The FDA has granted a fast-track approval to Gilead's new co-formulated FTC/tenofovir pill. It should be approved by September 12. This is sooner than had been expected but the company says it has sufficient manufacturing capacity to begin shipping soon after that date. The FDA speeded up approval after prodding by treatment activists and a recognition that seemingly small advances, such as co-formulation, are worthy of accelerated approval, because it can mean a big difference in treatment outcomes for people due to the improved adherence that comes with simpler regimens. GlaxoSmithKline (GSK) expects to add a third co-formulated pill to its line-up with a 3TC/abacavir combo that will likely be approved in August. GSK pioneered the combo concept for HIV drugs with their AZT/3TC pill, Combivir, approved in 1997, and followed it with Trizivir (abacavir/AZT/3TC) in 2000.
The FDA acted after issuing a draft guidance document in May 2004 encouraging manufacturers to develop co-formulated regimens. Specifically they were responding to a controversy about the co-formulated pills produced by several Indian generic drug makers that are widely used in treatment programs in the developing world. These medications have been evaluated and "prequalified" by the World Health Organization (WHO) for purchase by private and government sponsored treatment programs. The generic all-in-one pills (nevirapine, AZT and d4T is one common combo) are preferred by programs operating in resource-poor regions because adherence is better, education and dispensing is simplified, and procurement problems are minimized. Also, the generics typically cost only about a tenth what their branded counterparts do. But representatives of the multi-national pharmaceutical industry, perceiving a threat to their markets, have been fostering the impression that these drugs are of inferior quality and have convinced the U.S. government to only buy drugs that have received FDA approval. With $15 billion promised by President Bush for his international AIDS program, known as PEPFAR (President's Emergency Plan for AIDS Relief), the drug companies have a powerful motivation to keep the generic makers out of the loop. But the practical result of their obstruction will be far fewer people receiving treatment and suboptimal outcomes for those who do benefit from the U.S.-sponsored programs.
The FDA, to its credit, stepped into the middle of this argument and has offered a fast track for generic makers to receive FDA review of their products, even if they are not approvable in the U.S. due to patent issues. While many feel that the WHO prequalification process is sufficiently stringent and that FDA review is superfluous, given the political climate and the power of the pharmaceutical lobby, it is unlikely that U.S. dollars will become available without this extra step. Even so, the flap over prequalification of generics may prove to have been a feint, and the U.S. will simply continue to funnel money to the multi-national companies.
One significant byproduct of the FDA's shift in thinking is that unprecedented collaborations between drug companies may now be in the works to produce new co-formulated HIV regimens in the U.S. and Europe. Simultaneous with the FDA statement, a joint press release from Gilead Sciences, Bristol Myers Squibb and Merck announced that they were in discussions to offer an all-in-one pill containing efavirenz (Sustiva), tenofovir and FTC. Merck is involved because they market efavirenz in certain parts of the world as Stocrin. Another announcement from GSK and Boehringer Ingelheim suggested that they were exploring a combination with nevirapine (Viramune), AZT, and 3TC. This is an amazing step forward (after years of protest that FDA regulations and anti-trust laws would make these collaborations impossible) but in a perfect world we would see Sustiva hooked up with Combivir and Viramune paired with Gilead's nukes, too. One size doesn't fit all.
Abbott is looking ahead to a new once-a-day version of Kaletra and expects to show new data later in the year and file for FDA approval in the following months. The company is also cautiously excited about the early results from some small studies that have used Kaletra as a solo antiretroviral agent -- without nuke backup. A company representative recently told investors that this could "change the paradigm for HIV treatment." Hopefully more data will appear at this year's ICAAC conference in October.
The company also says it is working on a new, more stable formulation of ritonavir that will not require refrigeration. The new process is said to employ Abbott's proprietary melt-extrusion (Meltrex) technology, whereby drug molecules are stabilized in a solid dispersion within a special polymer that dissolves at a controlled rate. This could overcome one of the biggest limitations to using Kaletra in resource-poor settings, which has been the need for a cold distribution chain. But don't expect this new product very soon. Typically, pharmaceutical companies start to introduce new formulations only when their patent protections begin to sunset. This allows them extend the market life of their branded products. Abbott's Kaletra patents don't begin to expire until 2012.
One dark cloud over the potential for using Kaletra in other parts of the world: a recent report found resistance to Kaletra developing fairly rapidly in a treatment-naive woman in South Africa who had Subtype C HIV.
After a disappointingly slow start to the roll-out of their premier drug, Fuzeon (T-20, enfuvirtide), following approval in March of 2003, Trimeris is planning to make some improvements. Initially, distribution of Fuzeon was restricted because of limited manufacturing capacity and a desire by Trimeris' distribution partner, Roche, to be sure prescribers and patients had been properly educated about the techniques of reconstitution and injection. Its record-breaking price also slowed acceptance by some third-party payers (and even a year later it is not yet available through every state ADAP program). But the biggest impediment to an enthusiastic reception by patients is the need to inject the drug under the skin of the abdomen or arm, twice a day, every day. A high rate of injection site reactions has been reported, with symptoms ranging from redness to "golf ball size" nodules. Yet for those who can tolerate the routine, the drug has proven remarkably effective, even in people with extensive drug resistance to other classes of antiretrovirals.
Now Trimeris has announced that it is beginning studies of a needle-free injection system for the current generation of Fuzeon, and is moving forward with studies using the drug in a once-a-day regimen, although these improvements may not become generally available until 2006 or after. Trimeris is also pressing forward with the search for second-generation fusion inhibitors with better resistance profiles and more convenient dosing (possibly once a week) and says it may be able to announce a drug candidate by the end of 2004.
The company doesn't believe that the coming wave of oral CCR5 inhibitors will make Fuzeon obsolete. Since up to 40 percent of people with advanced HIV disease will have an X4-using virus that will not be susceptible to the new drugs, Trimeris thinks there will continue to be a place for fusion inhibitors in this population. They cite in vitro studies that show dramatic synergy between Fuzeon and other entry inhibitors when used in combination, and suggest that viral suppression could be achieved with only one tenth of the current dose of the drugs when used individually -- at one tenth the cost. One needle-free shot, once a week, costing only $40 may be just the thing to turn Trimeris' fortunes around.
There are several CCR5 blockers/entry inhibitors in development, including Schering's SCH-D, Pfizer's UK 237, Glaxo's GW873140, and Progenics' PRO140. These drugs are keenly anticipated by people who have developed resistance to all drugs in the conventional classes and the FDA has seemed to signal that they favor larger, Phase III clinical trials in people with multi-drug resistant virus. But there may be a hitch. People with few remaining treatment options tend to be people with more advanced HIV disease. And the longer people have had HIV, the more likely they are to have evolved virus that is capable of using CXCR4, a development associated with accelerated disease progression. These people won't be helped by a CCR5 blocker and they may be put in danger if the drugs force a shift to X4-using virus that speeds up immune deterioration. The possibility of this risk would seem to favor first investigating the CCR5 blockers in a more recently infected population, where the X4 virus will be less common. To do this safely, though, a sensitive and reliable screening test to detect low levels of X4-using virus must be developed. All of this may call for a rethinking of how to test these new drugs.
One fallback position (though it will likely slow enrollment) may be to require Fuzeon for every trial participant as a "safety net" to catch any virus that achieves coreceptor binding. A bonus to this is suggested by a bit of recently reported data that found Fuzeon may also block X4 coreceptor usage, in addition to mucking up fusion.
BI is set to widen access to tipranavir, its salvage-oriented protease inhibitor, by the end of summer. The drug is active against HIV that has been exposed to most every other PI, which will be welcome news to the growing number of people who are searching among limited treatment options to cobble together some kind of "salvage" regimen. Still, and this can't be stressed enough, a drug like tipranavir will work best over the longer term only if it is paired with at least one other drug that a person's HIV is susceptible to. For many, if not most, this is likely to be Fuzeon. One bit of disappointing news about tipranavir has surfaced: it seems to lower the blood levels of other PIs, making them unreliable partners, despite ritonavir boosting. Saquinavir in particular was seen to drop to sub-therapeutic concentrations in the presence of tipranavir. This means that the emerging salvage strategy of using dual boosted PIs may not be possible with tipranavir.
Also, BI has announced that a clinical trial with alovudine (MIV-310), an NRTI targeting multiresistant HIV has recently begun. Continuing BI's foray into salvage therapy, alovudine (say it with a Cockney accent) was licensed from Medivir in July 2003. The trial has been designed to evaluate short-term antiviral activity and safety in patients with HIV resistant to multiple NRTIs. The trial is a dose finding study in patients infected with HIV resistant to multiple NRTIs and with detectable viral load. They will be treated for one month with alovudine added to their standard regimens.
Gilead Sciences is working on a new prodrug technology that has the potential to all but revolutionize HIV protease inhibitor therapy. Prodrugs are "almost" drugs that are converted to their fully active form once they are in the body. The best known example is Glaxo's recently approved Lexiva, a prodrug of their earlier protease inhibitor, Agenerase (amprenavir), which suffered from poor solubility in the gut and required a large number of pills to simply get a sufficient amount of drug absorbed into the body. But Lexiva has a chemical modification that makes it much more soluble in the intestines than Agenerase, so fewer pills are needed to deliver an active dose to the bloodstream. Then, as Lexiva crosses the intestinal wall, the chemical modification is clipped by an enzyme there and the original, active drug goes on its merry way. The same potency is delivered with far fewer pills.
Now Gilead is working on a prodrug concept that goes one -- if not two or three -- steps further. The company's scientists have invented a chemical modification that specifically targets a drug to lymphocytes -- precisely the kind of cells that HIV infects. The prodrug modification is clipped by an enzyme specific to these cells and only turns into its active form once it is in or around lymphatic tissue. Details of the enzyme involved and how all this works have not yet been published. So far Gilead has tested its prodrug concept with a modified form of tenofovir (Viread), which, in a short term clinical trial, effectively lowered viral loads with only a fraction of the usual dose required.
Gilead is also developing a new protease inhibitor that uses the prodrug trick. The chemical modification is tailored to let the prodrug be easily absorbed in the gut, and also let it dodge premature clearance by the CYP 3A4 enzyme system in the liver, so no boosting should be required. The active form of the drug would only get down to business after it is modified in its target cells, where it would be trapped. If this all pans out -- and the PI version has yet to be tested in people with HIV -- protease inhibitor therapy may take a quantum leap in terms of activity, tolerability and pill burden. The inherent efficiency of the prodrug system means that much smaller dosages are required, which could open the door for a three-in-one, PI-based, single pill regimen. The specificity for lymphocytes might mean that collateral toxicity to other cell types could be greatly reduced. In lab tests, the PI appears to have a similar resistance profile to that of tipranavir, which is active against many HIV strains that are multi-PI resistant. It is yet to be determined if the prodrug will reach infected cells in reservoirs or sanctuary sites in the body. Despite the exciting potential, it may be another year before we know if this prodrug technology will survive the boot camp of Phase I trials, and then another year or two until it becomes available, most likely in a tenofovir version first.
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.