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Author Topic: Potential new combo meds for once daily dosing  (Read 2033 times)

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Offline veritas

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Potential new combo meds for once daily dosing
« on: June 03, 2009, 05:01:47 AM »

Tapping into combination pills for HIV

Bethan Hughes


Joint venture between GlaxoSmithKline and Pfizer in HIV illustrates opportunities to develop combination pills to challenge current market leaders.

On 16 April 2009, GlaxoSmithKline (GSK) and Pfizer announced that they will create a company focused on the research, development and commercialization of new antiretroviral (ARV) medicines for HIV. GSK will initially hold 85% of the new company's shares and Pfizer will hold the remaining 15%.

A key aim of the joint venture will be to create new fixed-dose combination (FDC) pills that improve adherence to ARV regimens and overcome viral resistance. The company will have access to 17 molecules, including 6 investigational drugs, which could form the basis of novel combinations. GSK already produces three widely used FDCs of nucleoside reverse transcriptase inhibitors (NRTIs) — Combivir (lamivudine (Epivir) and zidovudine (Retrovir)), Trizivir (lamivudine, abacavir (Ziagen) and zidovudine) and Epzicom/Kivexa (abacavir and lamivudine), launched in the United States in 1997, 2000 and 2004, respectively.

Regimens for patients who have recently been diagnosed with HIV and are starting therapy (also known as treatment-naive patients) typically include two NRTIs plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI), co-administered with the PI ritonavir (Norvir; Abbott) to boost their plasma concentrations. In treatment guidelines provided by the US Department of Health and Human Services, the preferred NNRTI is efavirenz (Sustiva; Bristol–Myers Squibb (BMS)), the preferred boosted PIs are atazanavir (Reyataz; BMS), lopinavir (available as a single pill with ritonavir, which is marketed as Kaletra; Abbott) or darunavir (Prezista; Tibotec, a subsidiary of Johnson & Johnson), and the preferred dual-NRTI combination is tenofovir (Viread; Gilead) and emtricitabine (Emtriva; Gilead), also co-formulated into one pill marketed as Truvada (Gilead).

Evolution of a market leader

Perhaps unsurprisingly, the most commercially successful FDCs are Truvada and the first cross-class combination, Atripla (efavirenz plus Truvada), launched in the United States in 2004 and 2006, respectively. "Trizivir and Combivir are past their prime," according to Mansi Shah and Holger Rovini, analysts at Datamonitor Healthcare in London, UK, "while Epzicom is less efficacious than Truvada, requires testing to avoid abacavir hypersensitivity reactions and is associated with an increased risk of cardiovascular events."

According to Norbert Bischofberger, Chief Scientific Officer at Gilead, Foster City, California, USA, 80% of treatment-naive patients with HIV in the United States are now prescribed Atripla. The success of this product can be attributed to its efficacy and once-daily dosing. "Regimens with two NRTIs and efavirenz have essentially never been beaten," says David Cooper, Director of the National Centre in HIV Epidemiology and Clinical Research, affiliated with the University of New South Wales, Sydney, Australia. "There are some caveats — ritonavir-boosted PIs and two NRTIs are generally equivalent but you still see that efavirenz regimens are somewhat better virologically, although the PI regimens are modestly better immunologically," he says.

"The other factor is convenience," continues Cooper. "Co-formulation has really been a major advance for patients and their doctors and you can see, when you look at the sales figures for Atripla, that patients and doctors are voting with their feet." Datamonitor predicts that peak sales of Atripla will be just under US$3.8 billion for the seven major markets (United States, Japan, France, Germany, Italy, Spain and the United Kingdom) by 2012, says Shah.

Richard Haubrich, Professor of Medicine in the Division of Infectious Diseases at the University of California, San Diego, USA, was sceptical when the FDCs were first developed. "Initially I didn't understand the importance of them. But I think, psychologically, for people with a chronic disease, the more compact the regimen, the more easily and quickly patients can take their therapy and achieve their treatment goals. Not all people can benefit from that particular therapy [efavirenz is not recommended for women of child-bearing potential and should be used with caution in patients who have an unstable psychiatric disease, as the drug is associated with central nervous system (CNS) toxicity], but certainly it's a goal for newer drugs and formulations coming down the research pipeline [to have one pill once a day]."

For ARV drug developers, this goal presents considerable hurdles. "The real challenge is finding the three drugs in combination that have the right pharmacokinetics (PK) and the same once-a-day characteristics that would make the combination equivalent to or better than an Atripla-based regimen," says Cooper. Haubrich adds that an FDC competitor to Atripla would also need to have similar or reduced toxicity, such as its effects on lipids, CNS toxicity and the risk to women of child-bearing potential.

When Gilead developed Atripla, the main development challenge was to achieve the stringent PK requirements to prove bioequivalence of the FDC to each single component. "At first we had three different formulations mixed together into one combination that we took into human PK studies until we finally realized that this approach may not be possible. Then we came up with a bilayer, one layer of efavirenz and another of Truvada," says Bischofberger. With this pill, Gilead was able to show bioequivalence to the single components and did not have to complete any additional clinical trials prior to regulatory approval.

Another hurdle for creating cross-class combinations such as Atripla could be the need to collaborate with another pharmaceutical company. However, for Gilead, says Bischofberger, the only challenge of working with BMS was related to decision making. "It just puts in another layer of review and approval as documents have to be signed by both organizations. It wasn't a big deal; it just takes some getting used to."

Upcoming FDCs

The only other FDC currently in clinical trials (in the United States and the European Union) is Gilead's once-daily FDC pill that consists of Truvada, their investigational integrase inhibitor elvitegravir (licensed from Japan Tobacco in March 2005 for Gilead to develop and commercialize the drug in all countries, excluding Japan) and GS 9350, a heat-stable boosting agent that increases drug PK by inhibiting the cytochrome P450 3A (CYP3A) metabolic enzymes. This 'quad' pill is currently in a Phase II trial versus Atripla in treatment-naive patients with HIV.

During the early stages of development of elvitegravir, Gilead discovered that, to achieve a PK profile that would allow once-daily dosing, the drug had to be boosted with low-dose ritonavir, which inhibits CYP3A enzymes and thereby increases the half-life of drugs metabolized by these enzymes, such as other PIs. The regulatory agencies initially advised Gilead that their ritonavir-boosted integrase inhibitor, together with NRTIs, could only be developed for use in treatment-experienced patients who were already taking a boosted PI-based regimen. "One of the concerns about using low-dose ritonavir with elvitegravir in a regimen that does not contain another PI is that, if you fail that regimen, you could have not only integrase inhibitor resistance but also protease inhibitor resistance," says Haubrich.

However, the only real commercial opportunity for ARV therapies is to develop a product for treatment-naive patients, says Bischofberger. "When patients start treatment today with a combination like Atripla or a boosted PI regimen, there is usually a great treatment success rate for 5–10 years, so it's no longer a big opportunity to study treatment-resistant patients," he says.

Cooper agrees: "We did have a lot of patients with multiple drug resistance [5–7 years ago] because they were getting serial monotherapy in the early '90s and unboosted PIs in the late '90s. But now those patients are doing extremely well with new drugs like darunavir, maraviroc [Selzentry; Pfizer's CC-chemokine receptor 5 (CCR5)-entry inhibitor], etravirine [Intelence; Tibotec's NNRTI] or raltegravir [Isentress; Merck's integrase inhibitor] ... If a pharmaceutical company is going to make money in this area, they have to move their product into earlier lines of therapy — that's the challenge."

Gilead therefore decided to develop its own CYP3A inhibitor to act as a booster in the quad pill for treatment-naive patients. "We looked at this as an opportunity to come up with a really good booster, and that's what we have now preclinically. It is more specific than ritonavir, it is as potent as ritonavir in terms of boosting, it doesn't need refrigeration and we can co-formulate it into a single pill," says Bischofberger. Cautiously, Haubrich adds, "We haven't seen quite enough data yet, but we hope that this new PK enhancer might have fewer of the downsides that ritonavir has in terms of lipids and other problems, including gastrointestinal toxicity."

In addition to the quad pill, Gilead is currently investigating the ability of GS 9350 to boost atazanavir. The company reported in a press release in April that it plans to initiate a Phase II clinical trial later this year evaluating the safety and efficacy of GS 9350-boosted atazanavir compared with ritonavir-boosted atazanavir, each in combination with Truvada. If successful, this could bring Gilead closer to solving another ARV challenge: to create a once-daily regimen in a single pill that contains a boosted PI. "There are probably many reasons why those haven't been developed," says Haubrich, "but it would be nice to have a fixed-dose combination with a PI."

Another company developing an alternative PK enhancer to ritonavir is Sequoia Pharmaceuticals. At the 16th Conference on Retroviruses and Opportunistic Infections, in February 2009, in Montreal, Canada, Sequoia presented in vivo preclinical data indicating that their PK enhancer SPI-452 boosted the levels of the three PIs saquinavir (Invirase; Roche), lopinavir and atazanavir to an extent comparable with that of ritonavir. They also presented results of a Phase I trial that showed that SPI-452 significantly increased the plasma concentrations of the PIs atazanavir and darunavir.

Pfizer has also initiated a Phase I clinical trial that will evaluate the safety and efficacy of its PK enhancer PF-3716539 as a CYP3A4 inhibitor, as well as assessing its interaction with darunavir or maraviroc. PF-3716539 is included in the pipeline of products to which the GSK/Pfizer joint venture will have access for the development of new FDCs (Table 1).

The clinical success of raltegravir shows that pursuing integrase inhibitors to include in a new once-daily FDC makes good commercial sense. "The Merck data on raltegravir versus efavirenz in naives was very positive and there were less CNS side effects in the raltegravir group. But raltegravir is given twice daily and no-one has announced any plans for co-formulation, so it will still be after Atripla in clinicians' minds," says Cooper. Gilead hopes that the new pill will have the same efficacy but better tolerability than Atripla and will therefore become another desirable once-daily FDC to help the company maintain its market leader status. If the quad pill is successfully developed, Datamonitor Healthcare predicts that it will achieve $3.5 billion peak sales in the seven major markets by 2018, says Shah.

The NRTI-sparing challenge

To try to challenge Gilead's dominance of the ARV therapy market, developers are testing regimens that avoid Truvada altogether. "In general there is a trend towards trying out NRTI-sparing regimens," says Rovini. For example, in a Phase II trial in treatment-naive patients, Schering–Plough is assessing the efficacy of their investigational CCR5-entry inhibitor vicriviroc combined with boosted atazanavir versus Truvada plus boosted atazanavir. Also, Merck and Tibotec are recruiting patients for a Phase IV trial to determine whether a combination of raltegravir and boosted darunavir is as effective as Truvada plus boosted darunavir in treatment-naive patients.

"Our choices for first-line NRTIs are reducing because of toxicity, such as potential increased risk of cardiovascular disease, so having NRTI-sparing regimens might be helpful," says Haubrich. If these NRTI-sparing regimens with new drug classes (such as the integrase inhibitors and CCR5 antagonists) and improved drugs in existing classes (such as boosted darunavir) prove to have similar potency and better tolerability than combinations that include Truvada in treatment-naive patients, there could be new opportunities for co-formulating FDCs.

GSK and Pfizer have the potential to develop such FDCs through their joint venture. "If you look at their pipeline, it is all early stage [table 1], but the products would be second to market so GSK and Pfizer can see how successful Merck and Tibotec are with their integrase–PI combination or how Schering–Plough and BMS fare with their CCR5 inhibitor and PI combination. They could do similar things with their own drugs — they have the integrase inhibitor and CCR5 inhibitor in Phase II. And they've got their own PK enhancer, so they could combine their own PI, Lexiva (fosamprenavir) with the CCR5 inhibitor or the integrase inhibitor," says Rovini.

Despite the popularity of the FDCs, Rovini cautions that future cost pressures may lead clinicians to change prescriptions from Atripla back to Truvada plus generic efavirenz after the US patent for Sustiva expires in 2013. Also, a number of FDCs are being developed by Indian manufacturers under the US President's Emergency Plan for AIDS Relief (PEPFAR) programme. "They are FDA-approved under PEPFAR, which means that when US patents expire they could launch these novel combination drugs in the United States," says Shah. Although FDCs may come under cost pressures when US patents expire, it is likely that a reversion to single component regimens would be met by considerable protest from patients and clinicians alike. "Once-daily dosing for the first regimen is clearly the standard of care now," concludes Haubrich.



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