The Secretary of the 20th Expert Committee on the Selection and Use of Essential Medicines Department of Essential Medicines and Health Products World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Switzerland

31 January 2015

Re: Rifapentine (Addition) – EML and EMLc Dear Expert Committee: We are writing to express our strong support for the addition of rifapentine to the World Health Organization Model List of Essential Medicines for adults (EML) and children (EMLc). As an agent with the potential to shorten therapy for drug-sensitive TB (DS-TB) and latent tuberculosis infection (LTBI), rifapentine will play an increasingly important role in country efforts to achieve the ambitious targets set forth in the WHO’s post-2015 Global TB Strategy, endorsed by Member States at the 67th World Health Assembly in May 2014.1 We write as members of the Community Research Advisors Group (CRAG), an international, community-based advisory body that works to ensure the meaningful participation and engagement of TB-affected communities in research conducted by the U.S. Centers for Disease Control and Prevention’s (CDC) Tuberculosis Trials Consortium (TBTC). The TBTC conducted Study 26, the phase III trial that established the safety and efficacy of using rifapentine together with isoniazid—the so-called 3HP regimen—to treat LTBI.2 Rifapentine’s use for treating TB infection was recently approved by a stringent regulatory authority (the U.S. FDA) in November 2014.3 Through our advisory capacity to the TBTC, we have participated in the development of rifapentine for nearly a decade. This letter reflects our longstanding experience evaluating the place of rifapentine in TB treatment from the perspective of TB-affected communities. The publication of the first-ever WHO Guidelines on the Management of Latent Tuberculosis Infection makes this an important moment to add rifapentine to the EML and EMLc.4 The Guidelines include the 3HP regimen as one of the recommended regimens for treating LTBI, and many countries may prefer its 3-month duration to the 6- and 9-month regimens of daily isoniazid (6H and 9H) that the Guidelines panel judged equivalent. Access to rifapentine for LTBI treatment will be especially important to the 33 countries and territories covered by the WHO’s TB Elimination Action Framework for Low-Incidence Countries.5 In TB high burden countries, rifapentine’s potential to shorten LTBI treatment could make therapy easier to tolerate and complete for high-risk populations including children. Available clinical evidence also supports the addition of rifapentine to the EMLc. In the application before the Committee, the WHO notes that an extension of TBTC Study 26 enrolled 1058 children between the ages of 2 and 17 years old, which not only confirmed the safety and tolerability of 3HP in children, but also provided evidence of efficacy consistent with

the main TBTC Study 26 population of adults. Sanofi, the manufacturer of rifapentine, is developing pediatric-friendly formulations of 3HP—including a water-dispersible, fixed-dose tablet (isoniazid 150mg/rifapentine 150mg) and a water-dispersible, stand-alone tablet (rifapentine 100mg)—to allow for simple dosing adjustments in younger children. TBTC Study 35 will evaluate the pharmacokinetics and safety of the rifapentine/isoniazid fixed-dose combination in children 0–12 years old, lending further evidence to the safety of rifapentine’s use in pediatric regimens. In 2015, the TBTC will initiate a phase III study to evaluate whether rifapentine can shorten the duration of DS-TB treatment from six months to four months when used as either a substitute for rifampicin or in combination with moxifloxacin in substitution for ethambutol. Should this trial demonstrate the safety and efficacy of a 4-month rifapentine-containing regimen for DS-TB, ensuring that countries are prepared to access rifapentine will become even more imperative for achieving the goals of the WHO’s Global TB Strategy. Including rifapentine on the EML and EMLc will lay the groundwork for facilitating greater access in the future. We draw your Committee’s attention to the public financing that has underwritten the majority of studies of rifapentine.6 Developed through a series public-private partnerships between Sanofi and research groups in the US, UK and South Africa, rifapentine has the potential to become a true “public health good,” and its introduction as a treatment-shortening therapy for LTBI in the US has sparked robust civil society- and patient-led advocacy to ensure the drug’s affordability. A coalition of stakeholders from academic institutions, non-governmental organizations, public health programs and patient groups successfully advocated for Sanofi to lower the price of rifapentine from US $71/32-tablet blister pack to US $32/32-tablet blister pack under 340b public health service pricing.7,8 This 51% price reduction is greater than the historic 20% reduction of the HIV drug azidothymidine (AZT) by Burroughs Wellcome in 1989 and makes rifapentine a more affordable treatment option for US TB programs. A cost-effectiveness analysis conducted after the price reduction found that, at the lower price, using 3HP instead of 9H to treat LTBI is cost-saving.9 The 3HP regimen has the potential to offer even greater cost-savings if on-going research by the TBTC shows that the regimen can be safely self-administered by patients. Under patient self-administration, U.S. TB programs would save $141 per individual treated by switching from 9H to 3HP. From a societal perspective, switching to 3HP would save the U.S. economy $231 per individual treated over a 20-year period. U.S. TB programs have already begun to switch to rifapentine-based 3HP, and the U.S. Federal Bureau of Prisons recently announced that it is now using the 3HP regimen in place of 9H as its preferred option for treating LTBI. While the price of rifapentine outside of the U.S. remains unknown—as the drug has not yet been registered in other countries—the successful price reduction in the U.S. signals that Sanofi is willing to negotiate on price. Additionally, the U.S. price should set a ceiling price for the sale of rifapentine globally, according to the tiered pricing framework Sanofi uses to set drug prices across high-, middle- and low-income countries. We are keenly aware that access to rifapentine outside of the United States remains limited by the drug’s lack of registration with regulatory authorities other than the U.S. FDA. However, we agree with the statement in the application submitted by WHO that adding rifapentine to the EML and EMLc will “greatly widen access to the drug by soliciting and possibly encouraging the manufacturer of RPT to submit approval applications to all relevant regulatory authorities

world-wide.” Our recent communications with Sanofi suggest that the company has already taken steps to register rifapentine in additional countries including South Africa, Peru and Brazil. The addition of rifapentine to the EML and EMLc would encourage moves toward wider registration by sparking greater demand for the drug from national TB programs and country governments. Given the strong clinical evidence of safety and efficacy, coupled with the manufacturer’s willingness to work with civil society and governments on affordability, we encourage your Committee to add rifapentine to the EML and EMLc. We welcome the opportunity to discuss this issue further and ask that you please contact Laia Ruiz Mingote (rmingotelaia@gmail.com) with questions or future communications. Sincerely, The Community Research Advisors Group, Carmen Contreras Dalene von Delft Mike Frick Cynthia Lee Dorothy Namutamba Dao Quang Nguyen Laia Ruiz Mingote Barbara Seaworth                                                                                                                1 Sixty-Seventh World Health Assembly. Global strategy and targets for tuberculosis prevention, care and control after 2015 (WHA67/11). 14 March 2014. Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_11-en.pdf?ua=1. 2 Sterling T, Villarino M, Borisov A, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. NEJM;365(23):2155–2166. doi: 10.1056/NEJMoa1104875. 3  Department of Health and Human Services. Supplemental approval (NDA 21-024/S-011). Silver Spring, MD: Food and Drug Administraiton, 25 November 2014. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/021024Orig1s011ltr.pdf  4 World Health Organization. Guidelines on the management of latent tuberculosis infection. Geneva, Switzerland: World Health Organization, 2015. Available from: http://www.who.int/tb/publications/ltbi_document_page/en/. 5 World Health Organization. Towards TB elimination: an action framework for low-incidence countries. Geneva, Switzerland: World Health Organization, 2014. Available from: http://www.who.int/tb/publications/elimination_framework/en/. 6 McKenna L. Punk’d by pharma: public funds for private products. TAGline. 2014;21(1):14–15. Available from: http://www.treatmentactiongroup.org/tagline/2014/spring/punked-pharma-public-funds-private-products. 7 DeLuca A, Frick M, Lessem E, Kanouse J, Wegener D, Ruiz Mingote L. Activism on rifapentine pricing: removing cost barriers to improve the uptake of tuberculosis research innovations. Public Health Action. 2014;4(4): 1–5. doi: 10.5588/pha.14.0089. 8 DeLuca A, Lessem E, Wegener D, Ruiz Mingote L, Frick M, von Delft D. 2014. The evolving role of advocacy in tuberculosis. The Lancet Respiratory Medicine. 2014;2(4): 258-9. doi:10.1016/S2213-2600(14)70035-9. 9 Shepardson D, MacKenzie WR. Update on cost-effectiveness of a 12-dose regimen for latent tuberculosis infection at new rifapentine prices. Int J Tuberc Lung Dis. 2014;18(6): 751. doi: 10.5588/ijtld.14.0052.