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): ____
Indicate
by check mark if the registrant is submitting the Form 6-K in paper
as permitted by Regulation S-T Rule 101(b)(7): ____
Issued: 10 July 2019, London UK - LSE Announcement
ViiV Healthcare announces phase III study meets primary endpoint,
demonstrating the ability to control HIV-1 with a 2-drug regimen of
dolutegravir plus lamivudine in virally suppressed patients
switching from a TAF-containing, 3-drug regimen
Week 48 results from
the TANGO study will be presented this month
at 10
th
International
AIDS Society Conference on HIV Science (IAS
2019)
London, UK, 10 July 2019
-
ViiV
Healthcare
, the global
specialist HIV company majority-owned by GSK, with Pfizer Inc. and
Shionogi Limited as shareholders, today announced positive Week 48
results from its phase III TANGO study. 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 tenofovir
alafenamide fumarate (TAF)-containing regimen of at least three
drugs, were able to maintain similar rates of viral suppression
after switching to the 2-drug regimen (2DR) of dolutegravir plus
lamivudine in a fixed dose combination, compared to continuing the
TAF-containing regimen.
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) using the FDA Snapshot algorithm at
Week 48. No patients met confirmed virologic withdrawal criteria or
developed treatment resistance in the dolutegravir plus lamivudine
arm of the study. The safety results for the 2DR of dolutegravir
plus lamivudine were consistent with the product labelling for the
medicines.
[1]
Full results from the study will be presented at
the
10
th
International
AIDS Society Conference on HIV Science
(IAS
2019)
, to be held from 21-24
July in Mexico City.
Kimberly Smith, M.D., Head of Global Research & Medical
Strategy at ViiV Healthcare, said
:
"When we developed the TANGO study, we asked if virally suppressed
people living with HIV could reduce the number of medicines in
their HIV treatment regimen while maintaining viral suppression.
These Week 48 data clearly indicate that they can - individuals who
are already on treatment can maintain viral suppression if they
switch from a 3-drug, TAF-containing regimen to a 2-drug regimen of
dolutegravir plus lamivudine."
The single-pill, 2DR of dolutegravir plus lamivudine, was
authorised in the United States earlier this year for the treatment
of HIV-1 infection in adults with no antiretroviral treatment (ARV)
history and with no known resistance to either dolutegravir or
lamivudine.
[2]
It
was also authorised in Europe in July 2019 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 (INI) class, or
lamivudine.
[3]
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 plus lamivudine in
HIV-infected adults who are virally suppressed and stable on a
TAF-containing regimen.
[4]
Study participants were HIV-1 infected adults on a TAF-containing
regimen with HIV-1 RNA<50c/mL for at least six months, without
prior virologic failure, no historical nucleoside reverse
transcriptase inhibitors (NRTI) or INI major resistance mutation,
and no evidence of hepatitis B infection. Participants were
randomised to switch to dolutegravir plus 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.
4
About dolutegravir and lamivudine
Dolutegravir is an INI for use in combination with other
antiretroviral agents for the treatment of HIV.
[5]
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 over 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
(Epivir
®
)
and generic forms.
[6]
Dolutegravir plus lamivudine is a once-daily, single-pill, 2-drug
regimen that combines the INI dolutegravir (Tivicay, 50 mg) with
the NRTI lamivudine (Epivir, 300 mg).
2
The
fixed dose combination of dolutegravir plus 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,
3
and
in the US for the treatment of HIV-1 infection in adults with no
antiretroviral (ARV) treatment history and with no known resistance
to either dolutegravir or lamivudine.
2
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 plus
lamivudine. Please consult the full Summary of Product
Characteristics for all the safety information.
Dolutegravir plus lamivudine (50mg dolutegravir/300mg
lamivudine)
Dolutegravir plus 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 plus lamivudine in adults and
adolescents is one 50 mg/300 mg tablet once daily.
Method of administration
Oral use. Dolutegravir plus 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 plus lamivudine, the
patient should take dolutegravir plus 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 characterized by rash, constitutional findings, and
sometimes, organ dysfunction, including severe liver reactions.
Dolutegravir plus 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
plus 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 plus 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 plus 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 plus 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 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 dolutegravir
plus lamivudine. Dolutegravir plus lamivudine contains dolutegravir
and lamivudine, therefore any interactions identified for these
individually are relevant to dolutegravir plus 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 plus 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 plus lamivudine.
When taken with food, dolutegravir plus lamivudine and supplements
or multivitamins containing calcium, iron or magnesium can be taken
at the same time. If dolutegravir plus 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 plus lamivudine.
Dolutegravir increased metformin concentrations. A dose adjustment
of metformin should be considered when starting and stopping
coadministration of dolutegravir plus 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 plus 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 plus lamivudine with cladribine is
not recommended.
Dolutegravir plus 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 plus lamivudine. WOCBP
who are taking dolutegravir plus 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 plus
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 plus 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 plus 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 plus 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 plus 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 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
.
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]
ViiV
Healthcare: TANGO headline results. Data on
file.
[2]
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
[3]
Dovato EU Summary of
Product Characteristics. July 2019. Available
at:
https://www.medicines.org.uk/emc/product/10446/smpc
Accessed
July 2019.
[4]
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
[5]
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.
[6]
European Medicines Agency.
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
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.
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GlaxoSmithKline plc
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(Registrant)
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Date: July
10, 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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