new immunomodulators - virology educationregist2.virology-education.com/2011/1hcvtherapy/... · why...

1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain

New immunomodulators

Alessandra Mangia San Giovanni Rotondo

ITALY


• Liver cirrhosis and end-stage liver disease! • Patients after liver transplantation! • Comorbidities (cardiovascular, renal, etc.) • Elderly,Children • Coinfections with HIV, HBV, etc. • Resistance, side effects, DDI, costs….

Why to search for additional strategies?

Unresolved issues with current SOC


Why immunomodulators?

• Recovery from hepatitis C is associated with a vigorous and multispecific CD4+ and CD8+ T cell response.

• Experience with IFN tx has demonstrated that chronic HCV infection can be controlled and HCV possibly eradicated while stimulating the host immune response by adoptive immunotherapy.


Immune Modifiers and Other Non-specific Drugs Human Genome Sciences ZALBIN (Albuferon albinterferon alfa-2b) (interferon / albuminfusion) Phase 3 SciClone Pharma SCV-07 immunomodulator - STAT3 signaling inhibitor Phase 2 Migenix MX3235 Celgosivir alpha-glucosidase I inhibitor Phase 2 inactive Intarcia Omega Interferon Phase 2 NABI Polyclonal antibody Civacir Phase 2 Romark Laboratories Alinia (Nitazoxanide) Phase 3 Biolex / OctoPlus Locteron controlled release interferon Phase 2 Kemin Pharma KPE02001003 Phase 2 Kemin Pharma KPE00001113 R & D VioQuest Pharmaceuticals Lenocta (sodium stibogluconate SSG) Phase 2 Conatus CTS-1027 MMP inhibitor Phase 2 Jenkin JKB-122 antiinflammatory Phase 2 Oklahoma University Health Sciences Center Fluvastatin Phase 2 Antipodean Mito-Q antiinflammatory Phase 2 Complete Phynova PYN17 antiviral anti-inflammatory anti-fibrotic Phase 2 Canopus CB5300 antiviral Phase 2 Medtronic continuous subcutaneous interferon external pump infusion system Phase 2 Flamel Technologies Medusa polymer controled release Interferon alpha-2b XL Phase 2 Phynova PYN18 anti viral plant extract Pre Clinical Can-Fite CF102 antiinflammatory Phase 2 Biotron BIT225 Phase 1 Peregrine Pharm Bavituximab Phase 2 Amarillo Bioscience / CytoPharm Low Dose Oral Interferon Phase 2 Bristol-Myers Squibb (was owned by ZymoGenetics) PEG-Interferon lambda Phase 2 Novelos NOV-205 immunomodulating and antiinflammatory Phase 2 Scynexis SCY-635 cyclophilin inhibitor Phase 1 Idera IMO-2125 TLR9 Agonist Phase 1 Anadys ANA773 TLR7 agonist Phase 1 Novartis / Debiopharm Debio 025 Cyclophilin Inhibitor Phase 3 Bristol-Myers Squibb / Ono MDX-1106 (ONO-4538) anti-PD1 Phase 1 Cytheris CYT107 Interleukin-7 Phase 2 Cubist CB-183872 Protein therapeutic - Formerly IB657 (Illumigen Biosciences) Pre Clinical REPLICor REP 9C broad-spectrum entry inhibitor Phase 1 Nautilus Oral Belerofon R & D Anadys AN 025-1 R & D Genodyssee GEA007.1 IFN alpha variant Pre Clinical Alios BioPharma Glycoferon Pre Clinical SciClone Pharma / Sigmatau Zadaxin - thymalfasin Phase 3 Bioenvision Suvus Phase 2 Enzo Biochem Immune Regulator ECH18 Phase 1 Immunomedics IMMU 105 Phase 1 Transition Therapeutics IET Interferon Enhancing Therapy Phase 2

Immune Modifiers and Other Non-specific Drugs

hcvdrug.com

PHASE II



Immunomodulatory agents

Antibodies -Therapeutical antibodies - nAbs Vaccines -Therapeutic - Prophylactic New IFNs Agonists of Toll-like receptor IFN-inducers


Benoit Callendret et al 2011


Immunotherapeutic potential of neutralizing anti-E2 antibodies

• HCV is universally recurrent after OLT • HBV Ig has been successfull at preventing

HBV recurrence after OLT • Similar approach has been attempted for

HCV


LB-12: Monoclonal Antibody MBL – HCV1 suppresses return of HCV following OLT

Gordon FD at al AASLD 2011

RCT double blind on human monoclonal antibody (mAb) to HCV E2 glycoprotein in pts with HCV 1.Three infusions at the day of OLT, at 7 and 14 days. 6 subjects mAb and 5 placebo.Well tolerated.Viral rebound delayed


The HCV escape from antibody-mediated neutralization

Angus AGN et al Future Micrbiology 2011



Human monoclonal antibodies Vaccines -Therapeutic - Prophylactic New IFNs Agonists of Toll-like receptor IFN-inducers


Eight vaccines have reached the clinics

They are divided in 2 types:

• aiming at inducing humoral, neutralizing responses

• aiming at inducing specific T-cell responses

They are tested in stand-alone,

a couple have reached the phase of testing as add-on to Peg/RBV

A diversity of therapeutic vaccine technologies has emerged


The major sites of action of different HCV preventive and therapeutic vaccines

vaccine

Torresi and Wedenmayer J Hepatol 2011


Therapeutic vaccines mechanism of action

is different

• small molecules = direct effect on virus (or key cell proteins)

effect on viral replication

• therapeutic vaccines = effect on host immune system

effect on infected cells


HCV therapeutic vaccines: first and second generation

Company Vaccine Innogenetics INNO10101 (E1) HCV + Intercell IC41-102 (5 HCV peptides) HCV + GlobeImmune GI-5005 (Yeast - NS3/Core) HCV + Novartis/CSL ISCOMATRIX (Core) HCV - Novartis HCV-MF59 (E1E2) HCV - Kurume Univ. ND (4 peptides) HCV + Okairos Ad/MVA (NS345) HCV+/HCV- Tripep/Inovio ChronVac-C® (NS3) HCV +

Transgene G4040 (MVA-NS345B)HCV+

Target populations Preclinical Phase I II III Lack of efficacy STOP

Lack of efficacy STOP

Ongoing

Safety, STOP

Safety, STOP

Safety, STOP ?

Early efficacy

Efficacy

Ongoing


Viral-vectored HCV Vaccine Studies Structure/vector (Investigator)

Phase (year)

Subjects Outcome Ref.

TG4040: MVA vector expressing NS3/4/5B proteins (Transgene)

I (2009) 15 chronically infected HCV patients

A total of six out of 15 declined HCV viral load (0.5–1.4 log) associated with weak T-cell response (IFN-γ ELISpot)

Halbersetzer et al 2009

Adenovirus vector (Ad6 and AdCh3) expressing NS3–5B proteins (Okairos and Oxford University)

I (2009) 36 healthy volunteers

Highly immunogenic (strong and multispecific T-cell response by IFN-γ ELISpot) and well tolerated

Halliday et al., 2011; Barnes et al., 2011 in press

Adenovirus vector (AdCh3) and MVA expressing NS3–5B proteins (Okairos and Oxford University)

I (2011) 10 healthy volunteers

Highly immunogenic (stronger T cell response than the regimen based on Adenovirus alone). Well tolerated.

Barnes et al., EASL 2011

Adenovirus vector (Ad6 and AdCh3) expressing NS3–5B proteins (Okairos and Oxford University)

I (2009) 30 chronically infected HCV patients

Immunogenic in 50% of patients. Well tolerated

Kelly et al., EASL 2011


25% 75% 100% % responders

dose 10 1

10 2

10 3

10 4

IFN

γ S

FC/1

0^6

PB

MC

52 weeks

Vector = AdCh3 encoding HCV antigen Subjects = healthy volunteers

POTENT AND LONG LASTING IMMUNITY IS INDUCED IN HEALTHY VOLUNTEERS BY A

NOVEL ADENOVIRAL VACCINE

Barnes E et al EASL 2011


4 8 0 16 20 24 40 44 48 52 56 60 64 68 72 28 32 36

4 8 12 16 20 0 40 44 48 52 56 60 64 68 72 28 32 36 76 80 84

TG4040, 107 pfu

Initiation of SOC

Second stopping rule if viral load detectable after 24 weeks of SOC (all Arms)

ARM A Control Arm n=31

Primary endpoint: cEVR evaluation First stopping rule if viral load decrease is

inferior to 2 log10 IU/mL (Arm A only)

4 8 0 16 20 24 40 44 48 52 56 60 64 68 72 28 32 36

SOC

ARM B n=63

ARM C n=59

Weeks

TG4040 monotherapy

12

12

24

*

* SAE occurrence (refer to section Adverse Events)

*

*

Wedemeyer et al., AASLD 2011

TG4040 vaccination alone is associated with an HCV RNA in about 40% of patients

HCV RNA decline >0.5log in 22/58 patients (0.5-5.1log 10 IU/mL) By vaccination alone


Observed Virologic Response Rate after 2, 4, 12 Weeks of SOC

59

7

30

61

10

46

72

22

64

0

10

20

30

40

50

60

70

80

W2 resp.(1) RVR (2) cEVR

Perc

enta

ge o

f eva

luab

le p

atie

nts

Study Endpoints

Arm A

Arm B

Arm C

p=0,003

*

*

Wedemeyer et al., AASLD 2011

Therapeutic Vaccination with TG4040 increases cEVR rates (primary endpoint)



Human monoclonal antibodies Vaccines -Therapeutic - Prophylactic New IFNs Agonists of Toll-like receptor IFN-inducers


Novel IFNs/formulations

Several novel interferons or formulations are in clinical development to offer

• prolonged duration • improved pharmacokynetic profile • better antiviral activity • improved side effects profiles

Novel Interferon Formulations (Subcutaneous Injection or Mini-Pump Device) AlbuferonHuman Genome Sciences/Novartis Phase III LocteronBiolex Therapeutics/OctoPlus N V IFN α 2bXLFlamel thecnologies Phase IIa Omega InterferonIntarcia Phase II Peg-Interferon Lambda ZymogeneticsPhase I


Study Visit PEG, N=28 Infusion 80, N=25 Infusion 120, N=27 Infusion 160, N=26

Week 1 0/28 (0%) 0/25 (0%) 2/27 (7%) 6/26 (23%)

Week 2 1/28 (4%) 3/25 (12%) 3/27 (11%) 7/26 (27%)

Week 4, RVR 2/28 (7%) 4/25 (16%) 7/27 (26%) 11/26 (42%)

Week 12, EVR 7/28 (25%) 7/25 (60%) 13/27 (48%) 11/26 (42%)

HCV RNA <LLOD, mITT

PEG, N=28 3 Infusion Arms, N=78

Discontinuation for AE 1/28 (4%) 14/78 (18%)

Withdrawal of Consent 0/28 (0%) 6/78 (8%)

Subjects with any SAE 1/28 (4%) 10/78 (13%)

Safety & Tolerability, mITT

LB-19: Interferonα -2b by continuous subcutaneous infusion (Mini-pump device) in combination with ribavirin for treatment-naїve HCV 1 patients: 12 week interim analysis

Muir A et al LB-18, AASLD 2011


Sustained release interferon alpha 2b

(IFN alfa 2bXL)

– Phase IIa trial of IFN alfa 2bXL versus PegIFN alfa 2b, plus RBV, in treatmentnaïve or non-responder HCV GT -1 and GT-4 patients

– Data obtained on the first 15 IFN alfa 2bXL patients was analysed by an independent safety board

Trepo C, et al. AASLD 2011. Abstract LB-21

8

IFN alfa 2bXL 27MIU + RBV

PegIFN alfa 2b 1.5 µg/kg + RBV

Week 12 4

IFN alfa 2bXL 36MIU + RBV IFN alfa 2bXL 36MIU

6-week interim analysis

IFN alfa 2bXL 27MIU

PegIFN alfa 2b


Sustained release interferon alpha 2b (IFN alfa 2bXL)

– There were no serious adverse events (AEs) or treatment withdrawal

– The 27MIU dose was associated with a reduced mean number of treatment-related AEs/patient

– PK data show lower circulating IFN levels with IFN alfa 2bXL, compared with PegIFN alfa 2b, hence improved tolerability • PK profiles were dose-proportional between 27MIU and 36MIU

Treatment-related AEs IFN alfa 2bXL 27MIU

(n=7) PegIFN alfa 2b

(n=7)

Mean treatment-related AEs/patient 4.6 6.9

Flu-like syndrome, % 57 100

Erythema at injection site, % 29 71

Skin dryness, % 0 43

Asethnia, % 71 86

CNS disorder (irritability and depression), % 14 42

Platelets (G/L) –26.2 –52.4

Trepo C, et al. AASLD 2011. Abstract LB-21


Emerge AI452004-Study

Zeuzem S. et al EASL 2011 Zeuzem et al., EASL 2010


aEach circle represents an individuai patient. bDotted lines represent reference LLN and ULN.

Change in Hb from baseline to week 2 vs change in reticulocyte count from baseline to

week 4 in patients receiving IFN λ/RBV

Plotting the association between Hgb decline at week 2 and change in reticulocyte count at week 4 revealed a greater erythropoietic response to hemolysis in Lambda recipients than in patients treated with alfa-2a. Everson G ., AASDLD 2011



Human monoclonal antibodies Vaccines -Therapeutic - Prophylactic IFNs/Cytokines Agonists of Toll-like receptor IFN-inducers


TLR agonists Among the 11 until now identified TLRs, TLR7and 8 detect viral RNA TLR9 detects unmethylated CpG DNA

sequences. Drugs that have an agonistic action with the TLR9 and 7 mimicking their function may restore a potent and innate and

adaptative immune response TLR9 designed to stimulate the immune

system causing the body to generate IFN and other antivirals cytokines.

IMO2125 evaluated in null responders in a phase I trial that has been discontinued for safety reasons


ANA 773 an oral inducer of endogenous IFNs that acts via TLR7

Double-blind placebo controlled study in 34 HCV pts chronically infected Naive or relapsers Four doses every-other-day for 28 or 10 days

Bergmann JF Aliment Pharmacol Ther 2011 Janssen HLA AASD 2009

Dose related IFN-dependent responses after ANA 773


Conclusions Therapies to control HCV have improved over the past decades but limitation still remain Mechanism of action of IFN based therapy includes induction of an antiviral adaptative immune state The ability of direct anti-virals alone to induce innate and HCV specific adaptive immune responses is currently unknown The combined use of DAA and immunomodulators may increase response rates in pts with treatment failure or unfavourable baseline caracheristics

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