Will once-daily Kaletra be enough to see off the threat of Reyataz?

Since the first case of HIV/AIDS was reported in 1981, HIV infection leading to AIDS has been a major cause of illness worldwide, with an estimated 40 million people currently infected with the disease. Indeed, in some parts of the world, HIV is associated with a high mortality rate, causing almost 3 million AIDS-related deaths.

However, in the developed world, the past two decades have witnessed rapid advances in the clinical management of HIV, with the development of antiretroviral drugs that effectively delay the progression from HIV to AIDS by reducing the levels of HIV in the body. With 26 marketed antiretroviral drugs, the HIV pharmaceutical market can be considered relatively mature, and, therefore, competition for market share is intense.

In addition to efficacy, attributes that increase drug uptake are a superior side effect profile, low pill burden and low dosing frequency. As patients are living longer, and HIV moves towards a chronic manageable disease, quality of life issues are becoming increasingly important in antiretroviral prescription choice. Indeed, decreasing the pill burden is not only key to ensuring a minimal impact on a patient's lifestyle, but is also vital in maintaining patient compliance with their drug regime.

Greater patient compliance

The last four years have seen a number of antiretrovirals with lower daily dosing and fewer pills being launched. In the nucleoside reverse transcriptase inhibitor (NRTI) class for example, Gilead's Viread (tenofovir) and Emtriva (emtricitabine) offer the convenience of one pill, once a day, while the fixed dose combinations of GSK's Combivir (lamivudine/zidovudine), Trizivir (lamivudine/zidovudine/abacavir) and Epzicom (lamivudine/abacavir) and Gilead's Truvada (tenofovir/emtricitabine) provide the benefit of taking two or three components of a drug regime in one single tablet.

The pill burden has been a particular issue for the PI class, with older drugs requiring up to 18 pills to be taken daily. However, in 2003, BMS's Reyataz (atazanavir) was launched, offering once-daily dosing and an improved side effect profile. Its uptake has been relatively rapid, with sales of $81 million in 2003 and $369 million in 2004. In fact, the drug now has the second largest share of PI sales, at 19.2% class share, behind Kaletra, with 35.6%.

Kaletra, manufactured and marketed by Abbott Laboratories, was first approved under accelerated review in September 2000 and granted full approval in November 2002. The product, which is the only fixed dose combination PI, and combined the active lopinavir with the booster component ritonavir, is currently approved for adults and children older than six months. Although considered one of the most potent antiretroviral drugs currently on the market, with a superior resistance profile compared to other PIs, it requires six pills twice daily, and is associated with a range of adverse effects.

Once-daily Kaletra

Although Kaletra is still the leading PI, generating sales of $682 million in 2004, the rapid uptake of Reyataz has affected sales growth - for example, between 2003 and 2004, sales grew by 9.3%, compared to 30.9% between 2002 and 2003. To combat the threat of Reyataz, Abbott has reformulated Kaletra to create a once-daily regime. Based on favorable results of a study comparing once-daily Kaletra in combination with the NRTIs Viread and Emtriva to twice-daily Kaletra as part of the same combination, Abbott was granted a supplemental new drug application (NDA) by the FDA on May 2, 2005. The European MAA, for which an application had also been submitted in July 2004, is still awaited.

Datamonitor's research found that physicians are unsure how successful this reformulation will prove to be. It is clear from reading interviews with industry professionals that opinions are split:

"It [once-daily Kaletra] won't change anything. I don't think it is a good idea to have QD [once daily] Kaletra," said a French interviewee, "It will be a negative aspect on the QD approach while BID [twice daily] is very convenient for the patients. So I don't think moving to QD will make any change in the market."

Contrasting opinion

In contrast an opinion leader from argued: "It will have a great impact because I think in the next few months, maybe the next few years, the main competitor to Kaletra in the field of PIs will be atazanavir and probably mainly in PI-naive patients, not so much as second line PI or rescue PI, experienced patients. But in those patients in whom you think PI may have a role atazanavir has a lot of advantages to be used as a first PI and one of them is you can give it in the QD schedule."

However, some have voiced concerns about the reformulation and its side effects:

"I think it is coming too late. I think that the PK profile once daily is not as good as twice daily. And I think that you have other PIs which are designed for once daily and I don't really think that the once-daily formulation is going to help," believes one German opinion leader.

"The once a day study with Kaletra, the 418 study, while it didn't show a virological disadvantage relative to twice a day dosing, what it did show was that there was a tolerability disadvantage with the rates of grade 3 diarrhea going from 6% to 16%," says a UK opinion leader.

Indeed, once-daily dosing is not perceived as the key advantage of Reyataz; rather it is the decreased incidence of lipid side effects which has led to its rapid uptake in the last two years. As such, while once-daily Kaletra provides a definite benefit for many patients, it is unclear how significant a boost this reformulation will be in protecting Kaletra from competition from Reyataz.

A key issue is the dosing frequency of other antiretrovirals commonly used in combination with Kaletra. For example, physicians are reluctant to prescribe combinations that include once-daily and twice-daily pills, preferring to stick with simple regimes. In cases where Kaletra is prescribed with the other once-daily drugs, such as Viread, Emtriva, Epzicom and Truvada, the once-daily reformulation will surely be welcomed. However, when it is used in combination with twice daily drugs, such as Combivir, it is less likely that physicians will switch to the new formulation.

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