NM283 - IHL Press
Transcription
NM283 - IHL Press
Progress with the clinical development of valopicitabine (NM283) in combination with peg-interferon for the treatment of chronic hepatitis C, in treatment-naïve patients and in non-responders to peg-interferon/ ribavirin Christopher O'Brien University of Miami, USA Progress in the Clinical Development of Valopicitabine (NM283) in Combination with Peg-Interferon for the Treatment of Chronic Hepatitis C, in Treatment-Naïve Patients and in Non-Responders to Peg-Interferon / Ribavirin Christopher O’Brien, M.D. Center for Liver Diseases University of Miami Hep DART Kohala Coast, Hawaii December 2005 Potential Targets of Hepatitis C Therapies capsid C envelope E1 NS3 Protease domain E2 protease/helicase p7 NS2 NS3 Helicase domain NS3 NS4A polymerase NS4B NS3 Bifunctional protease / helicase NS5A NS5B NS5B RNA-dependent RNA polymerase © 2002 JG McHutchison, DUMC Valopicitabine z NM107 – Ribonucleoside – NS5b polymerase inhibitor – NM107-triphosphate competitively inhibits viral polymerase and is incorporated into viral RNA, causing chain termination z NM283 NH2 NH O N HO O CH3 Val-O OH – Valyl ester pro-drug provides Valopicitabine (NM283) high oral bioavailability 2’-C-methylcytidine-3’-O-L-valine ester – Plasma half life (4-6 hrs) & intracellular half life (15 hrs) support once daily dosing NM107 is Active in a Surrogate Virus Model and Synergistic in Combination with IFN-α 8 No Drug IFN 200 units/mL 6 BVDV Titer Log10 Units/mL NM107 8µM 4 2 0 IFN 200 units/mL + NM107 8 µM 0 2 4 6 8 10 12 Days Cell-Based Persistent BVDV Infection Model Valopicitabine: Clinical Trial Plan Phase I Phase II Dose Dose Escalation Escalation (001) (001)** NM283 α PK NM283 /IFN /IFNα PK (003)* (003)* Treatment Treatment Naives Naives Food Food Effect Effect (002) (002)** Phase -1 Phase IIb IIb HCV HCV-1 Treatment Treatment Failures Failures (004)* (004)* Hepatic Hepatic Impairment Impairment Renal Renal Impairment Impairment Pharmaco -interaction Pharmaco-interaction ((Tacrolimus, Tacrolimus, RBN, RBN, Cyclosporin Cyclosporin)) Phase -1 Phase IIb IIb in in HCV HCV-1 Treatment ïves Treatment Na Naïves (006)* (006)* *Complete or ongoing Phase III Previous Previous Treatment Treatment Failures -1) Failures (esp. (esp. HCV HCV-1) Treatment ïve (esp. Treatment Na Naïve (esp. HCV -1) HCV-1) Final Phase I/II Trial Results for NM283: A New Antiviral for Hepatitis C: Antiviral Efficacy and Tolerance in Patients with HCV-1 Infection N Afdhal, E Godofsky, J Dienstag, V Rustgi, L Shick, L Duncan, X-J Zhou, G Chao, C Fang, B Fielman, M Myers, and N Brown AASLD 2004 Boston, Massachusetts Valopicitabine Phase I/II Trial (001): Study Overview z First-in-Man dose escalation trial z Objectives: safety, antiviral activity, and PK during 15-day treatment and 2 week posttreatment follow-up z 95 adult patients with chronic hepatitis C enrolled – – – HCV genotype 1, ~90% IFNα failures Serum HCV RNA ≥ 5 log10 IU/mL, ALT <5 x ULN Compensated liver disease, no cirrhosis z Dosing levels: 50 – 800 mg per day z Each dosing cohort of 12 eligible patients randomized 10:2 to NM283 vs. placebo Presented by N Afdhal, AASLD 2004 Valopicitabine Phase I/II Trial (001): Steady State (Day 15) NM107 PK after Valopicitabine Dosing Mean (SD) Single-Dose Plasma Profiles of NM107 10000 100000 NM107 Plasma Conc. 1000 Single-Dose NM107 AUC vs Dose NM107 AUC0-inf (ng/mL×hr) (ng/mL) 10000 100 10 50 mg 100 mg 200 mg 400 mg 800 mg 0 4 8 12 Hours 16 20 24 1000 100 1000 NM283 Dose (mg/day) Overall plasma exposure increases linearly with dose Mostly comparable single-dose and steady-state PK Presented by N Afdhal, AASLD 2004 Valopicitabine Phase I/II Trial (001): Inhibition of HCV-1 Replication in Patients 0.2 0 Serum HCV RNA Mean Log10 Change From Baseline Placebo -0.2 50 mg QD 100 mg QD -0.4 200 mg QD 400 mg QD -0.6 200 mg BID -0.8 Dose Titration 100-800 mg -1 Dose Titration 400-800 mg + antiemetic 800 mg QD -1.2 Treatment Period 1 2 3 4 5 8 11 Study Day 15 16 17 22 Presented by N Afdhal, AASLD 2004 Valopicitabine Phase I/II Trial (001): Safety & Tolerance z Clinical safety satisfactory overall z GI side effects in some patients – Typically transient nausea – Less frequent vomiting z No grade 3 or 4 lab abnormalities during treatment z No pattern of lab abnormalities Presented by N Afdhal, AASLD 2004 Valopicitabine (NM283) Alone And In Combination With Peg-Interferon In Patients With Genotype 1 Chronic Hepatitis C: Preliminary Results From An Ongoing Phase IIa (003), Multicenter Study M Rodriguez-Torres, E Lawitz, E Godofsky, N Afdhal, G Chao, B Fielman Constance, S Knox, and N Brown DDW Annual Meeting May 17, 2005 Chicago Valopicitabine Phase IIa Trial (003): Study Design z Safety, antiviral activity, & pharmacokinetics of NM283 vs. NM283 + peg-IFNα-2b z Open-label design: – – – 30 treatment-naïve adults with HCV-1 compensated CHC HCV RNA >5 log10 IU/mL, ALT <5 times ULN Eligible patients randomized 2:3 to: • Valopicitabine (dose escalation to 800 mg/day; n=12) vs. • Valopicitabine + peg-IFNα-2b (1.0 µg/kg QW; n=18) z Initial design called for 28 days’ treatment; encouraging early data led to treatment extension to 48 weeks z Extension provides exploratory longer-term efficacy and safety data for combination of Valopicitabine + peg-IFN z Study is ongoing to one year Presented by M Rodriguez-Torres, DDW 2005 Valopicitabine Phase IIa Trial (003): Patient Disposition 30 patients enrolled; EVR assessed at Wk 12 Valopicitabine MonoRx (n=12) Valopicitabine + Peg-IFNα ComboRx (n=18) 11 Patients 1 Patient 6 Patients 12 Patients No EVR (9) or discontinued (2) EVR No EVR (3) or discontinued (3) On therapy at Week 24 ↓ ↓ ↓ Treatment stopped at / before Week 12 ↓ Treatment continued to Week 24 Treatment stopped 9 Pts completed at / before Week 12 Week 24 Presented by M Rodriguez-Torres, DDW 2005 Valopicitabine Phase IIa Trial (003): Treatment-Naïve Patients Serum HCV RNA Levels, Baseline to Week 24 7 6 -1.9 log10 IU/mL 5 NM283 monoRx (n=1/12) Mean Serum 4 HCV RNA (Log10 IU/mL) 3 -3.58 log10 IU/mL 2 NM283 + Peg-IFNα-2b ITT (n=9/18) Amplicor LLOD = 50 IU/mL 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Study Week Adapted from Rodriguez-Torres, et al. DDW 2005 Valopicitabine Phase IIa Trial (003): Individual HCV RNA Plots All 9 ComboRx Patients Completing Week 24 At Week 24: 8 of 9 Patients <LLOQ Amplicor (600 IU/mL) 8 7 of 9 Patients <LLOD Amplicor (50 IU/mL) 7 6 of 9 Patients <LLOD TaqMan (10 IU/mL) 6 Serum HCV RNA 5 (Log10 4 IU/mL) 3 Poor Response 2 Late responses 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Study Week Presented by M Rodriguez-Torres, DDW 2005 Valopicitabine Phase IIa Trial (003): Safety and Tolerance z Clinical safety satisfactory overall z No serious adverse events or dose-limiting toxicities z Typical IFN side effects – no unexpected side effects z Nausea/vomiting common in both Rx groups, typically transient, probably related to both Valopicitabine and IFN z One lab grade abnormality observed during treatment: ANC ↓ (620/mm3) at Day 11 in a patient receiving combination therapy Presented by M Rodriguez-Torres, DDW 2005 Randomized Trial of Valopicitabine (NM283) Alone and in Combination with Peg-Interferon vs. Retreatment with Peg-Interferon plus Ribavirin (PegIFN/RBV) in Hepatitis C Patients with Previous Non-Response to PegIFN / RBV: First Interim Results C. O’Brien, E. Godofsky, M. Rodriguez-Torres, N. Afdhal, S. Pappas, P. Pockros, E. Lawitz, N. Bzowej, V. Rustgi, M. Sulkowski, K. Sherman, I. Jacobson, G. Chao, S. Knox, K. Pietropaolo, and N. Brown AASLD 2005 Annual Meeting San Francisco, CA Nov. 14, 2005 Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Key Inclusion Criteria z 18-65 years of age, male or female z HCV genotype 1 z Non-responders defined as adequate treatment course – – – – z Patients must have previously failed for efficacy, not tolerability At least 12 weeks of pegIFN alfa + RBV At least 75% of the prescribed doses of pegIFN and ribavirin Failed to clear HCV RNA to non-detectable levels (relapsers excluded) Baseline – HCV RNA > 105 IU/mL – ALT ≤ 5 x ULN z Compensated liver disease Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Study Design z Multicenter (22), randomized, active control design z 171 patients to be randomized in a 1:2:2:2:2 ratio z HCV RNA response criteria at Weeks 4, 12, 24 – Patients required to have HCV RNA drop ≥ 0.5 log at Week 4, ≥ 1.0 log at Week 12, and > 2.0 log at Week 24 to continue treatment – Early termination if viral response criteria not met z Primary efficacy endpoint: ITT analysis will be the SVR 6 months after the last dose of study medicine – HCV RNA: COBAS TaqMan™ PCR assay (10 IU/mL; Roche) – NM283 dosing groups pooled and compared to PegIFN + ribavirin Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Treatment Arms Valopicitabine (NM283) 800 monotherapy Arm A Valopicitabine (NM283) 400 monotherapy Valopicitabine (NM283) 400 + PEG-2a 180 µg Valopicitabine (NM283) 400-800 monotherapy Valopicitabine (NM283) 800 + PEG-2a 180 µg Valopicitabine (NM283) 800 monotherapy Valopicitabine (NM283) 800 mg + PEG-2a 180 µg Arm B Arm C Arm D PEG IFN α-2a + RBV 1000-1200 mg/daily (75 kg cutoff) Arm E 0 1 4 12 24 48 72 Weeks n = 171 HCV RNA Follow-up Endpoints Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Demographics 800 mg monoRx NM283 Arms 400 mg 400-800 + mg PegIFN + PegIFN 800 mg + PegIFN PegIFN + Ribavirin Number (n=190) 21 42 42 42 43 Gender (% Male) 81 67 67 71 61 Age (mean years) 51 51 50 52 51 Race: Caucasian (%) 71 76 69 64 51 Asian (%) 19 10 14 21 23 Mid-East/Indian (%) 10 14 14 12 23 Other (%) 0 0 2 2 2 Mean HCV RNA (log10 IU/mL) 6.9 6.9 7.0 7.0 6.9 No prior EVR (%) 81 81 81 81 81 Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Current Status z 190 patients were randomized (fully enrolled) – 12 patients withdrew prior to receiving study medications • 9 withdrew consent after randomization to Peg-IFN/RBV • 3 withdrew consent for other reasons z 178 patients received study medications – 21 patients discontinued by week 12 • • • z 5 withdrew consent for other reasons 9 virologic non-response at week 4 7 discontinued for adverse events 157 patients reached week 12 – Trial is ongoing Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): HCV RNA Responses at Week 12 p = 0.01 80% 67% 70% Patients In Category (%) PegIFN + RBV (ARM E) p = 0.03 60% 50% 800 mg Valopicitabine + PegIFN (combined ARM C + ARM D) 41% 41% p = 0.05 40% 21% 30% 21% 20% 6% 10% 0% >2 log >3 log >4 log Log10 HCV RNA Suppression from Baseline Valopicitabine (NM283) Phase IIb Non-Responder Trial (004) Partial Data: Mean Reduction HCV RNA at Week 24 Change from Baseline HCV RNA (log 10) 0 Preliminary data: ITT Analysis A 0.60 log -0.5 -1 -1.5 -2 E 2.31 log B 2.49 log -2.5 C 3.01 log* D 3.32 log* -3 -3.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study Week A NM283 800 mg QD B NM283 400 mg QD + Peg-IFN 180 µg QW C NM283 400-800 mg QD ramp (1st week) → 800 mg QD + Peg-IFN 180 µg QW D NM283 800 mg QD + Peg-IFN 180 µg QW E Ribavirin QD + Peg-IFN 180 µg QW * p = .001 vs. RBV + PegIFN Valopicitabine (NM283) Phase IIb Non-Responder Trial (004) Partial Data: HCV RNA Nondetectable Rate at Wk 24 z HCV RNA is PCR-negative in: – 0% of Arm A (NM383 monoRx) – 18% of Arm B (NM23 400 + pegIFN) – 11% of Arm C (NM283 400-800 + pegIFN) – 25% of Arm D (NM283 800 +pegIFN) – 19% of Arm E (PegIFN/RBV) z Median HCV RNA reduction at week 24 – Less (1.21 log10) in control arm (E) than in NM283+pegIFN arms B-D (2.31, 3.01, and 3.29 log10, respectively) Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Safety z Only 4% (n=7) discontinuations for adverse events by week 12 z Serious adverse events (SAE) in 6/178 patients (3%) through week 12 – Two attributed to study medication (anemia, dehydration) – All SAEs have resolved z Laboratory abnormalities – No hematologic toxicities (grade 1-4) for NM283 monotherapy; neutropenia and thrombocytopenia in all arms with pegIFN – Sporadic elevations of amylase, lipase, AST, ALT occurred, these were mild (grade 1 & 2) Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Conclusions z Proportionally greater antiviral efficacy for NM283 + pegIFN vs. pegIFN + RBV, in NonResponders – Statistically superior antiviral efficacy (↓ HCV RNA and EVR rate) for 2 higher NM283 + pegIFN doses z Overall safety / tolerance satisfactory to date z No viral breakthrough or resistance detected to date z Continued decline in HCV RNA levels in the two higher NM283 dosing groups encouraging Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Acknowledgments Valopicitabine 004 Trial Clinical Investigators z z Nezam Afdhal z z Natalie Bzowej z Gary Davis z Michael Fried z Eliot Godofsky z z Paul Kwo z Eric Lawitz z z Karen Lindsay USC School of Medicine, Los Angeles, CA z John McHutchison z z z z Mark Sulkowski Myron Tong Huntington Memorial Hospital, Pasadena, CA John Vierling Baylor College School of Medicine Idenix Pharmaceuticals, Inc., Cambridge, MA Nathaniel Brown George Chao Keith Pietropaolo Coleman Smith Johns Hopkins Univ. School of Medicine, Baltimore, MD Duke Clinical Research Institute, Durham, NC z z z Mitchell Shiffman Minnesota Clinical Research, Saint Paul, MN Alamo Medical Research, San Antonio, TX z z McGuire VA Medical Center, Richmond, VA Indiana University Medical Center, Indianapolis, IN z Lawton Shick Univ. Massachusetts Medical School, Worcester, MA Ira Jacobson Weill Medical College of Cornell University, New York, NY z Kenneth Sherman Univ. Cincinnati College of Medicine, Cincinnati, OH Stuart Gordon Henry Ford Health System, Detroit, MI z Vinod Rustgi Metropolitan Research, Fairfax, VA Bach & Godofsky, Bradenton, FL z Maribel RodriguezRodriguez-Torres Fundacion de Invest. de Diego, Santurce, PR UNC School of Medicine, Chapel Hill, NC z Paul Pockros Scripps Clinic, La Jolla, CA Baylor University Medical Center, Houston, TX z S. Chris Pappas St. Luke's Episcopal Hospital, Katy, TX Sutter Health, San Francisco, CA z Christopher O’Brien Univ. Miami Center for Liver Diseases, Miami, FL Beth IsraelIsrael-Deaconess Liver Center, Boston, MA Barbara FielmanFielman-Constance Steven Knox Richard Boehme Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Resistance Monitoring z Preclinical results: BVDV surrogate virus and replicon – NM283 resistance mutation may be S282T substitution in HCV Pol 1 – BVDV mutants with the S282T homolog have reduced sensitivity to NM283 but ~30-fold increased sensitivity to IFN1 z Clinical results: – No clear evidence of breakthrough in NM283 trials, with treatment to 3 months in >150 patients and to 6 months in ~50 pts – HCV RNA sequencing: • No S282 mutants detected in 33 serum samples from 18 patients (including poor responders) with treatment durations up to 169 days • No mutations detected in domains B or C (S282 is domain B) 1 V. Bichko et al. AASLD, 2005 Valopicitabine Phase IIa Trial (003): Serum ALT Response to Week 24 70 65 60 Median Serum ALT (IU/mL) 55 63% normal at Week 24 ↓ 43% normal at Week 12 ↓ 50 45 ULN (males) 40 35 ULN (females) 30 25 0 4 8 12 16 20 24 Study Week Presented by M Rodriguez-Torres, DDW 2005 Valopicitabine (NM283) Phase IIb Non-Responder Trial: Categorical ALT Responses at Week 12 800 mg Valopicitabine + PegIFN (combined ARM C + ARM D) Mean Serum ALT (Change from Baseline, IU/L) 20 15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40 Mean Baseline ALT 77 PegIFN + RBV (ARM E) Week 4 Week 8 87 Week 12 Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): Most Frequent Adverse Events to Week 12 % of Patients With Event, Regardless of Relation to Study Drug 800 mg Total with AE (%) Nausea Vomiting Fatigue Diarrhea Headache Insomnia Decreased appetite Myalgias Neutropenia Depression Pyrexia Arthralgias Influenza-like illness Rigors (n=21) 400 mg + PegIFN (n=41) 400-800 + PegIFN (n=41) 800 mg + PegIFN (n=41) RBV + PegIFN (n=34) (n=178) 95 67 48 10 33 10 0 24 0 0 14 10 5 0 5 100 68 49 44 32 37 5 12 27 17 5 17 10 5 12 100 78 51 46 54 34 24 15 15 22 20 10 15 20 10 100 78 78 59 27 27 20 22 17 24 15 17 22 22 15 100 32 6 56 15 24 32 15 18 12 27 15 12 15 15 99 66 48 46 33 28 17 17 17 17 16 14 14 14 12 Includes adverse events occurring in at least 10% of patients overall Total Valopicitabine Phase I/II Trial (001): Conclusions z Consistent, dose-related antiviral activity in HCV-1 infected patients, primarily (87%) previous interferon failures – Mean HCV RNA reductions 0.15 – 1.21 log10 IU/mL at doses of 50 to 800 mg/day – Individual patient range (800 mg/day cohort) 0.41 – 2.37 log10 IU/mL z Satisfactory safety – no dose-limiting toxicities, some transient nausea & vomiting, all compliant patients (78/79) completed treatment Presented by N Afdhal, AASLD 2004 Valopicitabine Phase IIa Trial (003): Conclusions z Marked antiviral activity for valopicitabine + peg-IFNα z For 9 ComboRx patients completing Week 24: – Mean HCV RNA ↓ 4.5 log10 IU/mL (range: -2.33 to -6.2 log10) – Continuing ‘late’ HCV RNA reductions: • 4 of 5 pts with detectable HCV RNA at Week 12 had multi-log drops after Week 12 • Results suggest kinetics of response to Valopicitabine + PegIFNα may differ from kinetics of response to peg-IFNα + ribavirin z No HCV RNA “breakthroughs” to date, with data to 24 weeks – Viral genotyping (HCV Pol) underway z Good Tolerability – Negligible hematologic side effects – possible safety advantage Presented by M Rodriguez-Torres, DDW 2005 Valopicitabine (NM283) Phase IIb Non-Responder Trial (004): EVR Results Week 12 Treatment Group n Mean ↓ HCV RNA Pts with EVR† (log10 IU/mL) Number (%) A NM283 monoRx 21 0.78 1 (5%) B NM283 400 + pegIFN 41 2.22 24 (54%) C NM283 400-800 + pegIFN 41 2.51 * 29 (71%) * D NM283 800 + pegIFN 41 2.77 * 26 (63%) * E PegIFN + RBV retreatment 34 1.92 14 (41%) * p < 0.001 vs pegIFN + RBV (comparisons of C and D to E) † EVR = early virologic response: ≥ 2 log10 (99%) drop in serum HCV RNA Christopher O’Brien, M.D. Center for Liver Diseases University of Miami School of Medicine z I have the following financial arrangements to disclose: – Grants/research support • Idenix Pharmaceuticals, Coley Pharmaceuticals, Valeant Pharmaceuticals, Hoffmann-La Roche Inc, Vertex Pharmaceuticals, Schering-Plough, IDUN Pharmaceuticals / Pfizer Inc, InterMune, Inc, GlaxoSmithKline Inc, Ortho Biotech, Otsuka Pharmaceutical Co., Ltd – Consultant • Schering-Plough – Speakers Bureau • Bristol-Myers Squibb, Axcan Pharma Inc, Schering-Plough, Gilead Sciences, Hoffmann-La Roche Inc z My presentation includes the investigational use for treatment of chronic hepatitis C: – Valopicitibine as monotherapy – And in combination with PegIFN alfa-2a