Market Overview

US FDA Approves LUMOXITI™ (moxetumomab pasudotox-tdfk) for Certain Patients with Relapsed or Refractory Hairy Cell Leukemia

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Approval of LUMOXITI, a first-in-class medicine for hairy cell
leukemia, marks first new treatment option for patients in over 20 years

AstraZeneca and MedImmune, its global biologics research and development
arm, announced today that the US Food and Drug Administration (FDA) has
approved LUMOXITI™ (moxetumomab pasudotox-tdfk) for the treatment of
adult patients with relapsed or refractory hairy cell leukemia (HCL) who
have received at least two prior systemic therapies, including treatment
with a purine nucleoside analog. LUMOXITI is not recommended
in patients with severe renal impairment (CrCl ≤ 29 mL/min). The Phase
III trial results demonstrated 75% (95% confidence interval [CI]: 64,
84) of patients receiving LUMOXITI achieved an overall response; 30%
(95% CI: 20, 41) had a durable complete response.

Dave Fredrickson, Executive Vice-President, Global Head Oncology
Business Unit, said: "Today's FDA approval of LUMOXITI represents a
significant milestone for people living with hairy cell leukemia, a rare
blood cancer that can result in serious and life-threatening conditions.
For patients, this approval provides the first FDA-approved medicine for
this condition in more than 20 years."

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical
Immunotherapy Section, Laboratory of Molecular Biology, Center for
Cancer Research, National Cancer Institute, and Principal Investigator
of the Phase III clinical trial, said: "While many patients with hairy
cell leukemia experience a remission with current treatments, 30% to 40%
will relapse five to ten years after their first treatment. With
subsequent treatments, durations of response diminish and toxicities
accumulate, and few approved treatment options exist. Moxetumomab
pasudotox represents a promising non-chemotherapeutic agent for HCL,
addressing an unmet medical need for physicians and their patients."

LUMOXITI was approved under FDA Priority Review. The approval is based
on data from the Phase III single-arm, open-label ‘1053' trial of
LUMOXITI monotherapy in 80 patients who have received at least two prior
therapies, including a purine nucleoside analog. The primary endpoint of
the trial was durable complete response. Summary of key results from the
trial, as determined by a blinded independent central review:

     
Efficacy Measure   Result %, (95% CI)
Durable Complete Response Ratea,b   30% (20, 41)
Overall Response Ratec   75% (64, 84)
Complete Responsed   41% (30, 53)
Partial Responsee   34% (24, 45)
Hematologic Remissionb   80%
a   Durable complete response is defined as patients who achieved
complete response with hematologic remission for a duration of more
than 180 days
b Hematologic remission is defined as hemoglobin > 11g/dL, neutrophils
> 1500/mm3, and platelets > 100,000/mm3
without transfusions or growth factor for at least 4 weeks
c Overall response rate is defined as best overall response of
complete response or partial response
d Complete response is defined as clearing of the bone marrow of hairy
cells by routine Hematoxylin and Eosin stain, radiologic resolution
of preexisting lymphadenopathy and/or organomegaly, and hematologic
remission
e Partial response is defined as ≥ 50% decrease or normalization (<
500/mm3) in peripheral blood lymphocyte count, reduction
of pre-existing lymphadenopathy and/or organomegaly, and hematologic
remission
 

The median time to hematologic remission was 1.1 months (range: 0.2 to
13). At data cut-off, the median duration of complete response was not
yet reached after a median 16.7 months of follow-up.

Capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS),
including life-threatening cases of each, have been reported among
patients treated with LUMOXITI. In the combined safety database of 129
HCL patients treated with LUMOXITI, Grade 3 or 4 CLS occurred in 1.6%
and 2% of patients, respectively. Grade 3 or 4 HUS occurred in 3% and
0.8% of patients, respectively.

In the ‘1053' trial of 80 patients, the most common Grade 3 or 4 adverse
reactions (reported in at least ≥ 5% of patients) were hypertension,
febrile neutropenia, and HUS. HUS was the most common adverse reaction
leading to discontinuation (5%). The most common adverse reactions (≥
20%) of any grade were infusion related reactions (50%), edema (39%),
nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation
(23%), anemia (21%), and diarrhea (21%). The most common laboratory
abnormalities (≥ 20%) of any grade were creatinine increased, ALT
increased, hypoalbuminemia, AST increased, hypocalcemia,
hypophosphatemia, hemoglobin decreased, neutrophil count decreased,
hyponatremia, blood bilirubin increased, hypokalemia, GGT increased,
hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline
phosphate increased.

The recommended dose of LUMOXITI is 0.04 mg/kg administered as an
intravenous infusion over 30 minutes on days 1, 3, and 5 of each 28-day
cycle up to 6 cycles, disease progression, or unacceptable toxicity.

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME

  • Capillary Leak Syndrome (CLS), including life-threatening cases,
    occurred in patients receiving LUMOXITI. Monitor weight and blood
    pressure; check labs, including albumin, if CLS is suspected. Delay
    dosing or discontinue LUMOXITI as recommended [see Dosage and
    Administration (2.3) and Warnings and Precautions (5.1)].
  • Hemolytic Uremic Syndrome (HUS), including life-threatening cases,
    occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet
    count, serum creatinine, and ensure adequate hydration. Discontinue
    LUMOXITI in patients with HUS [see Dosage and Administration (2.3)
    and Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS

  • Capillary leak syndrome (CLS), including life-threatening
    cases, has been reported among patients treated with LUMOXITI and is
    characterized by hypoalbuminemia, hypotension, symptoms of fluid
    overload, and hemoconcentration. In the combined safety database of
    HCL patients treated with LUMOXITI, CLS occurred in 34% (44/129) of
    patients, including Grade 2 in 23% (30/129), Grade 3 in 1.6% (2/129),
    and Grade 4 in 2% (3/129).

    Most cases of CLS occurred in
    the first 8 days (range: 1 to 19) of a treatment cycle, however, cases
    have also been reported on other days throughout the cycle. The median
    time to resolution of CLS was 12 days (range: 1 to 53).

    Monitor
    patient weight and blood pressure prior to each LUMOXITI infusion and
    as clinically indicated during treatment. Assess patients for signs
    and symptoms of CLS, including weight gain (increase in 5.5 pounds
    (2.5 kg) or ≥ 5% from Day 1 of current cycle), hypotension, peripheral
    edema, shortness of breath or cough, and pulmonary edema and/or
    serosal effusions. In addition, the following changes in laboratory
    parameters may help identify CLS: hypoalbuminemia, elevated
    hematocrit, leukocytosis, and thrombocytosis.

    CLS
    may be life-threatening or fatal if treatment is delayed. Counsel
    patients to seek immediate medical attention should signs or symptoms
    of CLS occur at any time. Patients who develop CLS should
    receive appropriate supportive measures, including concomitant oral or
    intravenous corticosteroids, and hospitalization as clinically
    indicated. Withhold LUMOXITI for Grade 2 CLS until resolution, and
    permanently discontinue for Grade ≥ 3 CLS.
  • Hemolytic Uremic Syndrome (HUS), including life threatening
    cases, has been reported in patients treated with LUMOXITI and is
    characterized by the triad of microangiopathic hemolytic anemia,
    thrombocytopenia, and progressive renal failure. In the combined
    safety database of HCL patients treated with LUMOXITI, HUS occurred in
    7% (9/129) of patients, including Grade 3 in 3% (4/129) and Grade 4 in
    0.8% (1/129).

    Most cases of HUS occurred in the first 9
    days (range: 1 to 16) of a treatment cycle, however, cases have also
    been reported on other days throughout the cycle. The median time to
    resolution of HUS was 11.5 days (range: 2 to 44). All cases resolved,
    including those who discontinued LUMOXITI.

    Avoid LUMOXITI
    in patients with prior history of severe thrombotic microangiopathy
    (TMA) or HUS. Administer prophylactic intravenous fluids before and
    after LUMOXITI infusions. In Study 1053, patients with a
    platelet count ≥ 100,000/mm received low-dose aspirin on Days 1
    through 8 of each 28-day cycle for prophylaxis of thrombosis.

    Monitor
    blood chemistry and complete blood counts prior to each dose and on
    Day 8 of each treatment cycle. Monitoring mid-cycle is also
    recommended. Consider the diagnosis of HUS in patients who develop
    hemolytic anemia, worsening or sudden onset of thrombocytopenia,
    increase in creatinine levels, elevation of bilirubin and/or LDH, and
    have evidence of hemolysis based on peripheral blood smear schistocytes.

    The
    events of HUS may be life-threatening if treatment is delayed with
    increased risk of progressive renal failure requiring dialysis. If HUS
    is suspected initiate appropriate supportive measures, including fluid
    repletion, hemodynamic monitoring, and consider hospitalization as
    clinically indicated. Discontinue LUMOXITI in patients with HUS.
  • Renal Toxicity has been reported in patients treated with
    LUMOXITI therapy. In the combined safety database of HCL patients
    treated with LUMOXITI, 26% (34/129) reported adverse events of renal
    toxicity, including acute kidney injury (2.3%), renal failure (2.3%),
    renal impairment (1.6%), serum creatinine increased (17%), and
    proteinuria (8%). Grade 3 acute kidney injury occurred in 1.6% (2/129)
    of patients.

    Based on laboratory findings, during
    treatment, serum creatinine increased by two or more grades from
    baseline in 22% (29/129) of patients, including increases of Grade 3
    in 1.6% (2/129) of patients. At the end of treatment, serum creatinine
    levels remained elevated at 1.5- to 3-times the upper limit of normal
    in 5% of patients. Patients who experience HUS, those ≥ 65 years of
    age, or those with baseline renal impairment may be at increased risk
    for worsening of renal function following treatment with LUMOXITI.

    Monitor
    renal function prior to each infusion of LUMOXITI, and as clinically
    indicated throughout treatment. Delay LUMOXITI dosing in patients with
    Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by
    ≥ 2 grades.
  • Infusion Related Reactions occurred in patients treated with
    LUMOXITI, and were defined as the occurrence of any one of the
    following events on the day of study drug infusion: chills, cough,
    dizziness, dyspnea, feeling hot, flushing, headache, hypertension,
    hypotension, infusion related reaction, myalgia nausea, pyrexia, sinus
    tachycardia, tachycardia, vomiting, or wheezing. In Study 1053,
    infusion related reactions occurred in 50% (40/80) of patients,
    including Grade 3 events in 11% (9/80) of patients. The most
    frequently reported infusion related events were nausea (15%), pyrexia
    (14%), chills (14%), vomiting (11%), headache (9%), and infusion
    related reaction (9%).

    Infusion related reactions may occur
    during any cycle of treatment with LUMOXITI. Premedicate with
    antihistamines and antipyretics prior to each LUMOXITI dose. If a
    severe infusion related reaction occurs, interrupt the LUMOXITI
    infusion and institute appropriate medical management. Administer an
    oral or intravenous corticosteroid approximately 30 minutes before
    resuming, or before the next LUMOXITI infusion.
  • Electrolyte Abnormalities: In the combined safety database of
    HCL patients treated with LUMOXITI, electrolyte abnormalities occurred
    in 57% (73/129) of patients with the most common electrolyte
    abnormality being hypocalcemia occurring in 25% of patients. Grade 3
    electrolyte abnormalities occurred in 14% (18/129) of patients and
    Grade 4 electrolyte abnormalities occurred in 0.8% (1/129) of
    patients. Electrolyte abnormalities co-occurred in the same treatment
    cycle with CLS, HUS, fluid retention, or renal toxicity in 37%
    (48/129) of patients.

    Monitor serum electrolytes prior to
    each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle
    is also recommended.

ADVERSE REACTIONS

  • Most common non-laboratory adverse reactions (≥ 20%) of any grade were
    infusion related reactions (50%), edema peripheral (39%), nausea
    (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation
    (23%), anemia (21%), and diarrhea (21%). The most common Grade 3 or 4
    adverse reactions (reported in at least ≥ 5% of patients) were
    hypertension, febrile neutropenia, and HUS.
  • Most common laboratory abnormalities (≥ 20%) of any grade were
    creatinine increased, ALT increased, hypoalbuminemia, AST increased,
    hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count
    decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT
    increased, hypomagnesemia, platelet count decreased, hyperuricemia,
    and alkaline phosphate increased.
  • Adverse reactions resulting in permanent discontinuation of LUMOXITI
    occurred in 15% (12/80) of patients. The most common adverse reaction
    leading to LUMOXITI discontinuation was HUS (5%). The most common
    adverse reaction resulting in dose delays, omissions, or interruptions
    was pyrexia (3.8%).

SPECIFIC POPULATIONS

  • Pregnancy: There are no available data on LUMOXITI use in
    pregnant women to inform a drug-associated risk of major birth defects
    and miscarriage. Advise pregnant women of the potential risk to a
    fetus.
  • Lactation: Advise women not to breastfeed.
  • Geriatric Use: Exploratory analyses suggest a higher incidence
    of adverse reactions leading to drug discontinuation (23% versus 7%)
    and renal toxicity (40% versus 20%) for patients 65 years of age or
    older as compared to those younger than 65 years.

Please see complete Prescribing
Information
, including Boxed WARNING, Patient Information
(Medication Guide), and Instructions for Use

NOTES TO EDITORS

About Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare, chronic, and slow-growing leukemia
in which the bone marrow overproduces abnormal B cell lymphocytes. HCL
can result in serious conditions, including infections, bleeding and
anemia. Approximately 1,000 people are diagnosed with HCL in
the US each year. HCL accounts for up to 3% of all adult
leukemias. While many patients initially respond to treatment, 30% to
40% will relapse five to ten years after their first treatment. With no
established standard of care and very few treatments available, there
remains significant unmet medical need for people with relapsed or
refractory HCL.

About LUMOXITI

LUMOXITI™ (moxetumomab pasudotox-tdfk, formerly CAT8015 or HA22) is a
CD22-directed cytotoxin and a first-in-class treatment in the US for
adult patients with relapsed or refractory hairy cell leukemia (HCL) who
have received at least two prior systemic therapies, including treatment
with a purine nucleoside analog. LUMOXITI is not recommended in patients
with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22
binding portion of an antibody fused to a truncated bacterial toxin; the
toxin inhibits protein synthesis and ultimately triggers apoptotic cell
death. LUMOXITI has been granted Orphan Drug Designation by the FDA for
the treatment of HCL.

About the ‘1053' Phase III Trial

The ‘1053' trial is a single-arm, multicenter 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, including
one purine nucleoside analog. The trial was conducted in 80 patients
across 34 sites in 14 countries. The primary endpoint was durable
complete response (CR), defined as CR with hematologic remission (blood
count normalization) for >180 days. Secondary outcome measures included
overall response rate, relapse free survival, progression-free survival,
time to response, safety, pharmacokinetic and immunogenic potential.

Early discovery of moxetumomab pasudotox was led by Dr. Ira Pastan and
colleagues at the National Cancer Institute (NCI). The collaboration
between NCI and MedImmune, AstraZeneca's global biologics research and
development arm, is an example of how scientific partnerships can lead
to important advances for cancer patients.

About AstraZeneca in Hematology

Leveraging its strength in oncology, AstraZeneca has established
hematology 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 hematology research and
development center of excellence, received US FDA approval for the first
medicine in this franchise in 2017.

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 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 hematology.

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

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 commercialization 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 centers, 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 commercialization of
prescription medicines, primarily for the treatment of diseases in three
therapy areas – Oncology, Cardiovascular, Renal & Metabolism and
Respiratory. AstraZeneca operates in over 100 countries and its
innovative medicines are used by millions of patients worldwide.

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

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