ライフサイエンスコーパス: telaprevir

1 a new efficient synthesis of antiviral drug telaprevir.

2 e was more rapid among patients who received telaprevir.

3 through occurred in 7% of patients receiving telaprevir.

4 e analogue and an NS5A inhibitor, but not to telaprevir.

5 ere randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours p

6 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 ho

7 The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours th

8 Telaprevir 2 (VX-950), an inhibitor of the hepatitis C v

9 V genotype 3 relapsed after therapy (2 given telaprevir, 3 given TPR, and 2 given PR) and 3 patients

10 bavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likel

11 By day 15, 0% (telaprevir), 40% (TPR), and 22% (PR) of patients with HC

12 Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial respond

13 Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8),

14 genotype 2, 26 with genotype 3) who received telaprevir (750 mg every 8 h), placebo plus PR (peginter

15 of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]).

16 (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavire

17 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h).

18 r placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir pl

19 of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750

20 In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 proteas

21 Telaprevir, a protease inhibitor specific to the HCV non

22 In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, th

23 d antiviral activity of 2 weeks therapy with telaprevir alone, peginterferon alfa-2a and ribavirin (P

24 In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were

25 In patients given telaprevir alone, viral rebound can result from the sele

26 nation regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and pegint

27 dditional and distinct from the FDA-approved telaprevir and boceprevir alpha-ketoamide inhibitors, ar

28 Telaprevir and boceprevir are structurally similar, and

29 ty, and potential for drug interactions with telaprevir and boceprevir had not been answered.

30 Telaprevir and boceprevir were approved in 2011 for use

31 4a(ED43) recombinant was highly resistant to telaprevir and boceprevir, but most sensitive to other p

32 ly developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with peg

33 In 2011, novel HCV NS3/4A PIs (PIs), telaprevir and boceprevir, were approved for use in comb

34 dministered hepatitis C protease inhibitors, telaprevir and boceprevir, were shown to have antiviral

35 These agents, telaprevir and boceprevir, when used in combination with

36 ally with the approval of two new DAA drugs--telaprevir and boceprevir--for use in pegylated interfer

37 ng patients with HCV genotype 3 who received telaprevir and decreased rapidly among patients given PR

38 However, the combination of telaprevir and PEG-IFN-alpha-2a inhibited both wild-type

39 on alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for S

40 and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treat

41 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at th

42 cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin.

43 protocol was a 24-week regimen: 12 weeks of telaprevir and PR followed by an additional 12 weeks of

44 he linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from c

45 In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir), detectable/BLOQ level

46 Boceprevir and telaprevir are inhibitors and substrates of the cytochro

47 were more frequent in patients who received telaprevir as part of hepatitis C treatment compared wit

48 an additional clinical classification of the telaprevir-associated eruption to better reflect the der

49 All patients received telaprevir at a dose of 750 mg every 8 hours, peginterfe

50 se of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group)

51 was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [

52 monstrated the benefit of retreatment with a telaprevir-based regimen for patients with well-characte

53 ples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affe

54 Treatment with a telaprevir-based regimen significantly improved sustaine

55 IV-coinfected patients achieved SVR24 with a telaprevir-based regimen.

56 10 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients wi

57 safety profile was similar to that known for telaprevir-based regimens.

58 ts who are currently receiving boceprevir or telaprevir-based therapy against HCV show cirrhosis.

59 -naive and prior relapser patients receiving telaprevir-based treatment are eligible for shorter, 24-

60 s study evaluated the safety and efficacy of telaprevir-based treatment in combination with PR in wel

61 During boceprevir- and telaprevir-based treatment, subjects with detectable/BLO

62 If patients do not achieve SVR with telaprevir-based treatment, their viral population is of

63 Boceprevir- and telaprevir-based treatments for chronic hepatitis C viru

64 Boceprevir-based and telaprevir-based triple therapy with pegylated interfero

65 o danoprevir and a broader efficacy range of telaprevir between genotypes than initially conceptualiz

66 confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the

67 inst the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in cli

68 endent manner by the NS3 protease inhibitors telaprevir, boceprevir, asunaprevir, simeprevir, vanipre

69 bination pegylated IFN-alpha, ribavirin, and telaprevir/boceprevir.

70 ng current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals

71 We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive und

72 single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a

73 Occurring at any time during the 12 weeks of telaprevir combination regimen, in more than 90% of case

74 Phase 1 to 3 studies of telaprevir combination therapy for hepatitis C.

75 Further investigation of telaprevir combination therapy in patients with HCV geno

76 Compared with PR, telaprevir combination therapy offers significantly impr

77 on to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribav

78 Telaprevir, combined with pegylated interferon alfa and

79 resistance to alpha interferon (IFN-alpha), telaprevir, daclatasvir, cyclosporine, and ribavirin, de

80 16 (boceprevir), C216 (telaprevir), and 108 (telaprevir), detectable/BLOQ levels were reported for ap

81 and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384]).

82 Current guidelines mandate telaprevir discontinuation in any patient with a severe,

83 ed in HCV isolates from some patients during telaprevir dosing.

84 evir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-

85 with 72.8% of patients who were treated with telaprevir every 8 hours (difference in response, 1.5%;

86 slightly higher among patients treated with telaprevir every 8 hours.

87 so telaprevir twice daily is noninferior to telaprevir every 8 hours.

88 ot reduced until after 12 h, suggesting that telaprevir exerts a direct effect on RNA synthesis.

89 we compare: (1) peginterferon + ribavirin + telaprevir for 12 weeks, followed by 12 or 24 weeks trea

90 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ri

91 f peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to th

92 l responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 w

93 Most patients (81%) who achieved SVR in the telaprevir group received </=12 weeks of treatment and t

94 to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and

95 the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs

96 In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 6

97 infected with HCV genotype 1 to one of three telaprevir groups or to the control group.

98 The telaprevir groups received telaprevir (1250 mg on day 1

99 e of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%)

100 One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of

101 of sustained virologic response in the three telaprevir groups--51% in the T12PR24 group, 53% in the

102 the subgroup of prior treatment "relapsers," telaprevir had greater relative efficacy than boceprevir

103 Telaprevir had greater relative efficacy than boceprevir

104 ased rapidly among patients given PR or TPR (telaprevir had no synergistic effects with PR).

105 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after a

106 Telaprevir has not been studied in organ transplant pati

107 n with PR, the HCV NS3-4A protease inhibitor telaprevir has recently been approved for treatment of g

108 previr response-guided therapy (TVR-RGT); 5) telaprevir IL28B genotype-guided strategy (TVR-IL28B).

109 ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and

110 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa

111 dy of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepa

112 igh-level (A156V/T and 36/155) resistance to telaprevir in vitro.

113 The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the

114 ugs to directly inhibit HCV NS3/4A protease, telaprevir (Incivik((R))) and boceprevir (Victrelis((R))

115 Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) e

116 In this study, telaprevir increased the blood concentrations of both cy

117 Coadministration with telaprevir increased the terminal elimination half-life

118 ncorporation into HCV genomes, we found that telaprevir inhibits RNA synthesis as early as 12 h at hi

119 Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV

120 A morbilliform eruption associated with telaprevir is a common adverse effect experienced by pat

121 The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450

122 ggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type viru

123 The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibitio

124 otease, co-crystallized with boceprevir or a telaprevir-like ligand, and then identified variants at

125 eling analysis suggests that the P2 group of telaprevir loses several hydrophobic contacts with the L

126 e residues conferred low level resistance to telaprevir (<25-fold).

127 according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 pa

128 spread morbilliform eruption associated with telaprevir may be able to continue triple therapy with c

129 eater activity than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4.

130 Telaprevir monotherapy for 2 weeks reduces levels of HCV

131 Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15

132 HCV genotype 2, including those who received telaprevir monotherapy.

133 HCV genotype 3 had viral breakthrough during telaprevir monotherapy.

134 ts (R155K and D168G) could affect binding of telaprevir more than boceprevir.

135 and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 week

136 rimary objective was to assess the effect of telaprevir on HCV RNA levels.

137 terferon and ribavirin without (46%) or with telaprevir or boceprevir (12%).

138 Study arms that evaluated telaprevir or boceprevir for unlicensed durations or wit

139 bination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of he

140 ents who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavir

141 luding those who failed earlier therapy with telaprevir or boceprevir.

142 bination of peginterferon and ribavirin with telaprevir or boceprevir.

143 d to the results of the phase III trials for telaprevir or boceprevir.

144 ients with no response to prior therapy with telaprevir or boceprevir.

145 lysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a

146 rferon and ribavirin plus either boceprevir, telaprevir, or simeprevir.

147 3-4/4) or cholestatic hepatitis treated with telaprevir- or boceprevir-based triple therapy at 6 cent

148 g 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, the A156V/T variant was det

149 orted rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%

150 (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin.

151 variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a (PEG-IFN-alph

152 ed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute

153 ination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and rib

154 s from 663 HCV genotype 1 patients receiving telaprevir/pegylated interferon/ribavirin in OPTIMIZE we

155 er CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin.

156 Retrospective analyses of the boceprevir and telaprevir phase 3 trial data demonstrate the clinical r

157 he most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), ane

158 receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or te

159 There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population.

160 es between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the

161 Telaprevir-related dermatitis occurs in a majority of te

162 Before treatment initiation, telaprevir-resistant variants (T54A, T54S, or R155K in 1

163 Population sequencing (PS) has shown that telaprevir-resistant variants are not typically detectab

164 HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN-a

165 ulation is often significantly enriched with telaprevir-resistant variants at the end of treatment.

166 , DS analysis revealed that the frequency of telaprevir-resistant variants before treatment was also

167 tients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K a

168 Telaprevir-resistant variants were classified into lower

169 Of 49 patients in whom telaprevir-resistant variants were detected by PS at the

170 nt variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of t

171 To gain insight into the evolution of telaprevir-resistant variants, their baseline prevalence

172 wild-type virus, which uncovers pre-existing telaprevir-resistant variants.

173 response (RVR)-guided strategy (BOC-RVR); 4) telaprevir response-guided therapy (TVR-RGT); 5) telapre

174 Indeed, telaprevir's development was once put on hold because of

175 e report highlights successful management of telaprevir skin rash and anal discomfort by switching to

176 imepoints (week 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had a

177 Lessons learned from the development of telaprevir suggest that makers of innovative medicines c

178 Telaprevir susceptibilities varied over a 4-fold range,

179 weeks, PEG-IFN/RBV plus boceprevir (BOC) or telaprevir (TEL) for 48 weeks, and sofosbuvir (SOF) plus

180 a higher incidence among patients receiving telaprevir than among those receiving peginterferon-riba

181 rious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation.

182 vious non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in a

183 In clinical trials with telaprevir (TLV) and boceprevir (BOC) renal impairment w

184 t of HCV from a patient who was treated with telaprevir to his sexual partner.

185 CV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa

186 us remains undetectable for an additional 8 (telaprevir) to 20 (boceprevir) weeks (extended RVR).

187 two new protease inhibitors, boceprevir and telaprevir, to enhance the modern treatment of HCV have

188 were 50%, 67%, and 44% among patients given telaprevir, TPR, or PR respectively; 7 patients with HCV

189 Boceprevir (BOC) and telaprevir (TPV), when added to pegylated interferon and

190 l responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic f

191 ment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR.

192 In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of

193 r-related dermatitis occurs in a majority of telaprevir-treated patients.

194 RESS or SJS requires particular vigilance in telaprevir-treated patients.

195 Virologic failure during the telaprevir-treatment phase was predominantly associated

196 Analyses of Phase 2 boceprevir and telaprevir trials indicated subjects with detectable/BLO

197 ased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and

198 avir +/- dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-dru

199 We measured sensitivity of telaprevir (TVR) and alisporivir (AVR) in different geno

200 substitution confers low-level resistance to telaprevir (TVR) and boceprevir and confers high-level r

201 kinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immun

202 Telaprevir (TVR) has been approved for response-guided-t

203 approving response-guided therapy (RGT) for telaprevir (TVR) in combination with pegylated interfero

204 ors on sustained virologic response (SVR) to telaprevir (TVR) in genotype 1 patients with hepatitis C

205 on alpha, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ri

206 Telaprevir (TVR) plus peginterferon-alpha2a (PEG-IFN-alp

207 Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A prote

208 In registration trials, triple therapy with telaprevir (TVR), pegylated interferon (Peg-IFN), and ri

209 ficantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better

210 apy (TT) compared with boceprevir (BOC)- and telaprevir (TVR)-based TT in untreated genotype 1 (G1) c

211 ly infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin.

212 These results support use of telaprevir twice daily in patients with chronic HCV geno

213 Based on a phase 3 trial, telaprevir twice daily is noninferior to every 8 hours i

214 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir ever

215 jective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing

216 subgroups of patients who were treated with telaprevir twice daily versus those who were treated eve

217 Of patients who were treated with telaprevir twice daily, 74.3% achieved SVR12 compared wi

218 ug Administration approval of boceprevir and telaprevir--two protease inhibitors--the standard-of-car

219 e (n = 1309) (OR, 3.24 [95% CI, 2.56-4.10]); telaprevir vs boceprevir (OR, 1.06 [95% CI, 0.75-1.47]).

220 d of care (n = 891) (OR, 8.32 [5.69-12.36]); telaprevir vs boceprevir (OR, 1.27 [95% CI, .71-2.30]).

221 e (n = 1417) (OR, 3.06 [95% CI, 2.43-3.87]); telaprevir vs standard of care (n = 1309) (OR, 3.24 [95%

222 e (n = 604) (OR, 6.53 [95% CI, 4.20-10.32]); telaprevir vs standard of care (n = 891) (OR, 8.32 [5.69

223 Telaprevir (VX-950) is a highly selective, potent inhibi

224 Telaprevir (VX-950) is an orally active, specifically ta

225 erent genotypes to danoprevir (ITMN-191) and telaprevir (VX-950) were observed.

226 Telaprevir was docked into the x-ray structure of the R1

227 Telaprevir was generally safe and well tolerated.

228 In addition to the active-site PI telaprevir, we examined an allosteric protease-helicase

229 n addition, the poor drug-like properties of telaprevir were a formidable hurdle, which the manufactu

230 A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total tr

231 sed 50% inhibitor concentration [IC(50)]) to telaprevir were observed as the dominant species in 0 to

232 spread morbilliform eruption associated with telaprevir were referred to dermatology for evaluation a

233 r to the availability of, or ineligible for, telaprevir were the comparator group.

234 These DAAs, boceprevir and telaprevir, when given with pegylated interferon alfa (P

235 ustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulato

236 Telaprevir with Peg-IFN/RBV had greater activity than Pe

237 ated patients without cirrhosis who received telaprevir with peginterferon and ribavirin.

238 The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the

239 able at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and

240 Telaprevir with peginterferon-ribavirin, as compared wit

241 ere similar to those in previous trials with telaprevir, with 9% of patients discontinuing due to an