UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form 6-K
REPORT OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16 OR 15d-16
UNDER
THE SECURITIES EXCHANGE ACT OF 1934
For the
month of July, 2019
Commission
File Number 001-15170
GlaxoSmithKline plc
(Translation
of registrant's name into English)
980 Great West Road, Brentford, Middlesex, TW8
9GS
(Address
of principal executive office)
Indicate
by check mark whether the registrant files or will file annual
reports under cover of Form 20-F or Form 40-F.
Form
20-F . . . .X. . . . Form 40-F . . . . . . . .
Indicate
by check mark if the registrant is submitting the Form 6-K in paper
as permitted by Regulation S-T Rule 101(b)(1): ____
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Issued: 3 July 2019, London UK - LSE Announcement
ViiV Healthcare receives EU Marketing Authorisation for Dovato
(dolutegravir/lamivudine), a new once-daily, single-pill,
two-drug regimen for the treatment of HIV-1
infection
Authorisation based on GEMINI pivotal trials in which Dovato
achieved non-inferior efficacy compared to a dolutegravir-based,
three-drug regimen through 48 weeks, with no cases of
resistance.
London, UK, 3 July 2019
-
ViiV Healthcare, the global specialist HIV company, majority owned
by GlaxoSmithKline, with Pfizer Inc. and Shionogi Limited as
shareholders, today announced that the European Commission has
granted Marketing Authorisation for Dovato
(dolutegravir/lamivudine) for the treatment of HIV-1 infection in
adults and adolescents above 12 years of age weighing at least 40
kg, with no known or suspected resistance to the integrase
inhibitor class, or lamivudine.
[1]
Deborah Waterhouse, CEO, ViiV Healthcare, said
: "For many years, the standard of care for
treatment-naïve people living with HIV in Europe has been a
three-drug regimen. The data from our dolutegravir-based two-drug
regimen development programme challenges this, and with the
authorisation of Dovato, people living with HIV can for the first
time start treatment on a once-daily, single-pill, two-drug regimen
with the knowledge that efficacy is non-inferior to a three-drug
regimen whilst containing fewer antiretrovirals. Dovato strengthens
ViiV Healthcare's industry-leading portfolio of innovative
treatment approaches for people living with
HIV."
With around 25,000 new HIV diagnoses in Europe every
year
[2]
,
and the fact that today HIV is considered a chronic condition which
requires people living with HIV (PLHIV) to remain on antiretroviral
(ARV) treatment for life, it is ever more important to provide
innovative treatment options.
Marketing Authorisation for Dovato is supported by data from the
landmark global GEMINI 1 and 2 studies that included more than
1,400 HIV-1 infected adults. In these studies, dolutegravir
and lamivudine demonstrated non-inferior efficacy based on
plasma HIV-1 RNA <50 copies per millilitre (c/mL), a standard
measure of HIV control, at week 48 when compared to a three-drug
regimen of dolutegravir and two nucleoside reverse transcriptase
inhibitors (NRTIs), tenofovir disoproxil fumarate/emtricitabine
(TDF/FTC), in treatment-naïve, HIV-1 infected adults. The
safety results for dolutegravir and lamivudine seen in GEMINI 1 and
2 were consistent with the product labelling for dolutegravir and
lamivudine.
Four patients (1%) in
both the dolutegravir and lamivudine, and the dolutegravir and
TDF/FTC, study arms experienced drug-related serious adverse
events, and 15 patients (2%) in the dolutegravir and lamivudine
arm and 16 patients (2%) in the dolutegravir and TDF/FTC arm
had adverse events that led to
discontinuation.
The most
common adverse reactions included headache, diarrhoea, nausea,
insomnia, and fatigue. No patient who experienced virologic failure
in either treatment arm developed treatment-emergent resistance
also up to week 48.
[3]
,
[4]
John C. Pottage, Jr, M.D.
Chief Scientific and Medical
Officer, ViiV Healthcare said
:
"The Marketing Authorisation of Dovato in Europe marks a
significant development for people living with HIV. This
treatment allows individuals to take a two-drug regimen in a single
pill with dolutegravir at the core, building on the established
potency and safety profiles of dolutegravir and lamivudine. ViiV
Healthcare's ambition and innovative R&D programme aims to
reduce the number of HIV drugs people living with HIV take over a
lifetime and Dovato is an important addition to our portfolio of
medicines to support this aim"
Dovato (dolutegravir 50 mg/ lamivudine 300 mg tablets) was
authorised by the US Food and Drug Administration in April
2019
[5]
(please see
US Prescribing
Information
including Box
Warning), and further regulatory applications have been submitted
worldwide.
- Ends -
Notes to editors
About Dovato (dolutegravir/lamivudine)
Dovato (dolutegravir 50 mg/ lamivudine 300 mg tablets) is
authorised in the EU for the treatment of HIV-1 infection in adults
and adolescents above 12 years of age weighing at least 40 kg, with
no known or suspected resistance to the integrase inhibitor class,
or lamivudine. Dolutegravir/lamivudine is a once-daily,
single-pill, two-drug regimen that combines the integrase strand
transfer inhibitor (INSTI) dolutegravir (Tivicay, 50 mg) with the
nucleoside analogue reverse transcriptase inhibitor (NRTI)
lamivudine (Epivir, 300 mg).1
In the US the Food and Drug Administration (FDA) authorised
Dovato, a complete, once-daily, single-tablet regimen of
dolutegravir (DTG) 50 mg and lamivudine (3TC) 300 mg for the
treatment of HIV-1 infection in adults with no antiretroviral (ARV)
treatment history and with no known resistance to either DTG or
3TC.
[5]
Like a dolutegravir-based three-drug regimen,
Dolutegravir/lamivudine uses two drugs to inhibit the viral cycle
at two different sites. INSTIs, like dolutegravir, inhibit HIV
replication by preventing the viral DNA from integrating into the
genetic material of human immune cells (T-cells). This step is
essential in the HIV replication cycle and is also responsible for
establishing chronic infection. Lamivudine is an NRTI that works by
interfering with the conversion of viral ribonucleic acid (RNA)
into deoxyribonucleic acid (DNA) which in turn stops the virus from
multiplying.
Trademarks are owned by or licensed to the ViiV Healthcare group of
companies.
Important Safety Information for Dovato (50mg dolutegravir/300mg
lamivudine) tablets in the EU
The following Important Safety Information is based on the Summary
of Product Characteristics for Dovato. Please consult the full
Summary of Product Characteristics for all the safety
information.
Dovato (50mg dolutegravir/300mg lamivudine)
Dovato is indicated for the treatment of Human Immunodeficiency
Virus type 1 (HIV-1) infection in adults and adolescents above 12
years of age weighing at least 40 kg, with no known or suspected
resistance to the integrase inhibitor class, or
lamivudine.
The recommended dose of Dovato in adults and adolescents is one 50
mg/300 mg tablet once daily.
Method of administration
Oral use. Dovato can be taken with or without food.
Contraindications
Hypersensitivity to the active substances or to any of the
excipients listed in section 6.1.
Dose adjustments
A separate preparation of dolutegravir is available where a dose
adjustment is indicated due to drug-drug interactions (e.g.
rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital,
St. John's wort, etravirine (without boosted protease inhibitors),
efavirenz, nevirapine, or tipranavir/ritonavir. In these cases the
physician should refer to the individual product information for
dolutegravir.
Missed doses
If the patient misses a dose of Dovato, the patient should take
Dovato as soon as possible, providing the next dose is not due
within 4 hours. If the next dose is due within 4 hours, the patient
should not take the missed dose and simply resume the usual dosing
schedule.
Special warnings and precautions for use
Transmission of HIV
While effective viral suppression with antiretroviral therapy has
been proven to substantially reduce the risk of sexual
transmission, a residual risk cannot be excluded. Precautions to
prevent transmission should be taken in accordance with national
guidelines.
Hypersensitivity reactions
Hypersensitivity reactions have been reported with dolutegravir,
and were characterized by rash, constitutional findings, and
sometimes, organ dysfunction, including severe liver reactions.
Dovato and other suspect medicinal products should be discontinued
immediately if signs or symptoms of hypersensitivity reactions
develop (including, but not limited to, severe rash or rash
accompanied by raised liver enzymes, fever, general malaise,
fatigue, muscle or joint aches, blisters, oral lesions,
conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical
status including liver aminotransferases and bilirubin should be
monitored. Delay in stopping treatment with Dovato or other suspect
active substances after the onset of hypersensitivity may result in
a life-threatening allergic reaction.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may
occur during antiretroviral therapy. Such changes may in part be
linked to disease control and life style. For lipids, there is in
some cases evidence for a treatment effect, while for weight gain
there is no strong evidence relating this to any particular
treatment. For monitoring of blood lipids and glucose reference is
made to established HIV treatment guidelines. Lipid disorders
should be managed as clinically appropriate.
Liver disease
Patients with chronic hepatitis B or C and treated with combination
antiretroviral therapy are at an increased risk of severe and
potentially fatal hepatic adverse reactions. In case of concomitant
antiviral therapy for hepatitis B or C, please refer also to the
relevant product information for these medicinal
products.
Dovato includes lamivudine, which is active against hepatitis B.
Dolutegravir lacks such activity. Lamivudine monotherapy is
generally not considered an adequate treatment for hepatitis B,
since the risk for hepatitis B resistance development is high. If
Dovato is used in patients co-infected with hepatitis B an
additional antiviral is therefore generally needed. Reference
should be made to treatment guidelines.
If Dovato is discontinued in patients co-infected with hepatitis B
virus, periodic monitoring of both liver function tests and markers
of HBV replication is recommended, as withdrawal of lamivudine may
result in an acute exacerbation of hepatitis.
Patients with pre-existing liver dysfunction, including chronic
active hepatitis have an increased frequency of liver function
abnormalities during combination antiretroviral therapy, and should
be monitored according to standard practice. If there is evidence
of worsening liver disease in such patients, interruption or
discontinuation of treatment must be considered.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an
inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been
observed within the first few weeks or months of initiation of
CART. Relevant examples are Cytomegalovirus retinitis, generalised
and/or focal mycobacterial infections, and Pneumocystis jirovecii
pneumonia (often referred to as PCP). Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves' disease and autoimmune
hepatitis) have also been reported to occur in the setting of
immune reactivation; however, the reported time to onset is more
variable and these events can occur many months after initiation of
treatment.
Liver chemistry elevations consistent with immune reconstitution
syndrome were observed in some hepatitis B and/or C co-infected
patients at the start of dolutegravir therapy. Monitoring of liver
chemistries is recommended in patients with hepatitis B and/or C
co-infection.
Osteonecrosis
Although the aetiology is considered to be multifactorial
(including corticosteroid use, biphosphonates, alcohol consumption,
severe immunosuppression, higher body mass index), cases of
osteonecrosis have been reported in patients with advanced
HIV-disease and/or long-term exposure to CART. Patients should be
advised to seek medical advice if they experience joint aches and
pain, joint stiffness or difficulty in movement.
Opportunistic infections
Patients should be advised that dolutegravir, lamivudine or any
other antiretroviral therapy does not cure HIV infection and that
they may still develop opportunistic infections and other
complications of HIV infection. Therefore, patients should remain
under close clinical observation by physicians experienced in the
treatment of these associated HIV diseases.
Undesirable effects
The most frequently reported adverse reactions are headache (3%),
diarrhoea (2%), nausea (2%) and insomnia (2%).
The most severe adverse reaction reported with dolutegravir was a
hypersensitivity reaction that included rash and severe liver
effects.
Tabulated list of adverse reactions is available in the full
information leaflet.
Changes in laboratory biochemistries
Dolutegravir has been associated with an increase in serum
creatinine occuring in the first week of treatment when
administered with other antiretroviral medicinal products.
Increases in serum creatinine occurred within the first four weeks
of treatment with dolutegravir plus lamivudine and remained stable
through 48 weeks. These changes are linked to the inhibiting effect
of dolutegravir on renal tubular transporters of creatinine. The
changes are not considered to be clinically relevant and do not
reflect a change in glomerular filtration rate.
Co-infection with Hepatitis B or C
In the Phase III studies for the dolutegravir single agent,
patients with hepatitis B and/or C co-infection were permitted to
enrol provided that baseline liver chemistry tests did not exceed 5
times the upper limit of normal (ULN). Overall, the safety profile
in patients co-infected with hepatitis B and/or C was similar to
that observed in patients without hepatitis B or C co-infection,
although the rates of AST and ALT abnormalities were higher in the
subgroup with hepatitis B and/or C co-infection for all treatment
groups. Liver chemistry elevations consistent with immune
reconstitution syndrome were observed in some subjects with
hepatitis B and/or C co-infection at the start of dolutegravir
therapy, particularly in those whose anti-hepatitis B therapy was
withdrawn.
Drug interactions
No drug interaction studies have been conducted using Dovato.
Dovato contains dolutegravir and lamivudine, therefore any
interactions identified for these individually are relevant to
Dovato. No clinically significant drug interactions are expected
between dolutegravir and lamivudine.
The recommended dose of dolutegravir is 50 mg twice daily when
co-administered with rifampicin, carbamazepine, oxcarbazepine,
phenytoin, phenobarbital, St. John's wort, etravirine (without
boosted protease inhibitors), efavirenz, nevirapine, or
tipranavir/ritonavir.
Dovato should not be co-administered with polyvalent
cation-containing antacids. Polyvalent cation-containing antacids
are recommended to be taken 2 hours after or 6 hours before
Dovato.
When taken with food, Dovato and supplements or multivitamins
containing calcium, iron or magnesium can be taken at the same
time. If Dovato is administered under fasting conditions,
supplements or multivitamins containing calcium, iron or magnesium
are recommended to be taken 2 hours after or 6 hours before
Dovato.
Dolutegravir increased metformin concentrations. A dose adjustment
of metformin should be considered when starting and stopping
coadministration of Dovato with metformin, to maintain glycaemic
control. Metformin is eliminated renally and, therefore, it is of
importance to monitor renal function when co-treated with Dovato.
This combination may increase the risk for lactic acidosis in
patients with moderate renal impairment (stage 3a creatinine
clearance 45- 59 mL/min) and a cautious approach is recommended.
Reduction of the metformin dose should be highly
considered.
The combination of Dovato with cladribine is not
recommended.
Dovato should not be taken with any other medicinal product
containing dolutegravir or lamivudine, except where a dose
adjustment of dolutegravir is indicated due to drug-drug
interactions.
Other established and theoretical interactions with selected
antiretrovirals and non-antiretroviral medicinal products are
listed in the full information leaflet.
Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential (WOCBP) should undergo pregnancy
testing before initiation of Dovato. WOCBP who are taking Dovato
should use effective contraception throughout
treatment.
Pregnancy
The safety and efficacy of a dual regimen has not been studied in
pregnancy. Preliminary data from a surveillance study has suggested
an increased incidence of neural tube defects (0.9%) in mothers
exposed to dolutegravir (a component of Dovato) at the time of
conception compared with mothers exposed to non-dolutegravir
containing regimens (0.1%).
The incidence of neural tube defects in the general population
ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). As neural
tube defects occur within the first 4 weeks of foetal development
(at which time the neural tubes are sealed) this potential risk
would concern women exposed to dolutegravir at the time of
conception and in early pregnancy. Due to the potential risk of
neural tube defects with dolutegravir, Dovato should not be used
during the first trimester unless there is no
alternative.
More than 1000 outcomes from second and third trimester exposure to
dolutegravir in pregnant women indicate no evidence of increased
risk of malformities and foeto/neonatal negative effects. However,
as the mechanism by which dolutegravir may interfere in human
pregnancy is unknown, the safety in use during the second and third
trimester cannot be confirmed. Dovato should be used during
pregnancy only if the expected benefit justifies the potential risk
to the foetus.
In animal reproductive toxicology studies with dolutegravir, no
adverse development outcomes, including neural tube defects, were
identified. Dolutegravir was shown to cross the placenta in
animals.
A large amount of data on the use of lamivudine in pregnant women
(more than 3000 outcomes from first trimester) indicates no
malformative toxicity.
Animal studies showed lamivudine may inhibit cellular DNA
replication (see section 5.3). The clinical relevance of these
findings is unknown.
Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated in vitro
and in vivo to cause a variable degree of mitochondrial damage.
There have been reports of mitochondrial dysfunction in
HIV-negative infants exposed in utero and/or post-natally to
nucleoside analogues, these have predominantly concerned treatment
with regimens containing zidovudine. The main adverse reactions
reported are haematological disorders (anaemia, neutropenia), and
metabolic disorders (hyperlactatemia, hyperlipasemia). These
reactions have often been transitory. These findings do not affect
current national recommendations to use antiretroviral therapy in
pregnant women to prevent vertical transmission of
HIV.
Breast-feeding
It is unknown whether dolutegravir is excreted in human milk.
Available toxicological data in animals has shown excretion of
dolutegravir in milk. In lactating rats that received a single oral
dose of 50 mg/kg at 10 days postpartum, dolutegravir was detected
in milk at concentrations typically higher than blood.
Based on more than 200 mother/child pairs treated for HIV, serum
concentrations of lamivudine in breastfed infants of mothers
treated for HIV are very low (< 4% of maternal serum
concentrations) and progressively decrease to undetectable levels
when breastfed infants reach 24 weeks of age. There are no data
available on the safety of lamivudine when administered to babies
less than three months old.
It is recommended that HIV infected women do not breast-feed their
infants under any circumstances in order to avoid transmission of
HIV.
Fertility
There are no data on the effects of dolutegravir or lamivudine on
human male or female fertility. Animal studies indicate no effects
of dolutegravir or lamivudine on male or female
fertility.
Effects on ability to drive and use machines
Dovato has no or negligible influence on the ability to drive and
use machines. Patients should be informed that dizziness and
somnolence has been reported during treatment with dolutegravir.
The clinical status of the patient and the adverse reaction profile
of Dovato should be borne in mind when considering the patient's
ability to drive or operate machinery.
Please refer to the full European Summary of Product
Characteristics for Dolutegravir/lamivudine
for full prescribing information, including
contraindications, special warnings and precautions for use. For
the US, please refer to the
US Prescribing
Information
.
About ViiV Healthcare
ViiV Healthcare is a global specialist HIV company established in
November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE)
dedicated to delivering advances in treatment and care for people
living with HIV and for people who are at risk of becoming infected
with HIV. Shionogi joined in October 2012. The company's aims to
take a deeper and broader interest in HIV/AIDS than any company has
done before and take a new approach to deliver effective and
innovative medicines for HIV treatment and prevention, as well as
support communities affected by HIV.
For more information on the company, its management, portfolio,
pipeline, and commitment, please visit
www.viivhealthcare.com.
About GSK
GSK is a science-led global healthcare company with a special
purpose: to help people do more, feel better, live longer. For
further information please visit www.gsk.com.
ViiV Healthcare media
enquiries:
Patricia O'Connor
+44 20 8047 5982
GSK Global media enquiries:
Simon Steel
+44 20 8047 5502
Tim Foley
+44 20 8047 5502
Mary
Rhyne
+1 919 412 9089 (US)
Analyst/Investor
enquiries:
Sarah Elton-Farr
+44 20 8047
5194
Danielle
Smith
+44 20 8047
0932
James Dodwell
+44 20 8047 2406
Jeff McLaughlin
+1 215 751
7002
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 2018.
Registered in England & Wales:
No. 3888792
Registered Office:
980 Great West Road
Brentford, Middlesex
TW8 9GS
References
[1]
Dovato EU Summary of Product
Characteristics.
[2]
European Centre for Disease Prevention
and Control, and World Health Organization. HIV/AIDS Surveillance
in Europe. 2018. 2017 data. Available at
https://ecdc.europa.eu/sites/portal/files/documents/hiv-aids-surveillance-europe-2018.pdf
.
Last accessed June 2019.
[3]
Cahn
J, Sierra Madero J, Arribas J, et al. Non-inferior efficacy of
dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus
tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in
antiretroviral treatment-naïve adults with HIV-1 infection -
48-week results from the GEMINI studies. AIDS
2018.
[4]
Cahn P, Sierra Madero J, Arribas JR,
et al. Dolutegravir plus lamivudine versus dolutegravir plus
tenofovir disoproxil fumarate and emtricitabine in
antiretroviral-naïve adults with HIV-1 infection (GEMINI-1 and
GEMINI-2): week 48 results from two multicentre, double-blind,
randomised, non-inferiority, phase 3
trials.
Lancet
. 2019;393(10167):143-155
[5]
Dovato US Prescribing
Information
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF
.
Last accessed June 2019.
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorised.
|
GlaxoSmithKline plc
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|
(Registrant)
|
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|
Date: July
03, 2019
|
|
|
|
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By:/s/ VICTORIA
WHYTE
--------------------------
|
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Victoria Whyte
|
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Authorised
Signatory for and on
|
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behalf
of GlaxoSmithKline plc
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