Last update 12 Dec 2024

Efavirenz

Last update 12 Dec 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(S)-6-chloro-4-(Cyclopropylethynyl)-1,4-dihydro-(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-chloro-4-(2-cyclopropyl-1-ethynyl)-4-trifluoromethyl-(4S)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

+ [18]

Target

Mechanism

RT inhibitors(Reverse transcriptase inhibitors)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesUrogenital Diseases

Active Indication

HIV Infections

Inactive Indication

Acquired Immunodeficiency SyndromeCoinfectionContraception+ [3]

Originator Organization

Bristol Myers Squibb Co.

Active Organization

Teva Pharmaceuticals Europe BVMerck Sharp & Dohme LLCMerck Sharp & Dohme BV

+ [3]

Inactive Organization

Merck Sharp & Dohme Corp.

Celgene Corp.

Bristol Myers Squibb Co.

+ [2]

Drug Highest PhaseApproved

First Approval Date

US (17 Sep 1998),

HIV Infections

RegulationAccelerated Approval (US), Orphan Drug (JP)

Structure

Molecular FormulaC14H9ClF3NO2

InChIKeyXPOQHMRABVBWPR-ZDUSSCGKSA-N

CAS Registry154598-52-4

260

Clinical Trials associated with Efavirenz

CTIS2023-505832-36-01 / Not yet recruitingIIT

OPEN-LABEL EXTENSION STUDY TO ASSESS THE SAFETY AND LONG-TERM EFFECTIVENESS OF ORALLY ADMINISTERED EFAVIRENZ IN PATIENTS DIAGNOSED WITH ADULT OR LATE-ONSET JUVENILE TYPE C NIEMANN-PICK DISEASE WITH COGNITIVE IMPAIRMENT - HUB-NEU-2023-01

Start Date16 May 2024

Sponsor / Collaborator

Bellvitge University Hospital

NCT06294561 / CompletedPhase 1

An Open-label, Two-cycle, Single Sequence, Self-controlled Study Evaluating Effects of Oral Itraconazole or Efavirenz on Pharmacokinetic Profiles of TGRX-326

This is a drug-drug interaction study for TGRX-326 to evaluate the effects of CYP3A inhibitor/inducer drugs on pharmacokinetic profiles of TGRX-326, an ALK inhibitor indicated for treatment of Non-small cell lung cancer.

Start Date04 Mar 2024

Sponsor / Collaborator

Shenzhen TargetRx, Inc.Startup

CTR20234305 / CompletedPhase 1

开放、两周期、单序列、自身对照研究设计，评价口服伊曲康唑或依非韦伦对TGRX-326片药代动力学的影响

[Translation] An open-label, two-period, single-sequence, self-controlled study design to evaluate the effect of oral itraconazole or efavirenz on the pharmacokinetics of TGRX-326 tablets

主要研究目的：评价健康受试者口服CYP3A强抑制剂伊曲康唑和CYP3A中效诱导剂依非韦伦对TGRX-326片药代动力学的影响。次要研究目的：评价健康受试者口服TGRX-326片以及与伊曲康唑、依非韦伦联合用药的安全性。评价TGRX-326片单次给药以及与伊曲康唑合并用药后对健康受试者QTc间期的影响。

[Translation]

Main study objectives: To evaluate the effects of oral administration of itraconazole, a strong CYP3A inhibitor, and efavirenz, a moderate CYP3A inducer, on the pharmacokinetics of TGRX-326 tablets in healthy subjects. Secondary study objectives: To evaluate the safety of oral administration of TGRX-326 tablets and its combination with itraconazole and efavirenz in healthy subjects. To evaluate the effects of single administration of TGRX-326 tablets and its combination with itraconazole on the QTc interval in healthy subjects.

Start Date28 Feb 2024

Sponsor / Collaborator

Shenzhen TargetRx, Inc.Startup

100 Clinical Results associated with Efavirenz

100 Translational Medicine associated with Efavirenz

100 Patents (Medical) associated with Efavirenz

5,239

Literatures (Medical) associated with Efavirenz

10 Dec 2024·STATISTICS IN MEDICINE

Causal Inference for Continuous Multiple Time Point Interventions

Article

Author: Díaz, Iván ; Denti, Paolo ; Schomaker, Michael ; McIlleron, Helen

ABSTRACT:

There are limited options to estimate the treatment effects of variables which are continuous and measured at multiple time points, particularly if the true dose–response curve should be estimated as closely as possible. However, these situations may be of relevance: in pharmacology, one may be interested in how outcomes of people living with—and treated for—HIV, such as viral failure, would vary for time‐varying interventions such as different drug concentration trajectories. A challenge for doing causal inference with continuous interventions is that the positivity assumption is typically violated. To address positivity violations, we develop projection functions, which reweigh and redefine the estimand of interest based on functions of the conditional support for the respective interventions. With these functions, we obtain the desired dose–response curve in areas of enough support, and otherwise a meaningful estimand that does not require the positivity assumption. We develop ‐computation type plug‐in estimators for this case. Those are contrasted with g‐computation estimators which are applied to continuous interventions without specifically addressing positivity violations, which we propose to be presented with diagnostics. The ideas are illustrated with longitudinal data from HIV positive children treated with an efavirenz‐based regimen as part of the CHAPAS‐3 trial, which enrolled children years in Zambia/Uganda. Simulations show in which situations a standard g‐computation approach is appropriate, and in which it leads to bias and how the proposed weighted estimation approach then recovers the alternative estimand of interest.

01 Dec 2024·Lancet Global Health

Cost-effectiveness of viral load testing for transitioning antiretroviral therapy-experienced children to dolutegravir in South Africa: a modelling analysis

Article

Author: Hyle, Emily P ; Davies, Mary-Ann ; Horsfall, Stephanie B ; Desmonde, Sophie ; Collins, Intira Jeannie ; Abrams, Elaine ; Crichton, Siobhan ; Freedberg, Kenneth A ; Ciaranello, Andrea L ; Bacha, Jason ; Penazzato, Martina ; Brenner, Isaac Ravi ; Webb, Karen A ; Flanagan, Clare F ; Neilan, Anne M

BACKGROUND:

For children with HIV on antiretroviral therapy (ART), transitioning to dolutegravir-containing regimens is recommended. The aim of this study was to assess whether introducing viral load testing to inform new nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) for children with HIV and viraemia alongside dolutegravir-based ART is beneficial and of good economic value.

METHODS:

We used the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model to project clinical and cost implications of three strategies among a simulated cohort of South African children aged 8 years with HIV receiving abacavir-lamivudine-efavirenz: (1) continue current ART (no dolutegravir; abacavir-lamivudine-efavirenz); (2) transition all children with HIV to dolutegravir, keeping current NRTIs (dolutegravir; abacavir-lamivudine-dolutegravir); or (3) transition to dolutegravir based on viral load testing (viral load plus dolutegravir), keeping current NRTIs if virologically suppressed (abacavir-lamivudine-dolutegravir, 70% of cohort) or switching abacavir to zidovudine (zidovudine) if viraemic (zidovudine-lamivudine-dolutegravir, 30%). We assumed 50% of children who had viraemia after abacavir-lamivudine exposure had NRTI resistance; with resistance, we assumed zidovudine-lamivudine-dolutegravir was more effective than abacavir-lamivudine-dolutegravir. We designated a strategy as preferred if it was most effective and least costly or had an incremental cost-effectiveness ratio less than half the South African 2020 gross domestic product per capita.

FINDINGS:

Under base-case assumptions, the viral load plus dolutegravir strategy would be the most effective (projected undiscounted life expectancy of 39·72 life-years) and least costly strategy (US$24 600 per person); the no dolutegravir strategy was the least effective (34·49 life-years) and most expensive ($26 480 per person). In sensitivity analyses, the 24-week virological suppression probability and subsequent monthly virological failure risks (ie, late failure) were most influential on cost-effectiveness. Only with a high late-failure risk for zidovudine-lamivudine-dolutegravir (ie, ≥0·3% per month in the base case or >0·5% per month if abacavir also confers low virological suppression probability in the presence of NRTI resistance [65%]) would the dolutegravir strategy become preferred above the viral load plus dolutegravir strategy.

INTERPRETATION:

For programmes transitioning to dolutegravir-based regimens, our model predicted that doing so would be more effective and less costly than continuing current ART regimens, regardless of NRTI choice. Whether viral load testing for children with HIV is necessary to inform NRTI choice depends substantially on the comparative outcomes of abacavir and zidovudine after switching to dolutegravir-containing ART.

FUNDING:

The Eunice Kennedy Shriver Institute for Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the Massachusetts General Hospital Executive Committee on Research, the Massachusetts General Hospital, and the Medical Research Council.

01 Dec 2024·Journal of the International AIDS Society

Impact of switching to a dolutegravir‐based regimen on body weight changes: insights from West African adult HIV cohorts

Article

Author: Tiendrebeogo, Thierry ; Ezechi, Oliver ; Ofotokun, Igho ; Minga, Albert ; Malateste, Karen ; Poda, Armel ; Jaquet, Antoine ; Ekouevi, Didier K. ; Lahiri, Cecile D.

Abstract:

Introduction:

Adverse metabolic effects related to dolutegravir (DTG) are increasingly reported as countries are adopting DTG‐based regimens as first‐line antiretroviral therapy (ART), but there is limited data from sub‐Saharan Africa. We explored changes in body weight pre‐ and post‐switch to a DTG‐based regimen and assessed the association between DTG switch and significant weight gain (SWG) defined as a ≥10% increase over a 12‐month period in people living with HIV (PLHIV) on ART in West Africa.

Methods:

We first included all PLHIV followed in the IeDEA West Africa cohorts between January 2017 and June 2021, with a documented switch to DTG during 2019–2021 and in care ≥36 months at the day of switch. Weight change was estimated using a two slope piecewise linear mixed model with change point at the switch date. Secondly, we emulated a sequence of target trials (ETT) based on the observational data, performing pooled logistic regression analysis to compare SWG occurrence between PLHIV who switched to DTG and those who did not.

Results:

We first included 6705 PLHIV from Burkina Faso, Côte d'Ivoire and Nigeria. Their median age at the time of switch was 48 years (IQR: 42–54) with a median follow‐up of 9 years (IQR: 6–12), 63% were female. Most patients switched from efavirenz (EFV)‐based ART (56.6%) and nevirapine (NVP)‐based ART (30.9%). The overall post‐switch annual average weight gain (AAWG) was significantly elevated at 3.07 kg/year [95% CI: 2.33–3.80] compared to the pre‐switch AWG which stood at 0.62 kg/year [95% CI: 0.36–0.88]. The post‐switch AWG was greater in patients previously on EFV and protease inhibitor (PI)‐based ART compared to those on NVP‐based ART. The pooled logistic regression analyses of a sequence of 24 ETT, including 9598 person‐trials, switching to DTG was significantly associated with an SWG (aOR = 2.54; 95% CI = 2.18–2.97).

Conclusions:

In West Africa, a 12‐month DTG exposure was associated with substantial weight gain, especially in PLHIV previously on EFV and PI‐based ARTs. Continuous weight monitoring and metabolic profiling is imperative in HIV cohorts to delineate the long‐term cardiometabolic impact of DTG as patients with, or at elevated risk for cardiovascular diseases might benefit from alternative ART regimens.

News (Medical) associated with Efavirenz

22 Oct 2024

·www.biospace.com

Gilead to Present Latest Research Across Key Liver Disease Indication at the American Association for the Study of Liver Disease (AASLD) Meeting 2024

- Key Insights from Viral Hepatitis, PBC, and MASH/Fibrosis Studies Highlight Gilead’s Ongoing Commitment to Advancing Life-Changing Liver Disease Research - FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new research to be presented at The Liver Meeting ® 2024, hosted by the American Association for the Study of Liver Diseases (AASLD) from November 15-19 in San Diego, Calif. More than 40 abstracts will be presented with key data, including 11 abstracts reporting new data on primary biliary cholangitis (PBC). The data will include findings from the RESPONSE trial that demonstrate the efficacy and safety pro Livdelzi ® (seladelpar) in people living with PBC and compensated cirrhosis. Additionally, data will be presented on the effects of Livdelzi on pruritus (chronic itching), a symptom that has significant impact on the quality of life of people living with PBC, along with interim long-term efficacy and safety results from the ongoing ASSURE study. Beyond PBC, Gilead will be presenting an interim analysis of the Phase 3 MYR301 study, which is evaluating people living with hepatitis Delta virus (HDV) who received bulevirtide monotherapy (2 mg for 144 weeks; 10 mg for 144 weeks; or 10 mg for 96 weeks) for chronic HDV and have been off treatment for 48 weeks. The study is evaluating whether or not patients treated with bulevirtide monotherapy for 2-3 years maintained virological and biochemical responses one year after stopping treatment. An additional 144-week analysis of patient-reported outcomes for individuals treated with bulevirtide 2 mg will also be presented, adding to the wealth of long-term data for the treatment for chronic HDV. “We’re excited to share our latest research at The Liver Meeting, as we push the boundaries of what’s possible in liver disease treatment. The breadth of this research reflects Gilead’s unwavering dedication to advancing life-changing science and shaping healthier futures for people living with liver disease,” said Anu Osinusi, Vice President of Clinical Development for Hepatitis, Respiratory and Emerging Viruses, Gilead Sciences. “The depth and range of our data, spanning both viral and inflammatory liver diseases, underscores our commitment to making a meaningful impact at every stage of a person’s journey in liver disease. Our goals go far beyond treatment alone—our work spans awareness, education, screening, diagnosis, and long-term care, all intending to address unmet needs and enhance treatment outcomes.” Gilead will also present hepatitis C virus (HCV) data which will include safety and tolerability outcomes for Epclusa ® (velpatasvir/sofosbuvir) in pregnant individuals with chronic HCV (the STORC study). As a special population that is often excluded from clinical research, these results may help clinicians better support pregnant people living with HCV, which in turn may reduce the risk of transmission to infants. Furthermore, real-world findings from the SVR10K study on HCV will be showcased, demonstrating the effects of direct-acting antivirals against all HCV genotypes across diverse regions. Late-breaking data from a Phase 2a open-label study assessing the safety and efficacy of novel combination therapies for chronic hepatitis B virus (HBV) will also be presented by Gilead. Key Abstracts at AASLD 2024: ID Abstract Title PBC 164 Efficacy and Safety of Seladelpar in Patients with PBC and Compensated Cirrhosis in the Phase 3 Placebo-controlled RESPONSE Trial 167 Attenuation, Near Resolution, and Prevention of Pruritis in Patients with PBC Treated with Seladelpar: A Secondary Analysis of Patterns of Pruritis Change in the RESPONSE Trial 4339 Alkaline Phosphatase Changes with Seladelpar Across Subgroups of Primary Biliary Cholangitis Patients in the RESPONSE Trial 4342 Seladelpar and Reductions in Lipids in Patients with Primary Biliary Cholangitis with and without Statin use in the Phase 3 Placebo-controlled RESPONSE Study 4341 Long-term Safety of Seladelpar 10 mg with up to 5 Years of Treatment in Patients with Primary Biliary Cholangitis Primary sclerosing cholangitis (PSC) 151 Associations Between Biomarkers and Magnetic Resonance Imaging-derived ANALI Score in Patients with Primary Sclerosing Cholangitis: Analysis from the Phase 3 PRIMIS Study HDV 1147 Efficacy and Safety of BLV Monotherapy for Chronic Hepatitis Delta: Post Treatment Results through 48 Weeks after the End of Treatment from an Interim Analysis of a Randomized Phase 3 Study MYR301 1193 Patient-reported Outcomes among Patients with Chronic Hepatitis Delta Treated with Bulevirtide 2 mg: A Long-term Analysis of the Phase 3 MYR301 Trial at 144 Weeks 139 Long-term Bulevirtide Monotherapy in Patients with HDV-related Compensated Cirrhosis: Effectiveness, Safety and Clinical Outcomes from the Retrospective Multicenter European Study (SAVE-D) HCV 222 Safety, Tolerability, and Outcomes of Velpatasvir/Sofosbuvir in Treatment of Chronic Hepatitis C Virus during Pregnancy (STORC) 1455 The SVR10K Study: A Real-world Data with Pangenotypic Direct-acting Antivirals across Multiple Diverse Regions 1476 Hepatitis C Treatment Uptake Differs by Gender among a Commercially Insured Population in the United States HBV 1380 Results from a Phase 2a, Open-label Study to Evaluate the Safety and Efficacy of Novel Combination Therapies Containing VIR-2218, Selgantolimod, and Nivolumab for the Treatment of Chronic Hepatitis B 1252 Effectiveness and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Suboptimal Response to Antiviral Therapy 1337 Characterization of Changes in Noninvasive Fibrosis Markers over 8 Years of Tenofovir-based Treatment in Chronic Hepatitis B Patients Enrolled in Two Phase 3 Trials Nonalcoholic steatohepatitis (NASH)/Fibrosis 1520 Prospective Validation of the Mediterranean Diet Adherence Screener (MEDAS) for Point-of-care Assessment of Diet Quality in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease For more information, including a complete list of abstract titles being presented at the meeting, please visit the AASLD website . In July 2023, the European Commission (EC) granted full Marketing Authorization (MA) for bulevirtide 2 mg for the treatment of adults with chronic HDV and compensated liver disease. Bulevirtide’s conditional MA license in Great Britain was converted to a full MA in August 2023 and a full MA was granted in Switzerland and Australia in 2024. In regions where it is not approved, including the U.S., bulevirtide 2 mg is an investigational product. In these regions, health authorities have not established the safety and efficacy of bulevirtide. Bulevirtide 10 mg is an investigational product and has not been approved anywhere. Cilofexor and selgantolimod are investigational compounds and are not approved by the FDA or any other regulatory authority; their safety and efficacy have not been established. Please see below for the U.S. Indications and Important Safety Information, including BOXED WARNINGS, for Epclusa and Livdelzi. U.S. Important Safety Information And Indication for EPCLUSA BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Contraindications If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. Warnings and Precautions Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers and/or Moderate to Strong Inducers of CYP2B6, CYP2C8 or CYP3A4 : Rifampin, St. John’s wort and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations. Adverse Reactions The most common adverse reactions (≥10%, all grades) with EPCLUSA in adults and pediatric patients 6 years of age and older were headache and fatigue; and when used with RBV in adults with decompensated cirrhosis were fatigue, anemia, nausea, headache, insomnia and diarrhea. The most common adverse reactions (≥10%, grade 1 or 2) in pediatric patients less than 6 years of age were vomiting and spitting up the drug. Drug Interactions Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan. Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir. Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments. Indication EPCLUSA is indicated for the treatment of adult and pediatric patients 3 years of age and older with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis. U.S. Important Safety Information for LIVDELZI Warnings and Precautions Fractures: Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care. Liver Test Abnormalities: LIVDELZI has been associated with dose-related increases in serum transaminase (AST and ALT) levels > 3 x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting LIVDELZI and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI. Biliary Obstruction: Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated. Adverse Reactions The most common adverse reactions (≥5%) with LIVDELZI were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%). Drug Interactions OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid coadministration with LIVDELZI due to increased LIVDELZI exposure. Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Coadministration may result in delayed or suboptimal biochemical response of LIVDELZI. Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (eg, cyclosporine): Monitor closely for adverse effects. Concomitant administration with LIVDELZI may increase LIVDELZI exposure. CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase LIVDELZI exposure and risk of LIVDELZI adverse reactions. Bile Acid Sequestrants: Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible. Pregnancy and Lactation Pregnancy: There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235. Lactation: There are no data on the presence of LIVDELZI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI. Indication LIVDELZI is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). About HDV HDV is considered the most aggressive or severe form of viral hepatitis, associated with more rapid progression towards liver-related death and liver cancer in people with HBV. On average, HDV progresses to cirrhosis within 5 years and to liver cancer within 10 years. Nearly 5% of people who have a chronic infection with HBV are estimated to have HDV, equating to 12-15 million people worldwide. The prevalence of HDV infection is largely underestimated due to lack of universal testing of HBV-positive individuals for HDV. About PBC PBC is a rare, chronic inflammatory liver disease primarily affecting women (1 in 1,000 women over the age of 40 or about 130,000 total people in the U.S.). PBC is characterized by impaired bile flow (known as cholestasis) and the accumulation of toxic bile acids in the liver, leading to inflammation and destruction of the bile ducts within the liver and causing increased levels of alkaline phosphatase (ALP), alanine transaminase (ALT) and gamma-glutamyl transferase (GGT), enzymes found primarily in the liver, as well as total bilirubin. The most common symptoms of PBC are pruritus and fatigue, which can be debilitating for some people. Progression of PBC is associated with an increased risk of liver-related mortality. About Gilead Sciences in Liver Disease For decades, Gilead has pioneered the way forward to improve the lives of people living with liver disease around the world. We have helped to transform hepatitis C from a chronic condition into one that can be cured for millions of people. For people living with hepatitis B or D, our focus on advancing our medicines drives hope that today’s research will turn into tomorrow’s cures. Beyond viral hepatitis, we’re working to deliver advanced treatments for people living with PBC. But our commitment doesn’t stop there. Through our ground-breaking science and collaborative partnerships, we strive to create healthier futures for everyone living with liver disease. We are committed to a future without liver disease. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials or studies, including those involving Epclusa, Hepcludex (bulevirtide), Livdelzi (seladelpar), cilofexor and selgantolimod (such as the ASSURE, RESPONSE, MYR301, STORC and SVR10K studies); uncertainties relating to regulatory applications and related filing and approval timelines, including the risk that the FDA and other regulatory authorities may not approve bulevirtide for the treatment of HDV, and the risk that any such approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of investigational programs for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Epclusa, Hepcludex, Livdelzi, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at , follow Gilead on Twitter (@Gilead Sciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. Contacts Meaghan Smith, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

Phase 2Clinical ResultDrug ApprovalPhase 3

23 Jul 2024

·www.businesswire.com

ViiV Healthcare announces positive data demonstrating 2-drug regimen Dovato is as effective as 3-drug regimen Biktarvy for maintenance therapy of HIV-1

LONDON--( BUSINESS WIRE )--ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer and Shionogi as shareholders, announces 48-week findings from PASO DOBLE (GeSIDA 11720 study), the largest head-to-head, phase IV randomised clinical trial (RCT) investigating the 2-drug regimen Dovato (dolutegravir/lamivudine [DTG/3TC]) compared to the 3-drug regimen Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide fumarate [BIC/FTC/TAF]) for the treatment of HIV-1 in people who are virologically suppressed and who could benefit from treatment optimisation. 1 Findings showed that switching to DTG/3TC in virologically suppressed adults living with HIV demonstrated non-inferior efficacy in maintaining viral suppression compared with switching to BIC/FTC/TAF. 1 These data will be presented at the 25 th International AIDS Conference (AIDS 2024), held in Munich, Germany (22-26 July). Harmony P. Garges, M.D., MPH, Chief Medical Officer at ViiV Healthcare, said: “ The results from PASO DOBLE show that Dovato demonstrated non-inferior efficacy compared to Biktarvy , and that the average weight gain for trial participants taking DTG/3TC was significantly lower than those taking BIC/FTC/FTC over the course of the year. This is a meaningful outcome, as treatment-related weight gain is an important topic for many people living with HIV. At ViiV Healthcare we're dedicated to bringing innovative HIV treatments to people living with HIV that are not only safe and effective, but also address their specific needs beyond viral suppression.” In the PASO DOBLE clinical trial, 553 people living with HIV and virally suppressed switched treatment to either DTG/3TC (n=277) or BIC/FTC/TAF (n=276). 1 The study population included individuals who were on therapy that could be optimised, such as multiple tablet regimens, or those containing pharmacokinetic boosting agents or drugs with cumulative toxicity, such as efavirenz or tenofovir disoproxil fumarate (TDF). 2 The study met its primary endpoint when DTG/3TC demonstrated non-inferior efficacy versus BIC/FTC/TAF based on the proportion of participants with viral RNA ≥50 copies/mL at 48 weeks using the FDA snapshot and a 4% non-inferiority margin in the exposed intention-to-treat population. 1 At 48 weeks, DTG/3TC was non-inferior to BIC/FTC/TAF (risk difference between DTG/3TC [2.2%] minus BIC/FTC/TAF [0.7%] of 1.4%, 95% CI -0.5 to 3.4). One participant in the BIC/FTC/TAF arm and zero in the DTG/3TC arm had protocol-defined confirmed virological failure through week 48 (HIV-1 RNA ≥50 c/mL followed by a second consecutive HIV-1 RNA assessment ≥200 c/mL). 1 The study found in a key secondary endpoint that weight increased significantly more in participants who switched to BIC/FTC/TAF (adjusted mean change 1.81kg, 95% CI 1.28-2.34) than in those who switched to DTG/3TC (adjusted mean change 0.89kg, 95% CI 0.37-1.41) [difference 0.92kg, 95% CI 0.17-1.66] through week 48. Equally, the proportion of participants with weight gain greater than 5% at week 48 was significantly higher at 29.9% for BIC/FTC/TAF compared to 20% for DTG/3TC (adjusted OR 1.81, 95% CI 1.19-2.76). 1 Weight change with DTG/3TC did not differ between men and women or based on the previous regimen of participants, whereas the proportion of trial participants experiencing greater than 5% weight gain with BIC/FTC/TAF was approximately 45% higher than those taking DTG/3TC when switching from a regimen with abacavir (30.6% BIC/FTC/TAF vs 21.1% DTG/3TC), and about 2-fold higher when switching from a regimen with TDF (40.7% BIC/FTC/TAF vs 19.5% DTG/3TC). Safety was comparable through week 48 and consistent with known safety profiles. There were few discontinuations due to adverse events in both study arms (DTG/3TC = 1, 0.4%; BIC/FTC/TAF = 2, 0.7%), with no differences between arms. 1 Esteban Martínez, MD, PhD, Chief Executive Investigator of the PASO DOBLE study and Senior Consultant in Infectious Diseases at Hospital Clínic of Barcelona, Spain said: “ The HIV treatment regimens that are commonly prescribed today are all highly effective, which makes it critical that we study the impact of these therapies beyond just viral suppression. The results from PASO DOBLE show Dovato , a 2-drug regimen, not just demonstrated the same efficacy as a 3-drug regimen, but also showed less weight gain compared to BIC/FTC/TAF through 48 weeks.” About PASO DOBLE 1,2 The PASO DOBLE (NCT04884139) randomised clinical trial is a phase IV, open-label, randomised multicentre clinical trial evaluating the efficacy of DTG/3TC versus BIC/FTC/TAF for the maintenance of virologic suppression in people living with HIV-1, conducted in 30 sites across Spain. Virologically suppressed people living with HIV on regimens containing ≥1 pill/day, boosters, or drugs with cumulative toxicity such as efavirenz or TDF were eligible and were randomised (1:1) to switch to either DTG/3TC or BIC/FTC/TAF. The primary endpoint was the proportion of people living with HIV with RNA ≥50 copies/mL at 48 weeks (FDA snapshot, 4% non-inferiority margin) in the intention-to-treat exposed population. Secondary outcomes measured included, among others, absolute weight gain, BMI change, and the proportion of participants with weight change greater than 5%. About Dovato Dovato is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of Dovato . Dovato is approved in the US, Europe, Japan, Australia, and other countries worldwide. Please consult the full Summary of Product Characteristics for all the safety information: Dovato 50 mg/300 mg film-coated tablets . Trademarks are owned by or licensed to the ViiV Healthcare group of companies. About SEIMC-GeSIDA Foundation (FSG) The SEIMC-GeSIDA Foundation (FSG) was created to encourage, promote, and support scientific and technical research and development, training, and publication of findings in the field of clinical microbiology and infectious diseases and associated conditions. FSG was founded by investigators from the Spanish Society of Clinical Microbiology and Infectious Diseases as a tool to promote high-quality investigation in the field of HIV infection and other infectious diseases. The Foundation also aims to respond to the scientific concerns of the group’s members. FSG is composed of qualified professionals with experience in the field of clinical trials and multicentre studies. Its streamlined infrastructure facilitates performance of clinical studies and responds to the needs of investigators in terms of methodology/statistical analysis and of logistics and management of trials and other multicentre studies. We also provide staff to run events such as scientific meetings and conferences (national and international) and to organise courses, lectures, talks, seminars, round-table talks, and specialised workshops. For more information on the FSG, please visit https://fundacionseimcgesida.org/en/quienes-somos/ About ViiV Healthcare ViiV Healthcare is a global specialist HIV company established in November 2009 by GSK (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 acquiring HIV. Shionogi became a ViiV shareholder in October 2012. The company’s aims are to take a deeper and broader interest in HIV and 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 viivhealthcare.com. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.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 “Risk factors” in GSK’s Annual Report on Form 20-F for 2023, and GSK’s Q1 Results for 2024. Registered in England & Wales: GSK plc No. 3888792 ViiV Healthcare Limited No. 06876960 Registered Office: GSK plc 980 Great West Road Brentford, Middlesex United Kingdom TW8 9GS ViiV Healthcare Limited GSK Medicines Research Centre Gunnels Wood Road, Stevenage United Kingdom SG1 2NY References 1 P. Ryan, et al. Non-inferior efficacy and less weight gain when switching to DTG/3TC than when switching to BIC/FTC/TAF in virologically suppressed people with HIV (PWH): the PASODOBLE (GeSIDA 11720) randomised clinical trial. Presented at the 25th International AIDS Conference. July 2024 2 Clinical Trials.gov - DTG/3TC vs. BIC/FTC/TAF Maintenance Therapy in People Living With HIV: (PASO-DOBLE). Available at https://clinicaltrials.gov/ct2/show/NCT04884139 . Last accessed July 2024

Clinical ResultPhase 3Drug Approval

23 Jul 2024

·firstwordpharma.com

GSK's Dovato holds its ground against Biktarvy in HIV treatment face-off

As HIV drug developers seek to differentiate their therapies beyond viral suppression, ViiV Healthcare has launched a new offensive in the battle for market dominance.On Tuesday, GSK's HIV-focused unit reported results from a head-to-head trial showing that its two-drug regimen Dovato (dolutegravir/lamivudine) not only demonstrated non-inferiority against Gilead Sciences' three-drug regimen heavyweight Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) as a maintenance therapy for HIV, but also suggested an ability to mitigate treatment-related weight gain.The Phase IV PASO DOBLE study enrolled 553 virologically suppressed adults living with HIV who were randomised to switch to either Dovato or Biktarvy. Those on regimens containing at least one pill a day, boosters or drugs with cumulative toxicity such as efavirenz or tenofovir disoproxil fumarate (TDF) were eligible to participate.The trial met its primary endpoint, demonstrating that Dovato was non-inferior to Biktarvy in maintaining viral suppression over 48 weeks of therapy.Specifically, 2.2% of participants in the Dovato arm had viral RNA ≥50 copies/mL at the 48-week mark, compared to 0.7% in the Biktarvy arm, according to results presented at the International AIDS Conference underway this week. The difference of 1.4% between the groups fell well within the predefined 4% non-inferiority margin.ViiV said one participant in the Biktarvy arm and none in the Dovato arm experienced protocol-defined confirmed virological failure over the 48-week timeframe.Weight gain gapMeanwhile, the study's key secondary endpoint revealed a significant difference in weight gain between the two regimens. Participants who switched to Biktarvy experienced an adjusted weight increase of 1.81 kg on average, compared to 0.89 kg among those who switched to Dovato. Moreover, a higher proportion of Biktarvy-treated participants (29.9%) experienced weight gain >5% compared to those on Dovato (20%), a difference that was also statistically significant."The HIV treatment regimens that are commonly prescribed today are all highly effective, which makes it critical that we study the impact of these therapies beyond just viral suppression," commented Esteban Martínez, chief executive investigator of the PASO DOBLE study. Harmony Garges, chief medical officer at ViiV, said "this is a meaningful outcome, as treatment-related weight gain is an important topic for many people living with HIV."The safety profiles were comparable between the two regimens, with few dropouts due to adverse events in both study arms; one patient in the Dovato arm discontinued, versus two on Biktarvy.Dovato generated sales of £1.8 billion ($2.3 billion) in 2023, up 32% from the previous year. Meanwhile, Biktarvy, Gilead's top-selling product, reached sales of $11.8 billion last year, up 14% from 2022.

Clinical ResultPhase 3Phase 2

100 Deals associated with Efavirenz

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KEGG	Wiki	ATC	Drug Bank
D00896	Efavirenz	J05AG03	DB00625

R&D Status

Approved

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Indication	Country/Location	Organization	Date
HIV Infections	US	Bristol Myers Squibb Co.	17 Sep 1998

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Phase 3	BR	Merck Sharp & Dohme Corp.	11 Sep 2015
Tuberculosis	Phase 3	CI	Merck Sharp & Dohme Corp.	11 Sep 2015
Tuberculosis	Phase 3	FR	Merck Sharp & Dohme Corp.	11 Sep 2015
Tuberculosis	Phase 3	MZ	Merck Sharp & Dohme Corp.	11 Sep 2015
Tuberculosis	Phase 3	VN	Merck Sharp & Dohme Corp.	11 Sep 2015
Coinfection	Phase 2	-	Abbott Laboratories	21 Jul 2005
Hepatitis C	Phase 2	-	Abbott Laboratories	21 Jul 2005
Acquired Immunodeficiency Syndrome	Phase 1	US	Bristol Myers Squibb Co.	01 Jul 2014
Contraception	Phase 1	US	Bristol Myers Squibb Co.	01 May 2007
Liver Diseases	Phase 1	US	Bristol Myers Squibb Co.	01 Nov 2004

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02777229 (NAMSAL-ANRS-12313, Pubmed \| Open Forum Infect Dis)	Phase 3	HIV Infections First line	613	Dolutegravir (DTG) 50mg with Tenofovir disoproxil fumarate and Lamivudine (TDF/3TC)	mhgomhkifo(bpvdeergwa) = ojuksmyqrm mgccdagobi (wugsndcbjl ) View more	Positive	01 Dec 2023
				Efavirenz 400 mg (EFV400) with Tenofovir disoproxil fumarate and Lamivudine (TDF/3TC)	mhgomhkifo(bpvdeergwa) = gefdeegyvg mgccdagobi (wugsndcbjl ) View more
NCT02777229 (NAMSAL ANRS 12313, Pubmed)	Phase 3	First line	613	Dolutegravir 50 mg (DTG)	cyoomaquha(ngyckopoeb) = decreased from 7.2 to 3.0 gjnrbqefne (qivclaeutl ) View more	Positive	01 Nov 2023
				Low-dose efavirenz (EFV400)
NCT04459598 (CTgov)	Phase 1	Medication interactions	32	Efavirenz+Quizartinib (Efavirenz 600 mg + Quizartinib 60 mg)	kvejzwudjg(lpbuyigvee) = bswildttwq llnjrlzecc (aylbwmfaqx, deifaxkoba - dfrazokqdb) View more	-	06 Jun 2022
				Quizartinib (Quizartinib 60 mg)	kvejzwudjg(lpbuyigvee) = ckvbehtaxk llnjrlzecc (aylbwmfaqx, hpjhceibob - tgxlofftit) View more
NCT00964002 (FAVE, CTgov)	Phase 2	Castration-Resistant Prostatic Cancer \| Metastatic Prostate Carcinoma	61	efavirenz	ezcbjigxnk(mnouopxdgt) = kuhjpsppgj zbfqdlrptf (msmddkmbob, ebypytvibj - lqyhwshiln) View more	-	16 May 2022
IAS2022	Not Applicable	Acquired Immunodeficiency Syndrome	92	Efavirenz-based regimens	znllohgggf(hnwzbmxfkc) = ttwguqbzmq waxckcbrkj (wygwkdxjmx ) View more	-	01 Jan 2022
				Dolutegravir-based ART	znllohgggf(hnwzbmxfkc) = nafyavfjww waxckcbrkj (wygwkdxjmx ) View more
NCT02273765 (Pubmed) Manual	Phase 3	Tuberculosis \| HIV Infections	460	Tenofovir Disoproxil Fumarate+lamivudine+raltegravir	objyvpidng(qjthfppnbv) = njsgbjnbkb bmypvvyjmo (sfrmbjrrff ) View more	Negative	01 Jun 2021
				Tenofovir Disoproxil Fumarate+lamivudine+efavirenz	objyvpidng(qjthfppnbv) = kckyeqbpqm bmypvvyjmo (sfrmbjrrff ) View more
NCT01878890 (ESCALE, CTgov)	Phase 1	Solid tumor \| Non-Hodgkin Lymphoma	25	Efavirenz 600mg (Efavirenz: 600 mg)	qqlrbxapxc(mkbpjzlaso) = ristirpshw pdfmednnxu (unnlldwkyu, cbpwyahrrf - dtehcurbzi) View more	-	27 Jan 2021
				Efavirenz 1200 mg (Efavirenz: 1200 mg)	qqlrbxapxc(mkbpjzlaso) = sgagupbwyh pdfmednnxu (unnlldwkyu, odpgghrsvh - rmtafmqipv) View more
NCT02777229 (NAMSAL, Pubmed \| Lancet HIV)	Phase 3	HIV Infections	820	Dolutegravir 50 mg	khenjfrfcy(iilfsekxjr) = arrppborlm jjcoivntde (dagdntjblv )	Positive	01 Oct 2020
				Efavirenz 400 mg	khenjfrfcy(iilfsekxjr) = vmjhdnbrdz jjcoivntde (dagdntjblv )
EASD2020	Not Applicable	-	-	Palmitate	shwoziinlf(ifzldxyzzq) = ircbwskidv szqhuolfgi (bqybhvxhux, 0.07)	Negative	24 Sep 2020
				Efavirenz	shwoziinlf(ifzldxyzzq) = iecpamoocb szqhuolfgi (bqybhvxhux, 0.5)
ANRS 12300 (IAS2020)	Not Applicable	Tuberculosis \| HIV Infections	460	Raltegravir 400mg BID	xtoiftlzrq(gpgmkogtmr) = trchusdmba mhguwlexkx (spoaptghfp )	Negative	01 Jan 2020
				Efavirenz 600mg QD	xtoiftlzrq(gpgmkogtmr) = vowbnclqdv mhguwlexkx (spoaptghfp )

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