Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia

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Overig advies 08/02/2021 09:31
?Designation in patients with chronic myeloid leukemia (CML) resistant or intolerant to prior treatments based on positive data from pivotal Phase III ASCEMBL trial evaluating asciminib, an investigational treatment specifically targeting the ABL myristoyl pocket (STAMP)1,2
?Despite advances in CML care, many patients are at risk of disease progression, and sequential TKI therapy may be associated with increased resistance and intolerance3-9
?Breakthrough Therapy designation is granted to medicines being evaluated for serious conditions where early clinical evidence indicates the potential for substantial improvement over available therapy10
?Asciminib is in development across multiple treatment lines of CML; first regulatory filing in pre-treated patients anticipated in first half of 2021 under the US FDA Real-Time Oncology Review program11-17

Basel, February 8, 2020 — Novartis today announced that asciminib – a novel investigational treatment specifically targeting the ABL myristoyl pocket (STAMP) – has been granted Breakthrough Therapy designation (BTD) by the US Food and Drug Administration (FDA) for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors (TKIs). Asciminib was also granted BTD for the treatment of adult patients with Ph+ CML in CP harboring the T315I mutation.

Despite tremendous advances in CML treatment over the past few decades, some of these pre-treated patients struggle to meet treatment goals due to resistance and intolerance18-23.
With few remaining treatment options, patients in later lines of care may be at risk of progression3-9.

These FDA designations, which may allow for an expedited development and review of asciminib, were based on:
?The pivotal, Phase III ASCEMBL trial, where asciminib was compared to Bosulif® (bosutinib)* in patients with Ph+ CML in CP previously treated with two or more TKIs1,2


?A Phase I trial that included patients with Ph+ CML, some of them harboring the T315I mutation24

Data from these trials were shared at the 2020 Annual Meeting of the American Society of Hematology (ASH), and details on positive findings can be found here.

The FDA previously granted Fast Track designation to asciminib, and Novartis plans for a submission in the first half of 2021 for review under the FDA Oncology Center of Excellence Real-Time Oncology Review program.

About asciminib (ABL001)
Asciminib (ABL001) is an investigational treatment specifically targeting the ABL myristoyl pocket (STAMP)11-17. As a STAMP inhibitor, asciminib is being studied in patients with chronic myeloid leukemia (CML) who experience resistance or intolerance to two or more tyrosine-kinase inhibitors (TKIs), and in several clinical trials in hopes of helping patients across multiple treatment lines of CML11-17, 25-32.

About ASCEMBL
ASCEMBL is the first head-to-head clinical trial in chronic myeloid leukemia using a second-generation tyrosine-kinase inhibitor (TKI) as a comparator. As a Phase III, multicenter, open-label, randomized study, ASCEMBL was designed to evaluate superiority in major molecular response rate at 24 weeks of the oral investigational treatment asciminib (ABL001) versus bosutinib in patients with Philadelphia-chromosome positive CML in chronic phase previously treated with two or more TKIs2. Patients with failure or intolerance to the most recently administered TKI therapy were included in the trial2.

Disclaimer
This media update contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking
etc. etc..

References
1.Novartis Data on File
2.Hochhaus A, et al. Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ?2 Tyrosine Kinase Inhibitors (TKIs). Oral presentation at: ASH Annual Meeting; Dec. 8, 2020.
3.Akard LP, et al. The “Hit Hard and Hit Early” Approach to the Treatment of Chronic Myeloid Leukemia: Implications of the Updated National Comprehensive Cancer Network Clinical Practice Guidelines for RoutinePractice. Clin Adv Hematol Oncol. 2013;11(7):421-432
4.Cortes JE, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91(12):1206-1214
5.Cortes JE, et al. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: Final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404
6.Garg RJ, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361-4368
7.Hochhaus A, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-984
8.Cortes JE., et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34:2333-2340.
9.Steegmann JL., et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648-1671.
10.U.S. Food and Drug Administration (FDA). Frequently Asked Questions: Breakthrough Therapies. Available from: https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies?.
11.Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature. 2017;543(7647):733-737
12.Schoepfer J, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61(18):8120-8135
13.Hughes TP, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019; 381(24):2315-2326
14.Hughes TP, et al. Expanded Phase 1 Study of ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Reveals Significant and Durable Responses in Patients with CML-Chronic Phase with Failure of Prior TKI Therapy Blood. Poster presented at: ASH Annual Meeting & Exposition; Dec. 5, 2016.
15.Ottmann OG, et al. ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Exhibits Safety and Promising Single- Agent Activity in a Phase I Study of Patients with CML with Failure of Prior TKI Therapy. Blood. 2015;126(23):138
16.Mauro MJ, et al. Combination of Asciminib Plus Nilotinib (NIL) or Dasatinib (DAS) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
17.Cortes J, et al. Combination Therapy Using Asciminib Plus Imatinib (IMA) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
18.Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2020.
19.Tasigna [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2020
20.Sprycel [package insert]. Princeton, NJ: Bristol-Myers Squibb; December 2018.
21.Bosulif [package insert]. New York, NY; Pfizer Laboratories; July 2020.
22.Iclusig [package insert]. Cambridge, MA: Takeda Pharmaceutical Company; June 2020.
23.Ongoren S, et al. Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: real-life data on a single center experience along with the review of the literature. Hematology. 2018; 23:4, 212-220.
24.Cortes J, et al. Asciminib, a First-in-Class STAMP Inhibitor, Provides Durable Molecular Response in Patients (pts) with Chronic Myeloid Leukemia (CML) Harboring the T315I Mutation: Primary Efficacy and Safety Results from a Phase 1 Trial. Oral presentation at: ASH Annual Meeting; Dec. 7, 2020.
25.Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature. 2017;543(7647):733-737
26.Schoepfer J, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61(18):8120-8135
27.Hughes TP, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019; 381(24):2315-2326
28.Hughes TP, et al. Expanded Phase 1 Study of ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Reveals Significant and Durable Responses in Patients with CML-Chronic Phase with Failure of Prior TKI Therapy Blood. Poster presented at: ASH Annual Meeting & Exposition; Dec. 5, 2016.
29.Ottmann OG, et al. ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Exhibits Safety and Promising Single- Agent Activity in a Phase I Study of Patients with CML with Failure of Prior TKI Therapy. Blood. 2015;126(23):138
30.Mauro MJ, et al. Combination of Asciminib Plus Nilotinib (NIL) or Dasatinib (DAS) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
31.Cortes J, et al. Combination Therapy Using Asciminib Plus Imatinib (IMA) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
32.“Asciminib OR ABL001 Search Results.” ClinicalTrials.gov, U.S. National Institutes of Health, 2020, www.clinicaltrials.gov/ct2/results?cond=&term=asciminib&cntry=&state=&city=&dist=?.

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