UK doctor calls for drug companies to work together on once-daily treatments

Companies should work together to create more co-formulations of drugs in order to make once-daily HIV therapy a reality, according to Dr Graeme Moyle of London’s Chelsea and Westminster Hospital, and recognise that competition between companies is harming the interests of patients.

Writing in the new edition of the AIDS Reader, published online by Medscape, Dr Moyle points out that individual drug patents remain in force even when different agents are combined in a new formulation, and new co-formulations are subject to new, potentially shared patents.

“Patents on these combination formulations help companies extend the patent-protected life of molecules” he notes. Thus, even if the patent for the use of a drug as a single agent had expired, its use as part of a triple combination would remain protected by patent, preventing replacement by the generic version. If, however, the patent on the single agent expired before companies reached agreement on the use of an agent in a co-formulation, there would be nothing to stop the other party to the agreement using a cheaper, generic version of the drug and entering into a joint venture agreement with another company.

Patents on several of the key nucleoside analogues in their existing form will start to expire from 2006 onwards (hence the advantage for the companies of moving to new formulations of AZT and 3TC (as Combivir), ddI (as Videx EC) and d4T (as Zerit ER). The original protease inhibitor and non-nucleoside reverse transcriptase inhibitor patents begin to expire from 2010 to 2013 [Source: Patent situation of HIV/AIDS-related drugs in 80 countries. UNAIDS/WHO 2000.

Potential co-formulations of anti-HIV drugs that would require competitors to overcome their differences include:

• Abbott’s ritonavir with protease inhibitors manufactured by Roche, Merck, Boehringer Ingelheim, Bristol Myers Squibb and Glaxo Smith Kline.
• Glaxo Smith Kline’s 3TC with Bristol Myers Squibb’s nucleoside analogues (d4T once daily and d4T twice daily) or Gilead’s tenofovir
• Bristol Myer’s Squibb’s efavirenz with Glaxo Smith Kline’s nucleoside analogues
• Boehringer Ingelheim’s nevirapine with nucleoside analogues from two different companies (d4T and 3TC)
• Bristol Myers-Squibb’s atazanavir with Roche’s saquinavir

Indian and Thai pharmaceutical companies have already co-formulated d4T, 3TC and nevirapine into one tablet, and this three-in-one pill will form the mainstay of antiretroviral programmes in a number of countries, including Thailand and Nigeria.

Drugs which cannot be co-formulated with others are:

• ddI, due to the presence of an antacid buffer
• ritonavir cannot be co-formulated with drugs that are delivered as tablets (nucleoside analogues and non-nucleoside reverse transcriptase inhibitors) because it is a liquid.

He also highlights the results of systematic review published last year by Clinical Therapeutics, which showed a trend towards better adherence with once daily dosing when compared with twice daily dosing (79% vs 69%).

Concern about once-daily therapy has focused on the potential for sub-optimal drug levels if doses are missed or delayed, but the systematic review found that taking doses on time was improved when once-daily therapy was compared with twice-daily therapy (74% vs 58%).

Dr Moyle suggests that these concerns may also be misplaced due to the long half-lives of compounds like efavirenz and tenofovir that have been developed for once daily therapy, and because viral breakthrough takes days rather than hours to emerge during a structured treatment interruption. In effect, it may do less harm to miss or delay a dose of drug given once daily than to frequently miss or delay doses of a drug given three times daily, where small declines in drug levels may be enough to select drug-resistant virus.