Pipeline Report » 2019 HCV Treatment PIPELINE REPORT 2019 Waiting for Generics By Annette Gaudino Since the adoption of theWorld Health Organization (WHO) health sector strategy to eliminate viral hepatitis as a public health threat, civil society has demanded care for all those living with chronic hepatitis C virus (HCV) infection. Sofosbuvir was approved in the United States as the first interferon-free curative treatment for HCV in December 2013. Yet in the years since, only 5.5 million of the 71 million people worldwide living with chronic HCV have been treated. And while Egypt and a handful of high-income countries make slow progress toward the WHO interim 2020 goals, global 2030 targets continue to recede over the horizon, with significant progress requiring more cures each year than new infections. This is an almost insurmountable challenge when drug use remains criminalized, and extrajudicial violence and social exclusion are the norm for people who inject and use criminalized substances. Despite overwhelming evidence of the efficacy of pangenotypic direct-acting antivirals (DAAs) across patient subgroups and among people actively injecting and using criminalized substances, barriers to universal treatment access remain stubbornly in place. Too often, national health ministries require in-country clinical trials to prove efficacy, and payers and providers require sobriety in order prescribe. Originator companies continue to ignore middle-income country markets or delay registration for generic manufacture under voluntary licenses. Multinational trade agreements, in particular as pursued by the United States Trade Representative, seek to strengthen patent monopolies and threaten the sovereignty of governments that put their people over corporate profits. Regional procurement mechanisms are weak or non-existent, further disadvantaging smaller, poorer nations with limited resources to invest in treatment scale-up. Nevertheless, the global supply chain for low-cost DAAs is robust, with generic sofosbuvir/velpatasvir manufactured in India for the domestic market now deemed cost-effective. Industry engagement is needed to bring affordable generic glecaprevir/pibrentasvir (G/P) to market. Indications for the current class of DAAs continue to expand with the recent FDA approval of G/P for adolescents, the first pangenotypic regime available for patients aged 12–17 years. In 2020 results are expected from ongoing trials in pregnant persons for cure and prevention of vertical transmission. China also reported phase II/III trial results showing high cure rates from three novel DAAs combinations abstract( #999, #1000 and #1001). However, these formulations are unlikely to be available outside of China. Emerging difficult to treat GT4r and non-1a/1b, non-4a/4d subtypes have been observed in patients in sub-Saharan Africa and among African migrants in Europe. Identifying and effectively treating these patients will challenge under-resourced HCV programs in African countries, and programs serving migrants from the region. This also highlights the public health impact of the lack of ethnic and geographic diversity in clinical registration trials. 1 PIPELINE REPORT 2019 Recent modeling studies suggest that achieving the WHO 2030 target of diagnosing 90 percent of people living with HCV infection is a prerequisite for achieving elimination goals, even with universal treatment access and comprehensive harm reduction services in place. Without reduction in the high cost of diagnostics—for both patients and public health systems—low- and middle-income countries (LMICs) will simply not benefit from low-cost generics. The scope of the challenge we face is such that all points in the care cascade must be affordable for LMICs in order to bring cure to all. The refrain should be familiar by now: we possess the therapeutic tools to eliminate HCV infection as a public health threat—at affordable prices and across all genotypes— if they can be delivered before patients develop decompensated cirrhosis. We also know these tools are effective among the key population driving incidence: people who inject drugs. Shall we go forward with this knowledge? Or shall we continue to wait? Advocacy points For companies: r Ensure generic sofosbuvir and daclatasvir is registered and available for sale in all countries covered under voluntary licenses. r Accelerate registration and access to generic glecaprevir/pibrentasvir (G/P) via voluntary licenses—and facilitate access to branded product for patients who would benefit (such as those with end-stage renal disease). r Complete phase II/III clinical trials of sofosbuvir/ravidasvir (SOF/RAV) in genotype 5 and 6 patients to confirm pangenotypic activity. r Complete phase II/III clinical trials of sofosbuvir-based regimes in patients younger than 6 years and weighing less than 17 kilograms. r Conduct phase II/III clinical trials of pangenotypic regimes—including sofosbuvir/daclatasvir (SOF/DAC), and SOF/RAV—in patients younger than 17 years and children weighing less than 35 kilograms. r Conduct phase II/III clinical trials of G/P in patients younger than 12 years and weighing less than 35 kilograms. r Complete phase II/III clinical trials in pregnant people to assess the safety and efficacy of DAAs as curative treatment and prophylaxis to prevent vertical transmission. r Conduct phase II/III trials of short-term (less than eight-week) treatment courses for acute infection. 2 3 PIPELINE REPORT 2019 For governments: r Waive any requirement for in-country clinical registration trials for proven DAA combinations from validated generic manufacturers. r Decriminalize the possession and distribution of harm reduction tools and interventions: syringe service programs, direct purchase and possession of syringes, and safe drug consumption spaces/safe-injection facilities. r Ensure competition between generics manufacturers. r Explore all available means to accelerate and expand access to generics: compulsory licenses using TRIPS flexibilities or other legal approaches, parallel importation, and patent challenges. r For high-income countries, refrain from retaliatory trade practices in response to the use of TRIPS flexibilities for access to medicines. r Enact opt-out HCV screening of all people upon incarceration, with robust linkage to care during incarceration and after release. r Align public health system payment/reimbursement to expand HCV screening beyond individuals born between 1945 and 1965 (the birth cohort) and people with identified high risk, with particular attention to pregnant people. For donors: r Commit to multilateral and bilateral funding for universal access to generic DAA treatment in LMICs. r Facilitate the integration of disease-specific programs by supporting treatment of HCV-monoinfected people who are at risk for HIV and other infectious diseases. r Expand access to regional and central procurement platforms, such as the Global Fund’s Pooled Procurement Mechanism, beyond HIV, TB, and malaria, at a minimum for DAA treatment for those with coinfections. 3 PIPELINE REPORT 2019 Table 1: Branded DAAS Compound Class/Type Company/Sponsor Patient Population Status Genotypes 1a/b, 2, 3, SOF/RAV NS5B/NS5A inhibitor DNDi/Pharco 4, 6; HIV coinfection; Approval pending PWID STORM-C-1 phase II/III trial, stage 1, of 12 weeks sofosbuvir/ravidasvir in non-cirrhotic patients and 24 weeks in cirrhotic patients r N = 300, overall 97% SVR12 (intent to treat analysis), 98.3% SVR12 rate per protocol analysis (288/293) r HIV coinfected 97% SVR12 (87/90) r Minimal enrollment of GT6 patients, 81% SVR12 (13/16), GT5/6 trials ongoing Efficacy in GT4 treatment-naive and interferon-experienced patients with and without cirrhosis previously established: r N = 298, 95.3% SVR 12 overall GT1-6 without G/P NS3-4A/NS5A inhibitor AbbVie cirrhosis; +/- HIV FDA approved coinfection Integrated analysis of GT1-6 patients without cirrhosis: includes 9 phase II (N = 201)/III (N = 1840) trials: SURVEYOR-I Part 2; SURVEYOR-II Parts 1 and 2, Part 4; ENDURANCE-1 (HIV coinfection) -2 -3 -4; EXPEDITION-2 (HIV coinfection) -4 r 98% SVR12 (943/965) with 8 wks r 99% SVR12 (1060/1076) with 12 wks r Overall ≥95% SVR12 across patient subgroups r No difference in SVR between TN and TE patients with 8 wks r TN GT3 had ≥95% SVR12 at both 8 and 12 wks r 99% SVR12 (no VF) with HIV-1 coinfection r 98% SVR12 (no VF) with severe renal impairment r Non-inferior as retreatment regime among GT1a patients without cirrhosis: relapse with SOF/VEL/VOX 8 wks = 8%, SOF/ VEL 12 wks = 0%, G/P 8 wks = 0% r Most common AE were headache and fatigue, reported by 13-18% of patients in both durations r 1 DAA-related serious AE, 10 AE leading to discontinuation, 3 DAA-related AE leading to discontinuation r Patients with HBV and TE with non-SOF-based DAAs were excluded G/P NS3-4A/NS5A inhibitor AbbVie GT5, 6 FDA approved ENDURANCE-5,6: a phase IIIb multicenter, open-label trial of TE and TN patients +/- compensated cirrhosis conducted in 24 hospitals and clinics in Europe (Belgium, France); Oceania (Australia, New Zealand); North America (Canada, U.S.); South Africa; and southeast Asia (Singapore, Vietnam); 8 weeks for patients without cirrhosis, 12 weeks for patients with compensated cirrhosis r N = 84, 98% (82/84) SVR12 r GT5 = 22/23 SVR12, GT6 = 60/61 SVR12 r N = 5 serious AE reported, but none was related to TX or resulted in discontinuation r One patient with GT6f with cirrhosis had VF at week 12; one patient with GT5a w/ SVR4 relapsed at week 12 post TX r 1 Black patient, 1 Multirace patient; 91% of GT5 patents were White; 92% of GT6 patients were from Vietnam, China and Cambodia r HBV and HIV coinfection were exclusion criteria r Only 5 participants reported history of IDU (all GT6) r No impact of baseline polymorphisms on SVR12 r All results consistent with registration trials 4 5 PIPELINE REPORT 2019 Compound Class/Type Company/Sponsor Patient Population Status Retreatment G/P NS3-4A/NS5A inhibitor AbbVie FDA approved after DAA failure MAGELLAN-3: phase IIIb open-label trial G/P + SOF + RBV for retreatment of G/P failure.