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GSK Submits EU Filing for Extended Use of Relvar Ellipta in Patients with Controlled Asthma on an ICS/LABA Combination

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GlaxoSmithKline plc (NYSE:GSK) and Innoviva, Inc. (NASDAQ:INVA)
today announced a submission to the European Medicines Agency (EMA) for
the extended use of once-daily Relvar Ellipta (fluticasone
furoate/vilanterol, FF/VI), an inhaled corticosteroid (ICS) /
long-acting β2-agonist (LABA) combination, in patients
already adequately controlled on an ICS/LABA combination.

FF/VI is currently indicated in Europe for the regular treatment of
patients aged 12 and over with asthma who are not adequately controlled
on both ICS and 'as-needed' short-acting β2-agonist (SABA)
and where use of a combination product (ICS and LABA) is appropriate.
The proposed indication, would also include those patients already
adequately controlled on an ICS/LABA combination.

The submission includes positive data from a previously reported1
non-inferiority lung function study which concluded that patients who
have well-controlled asthma are able to switch from twice-daily
fluticasone propionate/salmeterol, FP/SAL (Seretide Accuhaler) 250/50 to
once-daily FF/VI 100/25, without compromising their lung function.

Based on review of the data from this study (201378), no new safety
signals were identified and the adverse event data are consistent with
the known safety profile for FF/VI established in patients with asthma.
The study design was agreed with European regulatory authorities.

Full EU prescribing information is available at: EU
Prescribing Information for Relvar Ellipta.

Study Design

Following a 4-week open-label treatment period with FP/SAL 250/50
twice-daily, patients with well-controlled asthma were randomised to
receive either FF/VI 100/25 once-daily, FP/SAL 250/50 twice-daily or FP
250 twice-daily in a double-blind, double-dummy manner for 24 weeks at
multiple centres in 12 countries.

The primary objective of the study was to demonstrate non-inferiority of
Relvar Ellipta 100/25 once-daily with Seretide Accuhaler 250/50
twice-daily in adult and adolescent subjects 12 years of age and older
with persistent bronchial asthma, well-controlled on twice-daily
ICS/LABA. The endpoint for the study was the change from baseline in
clinic visit evening FEV1 (pre-bronchodilator and pre-dose)
at the end of the 24-week treatment period.

To demonstrate the non-inferiority of FF/VI vs FP/SAL the lower limit of
the 95% confidence interval for the mean difference in change from
baseline for evening FEV1 needed to be greater than the pre
defined margin of -100mL. This was to rule out the possibility that
FF/VI was more than -100mL inferior to FP/SAL.

About asthma

Asthma is a chronic lung disease that inflames and narrows the airways.
Asthma affects 358 million people worldwide. Despite
medical advances, more than half of patients continue to experience poor
control and significant symptoms impacting their daily life.

The causes of asthma are not completely understood but likely involve an
interaction between a person's genetic make-up and the environment. Key
risk factors are inhaled substances that provoke allergic reactions or
irritate the airways.

Important safety information for Relvar Ellipta in Europe

FF/VI is contraindicated in patients with hypersensitivity to either
fluticasone furoate, vilanterol, or any of the excipients.

FF/VI should not be used to treat acute asthma symptoms or an acute
exacerbation in COPD, for which a short-acting bronchodilator is
required. Increasing use of short-acting bronchodilators to relieve
symptoms indicates deterioration of control and patients should be
reviewed by a physician.

Patients should not stop therapy with FF/VI in asthma or COPD, without
physician supervision since symptoms may recur after discontinuation.

Asthma-related adverse events and exacerbations may occur during
treatment with FF/VI. Patients should be asked to continue treatment but
to seek medical advice if asthma symptoms remain uncontrolled or worsen
after initiation of treatment with FF/VI.

Paradoxical bronchospasm may occur with an immediate increase in
wheezing after dosing. This should be treated immediately with a
short-acting inhaled bronchodilator. FF/VI should be discontinued
immediately, the patient assessed and alternative therapy instituted if
necessary.

Cardiovascular effects, such as cardiac arrhythmias e.g.
supraventricular tachycardia and extrasystoles may be seen with
sympathomimetic medicinal products including FF/VI. Therefore
fluticasone furoate/vilanterol should be used with caution in patients
with severe cardiovascular disease.

For patients with moderate to severe hepatic impairment, the 92/22 mcg
dose should be used and patients should be monitored for systemic
corticosteroid-related adverse reactions. FF/VI 184/22 mcg is not
indicated for patients with COPD. There is no additional benefit of the
184/22 mcg dose compared to the 92/22 mcg dose and there is a potential
increased risk of pneumonia and systemic corticosteroid-related adverse
reactions.

An increase in the incidence of pneumonia has been observed in subjects
with COPD receiving FF/VI. There was also an increased incidence of
pneumonias resulting in hospitalisation. In some instances these
pneumonia events were fatal.

The incidence of pneumonia in patients with asthma was common at the
higher dose. In a previous study of FF/VI in asthma the incidence of
pneumonia in patients with asthma taking FF/VI 184/22 mcg was
numerically higher compared with those receiving FF/VI 92/22 mcg or
placebo.

Hyperglycaemia: There have been reports of increases in blood glucose
levels in diabetic patients and this should be considered when
prescribing to patients with a history of diabetes mellitus.

Systemic effects may occur with any inhaled corticosteroid, particularly
at high doses prescribed for long periods. These effects are much less
likely to occur than with oral corticosteroids. Possible systemic
effects include Cushing's syndrome, Cushingoid features, adrenal
suppression, decrease in bone mineral density, growth retardation in
children and adolescents, cataract and glaucoma and more rarely, a range
of psychological or behavioural effects including psychomotor
hyperactivity, sleep disorders, anxiety, depression or aggression
(particularly in children).

FF/VI should be administered with caution in patients with pulmonary
tuberculosis or in patients with chronic or untreated infections. Data
from large asthma and COPD clinical trials were used to determine the
frequency of adverse reactions associated with FF/VI.

Very common adverse reactions (occurring in >1/10 patients) with FF/VI
were headache and nasopharyngitis. Common adverse reactions (occurring
in >1/100 to <1/10 patients) were pneumonia, upper respiratory tract
infection, bronchitis, influenza, candidiasis of mouth and throat,
oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia,
abdominal pain, arthralgia, back pain, fractures, and pyrexia and muscle
spasms. Extrasystoles were observed as an uncommon adverse reaction
(occurring in >1/1,000 to <1/100 patients). Rare adverse reactions
(occurring in >1/10,000 to < 1/1,000) were hypersensitivity reactions
(including anaphylaxis, angioedema, rash and urticaria), anxiety,
tremor, palpitations, tachycardia and paradoxical bronchospasm. With the
exception of pneumonia and fractures, the safety profile was similar in
patients with asthma and COPD. During clinical studies, pneumonia and
fractures were more frequently observed in patients with COPD.

Relvar Ellipta is known as Breo Ellipta in the United States. Breo
Ellipta is licensed in the US for:

  • The once-daily treatment of asthma in patients aged 18 years and older.

Long-acting β2-adrenergic agonists (LABA), such as
vilanterol, one of the active ingredients in Breo Ellipta, increase the
risk of asthma-related death. Available data from controlled clinical
trials suggest that LABA increase the risk of asthma-related
hospitalization in pediatric and adolescent patients. Therefore, when
treating patients with asthma, physicians should only prescribe Breo
Ellipta for patients not adequately controlled on a long-term asthma
control medication, such as an inhaled corticosteroid, or whose disease
severity clearly warrants initiation of treatment with both an inhaled
corticosteroid and a LABA. Once asthma control is achieved and
maintained, assess the patient at regular intervals and step down
therapy (e.g., discontinue Breo Ellipta) if possible without loss of
asthma control and maintain the patient on a long-term asthma control
medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA
for patients whose asthma is adequately controlled on low- or
medium-dose inhaled corticosteroids.

  • Breo Ellipta is NOT indicated for the relief of acute bronchospasm.

Full US prescribing information, including BOXED WARNING and Medication
Guide is available at us.gsk.com or US
Prescribing Information for Breo Ellipta
.

About Seretide Accuhaler (fluticasone propionate + salmeterol)

Seretide Accuhaler is a twice-daily dual combination treatment
comprising fluticasone propionate /salmeterol, in the Accuhaler inhaler.

Seretide Accuhaler is indicated in Europe in the regular treatment of
patients aged 4 and over with asthma, where use of a combination product
(long-acting β2–agonist, LABA, and inhaled corticosteroid,
ICS) is appropriate: Patients not adequately controlled on both ICS and
'as-needed' short-acting β2-agonist (SABA); Patients already
adequately controlled on both ICS and LABA.

For the UK Summary of Product Characteristics (SmPC), please visit: https://www.medicines.org.uk/emc/medicine/2317/SPC/Seretide+100,+250,+500+Accuhaler

Important safety information for Seretide Accuhaler

Uses: Asthma: Regular treatment of asthma, where a long-acting β2-agonist
and inhaled corticosteroid is appropriate, i.e. patients uncontrolled on
inhaled corticosteroids and 'as needed' short-acting inhaled
bronchodilator or patients controlled on inhaled corticosteroid and
long-acting β2-agonist. Lowest strength Seretide (salmeterol
25mcg/fluticasone propionate 50 mcg and salmeterol 50mcg/fluticasone
propionate 100 mcg) not appropriate in severe asthma. COPD: Symptomatic
treatment of patients with COPD with a FEV1 <60% predicted normal
(pre-bronchodilator) and a history of repeated exacerbations, who have
significant symptoms despite regular bronchodilator therapy.

Dosage and administration: Inhalation only. Asthma: Adults and
adolescents 12 years and over: Seretide Accuhaler - one
inhalation b.d. of: Seretide 100 (salmeterol 50 mcg/fluticasone
propionate 100 mcg) or Seretide 250 (salmeterol 50 mcg/fluticasone
propionate 250 mcg) or Seretide 500 (salmeterol 50 mcg/fluticasone
propionate 500 mcg), Seretide Evohaler – two puffs b.d. of: Seretide 50
(salmeterol 25 mcg/fluticasone propionate 50 mcg) or Seretide 125
(salmeterol 25 mcg/fluticasone propionate 125mcg) or Seretide 250
(salmeterol 25 mcg/fluticasone propionate 250 mcg). Children 4-11
years
: Seretide 50 Evohaler (salmeterol 25 mcg/fluticasone
propionate 50 mcg): two puffs b.d. Spacer recommended for co-ordination.
Seretide 100 Accuhaler (salmeterol 50 mcg/fluticasone propionate 100
mcg) one inhalation b.d. Regularly review patients and reduce dose to
lowest that maintains effective symptom control. Where the control of
symptoms is maintained with the lowest strength of the combination,
patients may be prescribed an inhaled corticosteroid alone, or if a
long-acting β2-agonist is required, Seretide may be given
once daily. If rapid control of asthma in adults or adolescents with
moderate persistent asthma (defined as patients with daily symptoms,
daily rescue use and moderate to severe airflow limitation) is
essential, an initial dose of two inhalations b.d of Seretide 50
Evohaler (salmeterol 25 mcg/fluticasone propionate 50 mcg) or one
inhalation b.d of Seretide 100 Accuhaler (salmeterol 50 mcg/fluticasone
propionate 100 mcg) may be considered on a short-term basis. Once
control of asthma is attained treatment should be regularly reviewed and
stepped down. Doubling the dose of all strengths of Seretide may be
considered when adult patients require additional short-term (up to 14
days) inhaled corticosteroid therapy but this causes a small increase in
β-agonist-related adverse events. COPD: one inhalation b.d. of Seretide
500 Accuhaler (salmeterol 50mcg/fluticasone propionate 500 mcg).

Contraindications: Hypersensitivity to the active ingredients or
to any of the excipients.

Precautions: Pulmonary tuberculosis, fungal, viral or other
infections of the airway, severe cardiovascular disorders, heart rhythm
abnormalities, diabetes mellitus, hypokalaemia and thyrotoxicosis.
Increased reporting of pneumonia and bronchitis in patients with COPD
receiving Seretide compared with placebo. If a patient with severe COPD
has experienced pneumonia, treatment with Seretide should be
re-evaluated. Paradoxical bronchospasm post dose. Severe unstable
asthma
: Warn patients to seek medical advice if short-acting inhaled
bronchodilator use increases. Consider increased inhaled/additional
corticosteroid therapy. Acute symptoms: Not for acute symptoms.
Use short-acting inhaled bronchodilator. Systemic effects:
Systemic effects of inhaled corticosteroids may occur, particularly at
high doses for prolonged periods, but much less likely than with oral
corticosteroids. May include Cushing's syndrome, cushingoid features,
adrenal suppression, adrenal crisis, growth retardation in children and
adolescents, decrease in bone mineral density, cataract, glaucoma and,
more rarely, a range of psychological or behavioural effects including
psychomotor hyperactivity, sleep disorders, anxiety, depression or
aggression (particularly in children). Monitor height of children on
prolonged inhaled corticosteroid therapy. Tremor, palpitations and
headache, have been reported with β2-agonist treatment. In
asthma, therapy should be down titrated under physician supervision to
lowest effective dose and treatment should not be abruptly stopped due
to risk of exacerbation. Serious asthma-related adverse events and
exacerbations may occur during treatment with Seretide. Patients should
not be initiated on Seretide during an exacerbation, or if they have
significantly worsening or acutely deteriorating asthma. Data from a
large asthma trial suggested patients of black African or Afro-Caribbean
ancestry were at increased risk of serious respiratory-related events or
deaths when using salmeterol. All patients should continue treatment but
seek medical advice if asthma symptoms remain uncontrolled or worsen
when initiated on Seretide or using Seretide. In COPD cessation of
therapy may also be associated with decompensation and should be
supervised by a physician. Transfer from oral steroids: Special
care needed. Consider appropriate steroid therapy in stressful
situations.

Drug interactions: Avoid beta-blockers. Avoid concomitant
administration of ketoconazole or other potent (e.g. itraconazole,
telithromycin, ritonavir) and moderate (erythromycin) CYP3A4 inhibitors
unless benefits outweigh potential risk. β2 adrenergic
blockers may weaken or antagonise the effect of salmeterol. Potentially
serious hypokalaemia may result from β2-agonist therapy.
Particular caution is advised in acute severe asthma as this effect may
be potentiated by concomitant treatment with xanthine derivatives,
steroids and diuretics.

Pregnancy and lactation: Experience limited. Balance risks
against benefits.

Side effects: Very Common: headache, nasopharyngitis.
Common:
candidiasis of the mouth and throat, hoarseness/dysphonia,
throat irritation, pneumonia, bronchitis, hypokalaemia, sinusitis,
contusions, traumatic fractures, arthralgia, myalgia, muscle cramps. Uncommon:
respiratory symptoms (dyspnoea), anxiety, tremor, palpitations,
tachycardia, angina pectoris, atrial fibrillation, cutaneous
hypersensitivity reactions, hyperglycaemia, sleep disorders, cataract.
Rare: angioedema, respiratory symptoms (bronchospasm),
anaphylactic reactions including anaphylactic shock, Cushings syndrome,
cushingoid features, adrenal suppression, growth retardation in children
and adolescents, decreased bone mineral density, oesophageal
candidiasis, behavioural changes including psychomotor hyperactivity and
irritability (predominately in children), glaucoma, cardiac arrhythmias
and paradoxical bronchospasm. Not known: depression or aggression
(particularly in children). Paradoxical bronchospasm: substitute
alternative therapy.

Seretide Accuhaler is known as ADVAIR DISKUS in the United States.
ADVAIR DISKUS is licensed in the US for:

  • The treatment of asthma in patients aged 4 years and older.

Long-acting β2-adrenergic agonists (LABA), such as
salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the
risk of asthma-related death. Available data from controlled clinical
trials suggest that LABA increase the risk of asthma-related
hospitalization in pediatric and adolescent patients. Therefore, when
treating patients with asthma, physicians should only prescribe ADVAIR
DISKUS for patients not adequately controlled on a long-term asthma
control medication, such as an inhaled corticosteroid, or whose disease
severity clearly warrants initiation of treatment with both an inhaled
corticosteroid and a LABA. Once asthma control is achieved and
maintained, assess the patient at regular intervals and step down
therapy (e.g., discontinue ADVAIR DISKUS) if possible without loss of
asthma control and maintain the patient on a long-term asthma control
medication, such as an inhaled corticosteroid. Do not use ADVAIR DISKUS
for patients whose asthma is adequately controlled on low- or
medium-dose inhaled corticosteroids.

  • ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.

Full US prescribing information, including BOXED WARNING and Medication
Guide is available at us.gsk.com or US
Prescribing Information for Advair Diskus
.

GSK – one of the world's leading research-based pharmaceutical
and healthcare companies – is committed to improving the quality of
human life by enabling people to do more, feel better and live longer.
For further information please visit www.gsk.com.

RELVAR®, BREO®, ELLIPTA®, SERETIDE®,
ACCUHALER®, ADVAIR®, DISKUS® are
trademarks of the GlaxoSmithKline group of companies.

Innoviva – Innoviva is focused on bringing compelling new
medicines to patients in areas of unmet need by leveraging its
significant expertise in the development, commercialization and
financial management of bio-pharmaceuticals. Innoviva's portfolio is
anchored by the respiratory assets partnered with Glaxo Group Limited
(GSK), including RELVAR®/BREO®
ELLIPTA® and ANORO® ELLIPTA®,
which were jointly developed by Innoviva and GSK. Under the agreement
with GSK, Innoviva is eligible to receive associated royalty revenues
from RELVAR®/BREO® ELLIPTA®,
ANORO® ELLIPTA®. In addition,
Innoviva retains a 15 percent economic interest in future payments made
by GSK for earlier-stage programs partnered with Theravance Biopharma,
Inc., including the closed triple combination therapy for COPD. For more
information, please visit Innoviva's website at www.inva.com.

References

1. http://www.gsk.com/en-gb/media/press-releases/positive-results-for-relvar-ellipta-lung-function-study-in-patients-with-well-controlled-asthma/.

Cautionary statement regarding forward-looking statements

GSK cautions investors that any forward-looking statements or
projections made by GSK, including those made in this announcement, are
subject to risks and uncertainties that may cause actual results to
differ materially from those projected. Such factors include, but are
not limited to, those described under Item 3.D Principal risks and
uncertainties in the company's Annual Report on Form 20-F for 2016.

Innoviva forward-looking statements

This press release contains certain "forward-looking" statements as that
term is defined in the Private Securities Litigation Reform Act of 1995
regarding, among other things, statements relating to goals, plans,
objectives and future events, including the development, regulatory and
commercial plans for Relvar Ellipta (in patients already adequately
controlled on an ICS/LABA combination. Innoviva intends such
forward-looking statements to be covered by the safe harbor provisions
for forward-looking statements contained in Section 21E of the
Securities Exchange Act of 1934 and the Private Securities Litigation
Reform Act of 1995. Such forward-looking statements involve substantial
risks, uncertainties and assumptions. These statements are based on the
current estimates and assumptions of the management of Innoviva as of
the date of this press release and are subject to risks, uncertainties,
changes in circumstances, assumptions and other factors that may cause
the actual results of Innoviva to be materially different from those
reflected in the forward-looking statements. Important factors that
could cause actual results to differ materially from those indicated by
such forward-looking statements are described under the headings "Risk
Factors" and "Management's Discussion and Analysis of Financial
Condition and Results of Operations" contained in Innoviva's Annual
Report on Form 10-K for the year ended December 31, 2016 and Quarterly
Report on Form 10-Q for the quarter ended March 31, 2017, which are on
file with the U.S. Securities and Exchange Commission (SEC) and
available on the SEC's website at www.sec.gov.
Additional factors may be described in those sections of Innoviva's
Quarterly Report on Form 10-Q for the quarter ended June 30, 2017, to be
filed with the SEC in the third quarter of 2017. In addition to the
risks described above and in Innoviva's other filings with the SEC,
other unknown or unpredictable factors also could affect Innoviva's
results. No forward-looking statements can be guaranteed and actual
results may differ materially from such statements. Given these
uncertainties, you should not place undue reliance on these
forward-looking statements. The information in this press release is
provided only as of the date hereof, and Innoviva assumes no obligation
to update its forward-looking statements on account of new information,
future events or otherwise, except as required by law. (INVA-G).

Registered in England & Wales:
No. 3888792

Registered Office:
980 Great West Road
Brentford,
Middlesex
TW8 9GS

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