2003 will be the busiest year ever for new drug launches in HIV medicine, with at least five new products (two of them reformulations) reaching the market in North America and the European Union.
One company in particular, Bristol-Myers Squibb, will be highlighting the advantages of once daily regimens as it introduces atazanavir and once daily d4T to the market, joining its existing once daily products efavirenz and ddI.
Atazanavir
Atazanavir, the new protease inhibitor in development by Bristol Myers Squibb, has the potential to become the preferred option for second-line treatment – if the current consensus favouring first-line NNRTI use holds firm in the wake of BMS’s recent head to head study of atazanavir and efavirenz. This study showed that atazanavir was just as effective as efavirenz, the drug currently considered by many clinicians to embody the gold standard in viral suppression and tolerability. However, atazanavir is only likely to replace efavirenz if:
- data emerge from the DAD study indicating that lipid changes on HAART do correlate with an increased rate of cardiovascular events. The DAD study is due to report for the first time at the 2003 Retroviruses conference in February.
- Longer-term follow-up shows that atazanavir has a more durable effect than efavirenz
- Clinical data show that other PIs can be sequenced after atazanavir.
None of these data will emerge overnight, making it unlikely that atazanavir will replace efavirenz any time soon.
Fuzeon
Enfuvirtide (T-20) (Fuzeon), the fusion inhibitor developed by Trimeris and Roche, is likely to be first onto the market, with the biggest hullabaloo and the smallest return on investment. Fuzeon is a miracle of peptide engineering, as well as being the first of a new class of drug, but these very features make it a tricky product to handle.
Fuzeon will be in short supply at first; Roche estimates that it will be able to meet the needs of 15,000 patients next year, and this will only rise to 43,000 by the end of 2005. Initially Fuzeon will probably be licensed and marketed for the group of patients who can assemble one potent regimen with drugs they haven’t taken, or haven’t developed resistance to. As time goes on, Roche will want to develop the market for the first fusion inhibitor, looking at its use in primary infection and after first and second regimen failure.
For Roche, Fuzeon is a loss leader. The company has been able to develop a complicated manufacturing process for a new type of drug, and now has to crack the marketing of the first injectable HIV therapy. If it is successful in that bid, Roche could establish a commanding position in the HIV field during the coming decade as it forges partnerships with the developers of other peptide-based fusion and entry inhibitors. Roche already has partnerships with Trimeris and with Progenics, both of whom are developing the new generation of HIV drugs.
Roche will also re-work the formulation to make Fuzeon easier to take, using lessons learnt from the early development of T-1249, Trimeris’s other fusion inhibitor. The ultimate aim is a pegylated formulation that can be taken perhaps once a week. When T-20 reaches that point, the potential market is likely to be as large as the production capacity will allow, barring any unforeseen long-term side effects.
Telzir
Fosamprenavir (Telzir) is a new formulation of amprenavir designed to reduce the number of capsules that must be taken. Telzir is already available on expanded access for patients who may benefit from a protease inhibitor with a reduced pill burden.
The results of a recently completed study that showed Telzir to be more effective than nelfinavir in people with viral load above 100,000 copies/ml is likely to renew interest in the potential role of amprenavir as something more than a salvage drug, particularly for use as a once daily drug when boosted with ritonavir. However, in the future any protease inhibitor will be compared to atazanavir rather than nelfinavir, and amprenavir will show no distinct advantage in this respect, having a higher pill burden and an effect on lipids - according to the recently reported SOLO study - that is unfortunately typical of all the currently licensed PIs.
Coviracil
Coviracil (FTC, or emtricitabine) is a once-daily nucleoside analogue that looked like it was going nowhere – until Gilead Pharmaceuticals came along to rescue its manufacturer, Triangle Pharmaceuticals, and signalled its intention to combine Coviracil with its nucleotide analogue, tenofovir (Viread) in one pill, presenting a strong challenge to the current market dominance of Combivir, a coformulation of AZT and FTC’s sister drug, 3TC.
Until that time, Coviracil’s only distinct selling point will be its lower propensity to select the M184V mutation after virological failure compared to 3TC. However, once the coformulation is available, a convenient thymidine analogue-sparing regimen will be easier to assemble.
Thymidine analogues (AZT and d4T) have dominated HIV treatment for most of the last decade, but their days may be drawing to a close as more and more clinicians begin to express concern about their potential role in the development of lipoatrophy.
`Cleaner` nucleoside backbones will be a big theme of HIV drug marketing in the next few years, and studies to support – or query - a move towards these backbones will begin to report in late 2003 and 2004.
Zerit ER
D4T once daily (Zerit ER) is a more tricky addition to the HIV armamentarium.
Recently presented prospective studies showing that d4T and d4T/ddI are more strongly associated with fat loss are likely to make patients very reluctant to start treatment with d4T, and to make a success of Zerit ER, BMS will need to convince many people that once-daily d4T results in less lipoatrophy than twice-daily d4T – a brave study for any company to conduct, especially one that has fought as long and hard as BMS against the rising tide of negative evidence.
Alternatively, convincing evidence to show that lipoatrophy is not a drug effect, or that it can be ameliorated by co-therapy with agents such as acetyl carnitine, will be needed in order to encourage a return to Zerit.
Zerit ER is not likely to be launched until midway through the year, because Bristol Myers Squibb needs to tweak the formulation.
Once daily therapy
The move towards once daily dosing will accelerate in 2003, as efforts increase to reduce pill burden and dosing frequency. Time lines for licensing of two other once daily formulations are uncertain; once daily abacavir is still being tested, and once daily lopinavir/ritonavir (Kaletra) may require more study.
Even if it remains unlicensed, off label use of once daily Kaletra will be pioneered by more adventurous physicians who see once daily regimens as the only reasonable objective for HIV treatment.
However, once daily therapy is also likely to provoke increasing controversy in 2003, as more disinterested clinicians join the advocates of once daily treatment in the debate, and begin to ask the uncomfortable questions not heard yet in drug company satellite meetings, such as:
- Is it really true that the dosing frequency will always be the most influential factor in determining a patient’s choice of regimen? Whilst convenience is undoubtedly important, tolerability, pill burden and efficacy are also frequently cited by patients as important considerations.
- Once daily for patients means all the pills at the same time of day, at the time of the patient’s choice. But, once daily currently means juggling the effects of efavirenz (best taken before bed by many patients) with the need to take ddI on an empty stomach. How many people like to go to bed on an empty stomach? And have patients been asked their preferred time for taking medication?
- Does once daily therapy result in better adherence over months and years in HIV patients? We don’t know yet. The only data come from a meta-analysis of studies looking at adherence in other diseases, and this meta-analysis showed a trend, but not a significant difference, between once and twice daily regimens.
- Are the effects of good but imperfect adherence to once daily therapy more serious than a similar level of adherence to twice daily regimens? We don’t yet know.