Activists call Gilead Sciences on tenofovir alafenamide fumarate
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29.06.2013

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ТreatmentАctionGroup.org
With a phase II clinical trial of tenofovir alafenamide fumarate (TAF) yielding encouraging preliminary results and regulatory planning for TAF-inclusive fixed-dose combinations (FDCs) under way, we are compelled to reach out to you regarding the need for a stand-alone formulation of the drug.
We are concerned that Gilead’s current development plans, as we understand them, might limit TAF to a component of FDCs only. Though this exemplifies Gilead’s leadership in manufacturing simplified and convenient innovator company antiretroviral (ARV) regimens, it overlooks the potential importance of a stand-alone TAF formulation for use in combination with a variety of non-Gilead agents—notably low-cost generic ARVs in low-, middle-, and high-income countries—and as a component of tailored regimens for treatment-experienced people living with HIV, including those with mutated strains conferring resistance to tenofovoir disoproxil fumarate (TDF).
Based on our communications with senior Gilead staff, it is our understanding that TAF’s regulatory plans are limited to an FDC containing elvitegravir, cobicistat, emtricitabine, and TAF; an FDC containing darunavir, cobicistat, emtricitabine and TAF; and, possibly, an FDC containing emtricitabine and TAF. By extension, we are under the strong impression that a stand-alone formulation of TAF is not a part of Gilead’s development plans for the drug.
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Stand-Alone TAF for First-Line Treatment
Activists and the scientific community have known about the potential benefits of TAF, over those of tenofovir disoproxil fumarate (TDF), for twelve years; it is disappointing that its clinical development was delayed until the twilight of TDF’s patent protection. Still, the encouraging interim 24-week analysis from Study GS-US-292-0102, presented at the 20th Conference on Retroviruses and Opportunistic Infections, indicate that TAF shows significant potential as an effective alternative to TDF in first-line therapy regimens, with a potentially reduced impact on bone mineral density, serum creatinine, and eGFR.
The value of a stand-alone formulation of TAF cannot be overstated, and we urge Gilead to figure this into its regulatory plans for the drug, as the potential benefits for millions living with HIV may be significant.
Many providers and people living with HIV prefer FDCs. Yet there is a paucity of prospective clinical trial data supporting their potential advantages—either in adherence outcomes or biomarker endpoints—over once-daily, multiple-pill regimens. Moreover, of the four preferred initial combination regimens for ARV-naive HIV-infected adults and adolescents specified in the U.S. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, two require three tablets once a day and one requires twice-daily dosing. In effect, making TAF available as a stand-alone agent does not necessarily preclude its potential acceptance as a preferred first-line agent.
Going forward, we anticipate that generic efavirenz will be considered as a preferred first-line component of ARV therapy, combined with an innovator FDC (e.g., TDF/emtricitabine) or generic lamivudine plus TDF. Rochelle Walensky, MD, and colleagues project that uptake of these regimens could yield substantial cost savings during the first year of use in the United States alone, a factor guidelines authors, prescribers, people living with HIV, and payers now need to contend with—along with an ARV product’s efficacy, safety, and dosing convenience—in determining use.
We need to recognize that a shift toward generic ARVs is not so much a desire as it is a necessity and that the two-tier access to choice of ARVs in the United States—based on insurance coverage and ability to pay—will possibly widen further, potentially putting premium products such as TAF-inclusive FDCs out of reach for many. In Europe, national health systems have also had to make antiretroviral choices based on cost.
For these individuals, for whom generic-based therapy is either the most desirable or economically feasible, ensuring access to the safest, most effective regimen components is an imperative. It is therefore necessary that stand-alone TAF be studied and made available for use in combination with generic efavirenz, generic lamivudine, and other generic versions of HHS-preferred and -alternative ARVs with patents set to expire over the next five years.
TAF’s potential safety advantages and comparable efficacy, versus TDF, are also considerable in resource-poor countries, where TDF has emerged as a preferred component of first-line therapy. Yet in these settings, where highly effective ARV therapy is available for less than US$200 per patient, per year, the emphasis is now on developing and securing access to stand-alone agents and FDCs with ideal target product profiles: treatment that is simple, tolerable, durable, universal, and affordable. In these settings, there are also considerable numbers of children and adolescents who need treatment. TAF’s relatively low milligram dose—making co-formulation easier—and the possibility of reduced bone toxicity, could make it an important ARV for these individuals.    
At the 2nd Conference on Antiretroviral Dose Optimization (CADO 2), held in April 2013 in Cape Town, there was a very strong interest in TAF as a potential component of an ideal target regimen. We appreciate Gilead’s commitment to ensuring access to antiretroviral products in low- and middle-income countries over the past decade. Through work with generic licensing partners, the Medicines Patent Pool, and other stakeholders, the price of TDF has reduced by almost 75 percent since 2006, both as a stand-alone and in FDCs that are not always the same as the innovator products.  
Should TAF be confirmed to have safety advantages over TDF, its value as a component of low-cost regimens—notably those employing efavirenz and lamivudine—will need to be studied for superiority over existing first-line options. However, this will require the development, evaluation, regulatory approval, and market availability of TAF as a stand-alone component of combination ARV therapy in the United States. We implore Gilead to consider this, considering TAF’s potential in ongoing efforts to further optimize ARV treatment in resource-limited settings.
Stand-Alone TAF for Treatment-Experienced Patients
Also of great potential is TAF’s utility for treatment-experienced people living with HIV. According to in vitro data presented by Gilead researchers at the June 4–8, 2013, International Workshop on HIV and Hepatitis Virus Drug Resistance Curative Strategies in Toronto, 25 mg TAF leads to an intracellular 95 percent inhibitory quotient (IQ95) that is five times higher than the TDF IQ95, which is sufficient to overcome the K65R RT mutation, the multi-NRTI T69S and Q151M mutations, and other thymidine analog mutation (TAM)–inclusive variants.
TAF is therefore not just a promising alternative to TDF in first-line regimens, it is a candidate for second-line and salvage regimens for individuals who have developed HIV resistance to nucleoside/nucleotide reverse transcriptase inhibitors including, but not limited to, TDF. As many of these individuals likely developed resistance to other ARVs included in current and planned TAF-inclusive FDCs, development of a stand-alone TAF formulation is necessary so that it may be combined with other approved and experimental compounds as needed.
We understand that additional trials will likely be needed to confirm the appropriate dose for use in combination with other ARVs, at a cost that must be borne by Gilead alone. This must include complete pharmacokinetic (PK) evaluations. The TAF-inclusive FDCs currently in development contain cobicistat and there is an established relationship between TAF exposure when used in boosted and unboosted regimens. Without a full assessment of TAF’s Cmin, Cmax, and AUC as they correspond with safety and efficacy in an unboosted regimen, generic manufacturers will be unable to demonstrate bioequivalence of TAF when used without cobicistat or ritonavir.
Given TAF’s potential, however, we believe that the additional market value of combining TAF with multiple other regimens would more than cover the cost of these additional trials, and could have tremendous benefits in both high- and lower-income countries.
We appreciate your time and careful consideration of this request. We hope this letter will be followed by a meeting or teleconference to discuss this matter further. In the meantime, should you have any questions or immediate feedback, please do not hesitate to be in touch.