81 Idasanutlin for AML (March 31, 2020)
82 Venclexta for AML (March 23, 2020)
84 Venclexta for AML (February 28, 2020)
85 Oral Azacitidine for AML (December 10, 2019)
87 Eprenetapopt for AML (December 9, 2019)
88 Flotetuzumab for AML (December 9, 2019)
90 Keytruda for AML (December 9, 2019)
92 Magrolimab for AML (December 9, 2019)
94 MBG453 for AML (December 9, 2019)
96 Vidaza for AML (December 9, 2019)
97 BST-236 for AML (December 7, 2019)
98 Cusatuzumab for AML (December 7, 2019)
99 Vosaroxin for AML (December 6, 2019)
100 Oral Azacitidine for AML (September 12, 2019)
102 Pracinostat for AML (July 31, 2019)
103 DSTAT for AML (July 31, 2019)
104 Magrolimab for AML (July 11, 2019)
105 SNDX-5613 for AML (June 25, 2019)
106 JTCR016 for AML (June 24, 2019)
108 Quizartinib for AML (June 21, 2019)
109 Tibsovo for AML (June 3, 2019)
110 DSTAT for AML (June 1, 2019)
112 Magrolimab for AML (May 15, 2019)
112 Quizartinib for AML (May 14, 2019)
114 Quizartinib for AML (May 10, 2019)
115 XmAb14045 for AML (April 30, 2019)
116 Xospata for AML (April 1, 2019)
118 Tibsovo for AML (February 25, 2019)
120 XmAb14045 for AML (February 20, 2019)
121 Beleodaq for AML (January 17, 2019)
123 KEY UPCOMING EVENTS
124 KEY OPINION LEADER INSIGHTS
125 UNMET NEEDS
126 BIBLIOGRAPHY
126 Prescription information
127 APPENDIX
LIST OF FIGURES
18 Figure 1: Front-line treatment regimens for patients <60 years old
19 Figure 2: Front-line treatment regimens for patients ≥60 years old
20 Figure 3: Relapse treatment regimens
23 Figure 4: Trends in incident cases of AML, 2018–27
28 Figure 5: Overview of pipeline drugs for AML in the US
28 Figure 6: Pipeline drugs for AML, by company
29 Figure 7: Pipeline drugs for AML, by drug type
29 Figure 8: Pipeline drugs for AML, by classification
54 Figure 9: Probability of success in the AML pipeline
58 Figure 10: Clinical trials in AML
58 Figure 11: Top 10 drugs for clinical trials in AML
59 Figure 12: Top 10 companies for clinical trials in AML
59 Figure 13: Trial locations in AML
60 Figure 14: AML trials status
61 Figure 15: AML trials sponsors, by phase
63 Figure 16: Datamonitor Healthcare’s drug assessment summary for AML
69 Figure 17: Market dynamics in AML
70 Figure 18: Future trends in AML
77 Figure 19: Venclexta for AML (June 5, 2020): Phase III – Viale-A (w/Azacitidine, Elderly Naïve)
79 Figure 20: Pevonedistat for AML (May 29, 2020): Phase II – w/Azacitidine
81 Figure 21: Venclexta for AML (May 28, 2020): Phase I/II – w/Ivosidenib (MD Anderson)
82 Figure 22: Idasanutlin for AML (March 31, 2020): Phase III – MIRROS (w/Cytarabine)
84 Figure 23: Venclexta for AML (March 23, 2020): Phase III – Viale-A (w/Azacitidine, Elderly Naïve)
85 Figure 24: Venclexta for AML (February 28, 2020): Phase III – Viale-C (w/Cytarabine)
87 Figure 25: Oral Azacitidine for AML (December 10, 2019): Phase III – QUAZAR (Maintenance)
90 Figure 26: Flotetuzumab for AML (December 9, 2019): Phase I/II – MGD006-01
92 Figure 27: Keytruda for AML (December 9, 2019): Phase II – LCCC 1522
94 Figure 28: Magrolimab for AML (December 9, 2019): Phase Ib – w/Azacitidine (AML/MDS)
96 Figure 29: MBG453 for AML (December 9, 2019): Phase Ib – w/PDR001
97 Figure 30: Vidaza for AML (December 9, 2019): Phase II – w/Durvalumab
102 Figure 31: Oral Azacitidine for AML (September 12, 2019): Phase III – QUAZAR (Maintenance)
108 Figure 32: JTCR016 for AML (June 24, 2019): Phase I/II – AML/MDS/CML (Fred Hutch)
110 Figure 33: Tibsovo for AML (June 3, 2019): Phase Ib/II – w/Azacitidine
118 Figure 34: Xospata for AML (April 1, 2019): Phase III – ADMIRAL
120 Figure 35: Tibsovo for AML (February 25, 2019): Phase Ib/II – w/Azacitidine
123 Figure 36: Key upcoming events in AML
LIST OF TABLES
12 Table 1: 2016 revision of the World Health Organization classification of AML
14 Table 2: AML risk status based on cytogenetics or molecular abnormalities
22 Table 3: Incident cases of AML, 2018–27
25 Table 4: Marketed drugs for AML
30 Table 5: Pipeline drugs for AML in the US
72 Table 6: Historical global sales, by drug ($m), 2015–19
73 Table 7: Forecasted global sales, by drug ($m), 2020–24
75 Table 8: Pracinostat for AML (July 2, 2020)
76 Table 9: Venclexta for AML (June 5, 2020)
78 Table 10: Pevonedistat for AML (May 29, 2020)
80 Table 11: Venclexta for AML (May 28, 2020)
81 Table 12: Idasanutlin for AML (March 31, 2020)
83 Table 13: Venclexta for AML (March 23, 2020)
84 Table 14: Venclexta for AML (February 28, 2020)
86 Table 15: Oral Azacitidine for AML (December 10, 2019)
88 Table 16: Eprenetapopt for AML (December 9, 2019)
89 Table 17: Flotetuzumab for AML (December 9, 2019)
91 Table 18: Keytruda for AML (December 9, 2019)
93 Table 19: Magrolimab for AML (December 9, 2019)
95 Table 20: MBG453 for AML (December 9, 2019)
96 Table 21: Vidaza for AML (December 9, 2019)
98 Table 22: BST-236 for AML (December 7, 2019)
99 Table 23: Cusatuzumab for AML (December 7, 2019)
100 Table 24: Vosaroxin for AML (December 6, 2019)
101 Table 25: Oral Azacitidine for AML (September 12, 2019)
103 Table 26: Pracinostat for AML (July 31, 2019)
104 Table 27: DSTAT for AML (July 31, 2019)
105 Table 28: Magrolimab for AML (July 11, 2019)
106 Table 29: SNDX-5613 for AML (June 25, 2019)
107 Table 30: JTCR016 for AML (June 24, 2019)
108 Table 31: Quizartinib for AML (June 21, 2019)
109 Table 32: Tibsovo for AML (June 3, 2019)
111 Table 33: DSTAT for AML (June 1, 2019)
112 Table 34: Magrolimab for AML (May 15, 2019)
113 Table 35: Quizartinib for AML (May 14, 2019)
114 Table 36: Quizartinib for AML (May 10, 2019)
116 Table 37: XmAb14045 for AML (April 30, 2019)
117 Table 38: Xospata for AML (April 1, 2019)
119 Table 39: Tibsovo for AML (February 25, 2019)
121 Table 40: XmAb14045 for AML (February 20, 2019)
122 Table 41: Beleodaq for AML (January 17, 2019)
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