ライフサイエンスコーパス: telaprevir

1 to traditional enzymatic inhibitors such as telaprevir.

2 e performed to select for resistance against telaprevir.

3 e was more rapid among patients who received telaprevir.

4 a new efficient synthesis of antiviral drug telaprevir.

5 through occurred in 7% of patients receiving telaprevir.

6 and the structure-based lead optimization of telaprevir.

7 bitors with improved antiviral activity than telaprevir.

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

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

10 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 ho

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

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

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

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

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

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

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

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

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

20 (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavire

21 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h).

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

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

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

25 Telaprevir, a protease inhibitor specific to the HCV non

26 Telaprevir, a reversible-covalent inhibitor that binds t

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

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

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

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

31 Telaprevir also protected motor neurons and improved par

32 Furthermore, we discovered that telaprevir, an FDA-approved drug used for the treatment

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

34 V-D68 drug target, the 2A(pro), and identify telaprevir-an FDA-approved drug used to treat hepatitis

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

36 Telaprevir and boceprevir are structurally similar, and

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

38 Telaprevir and boceprevir were approved in 2011 for use

39 4a(ED43) recombinant was highly resistant to telaprevir and boceprevir, but most sensitive to other p

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

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

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

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

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

45 A-approved direct-acting antiviral compounds Telaprevir and Daclatasvir, as well as broad spectrum an

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

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

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

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

50 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at th

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

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

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

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

55 Boceprevir and telaprevir are inhibitors and substrates of the cytochro

56 viable antiviral drug target and identified telaprevir as a 2A(pro) inhibitor.

57 of EV-D68 2A(pro) and the identification of telaprevir as a potent EV-D68 2A(pro) inhibitor.

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

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

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

61 o) in complex with the a-ketoamide inhibitor telaprevir at near-physiological (22 C) temperature.

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

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

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

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

66 Treatment with a telaprevir-based regimen significantly improved sustaine

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

68 10 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients wi

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

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

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

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

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

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

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

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

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

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

79 n of the active-site protonation states upon telaprevir binding.

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

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

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

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

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

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

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

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

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

89 Compared with PR, telaprevir combination therapy offers significantly impr

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

91 Telaprevir, combined with pegylated interferon alfa and

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

93 16 (boceprevir), C216 (telaprevir), and 108 (telaprevir), detectable/BLOQ levels were reported for ap

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

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

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

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

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

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

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

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

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

103 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ri

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

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

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

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

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

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

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

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

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

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

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

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

116 Telaprevir had greater relative efficacy than boceprevir

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

118 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after a

119 Telaprevir has not been studied in organ transplant pati

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

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

122 structure, we predicted the binding pose of telaprevir in 2A(pro) using molecular dynamics simulatio

123 es, and this mutation reduced the potency of telaprevir in both the enzymatic and cellular antiviral

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

125 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa

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

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

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

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

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

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

132 Coadministration with telaprevir increased the terminal elimination half-life

133 Telaprevir inhibits EV-D68 2A(pro) through a nearly irre

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

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

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

137 Telaprevir is an FDA-approved antiviral that has been sh

138 Telaprevir is an food and drug administration (FDA)-appr

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

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

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

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

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

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

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

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

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

148 Telaprevir monotherapy for 2 weeks reduces levels of HCV

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

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

151 HCV genotype 3 had viral breakthrough during telaprevir monotherapy.

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

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

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

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

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

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

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

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

160 bination of peginterferon and ribavirin with telaprevir or boceprevir.

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

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

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

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

165 3-4/4) or cholestatic hepatitis treated with telaprevir- or boceprevir-based triple therapy at 6 cent

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

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

168 (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin.

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

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

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

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

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

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

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

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

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

178 The binding of telaprevir potently inhibits its enzymatic activity, and

179 Telaprevir reduces both viral titer and apoptotic activi

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

181 Telaprevir-related dermatitis occurs in a majority of te

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

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

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

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

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

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

188 Telaprevir-resistant variants were classified into lower

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

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

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

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

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

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

195 o inform structure-based optimization of the telaprevir's reactive warhead and P1-P4 substitutions.

196 In cell culture, telaprevir showed submicromolar-to-low-micromolar potenc

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

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

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

200 Telaprevir susceptibilities varied over a 4-fold range,

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

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

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

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

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

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

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

208 t and highlight the repurposing potential of telaprevir to treat EV-D68 infection.IMPORTANCE A 2014 E

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

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

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

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

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

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

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

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

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

218 of EV-D68 associated AFM to show that early telaprevir treatment improves paralysis outcomes in Swis

219 Telaprevir treatment preserved motor neuron populations

220 Here, we demonstrate that a telaprevir treatment that is given concurrently with an

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

239 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir ever

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

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

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

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

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

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

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

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

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

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

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

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

252 e show that the potent antiviral activity of telaprevir was due to 2A(pro) inhibition.

253 Telaprevir was generally safe and well tolerated.

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

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

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

257 The effects of telaprevir were not seen when the treatment was delayed,

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

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

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

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

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

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

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

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

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

267 Telaprevir with peginterferon-ribavirin, as compared wit

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