NEWS & ANALYSIS

From The Analyst’s Couch The acute myeloid leukaemia market

Jorrit Schaefer, Sorcha Cassidy and Rachel M. Webster kornienko alexandr/ Credit: Alamy Stock Photo

Acute myeloid leukaemia (AML) is one the for intensive induction and receive (Idhifa; Celgene) and ivosidenib (Tibsovo; most common types of leukaemia in adults; hypomethylating agents ( or Agios) are indicated for patients who ~21,000 new cases are expected in the ) or low-dose​ (LDAC). harbour IDH2 or IDH1 mutations, United States alone in 2019. The median However, the treatment paradigm for these respectively. However, IDH inhibitors age of diagnosis is 68 years and the 5-year patients is shifting towards combinations are associated with a high incidence of overall survival (OS) is 28%. that include the B cell lymphoma 2 (BCL2) differentiation syndrome, which prompted AML is a heterogeneous disease inhibitor (Venclexta/Venclyxto; an FDA warning in November 2018. Also characterized by the clonal expansion AbbVie/Roche). The ongoing phase III in late 2018, the FLT3 inhibitor gilteritinib of myeloid blasts. Analysis of molecular trials, VIALE-​A and VIALE-C,​ are intended (Xospata; Astellas Pharma) was approved abnormalities, including mutations in the as the confirmatory trials to support full for FLT3-mutated R/R AML in the United gene encoding FMS-like​ tyrosine kinase 3 approval. Glasdegib (Daurismo; Pfizer), States and Japan. In June 2019, another (FLT3; present in ~30% of patients), a Hedgehog pathway inhibitor, also received FLT3 inhibitor, quizartinib (Vanflyta; isocitrate dehydrogenase 1 (IDH1; 6–10% FDA approval in combination with LDAC Daiichi Sankyo), was approved in Japan of patients) and IDH2 (9–13% of patients) in 2018. for FLT3-internal tandem duplication has become routine, and influences (ITD)-mutated R/R AML. The FDA rejected diagnosis, prognosis and therapeutic Relapsed/refractory AML. Treatment of quizartinib after the Oncologic Drugs decisions. Recent approvals, including relapsed/refractory (R/R) AML is broadly Advisory Committee (ODAC) expressed drugs targeted at these mutations, have categorized as either intensive (often concerns over cardiac toxicity and the lack altered the therapeutic landscape for cytarabine-based​ salvage ) of robust OS data. Gemtuzumab ozogamicin AML, and novel therapies are in late-phase​ or less intensive (often FLT3 or IDH is also FDA-approved​ for CD33-expressing development. inhibitors). The IDH inhibitors enasidenib R/R AML.

Current treatments Newly diagnosed AML. The mainstay Table 1 | Select therapies in the pipeline for acute myeloid leukaemia of intensive induction therapy, typically Drug Company Target or mechanism Development for patients younger than 75 years, is of action status cytarabine plus an , with Crenolanib AROG Pharmaceuticals FLT3 and PDGFR Phase III or without targeted agents. The FLT3 inhibitor midostaurin (Rydapt; Novartis) in Guadecitabine Astex Pharmaceuticals/ DNA methyltransferase Phase III Otsuka Pharmaceutical combination with intensive chemotherapy is approved for FLT3-mutated AML Iomab-​B Actinium Pharmaceuticals CD45 Phase III (see Further information). Gemtuzumab CC-486 Celgene DNA methyltransferase Phase III ozogamicin (Mylotarg; Pfizer), an anti-​ Uproleselan GlycoMimetics E-​selectin Phase III CD33 antibody–drug conjugate, was Devimistat Rafael Pharmaceuticals/ Lipoate analogue Phase III granted FDA approval in 2000 for relapsed Ono Pharmaceutical AML, but Pfizer withdrew the drug in 2010 Idasanutlin Roche MDM2 Phase III after the failure of confirmatory trials and amidst safety concerns. Its 2017 approval Pevonedistat Takeda Oncology NAE Phase III in newly diagnosed CD33-expressing AML Pracinostat Helsinn Healthcare/MEI Pharma HDAC Phase III was based on phase III data supporting a Tolero Pharmaceuticals/ CDK9 Phase II lower recommended dose. Nevertheless, Sumitomo Dainippon gemtuzumab ozogamicin carries a boxed Syros Pharmaceuticals RARα Phase II warning for severe or fatal hepatotoxicity. A liposomal formulation of cytarabine Onvansertib Trovagene PLK1 Phase Ib/II plus , CPX-351 (Vyxeos; Annamycin Moleculin Biotech Liposomal anthracycline Phase I/II Jazz Pharmaceuticals), is also marketed for Flotetuzumab MacroGenics/Servier CD123–CD3 bispecific Phase I/II secondary AML, in which AML develops antibody subsequent to myelodysplastic syndrome, MB-102 Mustang Bio CD123 CAR T cell Phase I myeloproliferative neoplasia or prior therapy. CAR, chimeric antigen receptor; CDK9, cyclin-dependent​ kinase 9; FLT3, FMS-​like tyrosine kinase 3; Patients with comorbidities or elderly HDAC, histone deacetylase; MDM2, murine double minute 2; NAE, NEDD8-activating enzyme; patients (older than 75 years) are ineligible PDGFR, platelet-derived​ growth factor receptor; PLK1, polo-like​ kinase 1; RARα, receptor-α​ .

Nature Reviews | Drug Discovery volume 19 | April 2020 | 233 NEWS & ANALYSIS

3 radioimmunoconjugate being investigated Annamycin (Moleculin Biotech), 2,560 in the SIERRA trial. Unlike other pipeline a second-​generation liposomal anthracycline 2.5 210 therapies, it targets a niche R/R AML setting: that has demonstrated low cardiotoxicity, 310 as a conditioning treatment prior to bone is in phase I/II for R/R AML and holds FDA 2 1,940 170 360 marrow transplantation. CC-486 (Celgene), fast-​track designation. Two further phase I/II 260 an oral formulation of azacitidine, is also therapies for R/R AML target CD123, an 1.5 320 being assessed as maintenance (QUAZAR antigen that is elevated on AML blasts. 780 AML-001 trial). Flotetuzumab (MacroGenics/Servier) is 1 480

Sales (US$ millions) Uproleselan (GlycoMimetics) is an a bispecific (CD123–CD3) dual-affinity​

0.5 450 E-selectin​ antagonist that disrupts leukaemic re-targeting​ (DART) molecule and MB-102 900 200 710 stem cell resistance in the bone marrow. It is (Mustang Bio) is a chimeric antigen 0 130 being evaluated together with chemotherapy receptor-T​ cell therapy. 2018 2023 2028 for R/R AML (GMI 1271 301 trial), and has breakthrough therapy designation for this Market indicators Hedgehog pathway inhibitors IDH1/IDH2 inhibitors population. GlycoMimetics is collaborating The approval (and uptake) of nine drugs since Hypomethylating agents with the National Cancer Institute to assess 2017 is fuelling rapid growth of the AML FLT3 inhibitors uproleselan in older patients with newly market. These nine drugs are expected to BCL2 inhibitors diagnosed AML. occupy 85% of the market in 2028, reflecting Fig. 1 | Major-​market sales of key therapies Devimistat (Rafael Pharmaceuticals/ a rapid shift in standard of care. The sales of for acute myeloid leukaemia, by drug Ono Pharmaceutical) is a lipoate analogue therapies belonging to key drug classes are class (estimated). The figure shows the targeted to enzymes in the mitochondrial expected to reach US$2.56 billion in 2028 2018–2028 forecast for the seven major tricarboxylic acid cycle, which includes (Fig. 1). The sole BCL2 inhibitor, venetoclax, markets: the United States, France, Germany, other key AML targets such as IDH1 and is forecasted to be the top-selling​ agent in Italy, Spain, United Kingdom and Japan. B cell IDH2. A pivotal trial (ARMADA-2000 2028, driven by a lack of biomarker-restricted​ lymphoma 2 (BCL2) inhibitors: Venclexta/ trial) is recruiting R/R AML patients aged prescribing and entry into one of the largest Venclyxto. FMS-like​ tyrosine kinase 3 (FLT3) 60 years or older to receive devimistat with AML populations (newly diagnosed patients inhibitors: Rydapt, Xospata, Vanflyta and chemotherapy. ineligible for intensive treatment and/or crenolanib. Hypomethylating agents: azacitidine and decitabine. Isocitrate Similar to venetoclax, idasanutlin patients aged 75 years or older). Selective dehydrogenase 1 (IDH1)/IDH2 inhibitors: Idhifa (Roche) is an apoptosis-inducing​ agent: FLT3 inhibitors will also garner substantial and Tibsovo. Hedgehog pathway inhibitors: it prevents MDM2 from interacting with sales in 2028, largely from gilteritinib (85% of Daurismo. Drug classes with expected sales and degrading p53, thereby inducing class sales) because of its expanded approval of <$100 million in 2028 not shown. apoptosis. It is being evaluated in in multiple FLT3-mutated AML populations. combination with cytarabine in R/R AML Therapies combined with hypomethylating (MIRROS trial). Pevonedistat (Takeda agents will ensure continued uptake and Emerging therapies Oncology), an NEDD8-activating enzyme boost sales of this class, despite generic The current pipeline for AML is diverse and inhibitor that also promotes apoptosis, is erosion in Europe and Japan. IDH inhibitors includes approved drug classes (for example, under investigation in combination with (enasidenib and ivosidenib) and glasdegib FLT3 inhibitors) as well as novel mechanisms azacitidine for newly diagnosed AML (the only Hedgehog pathway inhibitor in the of action (Table 1). (PANTHER trial). market) are expected to garner a minority of Finally, the histone deacetylase inhibitor sales in 2028 relative to other drug classes, Phase III candidates. The FLT3 inhibitor pracinostat (Helsinn/MEI Pharma) is being owing to restricted eligibility based on crenolanib (AROG Pharmaceuticals) is evaluated in newly diagnosed AML in the IDH mutation status and competition from being evaluated in two trials enrolling PRIMULA trial. venetoclax-​based combinations, respectively. patients with FLT3-mutated newly diagnosed (ARO-021 trial) and R/R Phase I and II pipeline. The cyclin-​ Jorrit Schaefer, Sorcha Cassidy and Rachel M. Webster* (ARO-013 trial) AML. ARO-021 will dependent kinase 9 (CDK9) inhibitor Decision Resources Group, London, UK. compare crenolanib with midostaurin, alvocidib (Tolero Pharmaceuticals/ whereas ARO-013 is investigating crenolanib Sumitomo Dainippon) is in phase II *e-mail:​ [email protected] in FLT3 inhibitor-refractory​ patients studies for R/R AML after first line https://doi.org/10.1038/d41573-019-00142-4 with FLT3-ITD and/or D835 mutations. venetoclax-​based combination therapy. Competing interests Guadecitabine (Astex Pharmaceuticals/ Also in phase II, tamibarotene (Syros The authors declare no competing interests. Otsuka Pharmaceutical) is a next-generation​ Pharmaceuticals) is a retinoic acid Related links DNA that is being receptor-​α (RARα) agonist that is being FDA label for enasidenib: https://www.accessdata.fda.gov/ investigated as a treatment for R/R AML evaluated in newly diagnosed AML as drugsatfda_docs/label/2017/209606s000lbl.pdf FDA label for gemtuzumab ozogamicin: https://www. (ASTRAL-2 trial). However, in 2018, a non-intensive​ induction and in R/R accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf a phase III trial (ASTRAL-1 trial) assessing AML. It is approved for the treatment FDA label for gilteritinib: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/211349s001lbl.pdf guadecitabine as a first-line​ treatment of acute promyelocytic leukaemia in FDA label for ivosidenib: https://www.accessdata.fda.gov/ failed to meet its co-primary​ end points Japan. Onvansertib (Trovagene), a polo-​ drugsatfda_docs/label/2019/211192s001lbl.pdf FDA label for midostaurin: https://www.accessdata.fda.gov/ (complete response and OS). like kinase 1 (PLK1) inhibitor, is under drugsatfda_docs/label/2017/207997s000lbl.pdf Iomab-B​ (131I-apamistamab;​ Actinium phase Ib/II investigation in newly FDA label for venetoclax: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/208573s013lbl.pdf Pharmaceuticals) is a CD45-targeted diagnosed and R/R AML.

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