Non nucleoside reverse transcriptase inhibitors (NRTI’s) have long been the backbone of HIV regimens. Have recent advances in new HIV medications created a spiral effect that is resulting in us losing the development of new NTRI’s? Are we losing our backbone?
With the relative ease of which resistance to some NRTI’s develop, it is essential that new and improved NRTI’s are produced. Instead it seems this vital class of drug is being all but forgotten in the wake of new triple and quad combination drugs. The HIV drug development pipeline is low on NRTI’s for the first time in almost twenty years, leaving those with drug resistance, dwindling options for creating new regimens.
The approval of multi drug combinations, specifically Complera, Atripla as well as Gilead’s new Quad drug expected to be approved on August 27, has set a high standard, the results of which may equate to the development of blockbuster only drugs. The AIDS Clinical Trials Groups, NIAID’s, federally funded clinical trials system, which has investigated all of the approved HIV drugs in the U.S., measures the effectiveness of drugs, after safety studies, with inferiority/superiority studies. Basically when testing a drug, the trials are designed to determine which drug is better than the other. If a new drug does not do better than its predecessor it’s considered a failure regardless of its benefit. With the growing rate of drug resistance, is it always necessary for a drug to be ‘better’ than what’s out there. Will this lead to less new NRTI’s for people who need to complete drug regimens?
For new ARV drugs and fixed dose combinations (FDC’s) that have entered phase II or further since 2003, the success rate is an astonishing 32.6%. This is a far cry from the average of non HIV drugs which is around 11%. Because of this high rate of success, pharmaceutical investors have become accustom to great odds and pharmaceutical companies are unwilling to decrease the success rate by creating non blockbuster drugs that may not be ‘the biggest and best new thing’. Thus new drugs that work well but may not exceed expectations, like NRTI’s, are getting left behind for fear of diminishing investor confidence.
Although they report the general robustness of the HIV pipeline, The Treatment Action Group and iBase in The 2011 Pipeline report, state the need for new backbone drugs, “something cheaper than tenofovir (TDF) would be good; a TDF prodrug such as GS 7340 could fit in nicely here. Novel nucleoside backbones which do not use tenofovir or AZT could be helpful, both for toxicity reduction and for greater strategic options in second-line therapy and beyond”.
The HIV pipeline is robust with new classes of drugs like entry inhibitors, maturation inhibitors, PK enhancers and gene therapies. The development of new classes of drugs is essential for those who cannot tolerate ARV combo drugs and as second and third line regimens, but practically as salvage therapies. Some may also lessen the dependence and financial burden of the presently approved ARV’s.
In examining the past years NRTI pipeline, the disparity from year to year is apparent. Few drugs have survived regardless of their ability as a therapy.
Racivir is an NRTI very similar to Emtricbine, made by a company called Pharmasett. In 2011 Gilead Pharmaceuticals bought Pharmacassett. There is little information on Racivir. There are no ongoing or enrolling clinical trials of Racivir and the drug is not listed on Gilead’s website as in their pipeline.
Amdoxivir (DAPD) is a Phase II NRTI made by RFS Limited and appears to no longer be in development. This drug is posted on the RFS website but no information can be found for the past four years.
Festinivir, originally made by Oncolys BioPharma is currently in license negations with Bristol Myers Squibb. Festinivir is a once a day therapy active against viruses resistant to both tenofovir and abacavir,. AIDS Map stated in regards to Festinivir in a December 2010 article “Bristol-Myers Squibb will now take forward the development of the drug, seeking to establish the optimal dose. Phase 1a results indicated little difference in the degree of virlogical suppression between daily doses of 300mg or 600mg, and as 3TC (lamivudine) goes off patent, it could be tempting for Bristol-Myers Squibb to pursue a development path that co-formulates festinavir with its own generic version of 3TC, in a branded nucleoside analogue combination that competes with Gilead’s Truvada (tenofovir and FTC) and Glaxo SmithKline’s Kivexa (abacavair and 3TC)”.
CMX -157 is currently in phase II clinical trials. Chemerix shows Potential to Treat Multi-Drug-Resistant HIV and Improve the Activity and Toxicity Profile of Tenofovir.
Apricitabine (ATC) is a twice a day NRTI made by Avexa. Avexa had discontinued the development of this NRTI in 2010 but reinstated it as a priority the same year and is nearing Phase III development. Numerous clinical trials of ATC show it to be active against multi-drug resistant HIV.
Elvucitabine is in phase II development by Achillion Pharmacueticals. Achillion has signed a licensing agreement with GCA Therapeutics, Ltd. (GCAT) and its Chinese joint venture with Tianjing Institute of Pharmaceutical Research to clinically develop and commercialize elvucitabine in China, Hong Kong, and Taiwan. No further information on its development in the U.S.
An evident lack of Nucleoside analog development by Big Pharma can be seen almost across the board with the exception of Bristol Myers Squibb and Gilead.
Truvada is used by a significant percentage of HIV regimens as is Atripla. Drug resistance to Truvada and Atripla limits future drug options. Approximately 10% of new HIV infections in the U.S. contain strains of HIV already resistant to some HIV drugs.
The continued development of NRTI’s is essential for patients with limited therapeutic options. Forward looking drug development in regards to this class needs to occur before we find ourselves without a backbone.