GSK - ViiV Abandons Lersivirine - An Investigational NNRTI HIV Medication

Dear HIV Community Writer,

ViiV Healthcare has taken the decision to stop the development program investigating the non-nucleoside reverse transcriptase inhibitor (NNRTI), lersivirine.  This is not due to any safety concerns regarding the compound. ViiV Healthcare’s goal is to support the best possible outcomes for people living with HIV, and to deliver new therapies that offer improvement over current options. 

After much deliberation about how to proceed with lersivirine, it was determined that the compound would not provide an improvement over existing medicines in the NNRTI class, and that R&D resources for ViiV Healthcare should prioritize efforts to identify compounds that further HIV treatment.

We remain committed to exploring candidates that will advance HIV treatment and contribute to improving outcomes for people living with HIV.

Please don’t hesitate to reach out to me directly if you have any questions regarding this announcement.

Kind regards,

Marc Meachem | Director, External Affairs

GSK is Exploring a Once a Month Injectable HIV Treatment Regimen

Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults

         Presented at the International AIDS Conference in Washington this week

Discussion 

-- S/GSK1265744 long acting parenteral administration prolonged plasma levels (apparent t1/2of 2150days; Figure 4) compared with oral administration (oral t1/2of 30-40 hours)

-- AUC(0-∞)appeared to increase in a dose-proportional manner; Cmax increased greater than proportional to dose following 800 mg IM, suggesting the rate of absorption was higher for this dose (Table 2)

-- 800 mg IM achieved a mean S/GSK1265744 Cday 1021-fold above PA-IC90; this exposure is comparable to exposure observed with 30 mg oral, once-daily dosing, which produced a -2.5 log10decrease in HIV RNA following 10 days of monotherapy in HIV-infected subjects. Mean Cday28following 800 mg IM was 14-fold above PAIC90, making this a viable loading dose for S/GSK1265744 LAP

-- Modeling and simulation (not shown) suggest S/GSK1265744 LAP 200-400 mg monthly is an appropriate maintenance dose for HIV treatment

Conclusions

S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated in healthy adult subjects. Both IM and SC routes of administration will be evaluated in repeat-dose clinical trials 

Single SC or IM doses of the long-acting formulation yielded sustained S/GSK1265744 plasma concentrations previously shown to produce robust antiviral activity as oral monotherapy and suggest monthly to quarterly dosing intervals using clinically practical dose volumes

Study results support continued development; S/GSK1265744 is under evaluation for both HIV prevention as pre-exposure prophylaxis as well as HIV therapy with a partner antiretroviral agent, rilpivirine (TMC278-LA)

Abstract

Background: S/GSK1265744, an HIV integrase inhibitor with proven antiviral activity following oral monotherapy, is under development as a long-acting parenteral (LAP) depot formulation. Antiretrovirals dosed monthly to quarterly may provide clinical utility for HIV treatment and prevention. This study evaluated pharmacokinetics (PK), safety, and tolerability of single S/GSK1265744 LAP doses in healthy adults.

Methods: This was a phase I, randomized, double-blind, placebo-controlled, dose escalation study. S/GSK1265744 200 mg/mL nanosuspension was administered by intramuscular (IM) gluteal injection (100 mg, 200 mg, 400 mg, 800 mg [400 mg x2]) or subcutaneous (SC) abdominal injection (100 mg, 200 mg, 400 mg [200 mg x2]) to cohorts of eight (6 active/2 placebo) subjects. Safety and PK were assessed prior to dose escalation and continued until plasma S/GSK1265744 was <0.1 μg/mL by LC/MS/MS; PK parameters were determined by noncompartmental methods. 

Results: 25 females and 31 males were dosed; S/GSK1265744 LAP was generally well tolerated with mild-moderate, self-limited injection site reactions (ISR) reported as the most common adverse event (AE); ISR erythema and nodules were more frequent following SC dosing. Systemic safety was good with no drug-related serious AEs or grade 3-4 AEs. S/GSK1265744 was detected in plasma up to 48 weeks and exhibited absorption-limited kinetics; mean apparent terminal phase t1/2ranged 2150days vs. 40 h following oral dosing. S/GSK1265744 AUC(0-∞) appeared to increase proportionally to dose. Split dosing increased the apparent absorption rate. Mean S/GSK1265744 Cday 10 following 800 mg IM was similar to geometric mean CÏ„,ss of 3.28μg/mL associated with -2.5 log10mean change in plasma HIV RNA following 10 days of 30 mg PO QD monotherapy. 

Conclusions: S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated. Achievement of sustained plasma concentrations previously shown to produce >2.5 log10mean reduction of HIV RNA as monotherapy suggests S/GSK1265744 LAP may exhibit prolonged antiviral activity at clinically practical doses and supports continued development.

S/GSK1265744 is an integrase strand transfer inhibitor in development as both an oral formulation and LAP injection. The compound has attributes that enable formulation and delivery as a nanosuspension for injection: 

-- High potency: deliver monthly or longer dose in clinically practical volume

-- Low aqueous solubility and correct particle size to control release kinetics

-- Low metabolic clearance: reduced drug input requirement

-- Formulation prerequisites: withstand nanomilling forces, stability in formulation with excipients and stabilizers, a sterile product

Prior clinical studies have demonstrated S/GSK1265744 oral monotherapy produces a vigorous antiviral effect in HIV-infected subjects at 5 or 30 mg once daily for 10 days (Figure 1). In vitro resistance studies suggest a favorable profile. The current study was undertaken to evaluate the safety and PK of single IM or SC doses of S/GSK1265744 LAP formulation in healthy adult subjects

Shionogi-ViiV Healthcare announces initial data from pivotal phase III study of dolutegravir in HIV

This drug will compete against raltegravir (Merck) and elvitegravir (Gilead). 

It will be dosed once a day for treatment naive patients and twice a day for treatment experienced.

Issued: Monday 02 April 2012, London, UK

Press release issued by Shionogi-ViiV Healthcare LLC, a joint venture between ViiV Healthcare Ltd (a global specialist HIV company established by GlaxoSmithKline and Pfizer, Inc.) and Shionogi & Co., Ltd.

SPRING-2 study meets primary endpoint of non-inferiority of dolutegravir compared to raltegravir over 48 weeks in treatment-naïve HIV patients

ViiV Healthcare and Shionogi & Co., Ltd. today announced that initial results have been received from the SPRING-2 (ING113086) Phase III study of the investigational integrase inhibitor dolutegravir in treatment-naïve adults with HIV-1. The study met its primary objective, demonstrating non-inferiority of dolutegravir to raltegravir. Through 48 weeks, 88% of study participants on dolutegravir were virologically suppressed (<50 copies/mL) vs. 85% of participants on raltegravir [with a 95% confidence interval (CI) for the difference, -2.2% to + 7.1%; the lower end of the CI (-2.2%) was above the prespecified -10% non-inferiority limit]. 

SPRING-2 is an ongoing non-inferiority study designed to compare the efficacy and safety of dolutegravir 50mg administered once-daily versus raltegravir 400mg administered twice daily, both with two nucleoside reverse transcriptase inhibitors(NRTIs); 411 treatment-naïve study participants were randomised in each arm. The primary endpoint of the study was the proportion of study participants with undetectable HIV-1 RNA (<50c/mL) through 48 weeks.  The tolerability of dolutegravir was similar to that of raltegravir, with rates of adverse events leading to withdrawal at 2% in both arms. Drug-related nausea was reported by 10% of patients in each arm; no other adverse events related to study medication were reported by more than 5% of participants in either arm. 

“The SPRING-2 findings indicate that once daily unboosted dolutegravir may offer people living with HIV an additional treatment option in the future. These are the first large-scale safety and efficacy data in naïve patients, and we look forward to seeing further data in 2012 to build a more comprehensive picture of the role of dolutegravir” said Dr John Pottage, Chief Medical Officer, ViiV Healthcare. 

“At ViiV Healthcare we have a total focus on the needs of people living with HIV, and as a result we see the continued need for new, effective and convenient therapies.  We are committed to building connections and collaborations, like the Shionogi-ViiV Healthcare dolutegravir programme, to meet these needs.” said Dr. Dominique Limet, Chief Executive Officer, ViiV Healthcare. 

“The SPRING-2 study has met its primary endpoint for dolutegravir in treatment-naïve patients.  This marks an important milestone for the development of dolutegravir and the Shionogi-ViiV Healthcare joint venture. We look forward to completing further Phase III studies in a variety of clinical settings in order to fully understand the potential clinical benefit for a range of HIV patient populations” said Dr. Tsutae "Den" Nagata, Chief Medical Officer, Shionogi & Co., Ltd.

Full results of this study, including the full results of the secondary endpoints, will be presented at an upcoming scientific meeting.  SPRING-2 is the first of four Phase III studies that are due to be reported in 2012. Data from the clinical trials SINGLE (ING114467), VIKING-3 (ING112574) and SAILING (ING111762), will be received throughout the year and will allow further determination of the profile of dolutegravir.  These studies are designed to support a future regulatory file for dolutegravir. 

About SPRING-2

SPRING-2 (ING113086) is a Phase III, randomized, double-blind, multicentre, parallel group, non-inferiority study. The study included 822 HIV-1 infected treatment-naïve participants. The study compares the efficacy and safety of dolutegravir and raltegravir as part of an overall treatment regimen; both treatment arms are administered with investigator-selected dual nucleoside reverse transcriptase inhibitor therapy (either abacavir + lamivudine or tenofovir + emtricitabine).

The primary objective for SPRING-2 is to demonstrate the antiviral activity of dolutegravir 50mg administered once-daily compared to raltegravir 400mg administered twice daily over 48-weeks. Secondary objectives include the assessment of antiviral activity of dolutegravir compared to raltegravir at 96-weeks, to compare the tolerability, long-term safety and antiviral and immunologic activity of dolutegravir to raltegravir and to evaluate viral resistance in study participants experiencing virological failure.

About Dolutegravir

S/GSK1349572 (dolutegravir) is an investigational integrase inhibitor (INI) currently in development by Shionogi-ViiV Healthcare LLC for the treatment of HIV. It is currently the only once-daily, unboosted INI in Phase III clinical development.Integrase inhibitors 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. Given the stage of development of this investigational HIV therapy, the full picture of the efficacy and safety of dolutegravir has not been conclusively determined.

Activists Caution HIV+ Patients and their Physicians About Monotherapy in Upcoming Access Program

FOR IMMEDIATE RELEASE: February 9, 2012

Contact: Nelson Vergel (NelsonVergel@yahoo.com)

Activists Caution HIV+ Patients and their Physicians About

Monotherapy in Upcoming Access Program

New York, February 9, 2012—AIDS activists and physician advocates welcome the news that ViiV Healthcare will be providing  expanded access of dolutegravir (DTG), a new investigational integrase inhibitor for HIV patients with few remaining HIV treatment options.  However, they warn patients and physicians to avoid functional monotherapy, or the introduction of dolutegravir as an "add-on" to a failing treatment regimen if the patient’s virus is resistant to all other currently available antiretroviral drugs (ARVs).  Functional monotherapy has been shown to permit rapid HIV resistance to new medications, which can result in more rapid disease progression, health deterioration, and death.

Currently, the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines recommend three ARVs be given in combination to suppress HIV.  But many patients have HIV that has mutated rendering their virus multi-drug resistant (MDR-HIV).  Those with MDR-HIV cannot construct a viable HIV suppressive regimen with current FDA-approved and commercially available ARVs.  "The DHHS guidelines specify that patients that have developed HIV drug resistance to all commercially available antiretrovirals require access to at least two new active drugs to maximize their chances for treatment response.  However, “another new drug to combine with dolutegravir will not be commercially available for at least two years, and some patients cannot wait that long,” said Nelson Vergel, an activist founder of SalvageTherapies.org.  "For them, access to another research drug in combination with DTG is the only hope for survival," added Vergel.

In studies to date, dolutegravir (DTG) appears to be the most potent integrase inhibitor soon to enter the ARV market.  Unlike Gilead's upcoming elvitegravir, DTG has been shown to be effective against HIV that has developed resistance to Merck's Isentress (raltegravir), the only FDA-approved integrase inhibitor currently on the market.

Fortunately, another new ARV that can help patients with MDR-HIV is in active development and clinical trials.  Ibalizumab, a monoclonal antibody from a small biotech firm, Taimed Biologics, may soon be available via patient participation in research studies.  While ibalizumab has yet to enter phase three studies, it can also be provided to patients at risk of death via a named (or single) patient access application permitted by the FDA via a physician’s direct request to Taimed.  However, it is for the company to approve such requests for compassionate access.

There are no documented estimates of how many people have MDR-HIV in the United States.  A report in the Journal of Clinical Infectious Diseases estimates that about 260,000 patients are being treated with HIV in the United States.  However, it is virtually impossible to know how many are now without sufficient treatment options since no registry for such patients exists.  But most experts agree that this population is probably small – possibly up to 10% of the total in treatment.

"With little immune function left and resistance to all approved HIV medications, I have tried desperately to get access to two new drugs to help save my life,” said Christopher Cacioppo, a patient with MDR-HIV in  San Diego who believes he is running out of time. “My doctor tells me that I have little choice but to wait for the dolutegravir expanded access program and some as yet unknown and unavailable second new drug."

A coalition of activists and physicians have been in discussions with Taimed and ViiV for nearly two years to obtain compassionate-use access to their new ARVs in combination for those with MDR-HIV in greatest need of new treatment options.  The AIDS Community Research Initiative of America (ACRIA), a New York City-based community research and education organization, and physicians in San Francisco have proposed solutions to overcome this “two-drug access barrier” in an effort to secure urgent access to patients across the country.

Physicians and providers with patients with MDR-HIV in need of two new ARVs are urged to complete this form.

###

GSK- ViiV start their phase 3 study for their second generation integrase inhibitor (dolutegravir) in raltegravir experienced patients

http://clinicaltrials.gov/ct2/show/NCT01328041?term=dolutegravir&rank=1

For more on dolutegravir:

Report from CROI 2011

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. 

Dolutegravir, Trii and new abacavir data- How it all ties together

By Nelson Vergel

Powerusa.org

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.

This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii.  This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).

The development of Trii for approval as a first line treatment seemed risky to me due  to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV.  These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients.  So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?

Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation,  the US Food and Drug Administration (FDA)  presented  a surprising poster on  March 2 that reported  no evidence of an association between abacavir  and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug.  The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.

It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines.  Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to  pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills.   Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.

As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.

Sources:

DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB

Ding X et al. No association of myocardial infarction with ABC use: an FDA meta-analysis.  Poster abstract 808.


More on:
http://www.retroconference.org/2011/Abstracts/42541.htm

http://www.thebodypro.com/content/art60708.html

More on CROI:
http://www.thebody.com/content/art60501.html

The Forgotten Minority: HIV+ Patients With No Available HIV treatment Options

Most successful HIV medication combinations require 3 medications that are fully active, but a small portion of long term survivors with long treatment history and accumulated HIV resistance mutations do not have the luxury of constructing a viable regimen to save their lives.

Several potent antiretrovirals (ARVs) in the past 4 years have enabled many patients with multidrug resistance (MDR) to suppress their HIV viral load.

Due to several factors, there is still a relatively small number of patients that have developed resistance or toxicity to the new ARV’s

To protect them from functional monotherapy, these patients are not allowed in pre- approval studies.

Some HIV ARV’s in phase II studies may potentially help those patients, but combining them after their respective approvals may take at least 3 or 4 years.

Some of these patients may be at risk of clinical decline and death if no viable regimen is available for them before 2012

We do not know how many of these patients there are in the U.S.

I performed a physician survey with the help of some researchers and activists to find out how many patients may be present in the U.S. with HIV multidrug resistance in deep salvage (one or zero active medications to treat their HIV).

These figures summarize our findings (click on figures to enlarge):

These are the HIV medications in current development. The ones with an asterisk are the ones that may work for patients with no options left.

The closest ones to approval are Taimed's ibalizumab ( an IV once every two weeks) which may be two years away from approval, and GSK's integrase inhibitor GSK572 (2-3 years) . Avexa recently stopped the development of   Apricitabine and Myriad may follow suit with their maturation inhibitor. A combination of at least two compounds will probably not be feasible until 2013.  Efforts towards creating an expanded access program using multiple investigational agents is currently under way but it may not be a possibility until 2011.  All companies and the FDA are welcoming the concept in its early stages.  I will provide an update during the last quarter of 2010.

I wish we could help patients who need help now.

Nelson Vergel