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Five New Drugs Enter the Homestretch

December 2002

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

It's a busy season for the folks at the FDA who approve AIDS drugs. At least five new products have passed or are soon to pass under their scrutiny on the way to your medicine shelf. And while none is expected to cause a treatment revolution, each new drug offers something that will surely improve life for someone living with HIV. The question is, "who?" Soon, with more than 20 products to choose from, it will become harder to match up the right drugs with the right people.

The U.S. Food and Drug Administration (FDA) is the federal agency charged with assuring the public that its medicines are as safe and effective as promised and that the claims made by prescription drug makers reflect what the science shows. Before the FDA approves a drug for sale in the U.S., it conducts a thorough review of all the research results that the sponsor company has submitted from human, animal and laboratory studies. After the Agency has received the data (altogether known as an NDA, for New Drug Application), it must review the application within 10 months or, as has often occurred with HIV drugs, it may decide to grant a special six-month priority review to help speed important new drugs into use.

The current crop of drugs contains a mixed bag ranging from a first-of-its-kind fusion inhibitor that blocks HIV in a completely new way, to a kinder, gentler protease inhibitor with (hopefully) fewer toxicity problems, to a couple of renovated formulations that should give a new lease on life to existing drugs. Throw in the merger of two small HIV drug developers with synergistic product lines, and the outlook looks brighter for serving people with diverse treatment needs with ever more finely tailored options. Call it the boutiquing of HIV therapy.

But while any advancement in tolerability and convenience is welcome, there is still concern that further upstream the drug pipeline is dry. Some of this concern comes from drug companies who perpetually stir fears that research will cease unless prices continue their upward march. There is also nervousness that rumored mergers between huge pharmaceutical companies such as GlaxoSmithKline and Bristol-Myers Squibb will kill the competitive drive to improve HIV treatment. But while failure to innovate and take risks will certainly hurt our chances of ever seeing another revolution like HAART, there are signs that progress continues on drugs to attack new viral targets such as integrase and that stronger and safer versions of current generation drugs are coming.

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In the meantime, here's what's on the FDA's docket right now.


Zerit XR

Zerit XR is an extended-release formulation of d4T that had Champagne corks popping at Bristol-Myers Squibb (BMS or Bristol) when word of FDA approval arrived on New Year's Eve last year. The company is finalizing the label and ad copy in consultation with the agency. Next comes the advertising blitz promising a carefree world of once-daily dosing. But go slow: there are still a lot of questions that have to be answered. More convenient dosing may well be the wave of the future, but it may not be the right choice for everybody all at once.

The recommended dose of Zerit XR is 100 mg once daily for individuals weighing at least 132 pounds and 75 mg once daily for individuals weighing less than 132 pounds. A comparison between extended release Zerit and conventional Zerit in a clinical trial involving nearly 800 people demonstrated comparable efficacy and tolerability. While the total amount of drug present in the blood over time obtained from Zerit XR was similar to that obtained from immediate release Zerit, the initial peak concentration that followed each dose of the drug was lower with the XR version. This may be good news if the drug's tolerability or toxicity (chiefly peripheral neuropathy) profile can be improved by smoothing out those transient peaks of overly high drug concentrations. On the worrisome side, we have yet to see what happens to blood levels of Zerit XR between 24 and 48 hours after a dose. We still don't know if a skipped dose that results in a full day of exposure to sub-therapeutic drug levels will be more likely to allow resistance than 12 hours of inadequate viral suppression.

The timing of Zerit XR is worth examining. With the first patents on conventional Zerit expiring in 2008, this improved formulation gives BMS a new lease on an old drug far beyond the six years they had left. Remarkably, BMS also introduced the EC version of their Videx product with only six years left on the original patent in 2000. Could these improved formulations have hit the market sooner? Or does "extended release" carry more meaning than we think?


Fuzeon

Fuzeon (T-20) is the Godot of HIV therapy. The long awaited, much delayed, first agent of a completely new method of suppressing HIV infection is definitely at the top of the FDA's to-do list for the New Year. Accepted for priority review in October, the Agency has to deliver a verdict by March. And despite T-20 being a difficult-to-manufacture injectable drug, with inconvenient twice-daily dosing and unpleasant injection-site reactions as a prominent side effect, its novelty and unique value for people with resistance to all available regimens means that approval of Fuzeon is virtually a sure thing.

But a green light from the FDA won't be the end of the wait for some. Because of manufacturing difficulties, Hoffman La Roche (Roche), the drug's sponsor, has announced that availability of Fuzeon will be limited during the first year following approval. Allocating the drug fairly may be a challenge since there seems to be a gap between those in greatest need and those who might expect the greatest benefit from the drug. In a large clinical trial, people who added Fuzeon to a suite of other drugs active against their virus had a much better response than those who took it on top of their worn-out regimens. The catch here is that people with other options may not want to go through the unpleasantries of twice-daily injection, while those with no other options may not find Fuzeon the life preserver they need.

Another block to the widespread use of Fuzeon may be its breakthrough price. Rumors are rife that Roche will set a new record when pricing T-20. Because of budget shortfalls in many states' AIDS Drug Assistance Programs (ADAPs), it seems increasingly likely that coverage of Fuzeon may be limited to those with private insurance willing to pay for it. Some states have adopted a "budget neutral" policy about adding new drugs to their formularies and if plugging T-20 into the typical regimen means significantly boosting the cost of treating HIV, then people dependent on state assistance may be out of luck. Roche has promised that no one who truly needs Fuzeon will go without, but details of their plan to patch over access problems remain to be seen.


Atazanavir

Atazanavir is a nearly next-generation protease inhibitor from BMS making a big claim that may revitalize the class. The worrisome cholesterol and triglycerides abnormalities that have hit most long-time users of PIs seem blessedly absent in those who've received atazanavir in clinical trials. Going straight for the competition, atazanavir took on Sustiva (efavirenz), the once and future PI alternative, in a nearly year-long head-to-head comparison involving over 800 people starting HIV therapy for the first time. Of course, since BMS subsequently bought Sustiva when it acquired DuPont Pharmaceuticals, it has been in competition with itself, and the company clearly hopes to find itself holding the premier agents in both the non-nuke and PI classes of therapy. But that's not all. As the first daily-dosed PI, atazanavir will climb aboard Bristol's unstoppable once-a-day juggernaut, joining Sustiva, Videx EC and Zerit XR. Bristol filed the paperwork for FDA approval in December and if they made a good case for priority approval, atazanavir could be commercially available by June.

In the trial, atazanavir proved comparable to efavirenz in its ability to bring down viral load below 400 copies in most trial participants. There are also some tantalizing early indications that atazanavir may retain activity after resistance to other PIs has developed -- and even a suggestion that resistance mutations to atazanavir may possibly increase viral sensitivity to other PIs. While much more data is needed before making definite claims, it may behoove people with extensive resistance who are considering Fuzeon to wait a bit longer and add atazanavir at the same time. For those who can't wait, see the table below about early access programs.

Atazanavir holds no breakthrough in potency, since only about half of those who had viral load suppressed below 400 copies also went below 50 copies. And there is an apparently benign but unpleasant side effect that raised bilirubin levels and turned some people yellow with jaundice. Stopping the drug got the yellow out, but that's a poor justification for treatment interruption. These may be quibbling points in light of evidence that people with elevated cholesterol due to HIV therapy saw numbers normalize after going on atazanavir. Although long-term follow up must be conducted to be sure, the promise alone that atazanavir might dramatically lower the risk of heart disease or diabetes in people taking lifetime HIV therapy could mean eager acceptance after approval. Still, one nagging question returns, "What's up with that bilirubin?"


Fosamprenavir

On the same day in December that Bristol filed for FDA approval of atazanavir, GlaxoSmithKline (GSK or Glaxo) submitted data to support the approval of their PI hopeful, fosamprenavir (also known simply as "908"). Although Glaxo surely petitioned the Agency for priority review of 908, gaining that favor doesn't seem likely, which would mean approval by as late as October.

Why the lack of enthusiasm? To begin with, fosamprenavir isn't so much a new drug as it is a tricked-up version of Glaxo's Agenerase with a VIP pass to get into the bloodstream more efficiently. Agenerase (amprenavir) was approved by the FDA in 1999, but hasn't found many converts, mainly because of the need to gag down eight big fat pills twice a day. The problem is that very little of the drug in the pill gets from the intestines into the blood. But fosamprenavir is specially designed to be taken up by the gut and then immediately processed into amprenavir before being sent to the bloodstream. The "fos" means the difference between 16 pills a day and only two pills a day. Factor in improved tolerability and fewer side effects and it could be that amprenavir is finally ready for prime time. But is this too little, too late?

On its own, fosamprenavir given twice a day can produce viral suppression comparable to nelfinavir without the troublesome rise in triglycerides. But once-a-day is all the rage, and 908 can go that route too -- with a little boosting from ritonavir. Unfortunately, ritonavir brings more pills, elevated triglycerides and tolerability problems. And with atazanavir looming, nelfinavir is no longer the benchmark PI. Still, there may be benefits for some people lurking within amprenavir's resistance profile, although what that might be remains murky. There have been a few suggestions about a lack of cross-resistance between atazanavir and amprenavir. If so, then the possible benefit of using the two together should be explored for people with extensive and complicated treatment histories. This drug may not be for everyone, but those it helps will be happy to have it.


Coviracil

Coviracil (FTC) is another drug wending its way through the FDA. Its maker, Triangle Pharmaceuticals, filed for approval in September and, under standard review, the drug should become available by summer. But in a surprise, what went in as a Triangle drug is going to come out under the brand of Gilead Sciences, the makers of recently approved Viread, who announced the acquisition of Triangle in December.

Coviracil is difficult to distinguish from Glaxo's Epivir (3TC) although some have detected a possible resistance advantage, and in comparison with Zerit, Coviracil was shown more potent and less toxic. But the exciting potential for Coviracil under Gilead's roof is as part of a new once-a-day, all-in-one-pill alternative to Glaxo's Combivir as the nucleoside analog backbone of choice. In other words, no AZT.

The approval of Coviracil is step one. Already Gilead is said to be working on performing the necessary studies that the FDA will want to see when they are asked to approve a coformulated Viread/Coviracil. Hopefully, this data will be in the Agency's in-box by next year.


Next Steps

Gaining FDA approval for this bundle of drugs will be a nice step forward, but the story won't end there. We will have to wait to see how doctors and people with HIV will actually use these new drugs. Big budget ad campaigns in magazines and on bus shelters will certainly have their say, but personal experience and the constantly shifting consensus about therapy usually prevails. First, though, more data from clinical trials are needed to develop our understanding of these new options, and the next wave will come at February's Retrovirus Conference in Boston. The conference halls will be buzzing with opinions, but nothing is as convincing as research well done. In the years ahead, as these newcomers become established, we can expect them to be knocked down by newer -- and merely newly tweaked -- drugs to come. One question still begging an answer is, with twenty-plus HIV drugs to choose from in the U.S., what does our embarrassment of riches mean to the 90 percent of HIV-positive people in the world who have access to none?


Expanded Access Program for Atazanavir
Bristol-Myers Squibb is currently enrolling patients in an Early Access Program (EAP) to provide the investigational protease inhibitor, atazanavir, to eligible patients infected with HIV. An EAP provides medicines to patients in need of alternative therapy prior to the medicine's approval. Atazanavir is in Phase III clinical development as a product to treat HIV infection in combination with other antiretroviral agents.

HIV-infected patients who have experienced treatment failure with other available antiretroviral agents and who require alternative antiretroviral agent in order to construct a new treatment regimen may be eligible to participate in the atazanavir EAP. Reasons for treatment failure may also include antiretroviral resistance, intolerance or adherence problems. Physicians must use atazanavir in combination with two or more new or recycled antiretroviral agents. In addition, patients must meet other protocol-specified eligibility criteria. Pharmacokinetic interaction and safety data on the use of atazanavir with other antiretroviral agents (i.e., protease inhibitors, non nucleoside reverse transcriptase inhibitors) are outlined in the protocol.

Patients may be enrolled in the atazanavir EAP through physicians only. U.S. physicians may call 1-877-7-BMS-EAP (1-877-726-7327) or visit www.atveap.com for more information on the atazanavir EAP.

No expanded access programs for Coviracil or fosamprenavir have been announced. An expanded access program for Fuzeon has closed to enrollment.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 
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