Ann. N.Y. Acad. Sci. ISSN 0077-8923
`
`ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
`Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2014
`
`Development of sofosbuvir for the treatment of hepatitis C
`virus infection
`
`Eric Lawitz,1 Ira M. Jacobson,2 David R. Nelson,3 Stefan Zeuzem,4 Mark S. Sulkowski,5
`Rafael Esteban,6 Diana Brainard,7 John McNally,7 William T. Symonds,7
`John G. McHutchison,7 Douglas Dieterich,8 and Edward Gane9
`1Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. 2Icahn School of Medicine at Mount
`Sinai, New York, New York. 3University of Florida, Gainesville, Florida. 4Medical Center, Johann Wolfgang Goethe University,
`Frankfurt am Main, Germany. 5Johns Hopkins University School of Medicine, Baltimore, Maryland. 6Hospital Universitario Val
`d’Hebron, Barcelona, Spain. 7Gilead Sciences, Foster City, California. 8Mount Sinai School of Medicine, New York, New York.
`9Auckland City Hospital, Auckland, New Zealand
`
`Address for correspondence: Eric Lawitz, MD, Texas Liver Institute, 607 Camden St, San Antonio, TX 78215. lawitz@txliver.com
`
`The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration
`(FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin
`or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified,
`more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment
`regimens were especially required for patient populations with limited treatment options, including patients who
`had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either
`intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3
`HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen
`available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free
`regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its
`original FDA approval.
`
`Keywords: hepatitis C; sofosbuvir; direct acting antivirals; drug development
`
`Background: hepatitis C virus
`
`First identified in 1989 as the previously elusive
`causative agent of non-A, non-B hepatitis, hepatitis
`C virus (HCV) is a single-stranded RNA virus trans-
`mitted primarily through blood or blood product
`exposure. The incidence of acute infection in the
`United States declined dramatically following the
`introduction of universal HCV antibody screening
`of blood donors in 1992.1 While spontaneous erad-
`ication of acute infection occurs in 10–50% of cases,
`most patients develop chronic HCV infection.2
`Chronic HCV infection is a serious, progres-
`sive, and potentially life-threatening disease affect-
`ing an estimated 180 million people worldwide,
`including more than three million people in the
`United States.3,4 Asymptomatic progression of liver
`disease can occur gradually over several decades;2
`
`many with cirrhosis today were infected with HCV
`decades ago.
`Depending on several cofactors, 10–40% of
`patients with chronic HCV will develop cirrhosis
`of the liver and will be at risk for such complications
`as bleeding varices, ascites, hepatic encephalopathy,
`and hepatocellular carcinoma.5 Chronic HCV infec-
`tion results in approximately 10,000 deaths each year
`in the United States alone, and in 2007, HCV sur-
`passed HIV as a cause of death.5,6
`Belonging to the genus Hepacivirus in the fam-
`ily Flaviviridae, HCV is an enveloped virus with a
`positive-sense, single-stranded RNA genome.7 The
`virus has significant genetic (RNA sequence) vari-
`ability and is classified into at least six genotypes.
`The most common HCV genotype in North Amer-
`ica and Europe is genotype 1, followed by geno-
`types 2 and 3.8,9 Genotype 4 is most prevalent
`
`56
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`doi: 10.1111/nyas.12832
`Ann. N.Y. Acad. Sci. 1358 (2015) 56–67 C(cid:2) 2015 New York Academy of Sciences.
`
`Gilead 2009
`I-MAK v. Gilead
`IPR2018-00125
`
`

`

`Lawitz et al.
`
`Development of sofosbuvir for HCV treatment
`
`in the Middle East, while genotypes 5 and 6 are rare
`and found primarily in South Africa and Southeast
`Asia, respectively.10
`Patients with HCV genotypes 1 and 4 have histori-
`cally had lower response rates with interferon-based
`therapy than those with genotypes 2 or 3, while
`those with genotypes 5 and 6 have had intermediate
`response rates.11–15 The virus’ rapid replication—
`with an estimated 1012 virions produced per day
`in an untreated patient16—combined with the lack
`of a proofreading mechanism results in the devel-
`opment of many genetic variants, or quasispecies,
`within an infected individual,17 which can result in
`rapid selection of resistant variants during antiviral
`treatment.
`
`History of HCV therapy
`
`Unlike HIV and other chronic viral diseases, HCV
`can be cured by finite treatment. The established sur-
`rogate end point for cure in clinical trials is sustained
`virologic response (SVR), which is defined as HCV
`RNA below the limit of quantification a fixed inter-
`val (12 or 24 weeks) after the end of treatment. Two
`distinct periods mark the history of HCV treatment:
`the interferon era, beginning in the mid-1980s, and
`the era of direct-acting antivirals (DAAs), launched
`25 years later with the approval of first-generation
`DAAs for HCV.
`The first effective HCV treatment was injected
`recombinant interferon-␣ monotherapy. The effi-
`cacy of interferon was improved incrementally by
`extending treatment from 24 to 48 weeks, by com-
`bining with oral ribavirin, and later by substituting
`convention interferon with long-acting pegylated
`interferon (which also reduced the frequency of
`administration from three times per week to once
`weekly) (Fig. 1). Peginterferon/ribavirin remained
`the standard of care for more than a decade.
`The introduction of
`the first direct-acting
`antivirals—the protease inhibitors boceprevir and
`telaprevir in 2011—ushered in a new era in the
`management of HCV therapy. Up to 80% of HCV
`genotype 1 patients achieved SVR with 24–48
`weeks of therapy with a protease inhibitor plus
`peginterferon/ribavirin.18–21 However, their devel-
`opment has been described as a “holding strategy;”
`regimens composed of injected interferon plus first-
`generation protease inhibitors are still 24–48 weeks
`in duration; have a complex dosing schedule, requir-
`ing intensive on-treatment monitoring required for
`
`efficacy and futility; have a high pill burden; and
`carry undesirable side effects—including cytope-
`nias, depression, autoimmunity, and rash—that
`undermine the benefits of these DAAs.22 In addition,
`boceprevir and telaprevir were approved for use in
`only genotype 1 HCV patients; 24 weeks of peginter-
`feron/ribavirin remained the recommended treat-
`ment for patients infected with HCV genotype
`2 or 3.
`Peginterferon/ribavirin-containing regimens are
`associated with significant side effects and sub-
`optimal response rates, and are less tolerable in
`patient populations with the greatest clinical need,
`including the elderly and patients with cirrhosis.23,24
`The toxicity and tolerability issues associated with
`peginterferon-containing regimens, including those
`regimens that contain a first-generation protease
`inhibitor, left many patients unable or unwilling to
`be treated, including those with the most advanced
`liver disease.25
`There was a clear unmet medical need for shorter,
`safer, simplified HCV treatment regimens that
`were effective across all HCV genotypes and that
`eliminated or reduced the need for peginterferon.
`New treatment options were especially crucial for
`patients who could not tolerate interferon or for
`whom interferon was not recommended, including
`patients who had not responded to prior HCV ther-
`apy.
`Sofosbuvir was discovered in 2007 by a team at
`Pharmasset, Inc., led by Michael Sofia, who was
`the principal inventor of the drug. The compound,
`which was originally designated PSI-7977 and
`renamed GS-7977 when Gilead Sciences acquired
`Pharmasset at the end of 2011, received approval
`from the USAN Council for the non-proprietary
`name “sofosbuvir” in May 2012.
`
`Preclinical development of sofosbuvir
`
`structural
`three
`encodes
`The HCV genome
`and seven non-structural proteins.26,27 The non-
`structural protein NS5B polymerase replicates the
`viral RNA genome, and its catalytic site is highly
`conserved across HCV genotypes, making this pro-
`tein an attractive target for the development of
`nucleoside/nucleotide inhibitors.27,28 Sofosbuvir is a
`novel HCV NS5B–directed inhibitor discovered to
`confer potent inhibition of HCV RNA replication
`in vitro.
`
`Ann. N.Y. Acad. Sci. 1358 (2015) 56–67 C(cid:2) 2015 New York Academy of Sciences.
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`Development of sofosbuvir for HCV treatment
`
`Lawitz et al.
`
`1986
`
`Interferon-α, injected three times weekly, is first used to treat patients with “non-A, non-B hepatitis,” with
`an SVR rate of approximately 6% after 24 weeks of therapy.43
`
`Late 1990s
`
`Twice-daily oral ribavirin plus interferon-α injections three times weekly raises SVR rates to 42% with 48
`weeks of treatment.11,44
`
`Early 2000s
`
`Long-acting pegylated interferon plus ribavirin allows for once-weekly injection and increases SVR rates to
`between 56% and 63% with 48 weeks of therapy.12,13
`
`2011–2013
`
`The first HCV direct-acting antivirals—boceprevir, telaprevir, and simeprevir—are approved for use with
`peginterferon/ribavirin in genotype 1. SVR rates climb to ≤80% after 24 to 48 weeks of treatment.19–21
`
`2103
`
`2014
`
`Sofosbuvir is approved for use with ribavirin in the first all-oral treatment regimen for genotype 2 or 3
`HCV infection, and for use with peginterferon/ribavirin in genotype 1 and 4 HCV infection. SVR rates rise
`to 76% to 92% with 12 weeks of therapy in phase III trials.41
`
`FDA approves Gilead’s ledipasvir/sofosbuvir, the first combination pill to treat chronic HCV genotype 1 and
`the first approved regimen that does not require administration with interferon or ribavirin.
`
`Figure 1. Milestones in chronic hepatitis C treatment. SVR denotes sustained virologic response.
`
`In preclinical studies, sofosbuvir demonstrated
`activity against stable full-length genotype 1a, 1b,
`2a, 3a, and 4a HCV replicons at sofosbuvir EC50
`values of 0.040–0.11 ␮M. Potent antiviral activity
`was also observed against chimeric genotype 1b
`replicons encoding NS5B from genotypes 2b, 5a,
`and 6a (EC50 = 0.014–0.015 ␮M).9
`In addition, sofosbuvir was active against geno-
`type 1a and 2a HCV cell culture infectious virus
`(EC50 = 0.03 and 0.02 ␮M in genotype 1a and
`2a, respectively). No significant differences were
`observed in sofosbuvir EC50 or EC95 values in the
`presence or absence of human serum or human
`serum albumin. Overall, sofosbuvir demonstrated
`significant broad-genotypic inhibition of HCV
`replication in vitro, and was selected for clinical
`development.9 In vitro studies identified the S282T
`substitution in NS5B as conferring resistance to
`sofosbuvir.29 This variant is rare, however, and has
`low replicative fitness in vitro and in vivo.30
`
`Sofosbuvir clinical development program
`
`The clinical development program for sofosbuvir
`included 13 phase I studies, five phase II trials,31–35
`five phase III registration studies, one pretransplant
`trial, one HCV/HIV coinfection study, and three
`collaborative trials.
`The phase II and III studies evaluated sofosbu-
`vir in combination with ribavirin with or without
`peginterferon for treatment in HCV genotypes 1–
`6. Nearly 3000 patients received at least one dose
`of sofosbuvir in phase II or III trials. Additional
`studies were conducted in special HCV popula-
`tions, including patients awaiting liver transplan-
`tation and patients with HIV/HCV coinfection.
`A unique feature of the sofosbuvir development
`program was the broad number of “in need” patient
`populations studied. A significant proportion of the
`patients included in the sofosbuvir clinical stud-
`ies would have been excluded from participation in
`
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`

`Lawitz et al.
`
`Development of sofosbuvir for HCV treatment
`
`trials with interferon-containing regimens, such as
`those with advanced age, patients with higher body
`mass index, those receiving opiate replacement ther-
`apy, patients with advanced liver disease or cirrhosis,
`and those with relative or absolute contraindications
`to interferon therapy.
`
`Registrational phase III trials
`
`led to regulatory
`The phase III program that
`approval of sofosbuvir for the treatment of HCV
`included the FISSION, POSITRON, FUSION,
`and NEUTRINO clinical
`trials (NCT01497366,
`NCT01604850, NCT01542788, and NCT01641640)
`(Table 1). Four
`studies
`(FISSION, FUSION,
`POSITRON, and VALENCE) assessed sofosbuvir/
`ribavirin in patients infected with HCV genotype
`2 or 3. The NEUTRINO study assessed sofosbu-
`vir plus peginterferon/ribavirin in treatment-naive
`genotype 1, 4, 5, or 6 HCV-infected patients.
`The VALENCE trial (NCT01682720) studied sofos-
`buvir/ribavirin for treatment-naive or previously
`treated HCV genotype 2 and 3 patients, and the
`PHOTON-1 study evaluated sofosbuvir/ribavirin in
`patients with HIV/HCV coinfection.
`
`NEUTRINO
`As reported by Lawitz, et al.,36 the single-arm
`NEUTRINO trial evaluated the efficacy and safety of
`sofosbuvir-containing regimens in 327 previously
`untreated patients with HCV genotype 1, 4, 5, or
`6. The primary end point was sustained virologic
`response 12 weeks after therapy (SVR12).
`All participants received sofosbuvir plus peginter-
`feron/ribavirin for 12 weeks. Sofosbuvir was admin-
`istered orally at a dose of 400 mg once daily; ribavirin
`was administered orally as a divided dose according
`to body weight (1000 mg daily in patients with a
`body weight <75 kg 1200 mg daily in those weigh-
`ing ࣙ75 kg). Peginterferon was administered sub-
`cutaneously once weekly at a dose of 180 ␮g.
`All patients had rapid and substantial decreases
`in serum HCV RNA levels after the beginning
`of treatment, with no substantial differences in
`the rate or degree of decrease by HCV genotype,
`race, IL28B genotype, or presence or absence of
`cirrhosis. By week 2 of treatment, 91% of patients
`had HCV RNA levels below the lower limit of
`quantification (LLOQ, 25 IU/mL) (Table 2). By
`week 4, the proportion of patients with HCV RNA
`levels <LLOQ reached 99%. A total of 295 of
`
`327 (90%, 95% CI, 87–93) patients achieved the
`primary outcome of SVR12.
`Twenty-eight patients in the NEUTRINO study
`had virus relapse after the end of treatment. How-
`ever, deep-sequencing analysis of samples collected
`at post-treatment visits showed no new resistance-
`associated HCV variants developed.
`Treatment discontinuation due to adverse events
`was uncommon (2%), and rates of serious and
`severe adverse events were low. Fatigue, headache,
`nausea, and insomnia were the most common
`adverse events.
`
`FISSION
`In the randomized, open-label, active-control
`FISSION study, 499 previously untreated patients
`with HCV genotype 2 or 3 were randomly assigned
`in a 1:1 ratio to receive either 12 weeks of
`sofosbuvir/ribavirin or 24 weeks of peginterferon/
`ribavirin.36 As in the NEUTRINO trial, all patients
`had serum HCV RNA levels of ࣙ10,000 IU/mL at
`screening. The primary end point was SVR12.
`Sofosbuvir was administered orally at 400 mg
`once daily. For patients receiving sofosbuvir, rib-
`avirin was administered orally as a divided dose
`according to body weight (1000 mg daily in patients
`with a body weight <75 kg 1200 mg daily in those
`weighing ࣙ75 kg). The ribavirin dose for patients in
`the peginterferon/ribavirin group was 800 mg daily
`in two divided doses, in alignment with product
`labeling.37 Randomization was stratified by HCV
`genotype, HCV RNA level at study screening, and
`presence or absence of cirrhosis.
`Sofosbuvir/ribavirin therapy was shown to be
`non-inferior to peginterferon/ribavirin. All patients
`receiving sofosbuvir/ribavirin saw rapid and sig-
`nificant reductions in serum HCV RNA levels.
`By week 2 of treatment, 92% of patients in the
`sofosbuvir/ribavirin group had HCV RNA lev-
`els <LLOQ, compared with 32% of those receiv-
`ing peginterferon/ribavirin (Table 2). By week
`4,
`just under 100% of patients receiving sofos-
`buvir/ribavirin had HCV RNA levels <LLOQ,
`compared with 67% of those in the peginter-
`feron/ribavirin arm.
`The SVR12 rate was 67% among patients receiv-
`ing 12 weeks of sofosbuvir/ribavirin (97% of those
`with genotype 2 and 56% of those with genotype
`3) and 67% among those receiving 24 weeks of
`peginterferon/ribavirin (Table 2). There was high
`
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`Development of sofosbuvir for HCV treatment
`
`Lawitz et al.
`
`Table 1. Overview of sofosbuvir pivotal phase III studies
`
`Study
`number
`
`Design
`
`Study objectives
`
`Population
`
`Number of subjects
`by treatment
`
`Duration of
`treatment
`
`Genotypes 1, 4, 5, or 6
`NEUTRINO Phase III,
`open-label,
`multicenter
`study
`
`Genotypes 2 or 3
`FISSION
`Phase III, ran-
`domized,
`active-
`controlled,
`open-label,
`multicenter
`study
`
`POSITRON Phase III, ran-
`domized,
`double-
`blind,
`placebo-
`controlled,
`multicenter
`study
`
`FUSION
`
`Phase III, ran-
`domized,
`double-
`blind,
`multicenter
`study
`
`Assess the efficacy
`(proportion of patients
`with SVR12) and safety
`of SOF+PEG+RBV in
`treatment-naive
`patients with genotype
`1, 4, 5, or 6 HCV
`infection
`
`Assess the efficacy
`(proportion of patients
`with SVR12) and safety
`of SOF+RBV
`administered for 12
`weeks compared with
`PEG+RBV
`administered for 24
`weeks in
`treatment-naive
`patients with genotype
`2 or 3 HCV infection
`Assess the efficacy
`(proportion of patients
`with SVR12) and safety
`of SOF+RBV
`compared with placebo
`administered for 12
`weeks in patients with
`genotype 2 or 3 HCV
`infection who are
`unable or unwilling to
`take IFN
`Assess the efficacy
`(proportion of patients
`with SVR12) and safety
`of SOF+RBV
`administered for 12
`weeks compared with
`16 weeks in patients
`with genotype 2 or 3
`HCV infection who
`failed prior treatment
`with IFN
`
`Treatment-naive adult
`subjects with chronic
`genotype 1, 4, 5, or 6
`HCV infection; up to
`20% of participants
`may have cirrhosis
`
`12 weeks
`
`Overall: 327 treated;
`301 completed
`through SVR12
`assessment
`
`SOF+RBV group:
`12 weeks
`PEG+RBV group:
`24 weeks
`
`12 weeks
`
`SOF+RBV 12-week
`group: 12 weeks
`SOF+RBV 16-week
`group: 16 weeks
`
`Treatment-naive adult
`subjects with chronic
`genotype 2 or 3 HCV
`infection; up to 20% of
`participants may have
`cirrhosis
`
`Adult subjects with
`chronic genotype 2 or 3
`HCV infection who are
`unable or unwilling to
`take IFN; up to 20% of
`participants may have
`cirrhosis
`
`Treatment-experienced
`adult subjects with
`chronic genotype 2 or 3
`HCV infection; up to
`30% of participants
`may have cirrhosis
`
`Overall: 499
`treated; 464
`completed through
`SVR12 assessment
`SOF+RBV group:
`256 treated; 239
`completed
`PEG+RBV group:
`243 treated; 225
`completed
`
`Overall: 278
`treated; 171
`completed through
`SVR12 assessment
`SOF+RBV group:
`207 treated; 171
`completed
`Placebo group: 71
`treated; 0
`completed
`
`Overall: 201
`treated; 127
`completed through
`SVR12 assessment
`SOF+RBV 12-week
`group: 103 treated;
`54 completed
`SOF+RBV 16-week
`group: 98 treated;
`73 completed
`
`SOF, sofosbuvir; RBV, ribavirin; PEG, pegylated interferon; IFN, interferon; SVR, sustained virologic response.
`
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`

`Lawitz et al.
`
`Development of sofosbuvir for HCV treatment
`
`Table 2. Response during and after treatment period by treatment group in NEUTRINO and FISSION trials with
`previously untreated patients36
`
`Response
`
`NEUTRINO study
`HCV genotypes 1, 4–6
`SOF + PEG + RBV
`for 12 weeks
`(n = 327)
`
`FISSION study
`HCV genotypes 2 and 3
`SOF + RBV
`PEG + RBV
`for 12 weeks
`for 24 weeks
`(n = 253)
`(n = 243)
`
`HCV RNA <25 IU/mL during treatment period, n/total n (%)a
`At week 2
`299/327 (91)
`At week 4
`321/325 (99)
`326/327 (>99)
`At last observed on-treatment measurement
`HCV RNA <25 IU/mL after EOT
`302/327 (92)
`At week 4 (SVR4)
`295/327 (90)
`At week 12 (SVR12)
`0
`Virologic breakthrough during treatment, n
`Relapse in patients with HCV RNA <25 IU/mL at EOT, n/total n (%)a
`Patients who completed treatment
`25/320 (8)
`Patients who did not complete treatment
`3/6 (50)
`
`231/251 (92)
`249/250 (>99)
`249/253 (98)
`
`187/253 (74)
`170/253 (67)
`1 (<1)
`
`71/242 (29)
`3/7 (43)
`
`76/241 (32)
`158/236 (67)
`217/243 (89)
`
`181/243 (74)
`162/243 (67)
`18 (7)
`
`37/188 (20)
`9/29 (31)
`
`aData are for patients for whom HCV RNA results were available. An HCV RNA level of 25 IU/mL was the lower limit of quantification.
`SOF, sofosbuvir; PEG, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; EOT, end of treatment.
`
`concordance (>99%) between the SVR12 and
`SVR24 rates in patients who received sofosbuvir/
`ribavirin.
`A single patient in the FISSION study had viro-
`logic breakthrough during week 8 of treatment.
`However, plasma levels of sofosbuvir in this patient
`were undetectable at that time, suggesting non-
`adherence to the treatment regimen. Seventy-four
`patients who received sofosbuvir/ribavirin had a
`relapse after having HCV RNA levels <LLOQ when
`treatment ended. As in the NEUTRINO trial, deep-
`sequencing analysis showed no emergence of new
`resistance-associated HCV variants.
`The incidence of adverse events was lower among
`patients receiving sofosbuvir/ribavirin than among
`those receiving peginterferon/ribavirin without
`sofosbuvir. Fatigue, headache, nausea, and insom-
`nia were the most common adverse events in
`both study groups. Among patients receiving
`12 weeks of sofosbuvir/ribavirin, 1% discontinued
`the study due to adverse events, compared with 11%
`among patients receiving 24 weeks of peginterferon/
`ribavirin.
`
`FUSION
`The FUSION trial was a blinded, active-control
`study in patients with HCV genotype 2 or 3 who had
`previously failed an interferon-containing regimen.
`As described by Jacobson et al.,38 the primary end-
`
`point was the proportion of patients with SVR12.
`Patients (n = 202) were randomized in a 1:1 ratio
`to receive 12 weeks of sofosbuvir/ribavirin followed
`by 4 weeks of matching placebo, or 16 weeks of
`sofosbuvir/ribavirin. Randomization was stratified
`by HCV genotype and the presence or absence of
`cirrhosis.
`Sofosbuvir was administered orally at a dose of
`400 mg once daily. Weight-adjusted ribavirin was
`administered orally twice daily (totaling 1000 mg
`daily in patients weighing <75 kg, and 1200 mg
`daily in patients with a body weight ࣙ75 kg).
`SVR12 rates achieved with sofosbuvir/ribavirin
`were superior to the historic control of 25%, with
`rates of 50% (95% CI, 40–60) in the 12-week and
`73% (95% CI, 63–81) in the 16-week treatment
`groups (P < 0.001 for the comparison of each group
`individually to the 25% historical control). Sec-
`ondary analysis demonstrated that patients receiv-
`ing 16 weeks of treatment had a significantly higher
`SVR12 rate than patients receiving 12 weeks of treat-
`ment (difference, −23 percentage points; 95% CI,
`−35 to −11; P < 0.001 for the comparison).
`Cirrhosis was associated with a decreased SVR12
`rate. For patients with cirrhosis receiving 12 weeks of
`treatment, the SVR12 rate was 31% (60% with geno-
`type 2 and 19% with genotype 3), compared with
`61% in those without cirrhosis (96% with genotype
`2 and 37% with genotype 3 infection). For patients
`
`Ann. N.Y. Acad. Sci. 1358 (2015) 56–67 C(cid:2) 2015 New York Academy of Sciences.
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`Development of sofosbuvir for HCV treatment
`
`Lawitz et al.
`
`with cirrhosis in the 16-week treatment group, the
`SVR12 rate was 66% (78% with genotype 2 and
`61% with genotype 3), compared with 76% in those
`without cirrhosis (100% with genotype 2 and 63%
`with genotype 3).
`No patient receiving sofosbuvir/ribavirin expe-
`rienced on-treatment viral breakthrough or non-
`response. Among the 66 patients who relapsed after
`the end of treatment, deep sequencing analysis of
`samples collected at time of relapse showed no
`resistance-associated variants.
`The overall safety profile was similar between
`patients receiving 16 weeks of therapy and those
`receiving 12 weeks of therapy. Fatigue, headache,
`nausea, and insomnia were the most commonly
`reported adverse events in both study arms. One
`patient in the 12-week arm discontinued treatment
`owing to an adverse event; no patients discontinued
`treatment owing to an adverse event in the 16-week
`group.
`
`POSITRON
`The phase III, blinded POSITRON trial evaluated
`treatment with sofosbuvir/ribavirin in patients with
`HCV genotype 2 or 3 infection who could not or
`would not use peginterferon. The primary end point
`was the proportion of patients with an SVR12.38
`Over 80% of the patients were treatment-naive.
`Patients (n = 280) received sofosbuvir/ribavirin
`or matching placebo. Sofosbuvir was administered
`orally at a dose of 400 mg once daily. Weight-
`adjusted ribavirin was administered orally twice
`daily (totaling 1000 mg daily in patients weighing
`<75 kg, and 1200 mg daily in patients with a body
`weight ࣙ75 kg).
`Sofosbuvir/ribavirin treatment produced a rapid
`decline in circulating HCV RNA levels, with similar
`reductions among patients with HCV genotype 2 or
`3. In this population of patients unable or unwill-
`ing to take peginterferon, the SVR12 rate was 78%
`(95% CI, 72–83) among patients receiving sofos-
`buvir/ribavirin, compared with 0% among those
`receiving placebo (P < 0.001) (Table 3).
`Among patients with HCV genotype 2 infec-
`tion who received sofosbuvir/ribavirin, 93% had an
`SVR12, compared with 61% of those with HCV
`genotype 3. Similarly, 81% of patients without
`cirrhosis (92% with genotype 2, 68% with genotype
`3) had an SVR12, compared with 61% of patients
`
`with cirrhosis (94% with genotype 2, 21% with
`genotype 3).
`No patient receiving sofosbuvir/ribavirin had
`virologic breakthrough during treatment. Among
`the 42 patients who relapsed after the end of treat-
`ment, deep sequencing analysis of samples collected
`at time of relapse showed no resistance-associated
`variants.
`Treatment discontinuation due to adverse events
`was rare, with 2% of patients who received sofos-
`buvir/ribavirin discontinuing treatment, compared
`with 4% who received placebo. Serious adverse
`event rates were low: 5% in the 12-week group
`and 3% in the 16-week group. The POSITRON
`study showed higher rates of fatigue and insom-
`nia and greater incidence of anemia among patients
`receiving sofosbuvir/ribavirin compared with those
`receiving placebo.
`
`VALENCE
`The phase III VALENCE trial assessed sofos-
`buvir/ribavirin for treatment-naive or previously
`treated HCV genotype 2 and 3 patients. Origi-
`nally designed to treat all patients for 12 weeks,
`the VALENCE protocol was amended when results
`from the FUSION study suggested that extended
`treatment could benefit genotype 3 patients.38 As
`described by Zeuzem et al.,39 the trial was redefined
`as a descriptive study to characterize SVR rates in
`patients with HCV genotype 2 infection who were
`treated for 12 weeks (n = 73) and HCV genotype
`3 in patients with treated for 24 weeks (n = 250),
`with no hypothesis testing. The primary efficacy end
`point was SVR12.
`Patients were randomized in a 4:1 ratio to
`receive either sofosbuvir/ribavirin or matching
`placebo. Randomization was stratified according to
`treatment history (previous therapy or no previ-
`ous therapy) and presence or absence of cirrhosis at
`screening. Sofosbuvir was administered orally at a
`dose of 400 mg once daily. Ribavirin was adminis-
`tered orally twice daily at a weight-adjusted dose
`(1000 mg daily in patients with a body weight
`<75 kg and 1200 mg daily in those with a body
`weight ࣙ75 kg).
`Treatment with sofosbuvir/ribavirin resulted in
`a rapid decrease in HCV RNA levels. By week
`4, 99% of patients receiving sofosbuvir/ribavirin
`had an HCV RNA level <LLOQ. No patients
`receiving placebo achieved an HCV RNA level
`
`62
`
`Ann. N.Y. Acad. Sci. 1358 (2015) 56–67 C(cid:2) 2015 New York Academy of Sciences.
`
`

`

`Lawitz et al.
`
`Development of sofosbuvir for HCV treatment
`
`Table 3. Response during and after treatment in POSITRON and FUSION trials in patients with no treatment
`options38
`
`POSITRON study
`Interferon treatment not an option
`SOF + RBV
`× 12 weeks
`(n = 207)
`
`Placebo
`(n = 71)
`
`FUSION study
`Prior interferon treatment
`SOF + RBV
`SOF + RBV
`× 12 weeks
`× 16 weeks
`(n = 100)
`(n = 95)
`
`0/70
`0/70
`0/71
`
`0/68
`0/68
`–
`
`–
`–
`
`186/205 (91)
`202/204 (99)
`202/202 (100)
`
`81/100 (81)
`97/100 (97)
`100/100 (100)
`
`83/95 (87)
`93/95 (98)
`95/95 (100)
`
`172/207 (83)
`161/207 (78)
`0
`
`56/100 (56)
`50/100 (50)
`0
`
`73/95 (77)
`69/95 (73)
`0
`
`40/201 (20)
`2/4 (50)
`
`46/99 (46)
`1/1 (100)
`
`26/95 (27)
`0
`
`Response
`
`HCV RNA <25 IU/mL during treatment
`period, n/total n (%)a
`At week 2
`At week 4
`At week 12
`HCV RNA <25 IU/mL treatment, n/total
`n (%)
`At week 4 (SVR4)
`At week 12 (SVR12)
`Virologic breakthrough during
`treatment, n
`Relapse in patients with HCV RNA <25
`IU/mL at EOT, n/n (%)
`Patients who completed treatment
`Patients who did not complete
`treatment
`
`aData are for patients for whom HCV RNA results were available. An HCV RNA level of 25 IU/mL was the lower limit of quantification.
`SOF, sofosbuvir; RBV, ribavirin; SVR, sustained virologic response; EOT, end of treatment.
`
`<LLOQ at any time point in the study. Among
`HCV genotype 2 patients who received 12 weeks of
`sofosbuvir/ribavirin, 93% (95% CI, 85–98) achieved
`both SVR12 and SVR24. Among patients with HCV
`genotype 3 who received 24 weeks of sofosbu-
`vir/ribavirin, 85% (95% CI, 80–89) had SVR12. Of
`these, 97% subsequently had SVR24.
`Among patients with HCV genotype 3, overall
`response rates were 68% in those with cirrhosis and
`91% in those without cirrhosis. Response was more
`frequent in treatment-naive patients, with SVR rates
`of 92% among those with, and 95% among those
`without, cirrhosis. In contrast, previously treated
`patients with HCV genotype 3 infection experienced
`lower SVR rates, particularly in those with cirrhosis,
`in whom 62% had SVR versus 87% of those without
`cirrhosis.
`Four factors were independently associated with
`a sustained virologic response: baseline HCV RNA
`level <6 log10 IU/mL (odds ratio, 4.23; 95% CI,
`1.21–14.81; P = 0.02), female sex (odds ratio, 3.18;
`95% CI, 1.22–8.31; P = 0.02), absence of cirrhosis
`(odds ratio, 3.46; 95% CI, 1.60–7.48; P= 0.002), and
`
`age <50 years (odds ratio, 2.82; 95% CI, 1.21–6.57;
`P = 0.02).
`In HCV genotype 3 patients who experi-
`enced virologic failure, the sofosbuvir treatment–
`emergent variants V321A and L159F were detected
`in two and six patients, respectively. During in vitro
`testing, however, neither mutation was found to
`confer phenotypic resistance to sofosbuvir.
`Premature discontinuation of treatment due to
`adverse events was uncommon across all study
`groups. One patient with HCV genotype 3 infec-
`tion randomized to receive 12 weeks of treatment
`left the trial because of malaise and headache that
`started on day 31 of treatment; symptoms resolved
`on posttreatment day 10.40 One patient with HCV
`genotype 3 randomized to receive 24 weeks of
`treatment discontinued after attempting suicide on
`day 143. Investigators assessed the adverse event to
`be related to the study drug, given the temporal
`association of the patient’s symptoms (family- and
`work-related stress, worsened insomnia) with sofos-
`buvir/ribavirin treatment and their resolution with
`treatment discontinuation.
`
`Ann. N.Y. Acad. Sci. 1358 (2015) 56–67 C(cid:2) 2015 New York Academy of Sciences.
`
`63
`
`

`

`Development of sofosbuvir for HCV treatment
`
`Lawitz et al.
`
`Diarrhea and irritability were reported more fre-
`quently by patients in the 24-week treatment group
`than by those in the 12-week group. No single grade
`3 or 4 adverse event occurred in more than 1% of
`patients who received sofosbuvir for either 12 or
`24 weeks.
`
`PHOTON-1
`As reported by Sulkowski et al.,41 the open-label,
`non-randomized, phase III PHOTON-1 study
`assessed the efficacy, safety, and tolerability of sofos-
`buvir/ribavirin for 12 or 24 weeks in treatment-
`naive and/or treatment-experienced patients with
`genotype 1, 2, or 3 HCV infection who were
`coinfected with HIV. Patients were required to be
`receiving HIV antiretroviral therapy (ART) and to
`maintain HIV RNA values of ࣘ50 copies/mL and
`+
`T cell count>200 cells/␮ L, or to have
`a CD4
`+
`T cell count
`untreated HIV infection with a CD4
`>500 cells/␮L. Proportion of patients achieving
`SVR12 was the primary end point.
`Of the HCV treatment-naive patients, 114 had
`HCV genotype 1 and 68 had genotype 2 or 3, and
`41 participants previously been treated with pegin-
`terferon/ribavirin had HCV genotype 2 or 3, for a
`total of 223 participants. Treatment-naive patients
`with HCV genotype 2 or 3 received 400 mg of
`sofosbuvir and weight-based ribavirin for 12 weeks.
`Treatment-naive patients with HCV geno