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FARXIGA in Combination with ONGLYZA Demonstrates Similar Glycemic Control with Additional Benefits Vs. Insulin Glargine in Patients with Type 2 Diabetes

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Important short-term and long-term data on a potential new use of
Farxiga (dapagliflozin) showed significant reductions in HbA1c in
patients with type 1 diabetes

AstraZeneca (NYSE: AZN) presented key data on the use of FARXIGA®
(dapagliflozin) in diverse patient populations with type 2 and type 1
diabetes (T2D, T1D) at the American Diabetes Association (ADA) 78th
Scientific Sessions this week in Orlando, FL, June 22-26, 2018.

These studies reinforce the use of dapagliflozin as a treatment option
to help improve glycemic control when used with the DPP-4 inhibitor
ONGLYZA® (saxagliptin) versus older treatment options
(insulin, sulfonylurea) in patients with T2D. Data investigating
the impact of dapagliflozin across patients with a spectrum of
cardiovascular (CV) risks were also presented to help further the
scientific understanding of the effects of SGLT-2 inhibitors (SGLT-2i)
on CV events. In addition, new data investigating dapagliflozin in T1D
was also presented.

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and
Metabolism, Global Medicines Development, AstraZeneca said: "As
demonstrated by the broad data on Farxiga featured at ADA, we are firmly
committed to addressing the complex unmet needs of people affected by
diabetes, of whom many have interrelated CV risks. Through our completed
and ongoing research with Farxiga, we're proud to have developed a
highly representative clinical program that we believe will help change
clinical practice for diverse patient populations where there remains a
need for earlier and more aggressive treatment approaches with SGLT-2
inhibitors."

Highlights from the 23 dapagliflozin abstracts presented include:

Dapagliflozin in Combination with Saxagliptin Head-to-Head vs.
Insulin or Sulfonylurea in T2D

In T2D, two new phase IIIb studies evaluating the efficacy and safety of
dapagliflozin in combination with saxagliptin demonstrated non-inferior
HbA1c reduction compared to insulin glargine with or without
sulfonylurea and significant reduction in HbA1c vs. glimepiride in
patients inadequately controlled on metformin. Specifically, results
showed:

  • In a 24-week non-inferiority study (N= 643), dapagliflozin 10mg and
    saxaglipitin 5mg plus metformin in patients with T2D, compared to
    titrated insulin glargine plus metformin, resulted in similar HbA1c
    reductions (-1.7% vs. -1.5%, BL~9.0, p=0.118), reduction in body
    weight (-1.5 kg vs. 2.1 kg, BL~89 kg, p<0.001), reduction in mean
    24-hour glucose at week two (-48.5 mg/dL vs. -28.5 mg/dL, p<0.0001)
    and was associated with a lower prevalence of hypoglycemia (21.3% vs.
    38.4%, p<0.001). (Oral 260-OR)
  • In a 52-week study (N=443), dapagliflozin 10mg and saxaglipitin 5mg
    plus metformin in patients with T2D compared to titrated glimepiride
    plus metformin, resulted in significant reductions in HbA1c (-1.38%
    vs. -1.14%, BL~8.5, p<0.001), body weight (-3.22 kg vs. 0.89 kg, BL~90
    kg, p=0.001) and systolic blood pressure (SBP) (-2.6 mm Hg vs. 1.0,
    p=0.007). (Oral 261-OR)

Dapagliflozin and saxagliptin are not indicated for weight loss or for
treatment of hypertension.

AstraZeneca also presented extension data from the DURATION-8 study over
104 weeks (Late-breaking Poster 104-LB). In this two-year
follow-up analysis, the combination of once-daily dapagliflozin 10mg and
once-weekly exenatide extended-release 2mg showed greater HbA1c
reduction than either drug alone in adult patients with T2D inadequately
controlled by metformin alone. The combination and each treatment alone
were generally well-tolerated with no unexpected adverse events.

Evaluating CV Outcomes in the SGLT-2i Class

New data from the ongoing multinational CVD-REAL study, the first
real-world evidence, study of its kind, were also presented (Late-breaking
Poster 124-LB)
. The late-breaking poster compared the risk of CV
events in patients with T2D (N=363,240), 75% of whom did not have
established CV disease, starting treatment with dapagliflozin vs.
DPP-4is. Initiation of dapagliflozin was associated with lower rates of
all-cause death (Hazard Ratio [HR]: 0.61; 95% Confidence Interval [CI]:
0.54, 0.69), hospitalization for heart failure (hHF) (HR: 0.68; 95% CI:
0.60, 0.78), myocardial infarction (HR: 0.90; 95% CI: 0.81, 0.99) and
stroke (HR: 0.84; 95% CI: 0.76, 0.93) vs. treatment with DPP-4i.
Dapagliflozin is not indicated to reduce the risk of CV events, death or
hHF.

AstraZeneca also presented results from a post-hoc analysis of the
EXSCEL (Effects of Once-Weekly Exenatide on CV Event Lowering) study,
which evaluated CV outcomes for adult patients with T2D at a wide range
of CV risk in the placebo arm taking SGLT-2is (Late-breaking
Poster 130-LB)
. This analysis showed an adjusted HR for major
adverse cardiac event (MACE), a composite of CV death, nonfatal
myocardial infarction, or nonfatal stroke, of 0.79 (95% CI: 0.49,1.28)
with the SGLT-2i class and an adjusted HR for of 0.55 (95% CI:
0.26,1.15) with dapagliflozin specifically. Additionally, the adjusted
HR for all-cause mortality was 0.51 (95% CI: 0.27,0.95) with the SGLT-2i
class and 0.66 (95% CI: 0.25,1.72) with dapagliflozin. Estimated
glomerular filtration rate (eGFR) slope increased for both the SGLT-2i
class (increased by 0.87 mL/min/m2/year) and dapagliflozin
(1.24 mL/min/m2/year). Dapagliflozin is not indicated to
improve renal outcomes.

The CV outcomes trial (CVOT) for dapagliflozin, DECLARE (Dapagliflozin
Effect on Cardiovascular Events), will evaluate the CV safety and
efficacy of dapagliflozin in the largest SGLT-2i CVOT. DECLARE includes
a broad range of patients with T2D, including those with multiple CV
risk factors or established CV disease. The trial is anticipated to read
out in the second half of 2018.

Investigating Dapagliflozin as Add-on to Insulin in T1D to
Address an Unmet Need for Oral Therapy

In adults with T1D, AstraZeneca presented short-term and long-term
results from the DEPICT (Dapagliflozin Evaluation in Patients with
Inadequately Controlled Type-1 Diabetes) program. The new data included
results evaluating the efficacy and safety of dapagliflozin as add-on to
insulin over 52 weeks (from DEPICT-1) and 24 weeks (from DEPICT-2), as
well as a pooled analysis of continuous glucose monitoring (CGM) data
from both studies. Dapagliflozin is not indicated for T1D.

In both DEPICT-1 and 2, dapagliflozin demonstrated reductions in HbA1C
and body weight, and increased time in glycemic target range vs. placebo
in adult patients with T1D. Specifically, results showed:

  • DEPICT-1: At week 52 (N=747), dapagliflozin 5mg and 10mg,
    respectively, demonstrated a difference vs. placebo in HbA1c of -0.33%
    [95% CI: -0.49, -0.17] and -0.36% (95% CI: -0.53, -0.20) and percent
    change in body weight of -2.95% (95% CI: -3.83, -2.06) and -4.54% (95%
    CI: -5.40, -3.66). (Late-breaking Poster 119-LB)
  • DEPICT-2: At week 24 (N=813), dapagliflozin 5mg and 10mg respectively,
    demonstrated a difference vs. placebo in HbA1c (-0.37% [95% CI: -0.49,
    -0.26] and -0.42% [95% CI: -0.53, -0.30],], BL~8.4, p<0.0001) and
    percent change in body weight (-3.21% [95% CI: -3.96, -2.45] and
    -3.74% [95% CI: -4.49, -2.99], p<0.0001). HbA1c (Oral 213-OR)
  • Post-hoc pooled analyses from DEPICT-1 and 2: At week 24,
    dapagliflozin 5mg and 10mg, respectively, demonstrated a difference
    vs. placebo in reduced mean interstitial glucose (-15.48 and -18.90),
    increased percentage of time in the target glycemic range, (9.07%
    equating to more than 2 hours, and 10.67% equating to 2 hours 30
    minutes), reduced the Mean Amplitude of Glucose Excursions (MAGE)
    (-13.36 and -13.94) and reduced postprandial glucose (-8.55 and
    -12.76), compared to placebo. Dapagliflozin compared to placebo
    demonstrated no notable difference in hypoglycemia (≤70 mg/dL or ≤54
    mg/dL) or nocturnal glucose (≤70 mg/dL). (Late-breaking Poster
    125-LB)

Across treatment groups (dapagliflozin 5mg and 10mg compared to
placebo), in both DEPICT-1 and 2, hypoglycemic events, including severe
hypoglycemia, were similar. There were numerically more adjudicated
definite diabetic ketoacidosis (DKA) events observed in the
dapagliflozin group vs. placebo across studies (4.0% and 3.4% vs. 1.9%
for 52-week in DEPICT-1, and 2.6% and 2.2% vs. 0% for 24 weeks in
DEPICT-2). The majority of events were mild or moderate, with the most
common identified causes related to missed insulin doses or pump failure.

The full list of highlighted AstraZeneca scientific presentations is
available in our curtain raiser here,
and the comprehensive list can be accessed on the ADA website here.
You can also follow us live during ADA 2018 on Twitter.

INDICATION AND LIMITATIONS OF USE FOR FARXIGA (dapagliflozin) tablets
5 mg and 10 mg

FARXIGA is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or
for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

  • Prior serious hypersensitivity reaction to FARXIGA
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2),
    end-stage renal disease, or patients on dialysis

Warnings and Precautions

  • Hypotension: FARXIGA causes intravascular volume contraction,
    and symptomatic hypotension can occur. Assess and correct volume
    status before initiating FARXIGA in patients with impaired renal
    function, elderly patients, or patients on loop diuretics. Monitor for
    hypotension
  • Ketoacidosis has been reported in patients with type 1 and
    type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess
    patients who present with signs and symptoms of metabolic acidosis for
    ketoacidosis, regardless of blood glucose level. If suspected,
    discontinue FARXIGA, evaluate and treat promptly. Before initiating
    FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA
    may require monitoring and temporary discontinuation in situations
    known to predispose to ketoacidosis
  • Acute Kidney Injury and Impairment in Renal Function: FARXIGA
    causes intravascular volume contraction and renal impairment, with
    reports of acute kidney injury requiring hospitalization and dialysis.
    Consider temporarily discontinuing in settings of reduced oral intake
    or fluid losses. If acute kidney injury occurs, discontinue and
    promptly treat.

    FARXIGA increases serum creatinine and
    decreases eGFR. Elderly patients and patients with impaired renal
    function may be more susceptible to these changes. Before initiating
    FARXIGA, evaluate renal function and monitor periodically. FARXIGA is
    not recommended in patients with an eGFR persistently between 30
    and <60 mL/min/1.73 m2
  • Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the
    risk for urinary tract infections [UTIs] and serious UTIs have been
    reported with FARXIGA. Evaluate for signs and symptoms of UTIs and
    treat promptly
  • Hypoglycemia: FARXIGA can increase the risk of hypoglycemia
    when coadministered with insulin and insulin secretagogues. Consider
    lowering the dose of these agents when coadministered with FARXIGA
  • Genital Mycotic Infections: FARXIGA increases the risk of
    genital mycotic infections, particularly in patients with prior
    genital mycotic infections. Monitor and treat appropriately
  • Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur
    with FARXIGA. Monitor LDL-C and treat per standard of care
  • Bladder cancer: An imbalance in bladder cancers was observed in
    clinical trials. There were too few cases to determine whether the
    emergence of these events is related to FARXIGA, and insufficient data
    to determine whether FARXIGA has an effect on pre-existing bladder
    tumors. FARXIGA should not be used in patients with active bladder
    cancer. Use with caution in patients with a history of bladder cancer
  • Macrovascular Outcomes: There have been no clinical studies
    establishing conclusive evidence of macrovascular risk reduction with
    FARXIGA

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse
reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo
respectively were female genital mycotic infections (8.4% vs. 6.9% vs.
1.5%), nasopharyngitis (6.6% vs. 6.3% vs. 6.2%), and urinary tract
infections (5.7% vs. 4.3% vs. 3.7%).

Use in Specific Populations

  • Pregnancy: Advise females of potential risk to a fetus
    especially during the second and third trimesters.
  • Lactation: FARXIGA is not recommended when breastfeeding

Please read US
Full Prescribing Information
 and Medication
Guide
 for FARXIGA

INDICATION AND LIMITATIONS OF USE FOR BYDUREON® (exenatide
extended-release) for injectable suspension 2mg

BYDUREON is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus

  • Not recommended as first-line therapy for patients inadequately
    controlled on diet and exercise
  • Not a substitute for insulin. Should not be used to treat type 1
    diabetes mellitus or diabetic ketoacidosis
  • Use with prandial insulin has not been studied
  • Do not coadminister with other exenatide-containing products
  • Not studied in patients with a history of pancreatitis. Consider other
    antidiabetic therapies in patients with a history of pancreatitis

IMPORTANT SAFETY INFORMATION FOR BYDUREON

WARNING: RISK OF THYROID C-CELL TUMORS

  • Exenatide extended-release causes an increased incidence in thyroid
    C-cell tumors at clinically relevant exposures in rats compared to
    controls. It is unknown whether BYDUREON causes thyroid C-cell tumors,
    including medullary thyroid carcinoma (MTC), in humans, as the human
    relevance of exenatide extended-release-induced rodent thyroid C-cell
    tumors has not been determined
  • BYDUREON is contraindicated in patients with a personal or family
    history of MTC or in patients with Multiple Endocrine Neoplasia
    syndrome type 2 (MEN 2). Counsel patients regarding the potential risk
    of MTC with the use of BYDUREON and inform them of symptoms of thyroid
    tumors (eg, mass in the neck, dysphagia, dyspnea, persistent
    hoarseness). Routine monitoring of serum calcitonin or using thyroid
    ultrasound is of uncertain value for detection of MTC in patients
    treated with BYDUREON

CONTRAINDICATIONS

  • Personal or family history of MTC, patients with MEN 2
  • Prior serious hypersensitivity reactions to exenatide or product
    components

WARNINGS AND PRECAUTIONS

  • Acute Pancreatitis including fatal and non-fatal hemorrhagic or
    necrotizing pancreatitis has been reported. After initiation, observe
    patients carefully for symptoms of pancreatitis. If suspected,
    discontinue promptly and do not restart if confirmed. Consider other
    antidiabetic therapies in patients with a history of pancreatitis
  • Hypoglycemia Risk of hypoglycemia is increased when exenatide
    is coadministered with insulin or insulin secretagogues. Consider
    lowering the dose of these agents when coadministered with BYDUREON
  • Acute Kidney Injury and Impairment of Renal Function Altered
    renal function, including increased serum creatinine, renal
    impairment, worsened chronic renal failure, and acute renal failure,
    sometimes requiring hemodialysis and kidney transplantation have been
    reported. Not recommended in patients with severe renal impairment or
    end-stage renal disease. Use caution in patients with renal
    transplantation or moderate renal impairment
  • Gastrointestinal Disease Because exenatide is commonly
    associated with gastrointestinal adverse reactions, not recommended in
    patients with severe gastrointestinal disease (eg, gastroparesis)
  • Immunogenicity Patients may develop antibodies to exenatide.
    Patients with higher titer antibodies may have an attenuated HbA1c
    response. In clinical trials, attenuated glycemic response was
    associated with BYDUREON-treated patients. If worsening of or failure
    to achieve adequate glycemic control occurs, consider alternative
    antidiabetic therapy
  • Hypersensitivity Reports of serious hypersensitivity reactions
    (eg, anaphylaxis and angioedema). If this occurs, patients should
    discontinue BYDUREON and promptly seek medical advice
  • Injection-Site Reactions Serious reactions (eg, abscess,
    cellulitis, and necrosis), with or without subcutaneous nodules, have
    been reported
  • Macrovascular Outcomes No clinical studies establishing
    conclusive evidence of macrovascular risk reduction with exenatide

ADVERSE REACTIONS

Most common (≥5%) and occurring more frequently than comparator in
clinical trials: nausea (16.9%), diarrhea (12.7%), headache (8.0%),
vomiting (6.8%), constipation (5.9%), injection-site pruritus (5.9%),
injection-site nodule (5.3%), and dyspepsia (5.1%).

DRUG INTERACTIONS

  • Oral Medications BYDUREON slows gastric emptying and may reduce
    the rate of absorption of orally administered drugs
  • Warfarin Increased international normalized ratio (INR)
    sometimes associated with bleeding has been reported with concomitant
    use of exenatide with warfarin. Monitor INR frequently until stable
    upon initiation of BYDUREON

PREGNANCY

Use during pregnancy only if the potential benefit justifies the
potential risk to the fetus.

Please read US
Full Prescribing Information
 and Medication
Guide
 for BYDUREON.

INDICATIONS AND LIMITATIONS OF USE FOR ONGLYZA®
(saxagliptin) tablets 5mg

ONGLYZA is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.

ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus
or diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION FOR ONGLYZA

Contraindications

Prior serious hypersensitivity reaction to ONGLYZA

Pancreatitis: There have been postmarketing reports of acute
pancreatitis in patients taking ONGLYZA, and in the SAVOR cardiovascular
outcomes trial. Observe for pancreatitis. If pancreatitis is suspected,
discontinue ONGLYZA.

Heart Failure: In the SAVOR cardiovascular outcomes trial, more
patients treated with ONGLYZA were hospitalized for heart failure
compared to placebo. Patients with a prior history of heart failure or
renal impairment had a higher risk for hospitalization for heart
failure. Consider the risks and benefits of ONGLYZA in patients who have
known risk factors for heart failure. Monitor for signs and symptoms. If
heart failure develops, consider discontinuation of ONGLYZA.

Hypoglycemia: When ONGLYZA was used in combination with a
sulfonylurea or with insulin, the incidence of confirmed hypoglycemia
was increased over that of placebo. Consider lowering the dose of these
agents when coadministered with ONGLYZA.

Hypersensitivity Reactions: Serious reactions have been reported
in patients treated with ONGLYZA, including anaphylaxis, angioedema, and
exfoliative skin conditions. Onset of these reactions occurred within
the first 3 months after initiation of treatment with ONGLYZA, with some
reports occurring after the first dose. If a serious hypersensitivity
reaction is suspected, discontinue ONGLYZA. Use caution in patients with
a history of angioedema to another DPP-4 inhibitor.

Severe and Disabling Arthralgia has been reported in patients
taking DPP-4 inhibitors. The time to onset of symptoms following
initiation of drug therapy varied from one day to years. Patients
experienced relief of symptoms upon discontinuation. A subset of
patients experienced a recurrence of symptoms when restarting the same
drug or a different DPP-4 inhibitor. Consider discontinuing drug if
appropriate.

Bullous Pemphigoid: There have been postmarketing reports of
bullous pemphigoid requiring hospitalization in patients taking DPP-4
inhibitors. Tell patients to report development of blisters or erosions.
If suspected, discontinue ONGLYZA.

Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
ONGLYZA.

Most Common Adverse Reactions

Most common adverse reactions reported in ≥5% of patients treated with
ONGLYZA and more commonly than in patients treated with placebo were
upper respiratory tract infection (7.7%, 7.6%), urinary tract infection
(6.8%, 6.1%), and headache (6.5%, 5.9%).

Peripheral edema was reported more commonly in patients treated with the
combination of ONGLYZA 5 mg and a thiazolidinedione (TZD) than in
patients treated with the combination of placebo and TZD (8.1% vs. 4.3%,
respectively).

Drug Interactions

Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with
ONGLYZA significantly increases saxagliptin concentrations. Recommend
limiting ONGLYZA dosage to 2.5 mg once daily.

Use in Specific Populations

In patients with moderate or severe renal impairment, or end-stage renal
disease (eGFR <45 mL/min/1.73 m2), recommended dosage is
2.5 mg once daily regardless of meals. ONGLYZA should be administered
following hemodialysis. Assess renal function before starting ONGLYZA
and periodically thereafter.

Please see US Full Prescribing
Information
 and Medication
Guide
 for ONGLYZA.

NOTES TO EDITORS

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVMD)

Cardiovascular, renal and metabolic diseases together form one of
AstraZeneca's main therapy areas and platforms for future growth. By
following the science to understand more clearly the underlying links
between the heart, kidney and pancreas, AstraZeneca is investing in a
portfolio of medicines to protect organs and improve outcomes by slowing
disease progression, reducing risks and tackling co-morbidities. Our
ambition is to modify or halt the natural course of CVMD diseases and
even regenerate organs and restore function, by continuing to deliver
transformative science that improves treatment practices and
cardiovascular health for millions of patients worldwide.

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. 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 http://www.astrazeneca-us.com and
follow us on Twitter @AstraZenecaUS.

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