New all-in-one HIV drug, the Quad, goes before FDA

Good news for HIV treatment options: in October, Gilead Sciences submitted a New Drug Application (NDA) to the Food and Drug Administration (FDA) for approval of the “Quad,” a complete single-tablet HIV regimen. The other two such complete medications on the market are Atripla and Complera.

All three medications contain Truvada (Viread and Emtriva) from Gilead Sciences as the background drug. Atripla also contains Sustiva, from Bristol-Myers Squibb, while Complera’s third drug is Edurant, from Tibotec Therapeutics (now Janssen Therapeutics). Both Sustiva and Edurant are from the drug class called non-nucleoside reverse transcriptase inhibitors, or NNRTIs.

The Quad would be different in that its principle drug is elvitegravir, an HIV integrase inhibitor medication like Isentress. The Quad also contains the new drug level-boosting medication called cobicistat, which allows for once-daily use of elvitegravir. Therefore, the Quad is taken as one pill once daily, as are Atripla and Complera.

The NDA is based on results from two Phase 3 (advanced) studies showing non-inferiority (an FDA standard) at 48 weeks of research compared to either Atripla or boosted Reyataz. Both drugs are recommended by U.S. HIV treatment guidelines for first-time therapy.

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Drug makers sign agreements on new fixed-dose combo pills

Kudos to Bristol-Myers Squibb (BMS) and Tibotec (now Janssen) Therapeutics for signing a commercial agreement with Gilead Sciences to get that company’s new boosting medication, cobicistat, into a fixed dose pill with BMS’s Reyataz and Tibotec’s Prezista. The two HIV protease inhibitors, along with a booster medication, are the two PIs recommended for first-time antiviral therapy by U.S. treatment guidelines. Currently, Reyataz and Prezista use Norvir as a boosting agent, but that medication can be very intolerable. While the agreement with BMS is for a boosted Reyataz pill, the agreement with Tibotec is for a complete HIV regimen in one tablet that includes Prezista, cobicistat, Emtriva, and Gilead’s GS-7340, a pro-drug (an inactive substance that metabolizes into active form in the body) of its popular Viread (tenofovir, also found in Truvada, Atripla, and Complera).

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HIV treatment guidelines updated

On October 14, the Department of Health and Human Services (DHHS) updated its HIV treatment guidelines. The revised guidelines can be found at www.AIDSinfo.nih.gov. Many changes were made by the panel of experts that updates the guidelines. These changes, listed below, all apply to the recommendations of what to use for people going on HIV therapy for the first time.

• The new HIV non-nucleoside drug Edurant (rilpivirine, in the same class as Sustiva) was added as an acceptable option; a number of tables, such as the drug interactions table, also had Edurant information added.
• Prezista plus Epzicom, and Isentress plus Epzicom were upgraded to an “alternative regimen” from previously being considered “acceptable, but more definitive data are needed.”
• Combivir (the combination of AZT [zidovudine] plus lamivudine) was downgraded from an “alternative” to “acceptable” dual nucleoside background because it has twice-daily dosing and greater toxicity than the medications Truvada and Epzicom. However, Combivir remains preferred for the treatment of pregnant women due to its demonstrated ability to stop HIV transmission to infants.
• Lexiva has been removed as a protease inhibitor (PI) option because of inferior potency and the potential for developing resistance to Prezista, a recommended PI for first-time therapy.
• Viramune (nevirapine), a non-nucleoside, is now considered “acceptable” (but not “recommended” or “alternative”) for first-time therapy (depending on the sex and beginning T-cell count of the patient); see the guidelines for its upgrading and downgrading information.
• Videx or Videx-EC plus Epivir were removed as an option for dual nucleoside background because they have the least study data and greater toxicity than other background drugs available.

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Ziagen and the heart

The updated HIV treatment guidelines (see above) also expanded the discussion of a possible risk of heart attack with abacavir (Ziagen, also found in Epzicom and Trizivir). This association was first noted years ago, leading various groups of researchers around the world to try to confirm or eliminate the risk factor. The guidelines added an update on all this work, explaining that of the several studies looking at this issue, some have found an association while others haven’t. Additional studies have also looked at possible mechanisms of action for such an association, without success. All in all, the latest version of the guidelines states that “to date, no consensus has been reached either on the association of [abacavir] use with MI [myocardial infarction, or heart attack] risk or a possible mechanism for the association.”

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New side effect warnings for Isentress

The FDA added warnings in November to the package insert for the popular HIV drug Isentress (raltegravir). Although known for tolerability, the following adverse reactions have been seen with Isentress.

The “Warnings and Precautions” section now includes “severe skin and hypersensitivity [allergic] reactions.” Also added was rash with eosinophilia (elevated levels of a specific type of white blood cells), systemic symptoms [those that occur throughout the body, such as fever], and cerebellar ataxia, which is sudden, uncoordinated movement due to disease or injury of the cerebellum (part of the brain).

According to the updated information, “Delay in stopping Isentress treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.” The new information also states that, “Patients should be advised to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking Isentress and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or severe hypersensitivity: fever, general ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on the right side below the ribs). Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated.”

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Prezista label adds longer-term data

The Food and Drug Administration (FDA) in October approved a label update to the HIV protease inhibitor Prezista (darunavir) to add new 192-week data.

“Since its launch in 2006, Prezista has become one of the most prescribed antiretroviral agents in the protease inhibitor class,” said Vanessa Broadhurst, the president of Janssen Therapeutics, in a press release. “Having data showing the efficacy, safety, and tolerability of Prezista over 192 weeks should give added confidence to healthcare providers who are considering Prezista as an option for their patients who are starting treatment for the first time.”

Prezista showed superiority to Kaletra at 192 weeks in the ARTEMIS study of people on HIV therapy for the first time (Prezista is always boosted with Norvir and Kaletra has Norvir boosting in it). Seventy percent of the 343 individuals taking Prezista achieved undetectable viral load (less than 50 copies per mL) compared to 61% of the 346 people taking Kaletra. Virologic failure (not maintaining undetectable viral load) was 12% for Prezista vs. 15% for Kaletra.

The most common adverse reactions of moderate intensity (greater or equal to grade 2, with 5 being the highest) were diarrhea (9% for Prezista and 16% for Kaletra), headache (7% vs. 6%), abdominal pain (6% for each), and rash (6% vs. 7%).

Prezista was developed by Tibotec (now Janssen) Therapeutics. It is one of two protease inhibitors recommended by U.S. HIV treatment guidelines for people taking antiretrovirals for the first time.

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AMA supports research on HIV organ transplants

The American Medical Association (AMA) voted in November to support amending a federal law that bars clinical research of organ donations from HIV-positive donors, calling such research “a potentially lifesaving measure for people living with HIV infection.”

Indeed, according to an AMA press release, “Advances in the medical management of HIV infection coupled with improvements in transplant outcomes could make organ transplantation a viable clinical option for many HIV-infected patients. Despite these scientific advances, the Federal National Organ Transplant Act of 1984 precludes donations of HIV-infected organs, thereby prohibiting investigational studies on a source of organs for HIV-infected patients. It is estimated that there are approximately 500-600 potential HIV-infected kidney and liver donors per year in the United States.  Organs from these donors have the potential to save the lives of approximately 1,000 HIV-infected patients each year.”

The release goes on to quote AMA Board Member Ardis D. Hoven, MD. “Research is needed to fully evaluate the clinical risks and benefits of organ transplantation between HIV-infected individuals,” said Dr. Hoven. “The new policy adopted today extends the AMA’s support for a change in federal law that will permit the necessary scientific investigation.”

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First clinical trial of ARV vaginal ring underway

In the first clinical trial of a vaginal ring combining two antiretroviral (ARV) drugs, researchers from the Microbicide Trials Network (MTN) are collaborating with the International Partnership for Microbicides (IPM) to evaluate whether the ring is safe for use in women. If the ring does prove to be safe, it could be considered for further testing, and eventually be evaluated for its effectiveness as a microbicide for protecting women against HIV infection through vaginal sex.

The study, which is funded by the National Institutes of Health and goes by the name MTN-013/IPM 026, is evaluating a ring that contains dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and the entry inhibitor Selzentry (maraviroc). The dapivirine-maraviroc ring is the first combination microbicide to enter clinical trials. It is also the first vaginal microbicide containing an entry inhibitor. The belief is that combining the two drugs, which act at different points in the HIV life cycle, may provide greater protection against HIV than a single drug alone.

The ring was developed by IPM, a non-profit product development partnership headquartered in Silver Spring, Maryland, in collaboration with Queens University Belfast (Belfast, Northern Ireland).

Globally, women comprise half of the 34 million people living with HIV. In most cases, women acquire HIV through unprotected heterosexual sex with an infected partner. Because the use of condoms is often not an option, there is an urgent need for effective prevention strategies that women can control themselves. To that end, vaginal microbicides in the form of a gel or a ring are being developed to provide women with new tools to protect themselves against HIV.

MTN-013/IPM 026, which is now screening potential participants, will enroll 48 healthy, HIV-negative women ages 18–40 at the University of Pittsburgh, Fenway Institute in Boston and the University of Alabama at Birmingham. Researchers will evaluate the ring’s safety and how well women like or are willing to use the ring. In addition, different tests will be performed to help determine how much of each drug is taken up by the cells usually targeted by HIV and whether drug levels are sustained throughout the four weeks the ring is worn. Women will wear their assigned ring for 28 days. Different tests and procedures will be conducted during this time as well as during a 24-day follow-up period.

“IPM has been a pioneer in developing vaginal rings for delivery of antiretrovirals. Our collaboration marks an important juncture for the field as we begin to explore drugs with different mechanisms of action and methods that we hope will give women new, easy-to-use options for preventing HIV,” remarked MTN principal investigator Sharon Hillier, PhD, who is professor and vice chair for faculty affairs, and director of reproductive infectious disease research in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh School of Medicine.

“Our partnership with MTN on the first combination microbicide to enter clinical trials is an important milestone for the HIV prevention field,” said Zeda F. Rosenberg, ScD, IPM chief executive officer. “With extensive pre-clinical data on both drugs to support the combination ring’s development, we hope this product will one day expand women’s HIV prevention options and open the door to developing other combination HIV prevention methods.”

Next year, the MTN will launch a Phase 3 effectiveness trial of the dapivirine-only ring. The study, called ASPIRE—A Study to Prevent Infection with a Ring for Extended Use—will enroll approximately 3,475 women at sites in five African countries.

As part of IPM’s strategy to license the dapivirine ring, IPM will conduct The Ring Study (IPM 027), which will be done in parallel with ASPIRE, and collect long-term safety and efficacy data about the ring among approximately 1,650 women at multiple research centers in Africa.

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Capsaicin patch for neuropathy gets FDA review

NeurogesX, Inc., a biopharmaceutical company focused on developing and commercializing novel pain management therapies, announced on November 14 that the Food and Drug Administration (FDA) has accepted for review the company’s supplemental new drug application (sNDA) for Qutenza (capsaicin) for the management of neuropathic pain caused by HIV-associated peripheral neuropathy (HIV-PN). The FDA has granted Qutenza a priority six month review classification.

“The FDA’s filing and priority review of our sNDA for Qutenza in HIV-PN is a significant achievement for NeurogesX as we seek to expand our pain management franchise,” said Anthony DiTonno, president and CEO of NeurogesX in a press release. “This takes us another step forward in our effort to provide lasting relief from one of the most challenging chronic pain conditions. We look forward to our continued discussion with the FDA during the review of this application.”

The Qutenza sNDA seeks approval for a 30-minute application for the treatment of neuropathic pain associated with HIV-PN. Qutenza is currently FDA approved as a 60-minute application for the management of neuropathic pain associated with postherpetic neuralgia (PHN). If approved, the company believes that Qutenza would be the first and only product approved to treat HIV-PN in the United States.

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Early trial suggests rectal microbicide is safe, effective

A topically applied microbicide gel containing a potent anti-HIV drug has been found to significantly reduce infection when applied to rectal tissue that was subsequently exposed to HIV in the laboratory, according to a new study by the UCLA AIDS Institute. The gel was also found to be safe and acceptable to users.

The Phase 1 clinical trial of the rectal HIV-prevention drug known as UC781, a non-nucleoside reverse transcriptase inhibitor, is described in the current edition of the online journal PLoS ONE.

While anal-receptive intercourse is known to be the main route for new HIV infections in men who have sex with men, far more women than men worldwide practice anal intercourse. The risk of HIV infection, per sex act, is anywhere from 20 to 2,000 times greater with receptive anal sex than receptive vaginal sex—particularly if there are other infections present, such as herpes, gonorrhea or chlamydia, according to the study’s lead author, Dr. Peter Anton, a professor of medicine in the division of digestive diseases at the David Geffen School of Medicine at UCLA, and a member of the UCLA AIDS Institute.

“While the main goal of this trial was also to evaluate safety, these new tests enabled us to evaluate, indirectly, whether this drug and route of delivery might potentially reduce new HIV infections,” said Anton. “Of course, it is very gratifying that the results were so impressive. This approach reflects the kind of intensive analyses these dedicated participants in these early trials are willing to tolerate to help us evaluate a drug’s potential earlier in the pipeline of drug development.”

In the trial, researchers tested a formulation of the gel that was created for vaginal use in human trials and that contained two concentrations of UC781. They enrolled 36 male and female subjects at UCLA who were not infected with HIV, and they collected blood and rectal tissue samples at baseline, before participants were randomized to either a placebo group or to receive one of two concentrations of UC781. All participants were given the placebo or active drug as a single exposure by the team’s clinicians, with research samples collected 30 minutes later for analysis.

After two to three weeks, the participants resumed the second part of the trial by applying the gel or placebo once daily over seven days on their own at home. Afterwards, they returned to the clinic for another collection of samples. All participants completed the study once they were enrolled. In-depth interviews with each participant assessed their acceptability of the current form of the product.

Though the microbicide used for this study was formulated for vaginal use, the same team of researchers has also developed a rectal-specific microbicide gel, which they plan to start testing in a clinical trial in January 2012.

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Another setback for women’s HIV prevention

In the November/December issue of PA, it was reported that the VOICE study had stopped the use of Viread (tenofovir) tablets in its investigation of HIV prevention for women because it proved to be no better than a placebo.

In December, news came that an independent Data and Safety Monitoring Board (DSMB) recommended stopping the 1% tenofovir gel being studied because it was also no more effective than placebo (fake substance). The women given either the gel or the placebo had the same incidence of acquiring HIV from their sex partners, 6% in each group.

Tenofovir 1% gel was found to be effective in preventing HIV in women in the landmark CAPRISA 004 study, and it continues to be studied for prevention in FACTS 001, an advanced Phase 3 study.

VOICE, which stands for Vaginal and Oral Interventions to Control the Epidemic, will continue to study the daily use of Truvada pills for prevention. The study is being carried out by the Microbicide Trials Network (MTN) in 15 sites throughout Uganda, South Africa, and Zimbabwe, and has enrolled more than 5,000 women.

In a press release, AVAC, a U.S. organization working on global advocacy for HIV prevention, reported, “The announcement that the 1% tenofovir gel arm of a large-scale HIV prevention trial known as VOICE will stop early is disappointing but is not the end of the road for tenofovir gel or antiretroviral (ARV)-based microbicides.”

“This is a blow to the HIV prevention field but is not the definitive answer about whether 1% tenofovir gel is an effective HIV prevention product for women,” said Mitchell Warren, AVAC executive diirector.

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