Moxetumomab pasudotox pivotal data in patients with previously-treated hairy cell leukaemia presented at the 2018 ASCO Annual Meeting

Trial meets the primary endpoint of durable complete response

Majority of patients who had a complete response had no evidence of any
remaining detectable cancer cells

Phase III clinical trial results served as basis for recent US FDA regulatory submission

AstraZeneca and MedImmune, its global biologics research and development arm, today presented results from the Phase III (‘1053’) clinical trial that evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory hairy cell leukaemia (HCL) who had received at least two prior lines of therapy.¹

Moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin, showed a 75% objective response (OR) rate, a 41% complete response (CR) rate, and a 30% durable CR rate (primary endpoint). The majority of patients with a complete response had a durable response (73%; 24/33) and achieved a negative minimal residual disease (MRD) status (82%; 27/33). Findings from this pivotal trial were presented for the first time during an oral session at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, USA (Abstract #7004).

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “Moxetumomab pasudotox is an investigational, first-in-class immunotoxin which we believe has the potential to advance outcomes for patients with relapsed or refractory hairy cell leukaemia, a condition with a high unmet need. It is also the first agent to be submitted for regulatory review from our Antibody Drug Conjugates platform, and as such demonstrates our commitment to developing novel treatments for blood cancer.”

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, said: “Hairy cell leukaemia is a rare, chronic blood cancer with no established standard of care for patients with relapsed or refractory disease following purine nucleoside analogue therapy. With very few treatments available, there remains significant unmet medical need for people with relapsed or refractory disease. The response rates observed in this trial, and elimination of the residual leukaemia cells that cause relapse in some patients, highlight the potential impact this potential new medicine could have on patients and the management of this disease.”

Summary of key results from the Phase III ‘1053’ single arm, multicentre clinical trial in 80 patients with relapsed or refractory HCL (16.7 months median follow-up), as determined by a blinded independent central review:

*Haematologic remission (HR) is defined by: neutrophils > 1.5 x 10⁹ /L, platelets > 100 x 10⁹ /L, haemoglobin > 11 g/dL, no transfusions / growth factors > 4 weeks

The primary endpoint of the trial was durable CR, which is defined as CR with HR for >180 days. The median time to HR was 1 month. MRD refers to the small amounts of cancer cells that may remain after treatment.² A high rate of negative MRD after therapy may further improve outcomes.³ The median duration of OR and median progression-free survival were not reached.

The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral oedema (26%), headache (21%), and pyrexia (20%); 8% had infections and 3% had neutropaenia deemed treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. Treatment-related AEs leading to discontinuation were haemolytic uraemic syndrome (HUS; 4 [5%]), capillary leak syndrome (CLS; 2 [3%]), and increased blood creatinine (2 [3%]). Seven patients (9%) had CLS and seven (9%) had HUS; this includes four (5%) patients who had both CLS and HUS. CLS and HUS were manageable and reversible.

In April 2018, AstraZeneca announced that the US Food and Drug Administration (FDA) accepted the Biologics License Application (BLA) for moxetumomab pasudotox for the treatment of adult patients with HCL who have received at least two prior lines of therapy. The BLA is based on results from the Phase III ‘1053’ clinical trial. The FDA has granted Priority Review status with a Prescription Drug User Fee Act action date set for the third quarter of 2018.

NOTES TO EDITORS

About Moxetumomab Pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is an investigational anti-CD22 recombinant immunotoxin and a potential new medicine with the opportunity to be a first-in-class treatment in the US for patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior lines of therapy. Immunotoxins are a class of anticancer agents that combine the selectivity of antibodies to target drug delivery and the potency of toxins to kill target cancer cells.⁴ Moxetumomab pasudotox is composed of a binding portion of an anti-CD22 antibody fused to a toxin. CD22 is a B-lymphocyte restricted transmembrane protein with a higher receptor density in HCL cells relative to normal B cells, making it an attractive therapeutic target for the treatment of this cancer.⁵ After binding to CD22, the molecule is internalised, processed and releases its modified protein toxin that inhibits protein synthesis, leading to apoptotic cell death. Moxetumomab pasudotox has been granted Orphan Drug Designation by the FDA and Orphan Designation by the European Medicines Agency for the treatment of HCL.

About Hairy Cell Leukaemia

HCL is a rare, incurable slow-growing leukaemia in which the bone marrow overproduces abnormal B cells or lymphocytes.⁶ HCL can result in serious and life-threatening conditions, including infections, bleeding and anaemia.⁷ Approximately 1,000 people are diagnosed with HCL in the US each year.^8,9,10 While many patients initially respond to treatment, up to 40% will relapse.¹¹ With no established standard of care and very few treatments available, there remains significant unmet medical need for people with relapsed or refractory HCL.^12,13

About the ‘1053’ Phase III Trial

The ‘1053’ trial is a single-arm, multicentre Phase III clinical trial assessing the efficacy, safety, immunogenicity and pharmacokinetics of moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL who have received at least two prior therapies. The trial is being conducted in 80 patients across 34 sites in 14 countries.¹⁴ The primary endpoint was durable complete response (CR), defined as CR with haematologic remission (blood count normalisation) for >180 days. Secondary outcome measures included overall response rate, relapse free survival, progression-free survival, time to response, safety, pharmacokinetic and immunogenic potential.¹⁴

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca in Haematology

Leveraging its collective heritage in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus, and is accelerating development of a broad portfolio of potential blood cancer treatments. AstraZeneca and Acerta Pharma, its haematology research and development centre of excellence, received US FDA approval for the first medicine in this franchise, Calquence (acalabrutinib), in 2017.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology, Respiratory, Cardiovascular, Renal & Metabolic Diseases, and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, MD, one of AstraZeneca’s three global R&D centres, with additional sites in Cambridge, UK and South San Francisco, CA. For more information, please visit www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

CONTACTS

References

¹ Kreitman, R, Dearden C, Zinzani P, Delgado J et al. Moxetumomab Pasudotox in Heavily Pretreated Patients with Relapsed/Refractory Hairy Cell Leukemia: Results of a Pivotal International Study. Oral presentation at: American Society of Clinical Oncology 2018; June 2018; Chicago, IL. Abstract #7004

² Leukemia & Lymphoma Society. Glossary Results – Minimal Residual Disease^. http://www.lls.org/llssearch?search-terms=minimal+residual+disease&search_language=en Accessed April 2018.

³ Thomas, Deborah A., Ravandi, F. et al. Importance of minimal residual disease in hairy cell leukemia: monoclonal antibodies as a therapeutic strategy. Leuk Lymphoma. 2009 Oct; 50(0 1): 27–31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109291/ Accessed April 2018.

⁴ G Aruna. Immunotoxins: A review of their use in cancer treatment. J Stem Cells Regn Med. 2006; 1(1): 31-36. Published online 2006 Dec 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907961/  Accessed April 2018.

⁵ Park JH, Ross LL. Targeted Immunotherapy for Hairy cell leukemia. Journ Clin Onc 2012; 30: 1888–1890. http://ascopubs.org/doi/abs/10.1200/JCO.2011.39.8313. Accessed April 2018.

⁶ National Institutes of Health. Hairy Cell Leukemia. https://rarediseases.info.nih.gov/diseases/6560/hairy-cell-leukemia Accessed April 2018.

⁷ Hairy Cell Leukemia Foundation. Complications. https://www.hairycellleukemia.org/about-hcl/complications/ Accessed April 2018.

⁸Troussard X, Cornet E. Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment. AM J Hematol. 2017; 92(12):1382-1390. Published online 2017 Nov 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698705/ Accessed April 2018.

⁹ Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes. CA Cancer J Clin. 2016; 66:443-459. https://onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21357 Accessed April 2018.

¹⁰ Grever MR, Blachly JS, Andritsos LA. Hairy cell leukemia: Update on molecular profiling and therapeutic advances. Blood. 2014; 28(5):197-203. https://www.sciencedirect.com/science/article/pii/S0268960X14000514 Accessed April 2018.

¹¹ Hairy Cell Leukemia Foundation. Treatment. https://www.hairycellleukemia.org/about-hcl/treatment/ Accessed April 2018.

¹² López-Rubio, M., Garcia-Marco, J. A. Current and emerging treatment options for hairy cell leukemia. OncoTargets and Therapy. 2015; 8: 2147–2156. http://doi.org/10.2147/OTT.S70316 Accessed April 2018.

¹³ National Institutes of Health. Hairy Cell Leukemia. https://rarediseases.info.nih.gov/diseases/6560/hairy-cell-leukemia Accessed December 2017

¹⁴ ClinicalTrials.gov. Moxetumomab pasudotox for Advanced Hairy Cell Leukemia. https://clinicaltrials.gov/ct2/show/study/NCT01829711?term=moxetumomab&rank=4&show_locs=Y#locn Accessed April 2018.