Disease Analysis: Acute Myeloid Leukemia (AML)

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.
• 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. Potential approvals of Tibsovo and Idhifa in the EU will depend on the results of ongoing Phase III trials, which are evaluating these drugs in combination with intensive induction (7+3) and consolidation chemotherapy and as maintenance therapy in front-line AML. A Phase III trial evaluating Tibsovo combined with azacitidine in front-line patients not suited for intensive therapy recently reported positive 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 patients, 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 (ND) patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy) and is approved in the US, EU, and Japan. 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 ND 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 a hypomethylating agent is the new standard of care for ND AML patients not suited for intensive chemotherapy (approximately 40% of ND patients). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months versus 10 months) and supported regulatory approvals in the EU (May 2021) and Japan (March 2021). Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Onureg with and without Venclexta 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 ND 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 has been approved in the US (September 2020) and EU (June 2021) as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT. The maintenance setting is a new setting for Vidaza (azacitidine), which is currently used in the EU (and off-label in the US) to treat ND elderly AML patients.
• Devimistat (CPI-613) is 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 Q4 2021.
• 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 ND 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). The estimated primary completion date (PCD) for the DSTAT Phase III trial is May 2024, with interim data expected in 2022.
• DFP-10917 is a nucleoside analog that is structurally similar to cytarabine and delivered at low dose by continuous IV infusion for 14 days of each 28-day cycle. DFP-10917 initiated a Phase III trial in October 2019 against non-intensive therapy (low-dose cytarabine, hypomethylating agents, or Venclexta combination) or intensive therapy (high- or intermediate-dose cytarabine regimens) in AML patients in second or third relapse. Phase III results are expected in December 2022.
• Entospletinib is a first-in-class spleen tyrosine kinase (SYK) inhibitor being developed for NPM1-mutated ND AML patients. NPM1 mutations are detected in ~30% of AML patients. A pivotal Phase II/III trial is expected to initiate in 2021 and will evaluate entospletinib in combination with standard induction and consolidation chemotherapy. The primary endpoint is the rate of MRD-negative CR following two cycles of induction, and the estimated PCD is December 2023.
• Flotetuzumab is a bispecific antibody targeting CD123 and CD3, and is being evaluated in a single-arm, pivotal Phase I/II trial in patients with primary induction failure or early-relapse AML. The pivotal study will register up to 200 patients and has an estimated PCD of January 2022.
• Otsuka’s Inqovi, an oral formulation of decitabine combined with cedazuridine, is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with myelodysplastic syndrome, Inqovi met the trial’s primary endpoint of demonstrating pharmacokinetic equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML, but only in the EU. Otsuka is also developing ASTX030, an oral combination of azacitidine and cedazuridine. The ASTX030 trial has an estimated PCD of April 2023.
• Magrolimab is a monoclonal antibody specific for CD47 and blocks the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages. A Phase III trial, ENHANCE-2, is evaluating magrolimab + azacitidine in ND TP53-mutant AML patients. TP53 mutations are seen in 5–10% of AML patients. The ENHANCE-2 trial has an estimated PCD of September 2023.
• MBG453 (sabatolimab) is an antibody specific for TIM-3, an immune checkpoint inhibitor, and is being developed for ND AML patients unfit for chemotherapy. A pivotal, single-arm Phase II trial, STIMULUS-AML1, is evaluating MBG453 combined with azacitidine and Venclexta. Topline results are expected in 2024.
• Sarclisa is an anti-CD38 monoclonal antibody being developed for relapsed/refractory pediatric AML. A pivotal Phase II trial, ISAKIDS, is evaluating Sarclisa in combination with standard chemotherapy regimens. Pediatric AML is a niche setting, with about 500 children diagnosed in the US every year. About 90% of patients have a CR after induction; however, 20% of these patients will later relapse.
• Uproleselan is a first-in-class inhibitor of E-selectin that is being evaluated in a Phase III trial in combination with chemotherapy for relapsed/refractory AML. The trial has an estimated PCD of April 2022.
• Zeltherva is a therapeutic vaccine being developed as maintenance therapy for patients who have achieved hematologic complete remission and who are ineligible for HSCT. Zeltherva’s outlook in the specialized setting of second complete remission (CR2) will depend on results in REGAL, its Phase III trial. An interim analysis is expected in H1 2022.
• Not including FLT3 and IDH inhibitors, there are six drugs in late-phase development for ND adult AML patients. Dociparstat sodium and entospletinib are being developed in combination with intensive chemotherapy, while magrolimab, MBG453, Inqovi, and ASTX030 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 approvals Venclexta (May 2021) and Onureg (June 2021) in the EU, and positive results from AGILE, a Phase III trial evaluating Tibsovo + azacitidine in ND IDH1-mutant AML patients. In the ND setting, there have been Phase III failures for Helsinn’s pracinostat, Takeda’s pevonedistat, Astella’s Xospata, and Pfizer’s Daurismo. Pracinostat, pevonedistat, and Xospata were all combined with azacitidine, while Daurismo was combined with intensive chemotherapy. In the relapsed/refractory setting, there have been failures for Roche’s idasanutlin, Otsuka’s guadecitabine, and Bristol Myers Squibb’s Idhifa monotherapy in the third- and fourth-line settings.
• Key upcoming catalysts through 2022 include topline results from Phase III and/or pivotal trials for quizartinib (Q4 2021), flotetuzumab (January 2022), uproleselan (April 2022), Zeltherva (H1 2022), Iomab-B (mid-2022), devimistat (October 2022), crenolanib (November 2022), and DFP-1097 (December 2022), as well as a possible NDA submission for FT-2102.
• The overall likelihood of approval of a Phase I AML asset is 5.7%, and the average probability a drug advances from Phase III is 48.1%. AML drugs, on average, take 10.8 years from Phase I to approval, compared to 9.6 years in the overall oncology space.