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Disease Analysis: Acute Myeloid Leukemia (AML)

  • ID: 5009191
  • Report
  • April 2021
  • Region: Global
  • 120 Pages
  • Datamonitor Healthcare
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
  • The publisher 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.
  • Since 2017, there have been nine 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, crenolanib, and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or hematopoietic stem cell transplant (HSCT). 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 in the US 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 and as maintenance therapy in front-line AML. Tibsovo is also being investigated in combination with azacitidine in a Phase III trial in front-line patients. Approval of Tibsovo and Idhifa in the EU will depend on these Phase III results. 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. 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). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months versus 10 months) and supported regulatory submissions to European and Japanese authorities, with approvals expected in 2021. Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Venclexta combined with azacitidine as maintenance therapy for AML patients in first remission after conventional chemotherapy.
  • 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 over Daurismo.
  • Onureg, an oral formulation of azacitidine, increased overall survival and relapse-free survival in a Phase III trial and was approved in the US as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT. A European approval decision is expected in mid-2021. The maintenance setting would be a new setting for Vidaza (azacitidine) which is currently used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.
  • Rafael Pharmaceuticals is developing devimistat (CPI-613) as a first-in-class therapeutic targeting the altered mitochondrial metabolism present in many cancers, including AML. Devimistat’s outlook will depend on the efficacy and safety results from a Phase III trial evaluating the drug in combination with high-dose cytarabine and mitoxantrone in relapsed/refractory AML patients. The first interim analysis is expected in Q2 2021.
  • 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).
  • Otsuka’s Inqovi is an oral formulation of decitabine that is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with MDS, Inqovi met the trial’s primary endpoint of demonstrating pharmacokinetic equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML in the EU, but a trial with efficacy endpoints will be needed to secure a US AML approval.
  • Takeda’s pevonedistat targets the NEDD8-activating enzyme in the ubiquitin-proteasome pathway, and is being developed in combination with azacitidine for a subpopulation of newly diagnosed, elderly AML patients categorized as low-blast count AML. Pevonedistat is also being evaluated in a randomized Phase II trial in combination with Venclexta and azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy.
  • Zeltherva is a therapeutic vaccine being developed as maintenance therapy for patients who have achieved hematologic complete remission, with or without thrombocytopenia, after second-line therapy and who are ineligible for allogeneic stem cell transplantation. Zeltherva’s outlook in the specialized setting of CR2 will depend on results in REGAL, its Phase III trial. An interim analysis for safety and futility is expected in Q4 2021.
  • Not including FLT3 and IDH inhibitors, there are five drugs in late-phase development for newly diagnosed AML patients. Dociparstat sodium and entospletinib are being developed in combination with intensive chemotherapy, while MBG453, pevonedistat, and Inqovi are being developed for elderly patients.
  • Relapsed/refractory AML remains an area of unmet need, and new therapies are being developed. Not including FLT3 or IDH inhibitors, there are currently five late-stage therapies being evaluated for this setting (devimistat, DFP-10917, flotetuzumab, Iomab-B, and uproleselan).
  • Key recent events include the approval of Onureg and presentation of numerical data from Venclexta’s VIALE-A trial. There were Phase III failures for Helsinn’s pracinostat combined with azacitidine in the newly diagnosed setting and for Roche’s idasanutlin and Otsuka’s guadecitabine in the relapsed/refractory setting. Other Phase III failures include trials evaluting Xospata combined with azacitidine and Daurismo combined with intensive chemotherapy in front-line AML, and an Idhifa monotherapy trial in the third- and fourth-line setting.
  • Key upcoming catalysts for 2021 include topline results from Phase III trials for devimistat, Iomab-B, uproleselan, and Zeltherva, and a possible NDA submission for FT-2102.
  • The overall likelihood of approval of a Phase I AML asset is 6.3%, and the average probability a drug advances from Phase III is 50%. AML drugs, on average, take 10.8 years from Phase I to approval, compared to 9.6 years in the overall oncology space.
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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
  • Incidence methodology
MARKETED DRUGS

PIPELINE DRUGS

KEY REGULATORY EVENTS
  • Oncology, Rare Disease Drugs Dominate New China Approvals
  • Agios Withdraws MAA for Tibsovo
  • Onureg Offers New Dose Form, New Therapy Setting For Azacitidine
  • 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
PROBABILITY OF SUCCESS

LICENSING AND ASSET ACQUISITION DEALS
  • Sorrento Acquires Abivertinib Partner ACEA
  • Nippon Shinyaku Licenses Menarini’s Tagraxofusp For Japan
  • XOMA Gets Two Potential Revenue Streams From Viracta
  • Wugen Aligns With Alpha Biopharma For Asia Markets
  • CASI Obtains Greater China Rights To Cleave Cancer Candidate
  • Wugen To Use HCW Proteins In Cancer Cell Therapy Products
  • Medexus Licenses Exclusive Rights To Commercialize Medac’s Treosulfan
  • Agios Sells Cancer Portfolio To Servier To Focus On Genetic Diseases
  • Ireland’s ONK Expands To US, Options Three NK Candidates
  • Syros Obtains Arsenic-Based Leukemia Candidate From Orsenix
  • Vor Hopes NCI’s CAR-T Candidate Is Synergistic With Lead AML Therapy
  • Kite Will Partner With HiFiBiO On AML Discovery Efforts
  • Agios Announces Sales Of Idhifa Royalties To Royalty Pharma
CLINICAL TRIAL LANDSCAPE
  • Sponsors by status
  • Sponsors by phase
  • Recent events
DRUG ASSESSMENT MODEL

MARKET DYNAMICS

FUTURE TRENDS
  • Venclexta is set to become a blockbuster in AML
  • Immunomodulators are being developed for AML
  • New drug launches, including therapies for relapsed/refractory disease, will drive growth in the AML market over theforecast 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
  • Xospata for AML (December 21, 2020)
  • Magrolimab for AML (December 6, 2020)
  • Venclexta for AML (December 6, 2020)
  • Actimab-A for AML (December 5, 2020)
  • KO-539 for AML (December 5, 2020)
  • SY-1425 for AML (December 5, 2020)
  • Motixafortide for AML (November 23, 2020)
  • Guadecitabine for AML (October 14, 2020)
  • Idhifa for AML (August 25, 2020)
  • 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)
  • Onureg 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)
KEY UPCOMING EVENTS

KEY OPINION LEADER INSIGHTS

UNMET NEEDS

BIBLIOGRAPHY

APPENDIX

LIST OF FIGURES
Figure 1: NCCN recommended induction treatment regimens for patients < 60 years old
Figure 2: NCCN recommended consolidation regimens for patients < 60 years old
Figure 3: NCCN recommended induction treatment regimens for patients ≥60 years old
Figure 4: NCCN recommended consolidation regimens for patients ≥60 years old
Figure 5: Relapse treatment regimens
Figure 6: Trends in incident cases of AML, 2018–27
Figure 7: Overview of pipeline drugs for AML in the US
Figure 8: Pipeline drugs for AML, by company
Figure 9: Pipeline drugs for AML, by drug type
Figure 10: Pipeline drugs for AML, by classification
Figure 11: Probability of success in the AML pipeline
Figure 12: Clinical trials in AML
Figure 13: Top 10 drugs for clinical trials in AML
Figure 14: Top 10 companies for clinical trials in AML
Figure 15: Trial locations in AML
Figure 16: AML trials status
Figure 17: AML trials sponsors, by phase
Figure 18: The publisher’s drug assessment summary for AML
Figure 19: Market dynamics in AML
Figure 20: Future trends in AML
Figure 21: Xospata for AML (December 21, 2020): Phase II/III - LACEWING (w/Azacitidine)
Figure 22: Magrolimab for AML (December 6, 2020): Phase Ib - w/Azacitidine (AML/MDS)
Figure 23: Venclexta for AML (December 6, 2020): Phase Ib/II - w/FLAG-IDA (MD Anderson)
Figure 24: Actimab-A for AML (December 5, 2020): Phase I - w/CLAG-M
Figure 25: SY-1425 for AML (December 5, 2020): Phase II - AML/MDS
Figure 26: Motixafortide for AML (November 23, 2020): Phase IIb - BLAST (Consolidation)
Figure 27: Guadecitabine for AML (October 14, 2020): Phase III - ASTRAL-2
Figure 28: Idhifa for AML (August 25, 2020): Phase III - IDHENTIFY (IDH2 Mutation)
Figure 29: Venclexta for AML (June 5, 2020): Phase III - Viale-A (w/Azacitidine, Elderly Naïve)
Figure 30: Pevonedistat for AML (May 29, 2020): Phase II - w/Azacitidine
Figure 31: Venclexta for AML (May 28, 2020): Phase I/II - w/Ivosidenib (MD Anderson)
Figure 32: Idasanutlin for AML (March 31, 2020): Phase III - MIRROS (w/Cytarabine)
Figure 33: Venclexta for AML (March 23, 2020): Phase III - Viale-A (w/Azacitidine, Elderly Naïve)
Figure 34: Venclexta for AML (February 28, 2020): Phase III - Viale-C (w/Cytarabine)
Figure 35: Onureg for AML (December 10, 2019): Phase III - QUAZAR (Maintenance)
Figure 36: Flotetuzumab for AML (December 9, 2019): Phase I/II - MGD006-01
Figure 37: Keytruda for AML (December 9, 2019): Phase II - LCCC 1522
Figure 38: Magrolimab for AML (December 9, 2019): Phase Ib - w/Azacitidine (AML/MDS)
Figure 39: MBG453 for AML (December 9, 2019): Phase Ib - w/PDR001
Figure 40: Vidaza for AML (December 9, 2019): Phase II - w/Durvalumab
Figure 41: 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 ($m), 2016–20
Table 7: Forecasted global sales, by drug ($m), 2021–25
Table 8: Xospata for AML (December 21, 2020)
Table 9: Magrolimab for AML (December 6, 2020)
Table 10: Venclexta for AML (December 6, 2020)
Table 11: Actimab-A for AML (December 5, 2020)
Table 12: KO-539 for AML (December 5, 2020)
Table 13: SY-1425 for AML (December 5, 2020)
Table 14: Motixafortide for AML (November 23, 2020)
Table 15: Guadecitabine for AML (October 14, 2020)
Table 16: Idhifa for AML (August 25, 2020)
Table 17: Pracinostat for AML (July 2, 2020)
Table 18: Venclexta for AML (June 5, 2020)
Table 19: Pevonedistat for AML (May 29, 2020)
Table 20: Venclexta for AML (May 28, 2020)
Table 21: Idasanutlin for AML (March 31, 2020)
Table 22: Venclexta for AML (March 23, 2020)
Table 23: Venclexta for AML (February 28, 2020)
Table 24: Onureg for AML (December 10, 2019)
Table 25: Eprenetapopt for AML (December 9, 2019)
Table 26: Flotetuzumab for AML (December 9, 2019)
Table 27: Keytruda for AML (December 9, 2019)
Table 28: Magrolimab for AML (December 9, 2019)
Table 29: MBG453 for AML (December 9, 2019)
Table 30: Vidaza for AML (December 9, 2019)
Table 31: BST-236 for AML (December 7, 2019)
Table 32: Cusatuzumab for AML (December 7, 2019)
Table 33: Vosaroxin for AML (December 6, 2019)
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