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
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Form
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Issued: 24 July 2019, London UK - LSE Announcement
ViiV Healthcare announces positive Week 48 results in first study
to evaluate treatment switch from TAF-containing regimen with three
or more drugs to 2-drug regimen of dolutegravir/lamivudine for
HIV-1 infection
Data from the TANGO study presented at the 10
th
International
AIDS Society Conference on HIV Science (IAS 2019) demonstrate
non-inferior efficacy of Dovato
▼
(dolutegravir/lamivudine)
in virally suppressed adults with HIV-1
infection
London, UK, 24 July 2019
-
Today
ViiV
Healthcare
, the global
specialist HIV company majority owned by GSK, with Pfizer Inc. and
Shionogi Limited as shareholders, announced that data from the
phase III TANGO study showed that the 2-drug regimen (2DR) of
Dovato
▼
(dolutegravir/lamivudine)
has similar efficacy to a tenofovir alafenamide fumarate
(TAF)-containing regimen of at least three drugs in virally
supressed and stable adults with HIV-1. Full Week 48 findings were
presented today at the
10
th
International
AIDS Society Conference on HIV Science
(IAS
2019)
in Mexico City
.
[1]
Kimberly Smith, MD,
Head of Global Research &
Medical Strategy at ViiV Healthcare,
said: "With HIV now considered a chronic
condition and people living with HIV needing antiretroviral
treatments for life, taking fewer medicines over a lifetime has
become an important consideration for the community. The TANGO
study was designed to answer the question, can a 2-drug regimen of
dolutegravir/lamivudine maintain viral suppression as well as a
TAF-containing regimen? We're delighted that the Week 48 results of
the study confirm that it can. These data present evidence that a
dolutegravir/lamivudine 2-drug regimen is as effective as a
TAF-containing, 3-drug regimen for people living with
HIV."
The TANGO study was conducted to assess whether adults living with
HIV-1 who had maintained viral suppression for at least six months
on a TAF-containing regimen of at least three drugs, were able to
maintain similar rates of viral suppression after switching to the
2DR of dolutegravir/lamivudine in a fixed-dose combination,
compared to continuing the TAF-containing
regimen.
[2]
The
study met its primary endpoint for non-inferiority based on the
proportion of participants with plasma HIV-1 RNA ≥50 copies
per millilitre (c/mL) at Week 48, based on the FDA snapshot
algorithm. Results showed that switching to dolutegravir/lamivudine
was non-inferior to continuing a TAF-containing regimen at Week 48
(snapshot virologic failure: <1% vs. <1%; adjusted
difference: -0.3% [95% CI: -1.2, 0.7]).
1
The proportion of participants with plasma HIV-1 RNA <50 c/mL
was high and similar in both arms and demonstrated non-inferiority
(93.2% [344/369] of participants in the dolutegravir/lamivudine arm
compared with 93.0% [346/372] in the TAF-containing regimen
arm).
1
In the study, no participants on dolutegravir/lamivudine and one
participant (<1%) on the TAF-containing regimen met confirmed
virologic failure criteria, with no resistance mutations observed
at failure. The safety results for the 2DR of
dolutegravir/lamivudine were consistent with the product labelling
for the medicines.
1
The percentage of participants who withdrew due to AEs was 4%
(13/369) in the dolutegravir/lamivudine arm, versus <1% (2/371)
in the TAF-containing regimen arm. The most common AEs were
nasopharyngitis (12% [43] versus 11% [41] respectively), upper
respiratory tract infections (8% [31] versus 9% [32] respectively),
and diarrhoea (8% [30] versus 7% [26]
respectively).
1
About TANGO
TANGO is a phase III, randomised, open-label, active-controlled,
multicentre study to assess the antiviral efficacy and safety of
switching to a 2DR consisting of dolutegravir/lamivudine in
HIV-infected adults who are virally suppressed and stable on a
TAF-containing regimen.
2
Study participants were HIV-1 infected adults on a TAF-containing
regimen with HIV-1 RNA <50 c/mL for at least six months, without
prior virologic failure, no historical nucleoside reverse
transcriptase inhibitors (NRTI) or integrase inhibitor (INI) major
resistance mutation, and no evidence of hepatitis B infection.
Participants were randomised to switch to dolutegravir/lamivudine
or continue on the TAF-containing regimen through Week 148. The
primary endpoint was the proportion of participants with a viral
load of >50 c/mL at Week 48 (FDA snapshot algorithm) for the
Intention To Treat-Exposed (ITT-E) population.
2
About dolutegravir/lamivudine
Dolutegravir is an INI for use in combination with other
antiretroviral agents for the treatment of HIV.
[3]
INIs
block 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. Dolutegravir is
authorised in more than 100 countries across North America, Europe,
Asia, Australia, Africa and Latin America.
Lamivudine, commonly known as 3TC, is a nucleoside analogue used in
combination with other antiretroviral agents for the treatment of
HIV infection. Lamivudine is available in branded and generic
forms.
[4]
Dolutegravir/lamivudine is a once-daily, single-pill, 2-drug
regimen that combines the INI dolutegravir 50 mg with the NRTI
lamivudine 300 mg.
[5]
The
fixed dose combination of dolutegravir/lamivudine 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 INI class, or
lamivudine,
[6]
and
in the US for the treatment of HIV-1 infection in adults with no
antiretroviral treatment history and with no known resistance to
either dolutegravir or lamivudine.
5
Trademarks are owned by or licensed to the ViiV Healthcare group of
companies.
Important Safety Information for 50mg dolutegravir/300mg lamivudine
tablets in the EU
The following Important Safety Information is based on the Summary
of Product Characteristics for dolutegravir/lamivudine. Please
consult the full Summary of Product Characteristics for all the
safety information.
Dolutegravir/lamivudine (50mg dolutegravir/300mg
lamivudine)
Dolutegravir/lamivudine 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 dolutegravir/lamivudine in adults and
adolescents is one 50 mg/300 mg tablet once daily.
Method of administration
Oral use. Dolutegravir/lamivudine 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 dolutegravir/lamivudine, the
patient should take dolutegravir/lamivudine 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 characterised by rash, constitutional findings, and
sometimes, organ dysfunction, including severe liver reactions.
Dolutegravir/lamivudine 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
dolutegravir/lamivudine 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.
Dolutegravir/lamivudine 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 dolutegravir/lamivudine is used in patients co-infected
with hepatitis B an additional antiviral is therefore generally
needed. Reference should be made to treatment
guidelines.
If dolutegravir/lamivudine 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 occurring 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/lamivudine and remained stable
through to Week 48. 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
dolutegravir/lamivudine. Dolutegravir/lamivudine contains
dolutegravir and lamivudine, therefore any interactions identified
for these individually are relevant to dolutegravir/lamivudine. 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.
Dolutegravir/lamivudine 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 dolutegravir/lamivudine.
When taken with food, dolutegravir/lamivudine and supplements or
multivitamins containing calcium, iron or magnesium can be taken at
the same time. If dolutegravir/lamivudine 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 dolutegravir/lamivudine.
Dolutegravir increased metformin concentrations. A dose adjustment
of metformin should be considered when starting and stopping
coadministration of dolutegravir/lamivudine with metformin, to
maintain glycaemic control. Metformin is eliminated renally and,
therefore, it is of importance to monitor renal function when
co-treated with dolutegravir/lamivudine. 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 dolutegravir/lamivudine with cladribine is not
recommended.
Dolutegravir/lamivudine 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 dolutegravir/lamivudine. WOCBP who are
taking dolutegravir/lamivudine 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 dolutegravir/lamivudine) 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, dolutegravir/lamivudine
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. Dolutegravir/lamivudine 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
Dolutegravir/lamivudine 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 dolutegravir/lamivudine 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 aim is 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
.
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.
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:
Melinda Stubbee
+1 919 491
0831
Patricia
O'Connor +44 (0) 20
8047 5982
Audrey Abernathy +1
919 605 4521
GSK Global Media
enquiries:
Simon Steel
+44
(0) 20 8047 5502
Kristen Neese
+1 804 217 8147
Analyst/Investor
enquiries:
Sarah
Elton-Farr
+44 (0) 20 8047 5194
Danielle
Smith
+44 (0) 20 8047 0932
James
Dodwell
+44 (0) 20 8047 2406
Jeff
McLaughlin
+1 215 751 7002
References
[1]
Van
Wyk, J. Switching to DTG+3TC fixed dose combination (FDC) is
non-inferior to continuing a TAF-based regimen (TBR) in maintaining
virologic suppression through 24 weeks (TANGO
study). Presented at the 10
th
International
AIDS Conference for HIV Science (IAS 2019), 21-24 July 2019, Mexico
City, Mexico.
[2]
Clinical trials.gov Switch Study
to Evaluate Dolutegravir Plus Lamivudine in Virologically
Suppressed Human Immunodeficiency Virus Type 1 Positive Adults
(TANGO). Available at:
https://clinicaltrials.gov/ct2/show/NCT03446573?term=TANGO+dolutegravir&rank=1
.
Accessed July 2019
[3]
Tivicay (dolutegravir)
European Summary of Product Characteristics. Available
at:
https://www.ema.europa.eu/en/documents/product-information/tivicay-epar-product-information_en.pdf
.
Accessed July 2019.
[4]
Epivir (lamivudine)
European Summary of Product Characteristics. Available
at:
https://www.ema.europa.eu/en/documents/product-information/epivir-epar-product-information_en.pdf
Accessed
July 2019.
[5]
Dolutegravir plus lamivudine
Prescribing Information. U.S. Approval 8 April 2019. Available
at:
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF
Accessed
July 2019
[6]
Dovato EU Summary of Product
Characteristics. July 2019. Available at:
https://www.medicines.org.uk/emc/product/10446/smpc
Accessed
July 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
|
|
(Registrant)
|
|
|
Date: July
24, 2019
|
|
|
|
|
By:/s/ VICTORIA
WHYTE
--------------------------
|
|
|
|
Victoria Whyte
|
|
Authorised
Signatory for and on
|
|
behalf
of GlaxoSmithKline plc
|
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