A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients

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A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients
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  A phase I trial of an antisense inhibitor of hepatitis C virus(ISIS 14803), administered to chronic hepatitis C patients * John G. McHutchison 1,2, * , Keyur Patel 1,2 , Paul Pockros 2 , Lisa Nyberg 2 , Stephen Pianko 2 ,Rosie Z. Yu 3 , F. Andrew Dorr 3 , T. Jesse Kwoh 3 1 The Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center,P.O. Box 17969, Durham, NC 27715, USA 2 Scripps Clinic, Division of Gastroenterology, La Jolla, CA, USA 3  Isis Pharmaceuticals, Carlsbad, CA, USA  Background/Aims : ISIS 14803 is a 20-unit antisense phosphorothioate oligodeoxynucleotide that binds to hepatitis Cvirus (HCV) RNA at the translation initiation region of the internal ribosome entry site (IRES) and inhibits proteinexpression in cell culture and mouse models. This Phase I, open-label, dose-escalation trial of ISIS 14803 was performedin chronic HCV patients.  Methods : At least 7 days after receiving an initial single dose, twenty-eight patients received 0.5–3 mg/kg ISIS 14803thrice weekly for 4 weeks by intravenous infusion or subcutaneous injection.  Results : In most patients, the 4-week treatment did not reduce plasma HCV RNA. However, 3 patients receiving R 2 mg/kg had transient HCV reductions of 1.2–1.7 log 10  that persisted % 32 days. These reductions were accompaniedby asymptomatic, self-resolving elevations in serum alanine transaminase (ALT) levels to O 10 ! the upper limit of normal. Two other patients had ALT flares without plasma HCV reduction. No clinical signs, symptoms of hepaticdysfunction, or laboratory changes in albumin or prothrombin time accompanied ALT elevations. Conclusions : ISIS 14803 treatment was associated with HCV reductions in only 3/28 patients. ALT flares in 5 patientsalso occurred. Further studies to evaluate ISIS 14803 treatment and the mechanisms of the ALT flares are nowrequired. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.  Keywords : Hepatitis C virus; Treatment; Antisense therapy; New therapies; Nonresponders.1. Introduction Approximately 170 million people worldwide areinfected with hepatitis C virus (HCV), and infection persistsin approximately 75–85% of cases, making hepatitis Cinfection an important cause of chronic liver disease Lauerand Walker, (2001); NIH Consensus Development Con-ference Statement, (2002); Consensus, (2002); Alter et al.,(1999); Lavanchy and McMahon, (2000). Liver cirrhosisand end-stage liver disease due to HCV is now the mostcommon indication for liver transplantation in the UnitedStates. Moreover, the disease burden due to chronicinfection is expected to increase over the next decade(Kim, (2002)). Treatment with peginterferon and ribavirinprovides effective therapy in 50–60% of HCV patientsManns et al., (2001); Fried et al., (2002). However, thistherapy is costly, prolonged, not suitable for many patients,and has significant side effects (NIH Consensus Develop-ment Conference Statement, (2002)). Thus, numerousefforts to develop new therapies are in progress (Pawlotskyet al., 2004). Journal of Hepatology 44 (2006) 88–96www.elsevier.com/locate/jhep0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.jhep.2005.09.009  Received 11 April 2005; received in revised form 6 September 2005;accepted 12 September 2005; available online 25 October 2005 * The authors who have taken part in this study have declared arelationship with the manufacturers of the drugs involved and they receivedfunding from the drug companies involved to carry out their research. *  Corresponding author. Duke Clinical Research Institute, P.O. Box17969, Durham, NC 27715, USA. Tel.: C 1 919-668-7193; fax: C 1 919684 716. E-mail address:  mchut001@mc.duke.edu (J.G. McHutchison).  HCV genomic RNA is an attractive drug target because itis both the informational precursor for viral proteinsynthesis and an essential component of infectious virus(Penin et al., (2004)). Antisense therapeutics employ nucleicacids, usually oligonucleotides  ! 25 nucleotides long, todisrupt protein translation through Watson–Crick base-pairing of the antisense agent to the target RNA (Crooke,(1999); Crooke, (2001); Gerwitz et al., (1998); Scherer andRossi, (2003)). Phosphorothioate oligodeoxynucleotidespromote target RNA degradation via cellular RNase Henzymes (Crooke, 1999; Crooke, 2001; Gerwitz et al., 1998;Scherer and Rossi, 2003). Generally, the mechanisms thatdegrade RNA are the most potent (Crooke, 1999; Crooke,2001; Scherer and Rossi, 2003).Several groups have identified antisense oligonucleotidesthat inhibit HCV RNA and polyprotein synthesis in in vitro,cell culture, and mouse models (Mizutani et al., 1995; Sekiand Honda, 1995; Vidalin et al., 1996; Wakita and Wands,1994; Alt et al., 1995; Lima et al., 1997; Brown-Driveret al., 1999; Hanecak et al., 1996; Zhang et al., 1999). Oneof these oligonucleotides, ISIS 14803, is a phosphorothioateoligodeoxynucleotide that is complementary to the HCVtranslation initiation region within the internal ribosomeentry site (IRES) (Hanecak et al., 1996; Zhang et al., 1999).ISIS 14803 can reduce HCV RNA in immortalized humanhepatocytes expressing a portion of the HCV genome(Hanecak et al., 1996). In addition to having thephosphorothioate modification, ISIS 14803 also contains5-methyl-cytosine, instead of cytosine, which reduces thepro-inflammatory nature of this type of oligonucleotide(Zhang et al., 1999; Krieg, 2002; Levin et al., 2001). Here,we describe the first clinical study of this HCV-specificantisense approach. The study was performed in patientswith chronic hepatitis C infection who had previously notresponded to therapy or were unsuitable candidates forstandard therapies. 2. Methods 2.1. Study design In this open-label, dose-escalation study, sequential cohorts of 3patients were to be treated with 0.5, 1, 2, or 3 mg/kg of ISIS 14803. Patientswere assigned to the cohorts open at the time of their enrollment. Initiationof each cohort was contingent upon completion of ISIS 14803 treatment inprevious cohorts with an acceptable safety profile. Initially, doses weregiven by 2-h intravenous infusion. Each patient received an initial dosefollowed by a 7-day washout. Patients then were given thrice-weekly dosesfor 4 weeks and followed for 8 weeks post-treatment. After treatment wascompleted for the initial intravenous cohorts, separate sequential cohortsreceived treatment by subcutaneous injection. 2.2. Patient population Twenty-eight patients were enrolled and treated in this single-centerstudy. All patients had chronic HCV infection as documented by thepresenceofdetectable serumHCVantibodiesand quantifiableplasma HCVRNA. Patients were enrolled if they had previously not responded to, wereunwilling to take, or had a contraindication to conventional interferon-based therapy. Nonresponse to therapy was defined as retention of detectable serum or plasma HCV RNA after at least 3 months of interferon-based therapy. Patients with decompensated disease, hepatitis Bvirus (HBV) or HIV coinfection, or chronic liver disease from other causeswere excluded from this study. Other exclusion criteria included comorbidillnesses including clinically significant cardiovascular, neurologic,autoimmune, or thyroid diseases. All patients had a pretreatment liverbiopsy indicating chronic hepatitis, platelet count  R 1,00,000 cell/mm 3 ,hemoglobin  O 11 g/dL, and prothrombin time, white blood cell count,bilirubin and creatinine within the normal range. The study was approvedby the Scripps Clinic Institutional Review Board and performed inconformity with the Declaration of Helsinki. All patients provided writteninformed consent prior to enrollment. 2.3. Study evaluations Subjectswere evaluatedfrequentlyforsafetyand adverseevents.Safetyendpoints included clinical symptoms, physical examination findings, andlaboratory parameters. Serum chemistries, complete blood cell count withdifferential, urinalysis, and prothrombin and activated partial thromboplas-tin (aPTT) times were performed at baseline and weekly during therapy andthe initial 3 weeks of the 8-week follow-up. In addition, complement splitproducts (C3a, C5a, and Bb) were measured weekly before, during, andafter administration of ISIS 14803. Plasma interferon- g  (IFN- g ), tumornecrosis factor- a  (TNF- a ), and interleukin-4 (IL-4) were measured beforeand after each patient’s first dose.Plasma HCV RNA was measured at a single central laboratory(National Genetics Institute, Los Angeles, CA) by quantitative polymerasechain reaction, with a detection limit of 100 copies/mL (SuperQuant e ,2.5 copies/IU) (Tong et al., 1997; Pawlotsky et al., 2000). HCV genotypingwas performed with Inno-LiPA HCV II (Innogenetics, Zwijnaarde,Belgium) as described previously (Stuyver et al., 1993).The plasma pharmacokinetics of ISIS 14803 was evaluated for bothintravenous and subcutaneous administration. ISIS 14803 levels in plasmacollected before, during, and following the single dose and the last dose of the treatment period were measured by capillary gel electrophoresis aspreviously described (Leeds et al., 1996). ISIS 14803 levels were similarlymeasured in urine collected for 24 h after these doses. 2.4. Statistical analysis This Phase I study was designed to evaluate the safety and tolerabilityof 4 ISIS 14803 doses given by two routes of administration. The study wasnot powered to detect significant changes in antiviral response ratesbetween cohorts. Statistical comparisons between cohorts were notperformed. Descriptive statistics (mean, SD, median) were employed tosummarize selected findings. 3. Results 3.1. Study patients Twenty-eight chronic hepatitis C patients were enrolled.Twenty received ISIS 14803 intravenously, and 8 subcu-taneously. The first patient was screened on March 13, 2000,and the last follow-up visit was July 17, 2002. Patients weremiddle-aged with elevated alanine transaminase (ALT)values, and most were male and had high plasma HCV RNAlevels(Table1).Twenty-fourofthetwenty-eightpatientswerevirologic nonresponders to prior interferon-based therapy.Sequential 3-patient cohorts were treated intravenouslyat 0.5, 1, and 2 mg/kg ISIS 14803. Because of theunexpected ALT elevations in Patients 108 (598 U/L) and109 (411 U/L), treated at 2 mg/kg, 2 subsequent patients  J.G. McHutchison et al. / Journal of Hepatology 44 (2006) 88–96   89  (110 and 111) received 2 mg/kg for their single dose andthen were treated at 1 mg/kg for their repeat dosing. Further,enrollment into the study was suspended when Patient 111developed elevated ALT levels (830 U/L). A follow-uplasting several months indicated no clinical symptoms orsequelae amongst the 3 patients. Enrollment was resumed atthe lower dose levels only after additional stopping ruleswere introduced and regulatory bodies were informed of the safety data. Sequential cohorts of 3 patients were thenenrolled and treated intravenously at 1, 2, and 3 mg/kg.Patients received 3 mg/kg only after prior cohorts tolerated1- and 2-mg/kg therapy without experiencing any furtherevidence of ALT flares. In parallel, sequential cohorts weretreated subcutaneously with 0.5, 1, and 2 mg/kg. Enrollmentwas closed when dosing at the highest intravenous dose wascompleted. Additional subcutaneous dosing was notpursued to avoid subjecting patients to multiple injectionsat each dosing. 3.2. Plasma HCV RNA reductions Three of the 10 patients enrolled for treatment at 2 mg/kg(Patients 108, 111, and 208) had reductions in plasma HCVRNA of more than 1.0 log 10  (Table 2, Fig. 1). None of the other patients enrolled for treatment at 0.5 ( n Z 6), 1 ( n Z 9),and 3 mg/kg ( n Z 3) had similar reductions. Patients 108 and208 received all of their doses at 2 mg/kg, whereas Patient111 only received 1 dose at that level, and his subsequent 7doses were at 1 mg/kg. Treatment for Patients 108 and 111were stopped early (after 11 and 8 doses, respectively)becausetheirserumALTwaselevated O 10 ! ULN.Patients108 and 111 received ISIS 14803 intravenously, and Patient208 by subcutaneous injection. These 3 patients had ALTelevations in association with reductions in HCV RNA(Fig. 1).Thechangesinviralconcentrationsvariedbetweenthese3patients. Patient 108 had a pretreatment plasma HCV RNAlevel (average of Screen and Baseline values) of 12.4 millioncopies/mL. After initiation of thrice weekly dosing, HCVRNA levels progressively declined and reached a 1.4 log 10 reduction in 45 days. HCV was below pretreatment level forapproximately 74 days and was O 10-fold reduced for about32days.Patient111’sHCVRNAreductionoccurredafterhisseventh, and last, dose at 1 mg/kg. The nadir, a 1.2 log 10 reduction,was reached 44daysafterrepeatdosingbegan.HisHCVwasbelowpretreatmentforabout43daysandwas O 10-fold reduced for approximately 15 days. Patient 208 had apretreatmentHCVRNAlevelof4.3 millioncopies/mL,whichinitially increased to 39 million during treatment. Thepatient’s HCV RNA began to decline between 19 and39 days after receiving the last dose and reached a nadir of 80,000 copies/mL, 1.7 log 10  below pretreatment, at 81 daysafter starting repeat dosing. HCV was less than pretreatmentlevels O 82 days. 3.3. ALT elevations All 3 patients with HCV RNA reductions O 1.0 log 10  hadelevated serum ALT. In addition, two other patients (Patient105 treated at 1 mg/kg and Patient 109 treated at 2 mg/kg)also had ALT elevations (Fig. 1). For these 5 patients, peak ALT elevations ranged from 411 to 830 U/L, 8.6–18.4 ! ULN (upper limit of normal) (Tables 2 and 3). As with HCVRNA reductions, the time courses for ALT elevationsvaried. Peak ALT elevation occurred 18–25 days afterinitiation of thrice weekly dosing for Patients 105, 108, and111, and 60–67 days for Patients 109 and 208 (Table 3).During these transient ALT elevations, the number of daysduring which ALT was R 4-fold pretreatment levels rangedfrom 25 days to 84 days (Table 3). In 4 patients, their ALTelevations resolved to near baseline levels in 26–82 daysfollowing peak levels (Fig. 1). In contrast, Patient 109 had asecond, lesser, ALT elevation, which peaked at 399 U/L,8.3 ! ULN, 88 days after his first peak ALT elevation and123 days after the last dose of ISIS 14803. Coincident withthe resolution of this second peak, the patient’s plasma HCVRNA level declined 0.9 log 10 .Concurrent with ALT increases, elevations of aspartatetransaminase (AST) (to 133–494 U/L, 2.8–11.9 ! ULN) andgamma-glutamyl transpeptidase (GGTP) (to 67–231 U/L,2.3–7.9 ! ULN) occurred in all 5 patients. While alkalinephosphatase and bilirubin values remained within normalranges, alkaline phosphatase increases (to 76–129 U/L, 1.6–2.0 times pretreatment) were observed for Patients 108, 111,and 208, and a bilirubin increase to 1.6 mg/dL was observedfor Patient 111. No significant changes were seen in otherroutine clinical laboratory tests including prothrombin time,albumin, and hematology and urinalysis parameters. Anti-nuclear and anti-smooth muscle antibody levels were alsomeasured pre-study and during the ALT elevation in serumcollected from Patients 105, 108, 109, and 111. Nomeasurable antibody levels in these 4 patients suggestedthe induction of autoimmune liver injury (data not shown).Fatigue and headache were reported by 3 patients duringtheir ALT flares, and nausea was by 2 patients. Theassociation of these adverse events to the ALT flares is Table 1Patient characteristics at baseline Characteristic NumberPatients treated 28Age (years) (median, range) 47 (33–60)Male/Female 18/10ALT, IU/L (mean G SD) 69 G 41HCV RNA (copies/mL) (median, range) 7.7 ! 10 6 (0.3–37 ! 10 6 )HCV RNA O 1 ! 10 6 copies/mL 26HCV RNA O 10 ! 10 6 copies/mL 10Genotype 1 24Cirrhosis 2Bridging fibrosis 3Portal fibrosis 18Prior therapy 24ALT, alanine transaminase; HCV, hepatitis C virus.  J.G. McHutchison et al. / Journal of Hepatology 44 (2006) 88–96  90  unclear as their frequency and intensity were similar tothose observed in patients without ALT elevations, whoincluded patients treated at lower doses (e.g. 6 of 6 patientstreated with 0.5 mg/kg reported fatigue). Other less frequentand minor adverse events concurrent with ALT flares werereported for individual patients.Twenty-two days after a peak ALT elevation of 830 U/L,a liver biopsy was performed on Patient 111 when his ALTwas 424 U/L, and plasma HCV RNA was at its nadir.Histology revealed an intense inflammatory cell infiltratewithin the portal triads that was not present in the specimencollected 7 months prior to study entry. These biopsies were Table 2HCV RNA and ALT changes observed during and after ISIS 14803 therapy Patientno a Dose(mg/kg)No doses Plasma HCV RNA ALT ! 10 6 copies/mL MaximumobservedLog 10 reduction b U/L Peak  c Week 0 d Week 4 e Week 7 f  Week 0 g Week 4 e Week 7 f  ! Wk 0  ! ULN101 0.5 13 28.0 21.0 31.0  K 0.4 123 80 86 1.2 2.9102 0.5 13 8.7 8.5 5.4  K 0.2 114 129 126 1.2 2.9103 0.5 13 0.83 0.86 0.66  K 0.1 65 52 57 1.0 1.4201 0.5 13 16.3 4.2 3.5 h K 0.6 113 145 142 h 1.6 3.8202 0.5 13 9.4 31.0 14.0  K 0.1 32 19 18 2.5 1.8203 0.5 12 5.7 17.0 9.3  K 0.2 107 86 69 0.8 1.9104 1 13 4.1 5.6 4.8  K 0.1 91 93 126 1.4 2.7105 1 13 12.5 7.6 9.4  K 0.3 70 i 397 102 5.9 8.6106 1 13 16.6 17.0 28.0  K 0.2 35 77  j 67 2.2 1.6112 1 13 5.2 9.1 7.7 0.0 95 101 120 1.4 2.7113 1 13 4.9 14.0 15.0  K 0.1 75 67 69 1.0 1.6114 1 13 4.2 8.2 8.9  K 0.1 39 61 67 1.9 1.6204 1 13 5.9 14.0 29.0  K 0.2 35 i 31 28 1.1 0.8205 1 13 1.6 0.74 0.83  K 0.3 42 37 38 1.0 0.9206 1 13 10.0 4.7 27.0  K 0.3 154 161 158 1.4 4.8110 k  2 / 1 l 8 5.2 43.0 m Na  K 0.1 88 64 m na 0.8 1.6111 2 / 1 l 8 31.8 10.0 n 1.9  K 1.2 74 830 n 424 11.3 18.4107 2 13 0.51 2.4 1.2  K 0.1 29 34  j 32 1.2 0.7108 2 11 12.4 1.9 o 0.46  K 1.4 51 598 o 189 11.7 10.3109 2 13 33.4 25.0 29.0  K 0.6 50 261 346 9.5 10.4115 2 13 4.2 5.1 2.8  K 0.8 65 74 58 1.5 2.2116 2 13 1.9 2.7 3.8  K 0.6 30 43 46 1.6 1.0117 2 13 3.2 9.8 4.0  K 0.6 36 35 49 1.4 1.1207 2 12 3.6 7.4 3.5  K 0.2 160 207 185 1.6 4.0208 2 11 4.3 22.0 34.0  K 1.7 43 60 144 18.0 11.8118 3 13 6.9 3.6 3.4  K 0.7 47 52 56 1.3 1.4119 3 11 0.11 0.10 0.06 p K 0.5 68 65 48 p 0.8 1.5120 3 13 7.9 24.0 16.0 0.0 34 46 39 2.4 1.8Days below are relative to the first day of thrice weekly dosing. ALT, alanine transaminase; HCV, hepatitis C virus: ULN, upper limit of normal. a Patients 101–120 were treated intravenously, and 201–208 were subcutaneously. The patients are grouped by dose level; the proportion of ISIS 14803distributed to liver is equivalent between the two routes. b Maximal log 10  reduction of HCV RNA observed at any time during the entire treatment period. c The peak ALT value observed for each patient is shown in these two columns as the ratio to the pretreatment or baseline values at week 0, and also as theratio of this peak value to the upper limit of normal (ULN) for the ALT assay used in this study. d Geometric mean of Screen and Baseline values. e Day 25: day of last scheduled dose. f  Days 42–44. g Arithmetic mean of Screen and Baseline values. h Day 35 (Day 42 not done). i Screen only (Baseline sample was hemolyzed).  j Day 28 (Day 25 was hemolyzed). k  Patient 110 stopped early because of serious adverse events (SAE): psychosis and substance abuse. l Patients 110 and 111 received single doses at 2 mg/kg and thrice-weekly doses at 1 mg/kg. m Day 21 (early termination visit) instead of Day 25 (last dose on Day 14). n Day 22 (unscheduled visit) instead of Day 25 because of early dosing termination (ALT O 10 ! ULN, last dose on Day 14). o Day 28 (unscheduled visit) instead of Day 25 because of early dosing termination (ALT O 10 ! ULN, last dose on Day 21). p Day 45.  J.G. McHutchison et al. / Journal of Hepatology 44 (2006) 88–96   91  reviewed by two separate experts who independentlyconcluded that the histological findings were not suggestiveof drug-induced hepatotoxicity. A liver biopsy was alsoperformed on Patient 109 at 222 days after his first ALTpeak and 134 days after his second. Besides moderateperiportal hepatitis, there was no evidence of hepatotoxicity. 3.4. Safety Apart from the ALT flares, treatment with ISIS 14803 for4 weeks was generally well-tolerated. Excludingsubcutaneous injection site reactions, the most frequentadverseeventswereheadache( n Z 25),fatigue( n Z 15),pain( n Z 9), abdominal pain ( n Z 9), arthralgia ( n Z 6), insomnia( n Z 6), nausea ( n Z 6), dizziness ( n Z 5), myalgia ( n Z 5),dyspepsia ( n Z 5), diarrhea ( n Z 4), and constipation ( n Z 4).Allwerereportedasmildtomoderateinseverity.Allpatientstreated subcutaneously reported erythema and induration atsomeinjectionsites. Seven of8patients alsoreported pain atsome subcutaneous injection sites. The local injection sitereactions were judged by investigators and staff to be mildand did not require dose modifications or discontinuations. 10 5 10 6 10 7 10 8 01002003004005006000 40 80 120 160 Pt 108    H   C   V   (  c  o  p   i  e  s   /  m   l   ) A L T  (   U  /  L  )   Days from Baseline HCVALTDoses 10 4 10 5 10 6 10 7 10 8 01002003004005006007008000 40 80 120 160 Pt 208    H   C   V   (  c  o  p   i  e  s   /  m   l   ) A L T  (   U  /  L  )   Days from Baseline HCVALT 10 6 10 7 10 8 020040060080010000 40 80 120 160 Pt 111    H   C   V   (  c  o  p   i  e  s   /  m   l   ) A L T  (   U  /  L  )   Days from Baseline HCVALTDoses 10 5 10 6 10 7 10 8 0100200300400500-20 0 20 40 60 80 100 Pt 105    H   C   V   (  c  o  p   i  e  s   /  m   l   ) A L T  (   U  /  L  )   Days from Baseline HCVALTDoses 10 6 10 7 10 8 01002003004005000 40 80 120 160 200 240 280 Pt 109    H   C   V   (  c  o  p   i  e  s   /  m   l   ) A L T  (   U  /  L  )   Days from Baseline HCVALTDoses Fig. 1. Plasma hepatitis C virus (HCV) RNA and alanine transaminase (ALT) levels during and after treatment with ISIS 14803. Patients were giventheir single dose of ISIS 14803 on Day 0. After a washout R 7 days, patients were treated thrice weekly for up to 4 weeks. Patient 105 was treated at1 mg/kg.Patients108,109,and 208 were treatedat2 mg/kg.Patient111 received asingledose at 2 mg/kg andsubsequentdosesat 1 mg/kg.Patient208received the drug subcutaneously; all others did intravenously. Symbols: closed circles, plasma HCV RNA; open triangles, ALT; closed diamonds (on  x -axis), administered doses.  J.G. McHutchison et al. / Journal of Hepatology 44 (2006) 88–96  92
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