FDA Approves Dovato (dolutegravir/lamivudine) for HIV-1 Infection

In continuation of my update on Dolutegravir & Lamivudine

Dolutegravir (DTG)

Lamivudine, commonly called 3TC

ViiV Healthcare  announced the US Food and Drug Administration (FDA) approval of Dovato, a complete, once-daily, single-tablet regimen of dolutegravir (DTG) 50 mg and lamivudine (3TC) 300 mg for the treatment of HIV-1 infection in adults with no antiretroviral (ARV) treatment history and with no known resistance to either DTG or 3TC. Dovato, a two-drug regimen (2DR), reduces exposure to the number of ARVs from the start of treatment, while still maintaining the efficacy and high barrier to resistance of a traditional DTG-based three-drug regimen.

Deborah Waterhouse, CEO, ViiV Healthcare, said: “Building on our innovative portfolio of medicines, Dovato is powered by dolutegravir, an antiretroviral included in multiple combination therapies and the most prescribed integrase inhibitor in the world, 2 coupled with the established profile of lamivudine. With Dovato, the first complete, single-tablet, two-drug regimen for treatment-naïve adults, ViiV Healthcare is delivering what patients are requesting—a chance to treat their HIV-1 infection with as few drugs as possible, marking a significant step in HIV treatment.”

The approval of Dovato is supported by the landmark global GEMINI 1 and 2 studies that included more than 1,400 HIV-1 infected adults. In these studies, DTG + 3TC demonstrated non-inferiority based on plasma HIV-1 RNA <50 copies per milliliter (c/mL), a standard measure of HIV-1 control, at Week 48 when compared to a three-drug regimen of DTG and two nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), in treatment-naïve, HIV-1 infected adults. The safety results for DTG + 3TC seen in GEMINI 1 and 2 were consistent with the product labelling for DTG and 3TC. No patient who experienced virologic failure in either treatment arm developed treatment-emergent resistance.

Pedro Cahn, principal investigator for the GEMINI study program said: “People are now living longer with HIV and will spend a lifetime taking drugs to suppress their virus. The approval of the fixed dose combination of dolutegravir and lamivudine, a complete, single-tablet, two-drug regimen, marks a pivotal moment in the treatment of HIV-1. Treatment-naïve people living with the virus have a powerful option that delivers non-inferior efficacy to a dolutegravir-based three-drug regimen, allowing them to take fewer ARVs and get and remain suppressed.”

Jeff Berry, Test Positive Aware Network (TPAN), said: “The approval of Dovato is a welcome paradigm shift, as it brings an innovative treatment approach to newly diagnosed adults with HIV-1. By exposing patients to fewer drugs at the start of treatment, the hope is to help address concerns arising from overall management of prolonged ARV therapy.”

DTG/3TC as a complete, once-daily, single-tablet, two-drug regimen for HIV-1 therapy is currently under review by the European Medicines Agency (EMA) and regulatory authorities in Canada, Australia, Switzerland, and South Africa and several additional submissions are planned throughout 2019.

About Dovato (dolutegravir/lamivudine)

Dovato is approved as a complete regimen for the treatment of HIV-1 infection in adults with no known antiretroviral treatment history and with no known substitutions associated with resistance to either dolutegravir or lamivudine. Dovato is a once-daily, single-tablet, two-drug regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir (Tivicay, 50 mg) with the nucleoside analogue reverse transcriptase inhibitor (NRTI) lamivudine (Epivir, 300 mg).

Like a DTG-based three-drug regimen, Dovato uses only two drugs to inhibit the viral cycle at two different sites. INSTIs, like dolutegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Lamivudine is an NRTI that works by interfering with the conversion of viral RNA into DNA which in turn stops the virus from multiplying.

https://en.wikipedia.org/wiki/Dolutegravir
https://en.wikipedia.org/wiki/Lamivudine

FDA Approves Merck’s Pifeltro (doravirine) for the Treatment of HIV-1 in Appropriate Patients

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Pifeltro (doravirine, 100 mg), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines. Pifeltro is indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and is administered orally once daily with or without food. Pifeltro does not cure HIV-1 infection or AIDS.

The FDA also approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).

Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.

FDA Approves Merck’s Pifeltro (doravirine) for the Treatment of HIV-1 in Appropriate Patients

Merck,  known as MSD outside the United States and Canada,  announced that the U.S. Food and Drug Administration (FDA) has approved Pifeltro (doravirine, 100 mg), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines. Pifeltro is indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and is administered orally once daily with or without food. Pifeltro does not cure HIV-1 infection or AIDS.

The FDA also approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).

Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.

FDA Approves Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Appropriate Patients

In continuation of my update on Lamivudine and Tenofovir


    




doravirine                                 Lamivudine                                             Tenofovir

Merck  known as MSD outside the United States and Canada, announced that the U.S. Food and Drug Administration (FDA) has approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg) for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience. Delstrigo is administered orally once daily with or without food. Delstrigo contains a boxed warning regarding post-treatment acute exacerbation of hepatitis B (HBV) infection. Delstrigo does not cure HIV-1 infection or AIDS.

The FDA also approved Pifeltro (doravirine, 100 mg), the new non-nucleoside reverse transcriptase inhibitor (NNRTI) contained in Delstrigo, for administration in combination with other antiretroviral medicines.

Delstrigo is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Delstrigo. Delstrigo is contraindicated in patients with a previous hypersensitivity reaction to 3TC. For more information, see “Selected Safety Information” below.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. Delstrigo should be avoided with concurrent or recent use of a nephrotoxic agent, as cases of acute renal failure after initiation of high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Data Supporting the Approval of Delstrigo (doravirine 100 mg/3TC 300 mg/TDF 300 mg)

The FDA approvals of Delstrigo and Pifeltro are based on findings from the pivotal, randomized, multicenter, double-blind, active controlled Phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD, evaluating the efficacy and safety of Delstrigo and Pifeltro, respectively, in participants infected with HIV-1 with no antiretroviral treatment history.

FDA Approves Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Appropriate Patients

In continuation of my update on Imbruvica (ibrutinib)

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the U.S. Food and Drug Administration (FDA) approval of Imbruvica (ibrutinib) in combination with rituximab for the treatment of Waldenström’s macroglobulinemia (WM), a rare blood cancer.[1] The approval expands the label for Imbruvica in WM beyond its current approved use as a monotherapy to include combination use with rituximab. This approval represents the first approved non-chemotherapy combination option for the treatment of WM. Imbruvica first received FDA approval in WM as a monotherapy in January 2015 via the Breakthrough Therapy Designation pathway, making it the first FDA-approved therapy for the disease. The expanded label marks the ninth FDA approval for Imbruvica since 2013. Imbruvica is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

The combination of Imbruvica and rituximab provides health care professionals with a new treatment option for patients living with this serious blood cancer,” said Dr. Lia Palomba, hematologist-oncologist at Memorial Sloan-Kettering Cancer Center, New York, and iNNOVATE study investigator. “Before Imbruvica, there were no FDA-approved treatment options for patients with Waldenström’s macroglobulinemia, a disease first acknowledged nearly 75 years ago. Today, Imbruvica continues to provide an important therapeutic approach in the treatment of this complex disease.”

This approval is based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127), the largest Phase 3 study of a non-chemotherapy combination in WM patients. The iNNOVATE study evaluated Imbruvica in combination with rituximab versus placebo plus rituximab in 150 patients with either relapsed/refractory (r/r) disease or previously untreated WM. At a median follow up of 26.5 months, a significant improvement in the Independent Review Committee (IRC)-assessed primary endpoint of progression-free survival (PFS) was seen with Imbruvica plus rituximab when compared with placebo plus rituximab (30-month PFS rates were 82% vs. 28%, respectively). Patients in the Imbruvica plus rituximab treatment arm experienced an 80% reduction in relative risk of disease progression or death compared with patients treated with placebo plus rituximab (hazard ratio=0.20; confidence interval, 0.11-0.38, p<0.0001). The data were presented in an oral session at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, selected for Best of ASCO 2018 Meetings, and simultaneously published in The New England Journal of Medicine.

“Results from iNNOVATE showed significant improvement in progression-free survival at 30 months and demonstrated the superiority of Imbruvica plus rituximab over rituximab monotherapy in Waldenström's macroglobulinemia,” said Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and iNNOVATE lead study investigator. “Based on these results, Imbruvica in combination with rituximab may be considered as a first- and second-line option for appropriate people diagnosed and living with WM.”

“The clinical data generated for Imbruvica plus rituximab in the treatment of Waldenström’s macroglobulinemia offers physicians evidence to consider this combination regimen for newly-diagnosed patients. Today’s approval represents an important milestone for people living with this rare and incurable blood cancer who have limited FDA-approved treatment options,” said Andree Amelsberg, M.D., Vice President of Oncology Medical Affairs at Janssen Scientific Affairs, LLC. “We remain dedicated to a comprehensive clinical development program to explore the full potential of Imbruvica, including in combination with other therapies.”

Warnings and Precautions remain the same: hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity. The most common adverse reactions (occurring in 20% or more of patients) of all grades in patients treated with Imbruvica plus rituximab in the iNNOVATE study were bruising (37%), musculoskeletal pain (35%), hemorrhage (32%), diarrhea (28%), rash (24%), arthralgia (24%), nausea (21%), and hypertension (20%). Grade 3 or 4 infusion-related reactions were observed in 1% of patients treated with Imbruvica plus rituximab.

The recommended dose of Imbruvica for WM is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with rituximab. When administering Imbruvica in combination with rituximab, consider administering Imbruvica prior to rituximab when given on the same day.

Ref : https://en.wikipedia.org/wiki/Ibrutinib

Mylan Introduces Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) Triple Combo Once-Daily HIV Treatment in the U.S.

             

Tenofovir disoproxil fumarate                              Lamivudine                   Efavirenz           

In continuation of my update, on Tenofovir, Lamivudine and Efavirenz

Global pharmaceutical company Mylan N.V.  announced that it will introduce in the U.S. a third cost-saving HIV combination. The U.S. Food and Drug Administration (FDA) approved Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) 600 mg/300 mg/300 mg tablets, a once-daily, single-tablet regimen (STR), indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg.

"As the largest supplier of antiretrovirals by volume in the world, Mylan has a longstanding commitment to expanding affordable access to treatments for people living with HIV," said Mylan CEO Heather Bresch. "As we continue to grow our U.S. portfolio of ARV products, now including Symfi Lo™, Symfi™, and Cimduo™, we are providing access to patients and empowering them to choose the lower-cost ARV treatment option that is right for them."

The introduction of Symfi™ comes after the FDA's recent approval of two Mylan ARVs: Cimduo™ (lamivudine and tenofovir disoproxil fumarate) 300 mg/300 mg tablets, a once-daily combination of two nucleo(t)side reverse transcriptase inhibitors, which is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 35 kg.; and Symfi Lo™ (efavirenz, lamivudine and tenofovir disoproxil fumarate) 400 mg/300 mg/300 mg tablets, also approved for patients with HIV-1 in adults and pediatric patients weighing at least 35 kg.

Following FDA approval, Mylan launched Symfi Lo™ earlier in March. It expects Cimduo™ and Symfi™ to launch in the second quarter of 2018.

Symfi™ and Symfi Lo™ feature the same triple combination of molecules; however, Symfi Lo™ features a reduced dose of efavirenz while Symfi™ uses a dosing similar to other efavirenz products already on the market. The combination represented by Symfi™ (efavirenz, lamivudine and tenofovir disoproxil fumarate) 600 mg/300 mg/300 mg tablets is the most widely-taken ARV regimen outside of the U.S., with more than 7 million users worldwide in 2016¹.

In 2017, HIV was the category with highest pharmacy spend for Medicaid, the third highest for health exchange plans and the fifth highest for commercial plans.² According to IQVIA, total spending on HIV drugs has more than tripled since 2007, outpacing the approximate 60% growth in overall drug spending.

To help reduce the high cost of HIV treatment in the U.S, the list price of these Mylan ARVs will be discounted significantly from the wholesale acquisition cost of similar medicines on the market.

"Mylan has been on the forefront of bringing innovative delivery and dosage forms of ARVs to millions of patients in the developing world," said Mylan President Rajiv Malik. "We've already extended our reach to people in the U.S. living with HIV with the introduction of Symfi Lo™ and Cimduo™. Adding Symfi™ to our portfolio further strengthens our commitment to investing in developing and manufacturing these important products."

Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including lamivudine and tenofovir disoproxil fumarate. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus and HIV who have discontinued lamivudine and tenofovir disoproxil fumarate.

Mylan Introduces Symfi (efavirenz, lamivudine and tenofovir disoproxil fumarate) Triple Combo Once-Daily HIV Treatment in the U.S.

TDF, entecavir duo 'highly effective' for difficult-to-treat chronic HBV

The combination of tenofovir disoproxil fumarate (TDF) and entecavir induces a high rate of viral suppression in patients with chronic hepatitis B virus (HBV) infection who have failed multiple nucleos(t)ide analogue (NA) regimens, phase IIIb results indicate.

  

Entecavir                                                                         Tenofovir disoproxil fumarate 

The dual therapy could be "a highly effective option for difficult-to-treat multidrug-resistant" chronic HBV patients, the team writes in Liver International.

The 64 patients enrolled in this study had persistent viraemia, defined as serum HBV DNA levels above 60 IU/mL despite a minimum 24 weeks of rescue therapy, and documented genotypic resistance to one or more nucleoside analogue and a nucleotide analogue.

Treatment with TDF 300 mg and entecavir 1 mg once a day led to complete virological response (CVR), defined as HBV DNA levels under 60 IU/mL, in over half (56.3%) of the study population at 12 weeks. The CVR rate rose to 67.2% at week 24 and 85.9% at week 48.

The proportion of patients who achieved HBV DNA levels below 12 IU/mL, the lower limit of detection in this study, was 32.8%, 51.6% and 62.5% at weeks 12, 24 and 48, respectively.

The antiviral efficacy of the dual regimen was not affected by baseline viral load or the presence of baseline resistance mutations, report Sang Hoon Ahn (Yonsei University College of Medicine, Seoul, Republic of Korea) and fellow ESTEEM investigators.

However, a smaller proportion of participants with baseline triple resistance to lamivudine, adefovir and entecavir achieved CVR at week 48 relative to those with single or double resistance at baseline, at 67.7% versus rates ranging from 83.3% to 100.0%.

Virological breakthroughs occurred in five patients, but were transient in all cases and HBV DNA levels declined as treatment continued, say the researchers. And they add that none of the eight participants without CVR at week 48 had resistance mutations to TDF or any novel mutations.

TDF, entecavir duo 'highly effective' for difficult-to-treat chronic HBV: The combination of tenofovir disoproxil fumarate and entecavir induces a high rate of viral suppression in patients with chronic hepatitis B virus infection who have failed multiple nucleos(t)ide analogue regimens, phase IIIb results indicate.

FDA Approves Dutrebis (lamivudine and raltegravir) for HIV-1 Infection

   

The United States Food and Drug Administration (FDA) has approved Dutrebis, a fixed dose combination tablet containing 150 mg of lamivudine and 300 mg of raltegravir. Dutrebis tablet is approved for use in combination with other antiretroviral products for the treatment of HIV-1 infection in adults and pediatric patients greater than or equal to 6 years of age weighing at least 30 kg. The recommended dosage of Dutrebis is one tablet taken twice daily with or without food.

Dutrebis approval was based on an open-label, single dose, randomized, two-period, crossover study in healthy subjects (n=108). One Dutrebis fixed dose combination table was shown to provide comparable lamivudine and raltegravir exposures to one Epivir 150 mg tablet plus on Isentress 400 mg tablet. Due to the higher bioavailability of raltegravir contained in Dutrebis, the exposures provided by the 300 mg dose of raltegravir are comparable to 400 mg of ralegravir given as the raltegravir poloxamer formulation (Isentress), which accounts for the difference in raltegravir dose.

FDA Approves Dutrebis (lamivudine and raltegravir) for HIV-1 Infection

FDA Approves Triumeq for the Treatment of HIV-1 Infection

In continuation of my update on Triumeq

ViiV Healthcare announced today that the U.S. Food and Drug Administration (FDA) has approved Triumeq (abacavir 600mg, dolutegravir 50mg and lamivudine 300mg) tablets for the treatment of HIV-1 infection. Triumeq is ViiV Healthcare’s first dolutegravir-based fixed-dose combination, offering many people living with HIV the option of a single-pill regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir, with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine.

FDA Approves Triumeq for the Treatment of HIV-1 Infection

FDA Approves Triumeq for the Treatment of HIV-1 Infection

ViiV Healthcare announced today that the U.S. Food and Drug Administration (FDA) has approved Triumeq (abacavir 600mg (below-Ist), dolutegravir (below -IInd) 50mg and lamivudine (below IIIrd respectively) 300mg) tablets for the treatment of HIV-1 infection.  Triumeq is ViiV Healthcare’s first dolutegravir-based fixed-dose combination, offering many people living with HIV the option of a single-pill regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir, with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine.

FDA Approves Triumeq for the Treatment of HIV-1 Infection

Telbivudine Given to Mothers with Hepatitis B Reduces Infection Rate in Infants

We knew that, Telbivudine is an antiviral drug used in the treatment of hepatitis B infection. It is marketed by Swiss pharmaceutical company Novartis under the trade names Sebivo (Europe) and Tyzeka (United States). Clinical trials have shown it to be significantly more effective than lamivudine or adefovir, and less likely to cause resistance.

Now researchers from American Association for the Study of Liver Diseases (AASLD), lead by Dr. Calvin Pan, have come up with some interesting finding, i.e., Telbivudine in the second to third trimesters of pregnancy lead to  no transmission of HBV to newborns was detected at 28 weeks postbirth.  The study concluded that both the mothers and new born. 

For this study, pregnant women with high level of HBVDNA enrolled in the treatment arm of the study were given 600 mg daily of Telbivudine. All newborns received three doses of hepatitis B vaccine. Patients in the treatment arm achieved sustained virologic response rate (SVR) of 53 percent prior to delivery and 62 percent four weeks after delivery. None of the patients in the control arm achieved SVR at either point. 

Only four percent of newborns in the treatment arm tested positive for hepatitis B, whereas 23 percent of newborns from the control group tested positive. None of the patients treated with Telbivudine had to stop treatment due to adverse events. No congenital deformities were observed up to 28 weeks after birth. There were no measurable differences in postpartum health issues for mothers and newborns between the treatment and control groups. 

Dr. Pan realizes the limitations of this study, “The infant follow up is limited to 28 weeks after birth. Even though it is good enough to define the failure rate of transmission prevention, the long term safety data for the infant is missing. Hypothetically, antiviral therapy and immunoprophylaxis can be effective in blocking transmission that occurs during late pregnancy or delivery, but the mechanism of intrauterine transmission remains a puzzle. Though more studies are needed in the field to provide a comprehensive strategy to prevent HBV vertical transmission, in my opinion its is significant achievement......

Ref : http://www.aasld.org/lm/press/Pages/PressReleaseTelbivudine.aspx