Disease Analysis: Acute Myeloid Leukemia (AML)
Author: David Dahan
Publisher: Datamonitor Healthcare
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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.
- 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 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 is being evaluated in combination with standard chemotherapy and as a single-agent maintenance therapy, while Xospata and crenolanib are 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. Over 90% of AML patients are positive for CD33 expression.
- Vyxeos 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 generic 7+3 regimen of cytarabine and daunorubicin 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. 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 emerging as a standard of care for newly diagnosed AML patients not suited for intensive chemotherapy. This combination demonstrated a survival advantage in a 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 authorities.
- Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with low-dose 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 Daurismo.
- Oral Vidaza increased overall survival and relapse-free survival in a Phase III trial and could soon gain approval 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 used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.
- 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, guadecitabine, idasanutlin, Iomab-B, and uproleselan).
- The overall likelihood of approval of a Phase I AML asset is 8.2%, and the average probability a drug advances from Phase III is 54.5%. AML drugs, on average, take 10.1 years from Phase I to approval, compared to 9.3 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
29 PIPELINE DRUGS
59 KEY REGULATORY EVENTS
59 NICE Draft Guidance: Rejects Keytruda In Head & Neck Cancer, Xospata In AML
59 Daiichi Sankyo Plays Long Game With Quizartinib Outside Japan
59 Kiadis Crushed By EMA Rejection Of T-Cell Therapy
59 Quizartinib Looks Like A Good Drug, ODAC Says, But Needs Another Efficacy Trial Before Approval
60 Scottish HTA Body OKs Vyxeos & Prevymis, But Rejects Kymriah In Lymphoma
61 PROBABILITY OF SUCCESS
62 LICENSING AND ASSET ACQUISITION DEALS
62 Gilead Calls Forty Seven Buyout Complementary To Kite, Other IO Efforts
62 Apollomics Gains China-Plus Rights To GlycoMimetics’ E-Selectin Antagonists
62 Finance Watch: Forma Raises $100m In Quest To Become A Sickle Cell Leader
62 BerGenBio, Piramal Pharma Strike Deal For Bemcentinib
63 Immuno-Oncology Continues To Draw Pharma Companies To The Deal Table
63 With Celgene Acquisition Closed, Bristol Faces Major Milestones
63 Astellas Licenses Vector Cell Technology From RiKen
63 Chimerix Licenses AML Candidate From Cantex
64 Servier Deal Termination Fails To Dent MacroGenics’ Flotetuzumab Optimism
64 Ono Licenses Rafael’s Novel Chemo-Sensitizing Agent For Asia
64 Medigene Takes Center Stage In Roivant’s Latest ‘Vant’
65 Argenx SE licensed Janssen’s Cilag GMBH International exclusive global rights to its cusatuzumab (ARGX110) in blood cancers
66 CLINICAL TRIAL LANDSCAPE
67 Sponsors by status
68 Sponsors by phase
69 Recent events
71 DRUG ASSESSMENT MODEL
76 MARKET DYNAMICS
77 FUTURE TRENDS
77 New drug launches, including therapies for relapsed/refractory disease, will drive growth in the AML market over the forecast period
77 FLT3 inhibitors are expected to move into the first-line maintenance setting
78 IDH inhibitor combinations are expected to move into earlier stages of AML
78 Oral hypomethylating agents are under development in AML
79 CONSENSUS FORECASTS
83 RECENT EVENTS AND ANALYST OPINION
83 Venclexta for AML (March 23, 2020)
84 Venclexta for AML (February 28, 2020)
86 Oral Azacitidine for AML (December 10, 2019)
88 Vidaza for AML (December 9, 2019)
90 Keytruda for AML (December 9, 2019)
92 APR-246 for AML (December 9, 2019)
93 MBG453 for AML (December 9, 2019)
95 Flotetuzumab for AML (December 9, 2019)
96 Magrolimab for AML (December 9, 2019)
98 Cusatuzumab for AML (December 7, 2019)
99 BST-236 for AML (December 7, 2019)
100 Vosaroxin for AML (December 6, 2019)
101 Oral Azacitidine for AML (September 12, 2019)
103 Pracinostat for AML (July 31, 2019)
104 CX-01 for AML (July 31, 2019)
105 Magrolimab for AML (July 11, 2019)
106 SNDX-5613 for AML (June 25, 2019)
107 JTCR016 for AML (June 24, 2019)
109 Quizartinib for AML (June 21, 2019)
110 Tibsovo for AML (June 3, 2019)
111 CX-01 for AML (June 1, 2019)
113 Magrolimab for AML (May 15, 2019)
113 Quizartinib for AML (May 14, 2019)
115 Quizartinib for AML (May 10, 2019)
116 XmAb14045 for AML (April 30, 2019)
117 Xospata for AML (April 1, 2019)
119 Tibsovo for AML (February 25, 2019)
121 XmAb14045 for AML (February 20, 2019)
122 Beleodaq for AML (January 17, 2019)
123 Xospata for AML (December 3, 2018)
125 Iomab-B for AML (December 3, 2018)
126 Quizartinib for AML (December 3, 2018)
128 Tibsovo for AML (December 3, 2018)
130 Idhifa for AML (December 3, 2018)
132 Indoximod for AML (December 2, 2018)
134 AMG330 for AML (December 1, 2018)
136 KEY UPCOMING EVENTS
137 KEY OPINION LEADER INSIGHTS
138 UNMET NEEDS
139 BIBLIOGRAPHY
139 Prescription information
141 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
29 Figure 5: Overview of pipeline drugs for AML in the US
29 Figure 6: Pipeline drugs for AML, by company
30 Figure 7: Pipeline drugs for AML, by drug type
30 Figure 8: Pipeline drugs for AML, by classification
61 Figure 9: Probability of success in the AML pipeline
66 Figure 10: Clinical trials in AML
66 Figure 11: Top 10 drugs for clinical trials in AML
67 Figure 12: Top 10 companies for clinical trials in AML
67 Figure 13: Trial locations in AML
68 Figure 14: AML trials status
69 Figure 15: AML trials sponsors, by phase
71 Figure 16: Datamonitor Healthcare’s drug assessment summary for AML
76 Figure 17: Market dynamics in AML
77 Figure 18: Future trends in AML
84 Figure 19: Venclexta for AML (March 23, 2020): Phase III – Viale-A (w/Azacitidine, Elderly Naïve)
86 Figure 20: Venclexta for AML (February 28, 2020): Phase III – Viale-C (w/Cytarabine)
88 Figure 21: Oral Azacitidine for AML (December 10, 2019): Phase III – QUAZAR (Maintenance)
90 Figure 22: Vidaza for AML (December 9, 2019): Phase II – w/Durvalumab
92 Figure 23: Keytruda for AML (December 9, 2019): Phase II – LCCC 1522
95 Figure 24: MBG453 for AML (December 9, 2019): Phase Ib – w/PDR001
96 Figure 25: Flotetuzumab for AML (December 9, 2019): Phase I – MGD006-01
98 Figure 26: Magrolimab for AML (December 9, 2019): Phase Ib – w/Azacitidine (AML/MDS)
103 Figure 27: Oral Azacitidine for AML (September 12, 2019): Phase III – QUAZAR (Maintenance)
109 Figure 28: JTCR016 for AML (June 24, 2019): Phase I/II – AML/MDS/CML (Fred Hutch)
111 Figure 29: Tibsovo for AML (June 3, 2019): Phase Ib/II – w/Azacitidine
119 Figure 30: Xospata for AML (April 1, 2019): Phase III – ADMIRAL
121 Figure 31: Tibsovo for AML (February 25, 2019): Phase Ib/II – w/Azacitidine
125 Figure 32: Xospata for AML (December 3, 2018): Phase I – w/Induction & Consolidation Chemotherapy
128 Figure 33: Quizartinib for AML (December 3, 2018): Phase III – QUANTUM-R – vs. Chemotherapy (FLT3-ITD+)
130 Figure 34: Tibsovo for AML (December 3, 2018): Phase I – C-001 (Hematologic Malignancies w/IDH1 Mutation)
132 Figure 35: Idhifa for AML (December 3, 2018): Phase Ib – AG-120 or AG-221 w/ Intensive Chemotherapy (First-Line Combination Therapy)
134 Figure 36: Indoximod for AML (December 2, 2018): Phase Ib/IIa – w/Chemotherapy (Newly Diagnosed)
136 Figure 37: 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
31 Table 5: Pipeline drugs for AML
80 Table 6: Historical global sales, by drug ($m), 2014–18
82 Table 7: Forecasted global sales, by drug ($m), 2020–24
83 Table 8: Venclexta for AML (March 23, 2020)
85 Table 9: Venclexta for AML (February 28, 2020)
87 Table 10: Oral Azacitidine for AML (December 10, 2019)
89 Table 11: Vidaza for AML (December 9, 2019)
91 Table 12: Keytruda for AML (December 9, 2019)
93 Table 13: APR-246 for AML (December 9, 2019)
94 Table 14: MBG453 for AML (December 9, 2019)
95 Table 15: Flotetuzumab for AML (December 9, 2019)
97 Table 16: Magrolimab for AML (December 9, 2019)
99 Table 17: Cusatuzumab for AML (December 7, 2019)
100 Table 18: BST-236 for AML (December 7, 2019)
101 Table 19: Vosaroxin for AML (December 6, 2019)
102 Table 20: Oral Azacitidine for AML (September 12, 2019)
104 Table 21: Pracinostat for AML (July 31, 2019)
105 Table 22: CX-01 for AML (July 31, 2019)
106 Table 23: Magrolimab for AML (July 11, 2019)
107 Table 24: SNDX-5613 for AML (June 25, 2019)
108 Table 25: JTCR016 for AML (June 24, 2019)
109 Table 26: Quizartinib for AML (June 21, 2019)
110 Table 27: Tibsovo for AML (June 3, 2019)
112 Table 28: CX-01 for AML (June 1, 2019)
113 Table 29: Magrolimab for AML (May 15, 2019)
114 Table 30: Quizartinib for AML (May 14, 2019)
115 Table 31: Quizartinib for AML (May 10, 2019)
117 Table 32: XmAb14045 for AML (April 30, 2019)
118 Table 33: Xospata for AML (April 1, 2019)
120 Table 34: Tibsovo for AML (February 25, 2019)
122 Table 35: XmAb14045 for AML (February 20, 2019)
123 Table 36: Beleodaq for AML (January 17, 2019)
124 Table 37: Xospata for AML (December 3, 2018)
126 Table 38: Iomab-B for AML (December 3, 2018)
127 Table 39: Quizartinib for AML (December 3, 2018)
129 Table 40: Tibsovo for AML (December 3, 2018)
131 Table 41: Idhifa for AML (December 3, 2018)
133 Table 42: Indoximod for AML (December 2, 2018)
134 Table 43: AMG330 for AML (December 1, 2018)
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