TIDMGSK
RNS Number : 0093F
GlaxoSmithKline PLC
10 July 2019
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(R) )
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.
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END
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