Zadaxin

1
(No Transcript)
2
This symposium is sponsored by an educational
grant from
3
Alfred Rudolph, MDChief Medical OfficerSciClone
PharmaceuticalsSan Mateo, CA USA
4
Zadaxin (thymalfasin)
10
1
5
Ser
Asp
Ala
Ala
Ac -
Val
Asp
Thr
Ser
Ser
Glu
Ile
Thr
Thr
Lys
Asp

• Originally isolated from thymus
• The peptide responsible for reconstitution of
  immune function
• in thymectomized animal models
• Non-glycosylated, N-terminal acetylated, 28
  amino acids
• Highly conserved sequence (humans and various
  animal species)
• Comprises the N-terminus of prothymosin (113
  amino acids)
• Circulates at approximately 1 ng/ml (0.3 nM)

15
Leu
Lys
Glu
Lys
Lys
20
Glu
Val
Val
Glu
Glu
Ala
Glu
Asn
25
28
5
ZDX - Background

• Produced by solid phase peptide synthesis under
  cGMP
• Finished product is a lyophilized formulation for
  subcutaneous injection
• Peak plasma levels
• 50 ng/ml (15 nM)
• Obtained 2 hours after injection of 1.6 mg (23
  ug/kg)
• Half-life is about 2 hours
• Current dosing
• Hepatitis - 2 injections per week
• Cancer - 4 daily injections
• Toxicity MTD gt 20,000 ug/kg

6
(No Transcript)
7
Woodchuck HepatitisZDX decreases serum viral DNA
8
CD4CD8 CellsZDX reduces apoptosis
DEX - Dexamethasone
9
Cancer or Virally-infected CellsZDX increases
expression of MHC-1


10
Mechanism of Action

• Pleiotropic effects seen in vitro
• Stimulation of immunological functions
• Increased production of cytokines and receptors
• Increased T-cell proliferation/differentiation
• Inhibition of viral replication or growth of
  cancer cells
• Current supported research studies
• investigation of thymalfasins action on
  particular SUBCELLULAR PATHWAYS that lead to
  these actions

11
ZDX mechanism involvesTLR9 and TLR2
Romani et al. (2004) Blood 10 1182
12
Thank You!
13
Thymosin ? -1 in the Treatment of Chronic
Hepatitis B in China
Gui-Qiang Wang, MD Peking University First
Hospital Beijing, P.R.China
14
HBV infection in China

• 9.09 population with HBsAg positive in mainland
  China
• 2550 with Chronic Hepatitis
• The thymic extracts from calf have been used in
  China for the treatment of chronic hepatitis B
  for more than 20 years

15
Thymosin ? -1 in China

• Thymosin ? -1 the first synthetic polypeptide
  thymic hormone (ZADAXIN)
• Approved for use in China in 1996
• Thymosin ? -1 has been used in mono therapy or
  combination therapy with interferons or
  nucleoside analogs

16
Preliminary Study with Thymosin ? -1 in China

• Multi-center (8) open-labeled trial, with 64
• HBeAg positive CHB patients included.
• HBV DNA (), All except 4 with elevated ALT
• Medications Thymosin ? -1 1.6mg biw x 6 months
  with 6 months
  follow-up
• End Points Undetectable of serum HBV DNA
• and loss of HBeAg

Wang BE et al. Abstracts Hepatology October 1997
17
Treatment of chronic hepatitis B with Thymosin ?
- 1 in China

• At the end of 6 mo Treatment
• 25/64 (39) response
• At Month 12 (6 months follow up) 8 patients
  reactivated HBV DNA and 9 additional
  patients responded
• The total response 40.6 (26/64)
• NO SIGNIFICANT SIDE EFFECTS OBSERVED
  

Wang BE et al. Abstracts Hepatology October 1997
18
Thymosin ? -1 versus Interferon alpha for
patients with HBeAg negative Chronic Hepatitis B
in China

• Patients Methods
• Randomized Controlled trial
• 86 patients HBeAg (-) and HBV-DNA ()
• Two Arms Comparable groups (p0.05)

You Jing et al. World Journal of Infection. 2004
4(4)
19
Thymosin ? -1 versus Interferon alpha for
patients with HBeAg negative Chronic Hepatitis B
in China

• A Randomized Controlled Clinical Study
• Group A Thymosin ? -1 1.6mg biw for 6 months.
  n26
• Group B IFN 3-5 MU for 6 months. N30
• Group C Control group no treatment, n30
• Follow-up 12 months
• Complete response Serum ALT normalization
• and
  HBV-DNA loss

You Jing et al. World Journal of Infection. 2004
4(4)
20
Thymosin ?-1 vs IFN at end of treatment
60
50
46.7
46.2
38.5

30.8
10
6.7
3.3
You Jing et al. World Journal of Infection. 2004
4(4)
21
Thymosin ?-1 vs IFN at end of follow-up of 6
Months (Delayed response)
65.4
65.1
42.3

33.3
30
23.3
6.7
6.7
3.3
You Jing et al. World Journal of Infection. 2004
4(4)
22
Thymosin ? -1 monotherapy delayed response in
HBV
38.2
Chien et al (1998) Hepatology 27(5)
23
Thymosin ? -1 Combination Therapies in China
24
Combination Therapy of HBeAg () CHB with T ?-1
and IFN ?-2b

• Multi- center, open-label trial with 188 HBeAg
  ()
• CHB Patients included
• group1 94 with Thymosin ?-1, 1.6mg biw, 6mo.
• group 2 29 with IFN, 3MU, 3 mo., tiw
• group 3 64 with Thymosin ? -1 and IFN, 6 mo.
  
• End Points HBeAg seroconversion After 6
• month follow up

Wang BE et al. Beijing August 1997
25
HBeAg seroconversion at the end of 6 months
follow-up
70.3
46.3

32.3
Wang BE et al. Beijing August 1997
26
Combination Therapy of HBeAg () CHB with T ?-1
and IFN ?-2b

• 54 CHB IFN T ?-1
• 49 CHB IFN alone
• 6 months treatment and follow up 4 years

Hu YW, et al. Chin J Hepatol, 2001 9(4) 247
27
ALT normalization


90

83
76
73
68
63
57
55
49
41
Hu YW, et al. Chin J Hepatol, 2001 9(4) 247
28
HBeAg negative


78

68
57
55
50
47
41
37
35
28
Hu YW, et al. Chin J Hepatol, 2001 9(4) 247
29
HBV DNA negative


76

65

54
53
48
41
40
31
26
24
Hu YW, et al. Chin J Hepatol, 2001 9(4) 247
30
Short term efficacy of Thymosin ? -1 plus
Lamivudine in CHB

• 60 Patients, HBsAg Positive at least 12 months
• Randomized Controlled trial
• ALT Elevated 2-10 X ULN
• Group One lamivudine 100mg daily
• Group Two Thymosin ? -1 1.6mg biw
• Group Three Thymosin ? -1 lamivudine
• 6 months treatment

Lin BL, et al. J Gastroenterology hepatology
(2000) Suppl.Vol 15
31
Response at the end of 6 months treatment
100
87
80
73
53
53
50
40
26
26
13
7
Lin BL et al. Chinese J Infect Dis 2003,31930217
32
Conclusion from Short term combination of
Thymosin ?-1 plus Lamivudine in CHB

• HBV DNA levels in the combination group
• decreased approximately 4-5 log at the end of
  
• treatment
• No severe side effects were observed in all
• three groups
• No mutation observed

Lin BL, et al. J Gastroenterology hepatology
(2000) Suppl.Vol 15
33
Combination therapy withThymosin ?-1 and
Lamivudine in CHB

• Combination therapy (n35)
• T?1 1.6mg, Biw. 6 months.
• Lamivudine 100mg, QD. 1 year.
• Lamivudine alone (n37) 100mg, QD
• Follow up 1 year

Lin BL et al. Chinese J Infect Dis 2003,31930217
34
HBeAg Loss and Seroconversion
HBeAg Loss
HBeAg seroconversion
Lin BL et al. Chinese J Infect Dis 2003,31930217
35
Mutation

• PreC Mutation
  YMDD Mutation
• TLAM 0/35 0/35
  
• LAM 1/37 (2.9)
  10/37(27.0)
• ?2
  7.840
• p value
  0.006

36
Conclusions

• There is a extensive use of Thymosin ? -1 in
• China
• Studies with Thymosin ?-1 mono therapy
• and combination therapy show promising
• results in the treatment of CHB
• The combination with Thymosin ? -1 and
• lamivudine seems decrease the YMDD
• mutation significantly.
• Thymosin ? -1 has almost no side effects

37
??
Thank you!
38
Kenneth E. Sherman, MD, PhD

• Gould Professor of MedicineDirector, Division of
  Digestive Diseases
• University of CincinnatiCollege of Medicine
• Cincinnati, Ohio USA

39
World-Wide Prevalence of Hepatitis C

• WHO region Population (M) pos
  Infected (M)
• Africa 858 5.3 31.9
• Americas 785 1.7 13.1
• E. Mediterranean 466 4.6 21.3
• Europe 858 1.0 8.9
• S-E Asia 1500 2.2 32.3
• W. Pacific 1600 3.9 62.2
• Total 5811 3.1 169.7

Source WHO
40
Sustained Virologic Response Over Time
1998
2001
2002
1997
lt1996
IFN-a2b 6 mos
IFN-a2b 12 mos
IFN-a2b/ Ribavirin 12 mos
PEG IFN-a2b/ Ribavirin 12 mos
PEG IFN-a2a/ Ribavirin 12 mos
41
Therapy of Hepatitis CFuture Needs

• Large number of non-responders
• Side-effects of therapy
• Interferon / Pegylated Interferon
• Ribavirin
• Problem cases
• Decompensated
• Immunosuppressed

42
HCVThymalfasin combinationtherapies
43
Thymosin alpha-1 Standard Interferon
44
HCV Thymalfasin IFN sustained response (viral
RNA)

Genotype 1B
Total treated
80
70
60
Complete Response ()
50
39
40
40
30
20
10
11
5
5
9
7
6
6
12
18
6
12
18
months
months
months
months
months
months
End of FU
End of Rx
End of Rx
End of FU
Rasi et al (1996) Gut 39 679-683
45
HCV Thymalfasin IFN end-of-treatment response
(viral RNA)

37
40
35

• PCR response
• 6 months Rx
• 75 genotype 1

30
Complete Response ()
25
19
20
15
10
3
5
n 37
n 35
n 37
Placebo
IFN
THY IFN
Sherman et al (1998) Hepatology 27 11281135
46
Thymosin alpha-1 Peg-Interferon
47
Dose Ranging

• To investigate the effect of three different
  doses of thymalfasin in association with
  PEGinterferon alfa-2a on 12-week HCV RNA levels
  and peripheral blood T-cell populations

48
Inclusion Criteria

• Non-response to previous IFN or IFN ribavirin
  (HCV RNA positive at end of treatment)
• Genotype 1 infection
• HCV RNA load gt 2,000,000 copies/ml
• Elevated ALT
• Compensated liver disease

49
Methods

• Quantitative HCV RNA measured by Roche Amplicor
  test
• Lymphocyte subsets measured by dual-color flow
  cytometry

50
Treatment groups

• Group 1
• Thymalfasin 0.8 mg biw PEG IFNa-2a 180 mg qwk
• Group 2
• Thymalfasin 1.6 mg biw PEG IFNa-2a 180 mg qwk
• Group 3
• Thymalfasin 3.2 mg biw PEG IFNa-2a 180 mg qwk
• All patients treated for 12 weeks

51
Demographics
52
Median HCV RNA reduction from baseline

p lt 0.05 vs. 1.6 mg or 3.2 mg
53
Early Virologic Response
40
36
30
0.8 mg
20
20
1.6 mg
Percentage
3.2 mg
0
Early virological response is gt 2 log reduction
or negative HCV RNA at 12 weeks Thymalfasin
Peginterferon alfa 2a
54
CD3 lymphocytes in peripheral bloodChange from
baseline
8.3
10
7.5
0.8 mg
1.6 mg
5
Percentage
3.2 mg
0
0
55
CD4 lymphocytes in peripheral bloodChange from
baseline
20
14.8
15
8.8
0.8 mg
1.6 mg
10
Percentage
3.2 mg
5
-0.2
0
56
Side Effects

• Thymalfasin was well tolerated, no significant
  adverse events were observed
• Peginterferon associated with usual side effects

57
Conclusions

• Thymalfasin may have a role to play in
  combination with PEG-interferon alfa-2a in
  difficult-to-treat HCV non-responders
• 1.6 mg thymalfasin BIW appears to be a suitable
  dose for future study

58
HCV Phase 3 Program - US

• Patient population
• Non-responders to (PEG) IFNa or (PEG) IFNa
  ribavirin
• Non-cirrhotic to early cirrhosis (803)
• Bridging fibrosis to cirrhosis (804)
• Program design
• 1,000 patients total
• 2 complementary studies (n 500 per protocol)
• Thymalfasin PEG-IFN alfa-2a vs. PEG-IFN alfa-2a
  placebo
• 12 months treatment 6 months post Rx
  observation
• Endpoints (month 18) HCV RNA, histology

59
Study 803 Demographics
60
Study 803 72 Week Results
61
Efficacy of Triple Therapy Thymalfasin
(Thymosin-a1) in Combination with Peginterferon
a-2a (PEG-IFN2A) and Ribavirin for the Treatment
of HCV Non Responders

• Jorge L. Poo, Francisco Sanchez-Avila, Nahum
  Méndez, Misael Uribe.
• Presented at The European Association for the
  Study of the Liver (EASL) April 14-18, 2004,
  Berlin, Germany

62
Objective

• To investigate the efficacy of thymalfasin in
  combination with PEG-IFN a-2a and ribavirin as
• retreatment for HCV patients who failed to
  respond to a previous 6 month course of
  interferon plus ribavirin therapy.

63
Methods Study Design

• Study Design
• Open, single arm pilot study
• Treatment protocol
• 48 weeks of triple therapy treatment with
• Thymalfasin 1.6 mg / twice weekly
• PEG-IFN a-2a 180 µg / once a week
• Ribavirin 800 - 1000 mg / day

64
Methods Endpoints

• Primary Endpoints
• Sustained Virological Response (SVR) at week
  72
• Secondary Endpoints
• Early Virological Response (EVR) at week 12
• End of Treatment Response (EOTR) at week 48
• undetectable viral load (lt600 IU/mL)

65
Methods Patients
Thirty patients from Mexico were included (9M
/ 21F) Average age 57 (range 27-64) All
with positive viral load 19 with high viral
load HCV genotypes 1a 11, 1b 15, 2 4
66
Results HCV Viral Response
HCV RNA (log10)
p 0.043 4.23
p 0.043 3.15
p 0.042 2.72
p 0.027 2.52
p 0.043 2.46
p 0.042 2.36
Weeks
67
Results

• EVR - 56.6 of patients at week 12
• EOTR - 50 at week 48
• SVR - 21.4 at week 72
• SVR in genotype 1 patients at week 72 - 25
• Thymalfasin was well tolerated, without side
  effects

68
Next Steps

• A large, randomized study evaluating the
  efficacy and
• safety of this triple therapy regimen is
  needed to confirm these promising results.

69
European Phase 3 TrialPrimary Investigator
Mario Rizzetto, MD
HCV NON-RESPONDERS TO PRIORPEG-INTERFERON ALPHA
RIBAVIRIN THERAPY COMPARING TREATMENT WITH
THYMOSIN ?1 PEG-INTERFERON ?2a RIBAVIRIN vs
PEG-INTERFERON ?2a RIBAVIRIN
PLACEBOMULTICENTRE DOUBLE BLINDED, 550 PATIENTS
70
STUDY DESIGN
Treatment Phase (48 weeks)
Week 48 EOT
Week 24 Stopping rule If HCV RNA
Week 12 EVR
Follow up (24 weeks)
Randomization day
responder
Screening Phase (8 weeks)
Non-responder
PEG IFN ?-2a 180 ?g/week RBV 1000 - 1200 mg qd
Thymosin ?1 1.6 mg/ biw
responder
Non-responder
PEG IFN ?-2a 180 ?g/week RBV 1000 - 1200 mg qd
Placebo TA-1
71
Stratification Criteria

• Viral load gt 800,000 IU/ml or lt 800,000 IU/ml
• PEGinterferon alfa-2a treatment
  failures(Pegasys)PEGinterferon alfa-2b
  treatment failures(Peg-Intron)
• Histological cirrhosis or absence of cirrhosis.

72
Robert Gish, MD

• Medical Director Liver DiseaseManagement and
  Transplant Program
• California Pacific Medical Center
• San Francisco, CA USA

73
Protocol Ta1-HCC-2K1001

• A Trial of Zadaxin (Thymalfasin) with Trans
  Arterial Chemo-Embolization (TACE) in the
  Treatment of Adult Patients with Unresectable
  Hepatocellular Carcinoma A Phase II Trial
• presented at the
• Satellite Symposium - EASL 2006

74
Background

• More than 500,000 patients die each year from HCC
  world wide
• In the top 3 leading causes of cancer death in
  the world
• No medication(s) are approved by regulatory
  authorities for the treatment of HCC in the US,
  EU or globally
• LT is the only proven treatment that can cure HCC
  but there is a marked limitation on organ
  availability and most patients present with
  advanced disease not amenable to LT or surgery
• Ablative therapies increase survival short term
  only
• TACE is the sole therapy proven in RCT to
  increase survival
• Thermal (RFA) and injection therapy are being
  evaluated in large randomized studies

75
Materials and Methods

• Study design
• 57 cases were divided into three groups.Group A
  (n18) hepatectomy plus TACE T a1 postopGroup
  B (n23) hepatectomy plus TACE postopGroup C
  (n16) hepatectomy only

Dr. Cheng Shuqun Eastern Hepatobiliary
Surgery Hospital, Shanghai, P.R. China
76
Treatment groupControl groupp0.0039 (Log Rank)
1.0
.8
.6
Accumulated survival rates
.4
.2
0.0
30
24
18
12
6
0
Time (month)

• Fig. 1 Comparison of accumulated survival rate
  between
• treatment group(Ta1) and control
  group(No Ta1)

77
Materials and Methods

• Eligible patients assigned to two groups
• Control group hepatectomy only
• Treatment group hepatectomy and lamivudine plus
  thymosina1 therapy postoperatively

Dr. Cheng Shuqun Eastern Hepatobiliary
Surgery Hospital, Shanghai, P.R. China
78
Treatment groupControl groupp0.023(Log Rank)
Fig. 1 Comparison of accumulated survival rate
between treatment group and control
group
79
Protocol Ta1-HCC-2K1001

• An open label, Phase II pilot study investigating
  the safety and effects of 1.6 mg thymalfasin
  (thymosin-a-1) 5 times weekly for 6 months with
  TACE in comparison with TACE alone was performed
  at
• Five (5) Study Centers (total of 28 subjects
  enrolled)
• California Pacific Medical Center (San Francisco,
  California)
• William Beaumont Hospital (Detroit, Michigan)
• University of Florida, Gainesville (Gainesville,
  Florida)
• Metropolitan Liver Disease Gastroenterology
  Center (Fairfax, VA)
• Columbia University (New York, New York)
• Of the 28 subjects randomized, 3 subjects
  discontinued prior to receiving study treatment
  and therefore were excluded from the analysis (N
  25)

80
Protocol Ta1-HCC-2K1001 Patient Population

• Inclusion Criteria
• Subjects had unresectable HCC and were determined
  not to be liver transplant candidates
• Presence of HCC on biopsy, or, if no biopsy was
  available, either
• A hepatic mass gt2cm and an AFP of gt1000ng/mL or
• AFP lt1000ng/mL, and additional evidence of HCC by
  additional CT or MRI
• On imaging studies, if hepatic mass had doubled
  over time
• if AFP has risen to gt200ng/mL and triples the
  mean baseline.
• Additional Inclusion Criteria included
• Child-Pugh category A or B
• MELD score lt20
• Serum Creatinine lt1.5mg/dL
• No main portal vein invasion

81
Protocol Ta1-HCC-2K1001 Study Design
N25 Group 1 11 Group 2 14
TACE thymosin-alpha-1 1.6mg 5x/week 24 weeks
(120 injections)

• Stratification by

Tumor Stage (Okuda 1, 2)
Post-Treatment through Wk. 72 TACE as
needed if tumor growth
Survival Follow-up for 30 months Post-randomizat
ion

• Randomization

TACE alone

Tumor Stage (Okuda 3)
TACE thymosin-alpha-1 1.6mg 5x/week for 24
weeks (120 injections)
82
Protocol Ta1-HCC-2K1001 Study Design

• Study compared
• tumor response by imaging RECIST
• overall survival and progression free survival
• reduction in AFP levels
• ECOG performance status

83
RECIST Response EvaluationCriteria in Solid
Tumors
Response Criteria
84
Baseline Characteristics at Screening
Both groups comparable for Age Gender AFP Okuda
Status ECOG Score ALT AST Alkaline Phosphatase
85
Survival Analysis
Percent of Patients Alive, by Treatment Group
1.00
0.75
Survival Distribution Function
0.50
0.25

• TACE Alone Median Survival 399 days
• TACEThymosin-a-1 Median Survival 994 days

Censored Group 1 No Thymosin Censored Group 2
Thymosin
Group 1 No Thymosin Group 2 Thymosin
Log-Rank p-value 0.34 Wilcoxon p-value 0.36
86
Best Response by RECIST CT/MRI Data
Group 1
Group 2 TACE TACE /
Thymosin-a-1 Patients Enrolled
N () 11 (44.0) 14
(56.0) Patients with
Transplant


N () 0
4 (16.0) Best Response



Progressive Disease 2
(8.0) 2 (8.0) Partial
Response 2 (8.0) 2
(8.0) Stable Disease
2 (8.0) 3 (12.0)
Not Enough Data 5
(20.0) 7 (28.0)
87
Serious Adverse Events Summary
Group 1 Group 2 TACE
TACE / Thymosin-a-1 Number of Patients Treated



N () 11
(44.0) 14 (56.0) Patients Reporting
SAEs N () 5
(45.5) 4 (28.6) All SAEs
Reported N ()
17 (68.0) 8 (32.0) SAEs by Severity



Moderate 8 (47.1) 1
(12.5) Severe 8 (47.1) 5
(62.5) Life Threat 0 2
(25.0) Fatal 1 (5.9) 0
88
All System Events
Group 1
Group 2 TACE
TACE / Thymosin-a-1 Number of Patients Treated


N () 11
(44.0) 14 (56.0) CARDIAC DISORDERS 1
(9.1) 0 GASTROINTESTINAL DISORDERS 4
(36.4) 4 (36.4) HEPATOBILIARY DISORDERS
1 (9.1) 1 (7.1) INFECTIONS
2 (18.2) 0 RENAL AND URINARY DISORDERS
3 (27.3) 1 (7.1)
89
Questionand Answer Session
90
(No Transcript)