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Gilead 2-in-1 Opens Door to Impending One-Pill Triple Combo

tagline 2004 October

GSK's, a Sort of Snoozer

In early August the FDA announced the approvals of two fixed-dose combination (FDC) antiretroviral drug products. FDCs are combinations of two previously approved drugs (à la the Combivir or Trizivir model) in what is understood to be a more convenient form: in both cases, one pill a day. The two new FDCs are GlaxoSmithKline's Epzicom (abacavir+3TC) and Gilead's Truvada (tenofovir+FTC).

These approvals, which allow for one fewer (in the case of Truvada) to three fewer (in the case of Epzicom) pills per day, promise to lessen pill burden for one component of HIV therapy. But neither represents a stand-alone regimen; they still must be taken with additional antiretroviral(s) in order to constitute an effective regimen. An FDC that combines all needed antiretrovirals into one pill is ultimately preferable (and is said to be in development by a surprising collaboration between BMS and Gilead). While these recent approvals represent a new and interesting option, both coformulations consist of previously available agents, and thus are not, in and of themselves, any great leap forward. Rob Camp reports.

"Epzicom is a laser-based radio system used in inter-galactic android battles -- by robots from francophone families."

"Oh well, Epzicom sounds like a hiccup."

-- U.S. treatment activists with too much time on their hands

Epzicom is an FDC of the antiretroviral drugs abacavir sulfate (Ziagen) 600 mg and lamivudine (Epivir) 300 mg. Epzicom is approved based on a large well-controlled clinical study (CNA30021 or Zodiac) that showed that abacavir dosed once daily had similar antiviral effect as abacavir dosed twice daily, both taken with lamivudine and efavirenz. (For a complete listing of trials, please see www.treatmentactiongroup.org.)

Epzicom is active against HIV in a variety of different patient groups. But use of abacavir (one of Epzicom's components) has been associated with potentially fatal hypersensitivity reactions in a growing number of patients.

TAG sees no cost or safety benefits for Epzicom over Combivir, and we caution against GSK's petition to place Epzicom as a first-line backbone. TAG believes that the company's application for approval of Epzicom for treatment of HIV infection in adults and adolescents was correctly approved by the FDA. However, the FDA should carefully monitor the company's education programs for both doctors and patients.

Studies of Epzicom leave some uncertainty about the relative benefits for it compared to other marketed NRTI backbones. In deciding whether to use any abacavir-containing regimen, physicians and patients should be aware that the existing double-nucleoside combinations of AZT/3TC (Combivir) or AZT/FTC, d4T/3TC (or d4T/FTC), TDF/FTC (Truvada, see page 4), AZT/TDF, etc. may be as useful as Epzicom, without the risk of hypersensitivity or the "low genetic barrier" that could lead and has led to excess virologic failure.

Safety/Tolerability

In studies like CNAAB3005, common adverse effects for the ABC group were nausea (42%), headache (45%), malaise/fatigue (100%), diarrhea (27%), vomiting (25%) rash (80%) and fever (60%). In the Zodiac study, adverse events of grade 2 (mild) or greater are reported in 65% of those taking Epzicom once daily.

There were a number of failures and losses in both groups (ABC QD vs. itself BID): 10 vs. 8 virologic failure, 13 vs. 11 adverse events withdrawals, 11 vs. 13 "other" (consent withdrawn, protocol violation, clinical progression, changed therapy, other other). BID vs. QD had about 5% more CD4 gain. Treatment discontinuations in both groups hover at 24%. Add that to clear virological failures, and 30% of the original patients did not finish the one-year study.

Is ABC a (Safe) Alternative for Lipodystrophic Events?

Cholesterol and triglycerides went up significantly more in the ABC groups than in the AZT groups in CNA30024. AST and absolute neutrophils also went up. Although all these measurements were non-fasted (and the significance is thus not clear), at week 8, ABC was 50mg/dL higher in lipids!

In study ESS40001, ABC/3TC as background with an NNRTI, fasting total cholesterol rose 40 points, with a PI it rose 60, and with an NRTI it rose 32. Triglycerides all rose as well, with an NNRTI, +66, with a PI +90, and with an NRTI +70, all 3 classes going above the "safety zone" for NCEP III, calling for medical intervention. ABC/3TC does not help with these events, or with fat changes in any of the regimens.

Because 3TC requires dose adjustment in the presence of renal insufficiency, Epzicom is not recommended for use in patients with creatinine clearance Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because Epzicom is a fixed-dose combination and cannot be dose adjusted, Epzicom is contraindicated for patients with hepatic impairment.

 

Important Reminder: Deaths From Rechallenge After Abacavir (i.e., Ziagen, Trizivir, Epzicom) Hypersensitivity Reactions

Death has resulted in individuals who have been rechallenged with abacavir following a hypersensitivity response. In the Zodiac study of the fixed-dose 3TC/ABC (Epzicom), the reported incidence of hypersensitivity reaction (at 9%) was nearly twice the rate reported in earlier studies of ABC (at <5%) -- which, Rob notes, may be simply due to closer monitoring for which GSK has been "responsibly cautious."

GlaxoSmithKline has developed language recommending that patients who develop a hypersensitivity response while taking Epzicom be discontinued from therapy, and never re-challenged. The FDA has adopted this language in a black-box warning about hypersensitivity in all abacavir-containing products.


Hypersensitivity-Rechallenge = Risk of Death

Hypersensitivity (HSR) is a serious allergic reaction. Epzicom should be discontinued as soon as a hypersensitivity reaction is suspected. Epzicom or other abacavir-containing products must not ever be restarted following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Information on this serious allergic reaction has been updated in the Epzicom package insert as well as the patient Medguide/Warning Card.

In Zodiac the incidence of HSR was higher than what had been reported in earlier studies. HSR is currently reported at <5%. This has now risen to 9% (vs. 7% in the BID group). The clinical meaning of this is that 90/1,000 persons will experience hypersensitivity. In light of this, FDA is requiring GSK to work with the community (via conference calls, meetings, etc.) to help educate people on HSR and what to do about it.

HSR may involve a low-grade fever, nausea, vomiting, malaise and rash, in a minimum grouping of three of these. All five of these present upwards of 58% of the time in a 10-trial meta-comparison. Intensity of these symptoms tends to increase with duration of therapy, and resolves upon therapeutic discontinuation. In a safety analysis of Zodiac, Hernandez et al. showed that most symptoms occur within the first 6 weeks, median time to onset being 9 days.


"Truvada sounds like a brand of Hungarian cigarettes. Or did they simply retool BMS' Zrivada (the working title for atazanavir)?"

Truvada is a single pill containing 300 mg of tenofovir disoproxil fumarate (TDF) and 200 mg of emtricitabine (FTC). These two drugs were previously approved individually under the brand names of Viread in 2001, and Emtriva in 2003.

Summary

When administered separately, Viread is one pill once a day, and Emtriva is one pill once a day. Truvada is administered as one tablet once per day, and thus, represents a marginal improvement in pill burden over the two separate components. Like Epzicom, Truvada is not a stand-alone combination -- it still requires additional antiretroviral(s) in order to constitute an effective regimen.

TAG agrees with the accelerated approval of Truvada for use, in combination with many -- but not all -- antiretrovirals, in the treatment of adults with HIV infection. Any triple nucleoside regimens, including those containing Truvada, are not recommended. Triple nucleoside combinations of any sort have not worked well, and are not recommended (without a fourth drug -- either an NNRTI or a PI).

Ziagen (ABC) and Videx (ddI) should probably never be used with Truvada, due to concerns about resistance and ultimately efficacy.

Discussion

The approval of Truvada is based on bioequivalence studies demonstrating similar pharmacokinetic parameters to the individual products. Efficacy results from studies using the combination of TDF and lamivudine (3TC) [3TC has many similarities to FTC] are being extrapolated to support the use of Truvada, specifically the Viread registration studies 903 (TDF+3TC+EFV vs. d4T+3TC+EFV) and 907 (TDF+standard background vs. placebo+standard background), and the Emtriva registration studies 301A (FTC+ddI+EFV vs. d4T+ddI+EFV) and 303 (FTC+stable background vs. 3TC+stable background).

Safety

  • Bone Density

Since osteomalacia (softening of the bones in adults) was observed pre-clinically in rats, dogs, monkeys and juvenile monkeys, close monitoring for bone toxicity in humans was done. There was no evidence of bone abnormalities in two studies, 902 and 907.

The three-year results from 903 were presented this year at Bangkok and are also summarized in JAMA. Study 903 was a Phase III, blinded, placebo-controlled trial comparing TDF to d4T, with a backbone of 3TC+Sustiva. This was an international study, and 26% of the participants were women. Significant bone density decreases occurred during the first year with TDF; decreases leveled off after the first year.

The JAMA article and Bangkok abstracts summarize subgroup findings, which found significant hip (-2.2%) and spine (-2.8%) bone mineral density (BMD) decreases from baseline in women taking TDF (but not women in the d4T group). This analysis did not find significant BMD decreases from baseline in men taking TDF.

In a small study pre-approval, TDF showed BMD issues in children. The pediatric development process stopped. Now, five years later, Gilead promises development of a TDF pediatrics dosing. The liquid that was developed is not bioequivalent, so it will be a pill form. PACTG will begin a 100-person study of this by the end of 2005. Once again, children get short shrift (no pun intended). A Truvada liquid will not be developed.

Closer monitoring along with calcium and vitamin D intake should become routine in the HIV clinic, particularly for post-menopausal women, people with extensive PI experience, and people over 50. Outside of HIV, other risk groups for BMD decreases include Caucasians, Asians, and people who are slender, and/or have a family history of osteoporosis.

  • Kidney

Phase III Viread studies excluded individuals with renal impairment. Subjects were closely monitored for evidence of renal toxicity. No nephrotoxicity was seen and changes in serum creatinine and phosphate were similar to those seen with placebo. However, clinical experience has since turned up evidence of kidney toxicity in some patients taking TDF.

In the 144-week data from 903, no one developed tubulopathy or Fanconi's syndrome (out of 600 patients). 4% of people on TDF had grade 1 serum creatinine toxicity, and less than 2% had grade 2. No other events were reported. Serum phosphorus was the same for both the TDF group and the d4T group, at 4%. All 10/296 patients who developed grade 2 or 3 serum phosphorus increases did so before week 48. Proteinuria increases were similar between groups, at 12% and 17% for grade 1, 6% and 7% for grade 2. Glucosuria, grades 1-3, was reported not above 1% in any group. Creatinine clearance quickened by 5 at week 144 for TDF, and by 19 for d4T.

In the European and Australian Expanded Access Cohorts, 0.3% and 0.6% of people had grade 3 or 4 elevations in serum creatinine and reductions in serum phosphate, although any report was 2.5% (all grades) at 6 months for creatinine, and 18.9% for phosphate abnormalities.

People with abnormal renal function may need to lower the dose of TDF, which of course can't be done with Truvada. What may have to be done is a different timing of medications, TDF every 36 hours or 3 times a week (M-W-F) or never (for those severely renally impaired), while FTC stays QD, which means two different drugs and not the Truvada pill (see package insert). A small Truvada study is planned in renally impaired people.

  • Liver

They have looked at hepatic impairment and there is no adjustment needed. There is a black box warning about HBV flare-ups in the HBV co-infected population. Up to 25% of people when stopping TDF can get flare ups, including grade 4. People with HBV need to be "monitored more closely." Sequencing and safety/efficacy of FTC need to be studied in a co-infected population. A strategy for avoiding this isn't clear.

  • Pancreas

Pancreatitis can be a concern with TDF+ddI. TDF inhibits the phosphorylation of ddI, and as a result, ddI stays in the blood at a higher concentration than is safe. Even with ddI at a reduced dose (the recommended dose of ddI with TDF is 250 mg/day), women, people who weigh less than 60 kg, and women who weigh less than 60 kg all independently have increased risks for pancreatitis. People who already are on the lower dose (250 mg) should probably be lowered again to 125 mg, but there is no recommendation currently.

  • Skin

With FTC, skin discoloration has been seen in up to 6% of patients. Medium time to onset is 88 days (range 10-490 days). Resolution happens without changing treatment in some 17% of those affected. Although no one has discontinued due to this hyperpigmentation on the palms and/or soles, sometimes the tongue, sometimes "other" places, it has been seen in a higher rate in black patients (up to 13% vs. 6% overall). In Asians it is seen in up to 4% of people, and in Hispanics up to 3%. Caucasians get it much less (For the complete report, please visit our Web site.