FDA Approves Four-in-One HIV Pill Stribild

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.