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Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir
in Children With Chronic HCV: Part 2 of the DORA Study
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Hepatology July 2021 - Maureen M. Jonas,1,2 Susan Rhee,3 Deirdre A. Kelly,4 Antonio Del Valle- Segarra,5 Cornelia Feiterna- Sperling,6 Susan Gilmour,7 Regino P. Gonzalez- Peralta,8 Loreto Hierro,9 Daniel H. Leung,10,11 Simon C. Ling,12,13 Yuri Lobzin,14 Steven Lobritto ,15 Tatsuki Mizuochi,16 Michael R. Narkewicz,17 Vishakha Sabharwal,18 Jessica Wen,19 Hoi Kei Lon,3 John Marcinak,3 Andrew Topp,3 Rakesh Tripathi,3 and Etienne Sokal 20
Abstract
Background and Aims
Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years.
Approach and Results
Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks.
Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg).
Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults.
Conclusions
A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.
Globally, 71 million people are infected with HCV; of those, approximately 13.2 million are children between 1 and 15 years of age.(1, 2) Vertical transmission is the primary route of viral acquisition in pediatrics.(2) While 20% of children infected this way may clear HCV infection spontaneously in the first few years of life, 80% will go on to develop long-term infection. HCV infection acquired during infancy or childhood can lead to chronic hepatitis and cirrhosis; HCC has also been reported in children.(2-4) Guidance from the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition; the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the American Association for the Study of Liver Diseases (AASLD) recommends that all children and adolescents aged ≥ 3 years with HCV infection will benefit from treatment with an approved direct-acting antiviral (DAA) regimen, regardless of disease severity.(2, 5, 6) The goals of HCV treatment in pediatric patients are cure of infection and prevention of progression of liver disease.(2, 6)
DAA therapy has demonstrated high sustained virologic response at posttreatment week 12 (SVR12) in adolescents (12 to < 18 years of age); however, options in children remain limited. While combinations of ledipasvir/sofosbuvir (LDV/SOF) and SOF + ribavirin (RBV) have been approved in adolescents and children ≥ 3 years of age, neither combination is pangenotypic.(6-12) Currently, SOF/velpatasvir is the only pangenotypic, RBV-free, DAA regimen approved for HCV-infected children ages 6 and older; pangenotypic options in children ≥ 3 years of age remain an unmet need.(13, 14)
A combination of glecaprevir (GLE) 100 mg and pibrentasvir (PIB) 40 mg, coformulated as GLE/PIB into a fixed-dose tablet, has been approved in adults and adolescents > 12 years (or ≥ 45 kg) as a pangenotypic treatment option for chronic HCV infection.(15, 16) Efficacy of GLE/PIB has been demonstrated in treatment-naive adult patients with chronic HCV infection with SVR12 rates of 96%-99.7%; it is approved for durations as short as 8 weeks in all major genotypes (GTs) in treatment-naive patients both with and without cirrhosis and in GT1-infected, GT2-infected, and GT4-6-infected patients without cirrhosis who are treatment-experienced with pegylated interferon (pegIFN), RBV, and/or SOF.(15-20) Part 1 of the DORA study evaluated the efficacy and safety of the coformulated GLE/PIB tablet in adolescents between the ages of 12 and < 18 years for 8, 12, or 16 weeks depending on treatment experience and geographic location.(21) Of 47 chronic HCV GT1-4-infected adolescents receiving GLE/PIB, 100% achieved SVR12 with a safety and tolerability profile comparable to that of adults. Part 2 of the DORA study aimed to study the pharmacokinetics (PK), efficacy, and safety of a pediatric formulation of GLE/PIB in chronic HCV-infected children with GT1-6, using the same treatment durations used in adults and adolescents.
Discussion
Several DAA regimens are licensed to treat adults with chronic HCV infection, but therapeutic options for children are limited. IFN and RBV-based therapies are less effective and more toxic than DAA regimens, and few studies have evaluated DAA therapy in children < 12 years old.(6) In one study, HCV-infected children ages 6-11 years who received 12 weeks of SOF/LDV achieved an SVR12 of 99% (91/92); in another study, children 3 to ≤ 6 years of age who received 12 weeks of SOF/LDV achieved an SVR12 of 97% (33/34).(11, 12)
GLE/PIB treatment was associated with SVR12 of 100% in part 1 of the DORA study evaluating 48 adolescents, 47 of whom received the adult formulation; the other participant was not dosed.(21) Subsequently, the AASLD guidance included the recommendation for a fixed-dose regimen of GLE/PIB 300/120 mg for 8-16 weeks in HCV-infected GT1-6 adolescents, aged ≥ 12 years or weighing ≥ 45 kg.(6) For children ≥ 3 years of age with HCV GT 1, 4, 5, or 6, weight-based LDV/SOF is recommended for 12 weeks.
In part 2 of the DORA study, 80 pediatric study participants, 3 to < 12 years of age, received a pediatric formulation of GLE/PIB, based on age and weight; the majority (98%) were treated for 8 weeks. Seventy-seven participants achieved SVR12 (96%). Of the 3 who did not achieve SVR12, 1 HCV GT3b-infected participant relapsed by PTW4, 1 discontinued GLE/PIB due to an AE of a rash, and 1 was enrolled but received only one dose of GLE/PIB. As only 1 child relapsed on the initial dose ratio, negative baseline predictors/trends such as demographics, baseline HCV RNA level, genotype, or presence of baseline polymorphisms were not identified. AEs were mostly mild in severity and similar to the safety profile established in adults and adolescents; no treatment-emergent serious AEs and no liver-related toxicities were reported. The taste of GLE/PIB was disliked by 82% of participants at the final treatment visit; in comparative HCV medication therapies for children, 5 participants reported disliking the taste of LDV/SOF; however, only 17 children in that study were assessed for palatability.(11) Despite disliking the taste or texture of GLE/PIB, most participants were able to take the medication in 5 minutes or less, including in the younger 3 to < 6 year age cohort, and high SVR12 rates were similar to those seen in adults and adolescents treated with GLE/PIB.
The noncompartmental PK analysis was based on 38 participants with IPK samples, who received the final GLE/PIB daily dose ratio of 50/20 mg. Overall, the distribution of the AUC of GLE and PIB in HCV-infected children at each 12 to < 20 kg, ≥ 20 to < 30 kg, and ≥ 30 to < 45 kg weight group, as well as adolescents, was within the efficacious and safe exposure ranges of those in HCV-infected adults without cirrhosis.
Although participation allowed for enrollment, there were no GT5-infected or GT6-infected children enrolled and a small number of children with GT2 and GT4. The study recruited participants from North America, Japan, and Europe; and given the prevalence of GT and region, the lower number of participants of GT2 and GT4 is understandable. Given PK exposure profiles similar to adults and adolescents, it may stand to reason that data may be extrapolated from these populations to children with similar GTs.
A weight-based pediatric formulation of GLE/PIB in HCV-infected children, 3 to < 12 years old, had a PK, efficacy, and safety profile similar to that observed in adults and adolescents.(21) The PK results, combined with the efficacy and safety profile, support the use of using the weight-based pediatric GLE/PIB dose ratio of 50/20 mg in HCV-infected children aged 3 to < 12 years of age.
Overall, the data from DORA part 2 demonstrate that GLE/PIB is a highly efficacious and safe pangenotypic treatment option for young children with chronic HCV infection. The pediatric formulation was well tolerated and provides a short, 8-week treatment option for children with HCV.
Results
Eighty-one HCV-infected children, ages 3 to < 12 years, were enrolled; 80 children were dosed and divided into three cohorts based on age; one participant in cohort 4 was enrolled but not dosed. The majority of participants were treatment-naive (78/80, 98%) and infected with HCV GT1 (58/80, 73%) (Table 1); the 2 treatment-experienced study participants had been treated with pegIFN and RBV. Eleven participants had FibroScan scores prior to study day 1, and 77 participants had baseline FibroTest scores; although allowed by inclusion criteria, none of the enrolled study participants had cirrhosis.
Seventy-eight participants received DAA therapy for 8 weeks. One GT3-infected participant in Japan received therapy for 12 weeks, and 1 GT3, treatment-experienced participant received therapy for 16 weeks, both in accordance with the local adult prescribing label duration. One participant who was coinfected with HIV received 8 weeks of treatment.
Following the IPK analysis from the first 17 enrolled participants who received the initial GLE/PIB dose ratio of 40/15 mg, the dose was adjusted to the final GLE/PIB dose ratio of 50/20 mg. The final doses of GLE 250 mg + PIB 100 mg (in children weighing ≥ 30 to < 45 kg), GLE 200 mg + PIB 80 mg (in children weighing ≥ 20 to < 30 kg), or GLE 150 mg + PIB 60 mg (in children weighing 12 to < 20 kg) were used in the remaining IPK participants and in the non-IPK group. The geometric mean steady-state exposures of the final doses of GLE and PIB were 4,600 ng · hour/mL and 1,720 ng · hour/mL, respectively, for participants weighing ≥ 30 to < 45 kg; 6,020 ng · hour/mL and 1,700 ng · hour/mL, respectively, for participants weighing ≥ 20 to < 30 kg; and 6,340 ng · hour/mL and 1,410 ng · hour/mL, respectively, for participants weighing 12 to < 20 kg, compared to 4,800 ng · hour/mL and 1,430 ng · hour/mL, respectively, for adults (Table 2). Figure 2 shows the distribution of AUC in adults and adolescents (who received the adult GLE/PIB formulation at the 300/120 mg dose), as well as in children across the three cohorts who received the pediatric formulation of GLE/PIB at the final doses.
No participants experienced virologic failure on the final GLE/PIB dose ratio of 50/20 mg, and no new HCV infections or reinfections were reported. One 9-year-old treatment-naive participant with HCV GT3b infection who received the initial dose ratio of GLE/PIB 40/15 mg for 8 weeks relapsed by PTW4. This child had no baseline polymorphism or treatment-emergent substitutions in nonstructural protein 3 (NS3) but had K30R and V31M in NS5A at baseline and treatment-emergent substitution Y93H in NS5A. There were two premature discontinuations. One 3-year-old child refused to swallow the GLE/PIB granule formulation; the participant was partially dosed on day 1 without subsequent doses and thus included in the ITT population analysis. Another 11-year-old participant discontinued treatment by day 4 due to a drug-related rash.
AEs occurred in 71% of children, with 29% being deemed reasonably related to GLE/PIB by the study investigators (Table 3). The most common AEs (occurring in ≥ 10% of participants) were headache (14%), vomiting (14%), and diarrhea (10%). One child experienced a nonserious, grade 3 drug-related AE of erythematous rash and discontinued GLE/PIB by day 4; and another child experienced an unrelated AE of respiratory tract infection, which led to a brief interruption of GLE/PIB. This participant resumed GLE/PIB to completion and achieved SVR12. No participants experienced clinically significant laboratory abnormalities, and there were no cases of liver-related toxicities. No treatment-emergent serious AEs were reported. One serious AE of osteomyelitis (considered unrelated to GLE/PIB) was reported in the posttreatment period on day 171.
Seventy-seven study participants or their caregivers completed the palatability questionnaire at week 2, 68 participants or their caregivers completed the questionnaire at week 8, and 78 participants or their caregivers completed the questionnaire at the final treatment visit. At the final treatment visit, 32% of participants/caregivers rated the formulation/dosing very convenient, and an additional 40% of participants/caregivers rated the formulation/dosing as convenient; 82% of participants disliked the taste of the medicine, and 53% reported disliking the texture. Most study participants/caregivers reported taking the dose within 5 minutes or less (85%).
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