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The HCV Treatment Pipeline

July 2018
Annette Gaudino

HCV TREATMENT PIPELINE: THE DEFERRED DREAM OF TREATMENT FOR ALL

Generic combinations of direct-acting antivirals (DAAs), including sofosbuvir/daclatasvir show bioequivalence compared to originators with equivalent sustained virological responses (SVR). Both sofosbuvir/daclatasvir and sofosbuvir/ravidasvir demonstrate SVR rates of 97% at 12 weeks of treatment across genotypes, with further studies underway for genotypes 3, 4, and 6, people with cirrhosis, and those with decompensated liver disease. Generic DAAs have become increasingly affordable at less than USD 100 per 12-week treatment course, which opens up access for people living with HCV in low- and middle-income countries (LMICs). Yet overall treatment uptake is still low: Of the estimated 71 million people living with chronic HCV, roughly 1.75 million people initiated treatment globally in 2016. By comparison, global diagnosis was only 8% in LICs compared to 43% in HICs.

Furthermore, the evidence that people with substance use disorders can achieve SVR with DAAs is now overwhelming. With each passing year, the story remains the same: we possess the necessary therapeutic tools to eliminate HCV infection as a public health threat, at affordable prices, and across all genotypes, if they can be delivered before liver function decompensates due to advanced cirrhosis. We also know these tools are effective among the key population driving incidence, people who inject drugs. Treatment for all is a necessity; treatment for all remains an unfulfilled promise.

Advocacy points

For companies:

  • Close registration gaps for generic sofosbuvir and daclatasvir in countries covered under voluntary licenses to provide 100% access.
  • Complete phase II/III clinical trials of sofosbuvir/ravidasvir in genotype 6 patients, and additional trials in genotype 5 patients, to confirm pangenotypic activity.
  • Complete phase II/III clinical trials of sofosbuvir based regimes in patients younger than 12 years and weighing less than 35 kg.
  • Conduct phase II/III clinical trials of pangenotypic regimes including G/P, SOF/DAC and SOF/RAV in adolescent patients younger than 17 years, and children weighing less than 35 kg.
  • Complete phase II/III clinical trials in pregnant women to assess the safety and efficacy of DAAs as curative treatment and prophylaxis to prevent vertical transmission.

For governments:

  • Waive in-country clinical registration trials for proven DAA combinations from validated generic manufacturers.
  • 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.
  • Ensure competition between generic manufacturers.
  • 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.
  • High-income countries must refrain from retaliatory trade practices in response to the use of TRIPS flexibilities for access to medicines.
  • Enact opt-out screening of all individuals upon incarceration, with robust linkage to care during incarceration or post release.
  • Align public health system payment/reimbursement to expand HCV screening beyond the birth cohort and individuals with identified high risk, with particular attention to pregnant women.

For donors:

  • Commit to multilateral funding for universal access to generic DAA treatment in low- and middle-income countries.
  • Facilitate the integration of disease-specific programs by supporting treatment of HCV monoinfected individuals at risk for HIV and other infectious diseases.

 

Compound

Class/Type

Company/Sponsor

Patient Population

Status

EBR/GZR + SOF

NS5A/NA3-4A + NS5B inhibitor

Merck

Genotype 3 PEG-INF experienced

Approved

C-ISLE STUDY:  Elbasavir/grazoprevir and sofosbuvir for genotype 3 treatment naïve and peginterferon/RBV experienced patients with compensated cirrhosis, a phase 2, randomized, open label study

 

Treatment naïve:

  • 8 weeks + RBV, 91% SVR12 (21/23)
  • 12 weeks, 96% SVR12 + (23/24)

 

Treatment experienced:

  • 12 weeks, 100% SVR12 (17/17)
  • 12 weeks + RBV, 94% SVR12 (17/18)
  • 16 weeks, 94% SVR12 (17/18)

 

Virologic failure = 2; Relapse = 2; Discontinued due to AE = 1; presence of baseline RASs and addition of ribavirin did not impact SVR.

SOF/RAV

NS5B/NS5A inhibitor

DNDi/Pharco

Genotypes 1a/b, 2, 3, 4, 6; HIV coinfected; PWID

Approvals pending

STORM-C-1 phase II/III trial stage 1 of 12 weeks ravidasvir/sofosbuvir in non-cirrhotic patients and 24 weeks in cirrhotic patients.

  • N = 300, overall 97% SVR12 (intent to treat analysis), 98.3% SVR12 rate per protocol analysis (288/293)
  • HIV coinfected 97% SVR12 (87/90)
  • Minimal enrollment of GT6 patients, 81% SVR12 (13/16), GT5/6 trials ongoing

 

Efficacy in GT4 treatment naïve and interferon experienced patients with and without cirrhosis previously established:

  • N = 298, 95.3% SVR12 overall

G/P

NS3-4A/NS5A inhibitor

AbbVie

GT 5, 6

FDA approved

ENDURANCE-5,6 Study: ongoing phase 3b, non-randomized, open-label, multicenter study of glecaprevir/pibrentasvir in South Africa (GT5), Myanmar, and Vietnam (GT6).

  • N = 61, 8 weeks in non-cirrhotic patients
  • N = 6, 12 weeks in cirrhotic patients
  • 66 patients have completed treatment; 98% SVR4 (61/62, data available at press time)

G/P

NS3-4A/NS5A inhibitor

AbbVie

HIV Coinfected

FDA approved

EXPEDITION 2 Study: a phase II, open label, multicenter study of glecaprevir/pibrentasvir in HIV-1 coinfected patients for 8 weeks in patients without cirrhosis and 12 weeks in patients with compensated cirrhosis.

  • N = 153, 98% SVR12 rate overall (150/153)
  • Virologic failure with 1 GT3 infected with cirrhosis
  • Treatment experience GT3 patients excluded
  • No GT5 patients enrolled

G/P

NS3-4A/NS5A inhibitor

AbbVie

Retreatment after DAA failure

FDA approved

A phase 3b, open-label, multi-arm randomized study of glecaprevir/pibrentasvir +/- RBV for GT1 patients who previously failed an NS5A inhibitor + SOF therapy; patients with and without compensated cirrhosis evaluated; interim results reported:

  • 12 weeks, 96% SVR12 (47/49)
  • 16 weeks, 100% SVR12 (16/16)
  • patients with cirrhosis, 12 weeks + RBV, 82% SVR12 (14/17)
  • patients with cirrhosis, 16 weeks + RBV, 100% SVR12 (11/11)

 

MAGELLAN-1 Part 2: phase 3, open label, randomized study to evaluate the efficacy and safety of ribavirin free glecaprevir/pibrentasvir in patients with previous virologic failure on therapy containing NS3/4A protease and/or NS5A inhibitor; GT 1, 4, 5, 6; patients with compensated cirrhosis were included.

  • 12 weeks 89% SVR12 (39/44)
  • 16 weeks, 91% (43/47)

SOF/LDV

NS5B/ NS5A inhibitor

Gilead

Adolescents 12-17 years old

FDA approved

Safety and efficacy of SOF/LDV for 12 weeks in GT1 patients 12 years of age and older, or weighing at least 35kg (~70 lbs), without cirrhosis or with compensated cirrhosis, a phase 2, open label, multicenter study.

  • N = 100, 98% SVR12 overall (98/100)
  • No virologic failures among the 99 patients who completed treatment
  • 1 patient lost to follow-up prior to completion, 1 patient lost to follow up following completion
     

Sofosbuvir and ribavirin in adolescents 12-17 years old with GT 2,3 infection: GT2 received 12 weeks, GT3 received 24 weeks; 40% assessed as non-cirrhotic, remainder were undetermined.

  • N = 52, 98% SVR12 overall (51/52)
  • 1 GT3 patients lost to follow-up after achieving SVR4

SOF/LDV

NS5B/ NS5A inhibitor

Gilead

HIV coinfected

FDA approved

ANRS TAC Trial: open label multicenter trial in Senegal, Cote d’Ivoire and Cameroon, GT 1, 4 patients with or without compensated cirrhosis receiving 12 weeks of treatment with SOF/LDV.

  • N = 80, overall 90% SVR12
  • N = 40 treated with 12 weeks SOF + RBV
  • 36% HIV coinfected

EBR/GRZ

NS5A/NS3-4A inhibitor

Merck

GT 1, 4 HIV coinfected MSM

FDA approved

DAHHS 2 Study: 8 weeks of grazoprevir/elbasvir for acute HCV, single arm, prospective multicenter clinical trial; all patients with acute infection and all but one patient coinfected with HIV.

  • N = 53, 98% SVR12 (52/53)
  • 10/53 were reinfections
  • Treatment initiated no later than 26 weeks post infection

EBR/GRZ

NS5A/NS3-4A inhibitor

Merck

GT 4, treatment naïve

FDA approved

Ongoing randomized phase IV clinical trial of 8 weeks vs 12 weeks of EBR/GRZ in GT4 treatment naïve patients with F0-F2 fibrosis

  • N = 31
  • 18/18 had HCV RNA <15IU/ml at the end of the 8-week treatment
  • 12/12 participants had no detectable HCV RNA at follow up week 4 (SVR4)

 

ABBREVIATIONS

ALT: Alanine aminotransferase

APRI: AST to Platelet Ratio Index

CE: Conformité Européene/European Conformity

DAA: Direct-acting antivirals

DAC: Daclatasvir

EBR/GRZ: Elbasvir/grazoprevir

F0-F4: Fibrosis stage range

FIB-4: Fibrosis-4 index

GT: Genotype

G/P: Glecaprevir/pibrentasvir

HCV: Hepatitis C virus

HIC: High-income countries

HIV: Human immunodeficiency virus

HRCs: Harm reduction centers

IDU: Injection drug use

IU/mL: International unit per milliliter

LDV: Ledipasvir

LMIC: Low- and middle-income countries

MSM: Men who have sex with men

ND: No data

OAT: Opioid agonist therapy

OST: Opioid substitution therapy

PQ:  Prequalification

PWID: People who use drugs

RAV: Ravidasvir

RBV: Ribavirin

RNA: Ribonucleic acid, or HCV RNA test

SOF: Sofosbuvir

SVR: Sustained virological response

TRIPS: Trade-Related Aspects of Intellectual Property Rights 

uL: unit of liquid volume equal to one millionth of a liter, or 1 mm3

VEL: Velpatasvir

VL :Viral load

WHO: World Health Organization