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1
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|
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2
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|
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3
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|
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4
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5
|
- 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 > 20,000 ug/kg
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6
|
|
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7
|
- 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 thymalfasin’s action on particular SUBCELLULAR
PATHWAYS that lead to these actions
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|
8
|
|
|
9
|
|
|
10
|
|
|
11
|
|
|
12
|
|
|
13
|
|
|
14
|
|
|
15
|
|
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16
|
|
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17
|
|
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18
|
|
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19
|
|
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20
|
|
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21
|
- Phase 2 RCT (Japan)
- 6 months Rx
- 6 months follow-up
- Endpoints: HBV DNA 0
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22
|
-
Patients & Methods
- Opened labeled. Randomized
- 317 patients enrolled (49 sites)
- 1.6mg b.i.w vs. 0.8mg b.i.w
- 6 months therapy + 12 months
follow-up
- 283 patients completed Tx & F U. 139 patients had
1.6mg Ta1 b i w
144 patients had 0.8mg Ta1 b i w
|
|
23
|
|
|
24
|
- Results
- No significant drug related side effects or toxicities
|
|
25
|
|
|
26
|
|
|
27
|
|
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28
|
|
|
29
|
|
|
30
|
- Both doses were efficacious against HBV
- HBeAg seroconversion to HBeAb ≥ to interferon (6 months
treatment), or lamivudine and adefovir (52 week treatment, historical
data)
|
|
31
|
- Thymalfasin:
- Safe and well tolerated
- Effective as monotherapy in HBV
|
|
32
|
|
|
33
|
- University of Santo Tomas
- Manila, Philippines
|
|
34
|
|
|
35
|
|
|
36
|
|
|
37
|
- Rasi G et al
- Hepatology 1995 20:p 299A
|
|
38
|
- STUDY DESIGN:
- Phase II Open Label
- Six months treatment
- Six months observation
- Additional six months observation
- 15 patients, 11 previous IFN non-responders
- Rasi G. et al. Hepatology 1995 20:p 299A
|
|
39
|
- DOSAGE:
- Loading dose: Ta1 1 mg SC for 4
days
- IFN 3
mu IM day 4
- Maintenance dose (week 2-26):
- Ta1
1mg SC biw
- IFN 3
mu IM biw
- END POINTS:
- ALT Normalization
- HBV-DNA clearance
- Rasi G. et al. Hepatology 1995 20:p 299A
|
|
40
|
- RESPONSE: Normal ALT /HBV-DNA Negative
- No. of patients Total
treated IFN Failures
- Responding____N=15________N=11__________
- 6 mo. 6
(40%) 4 (36%)
- 12 mo. 8
(53%) 5 (46 %)
- 18 mo. 9
(60%) 6 (55%)
- Rasi G. et al. Hepatology 1995 20:p 299A
|
|
41
|
- CONCLUSIONS:
- The combination of Ta1 +IFN results in greater response rates than would
have been expected with IFN alone.
- No additional toxicity due to Ta1 (thymalfasin) was seen.
- Rasi G. et al. Hepatology 1995 20:p 299A
|
|
42
|
|
|
43
|
- Treatment protocol: Group-3, n=27
|
|
44
|
- Treatment protocol: Group-2, n=15
|
|
45
|
- Treatment protocol: Group-1, n=10
|
|
46
|
|
|
47
|
|
|
48
|
|
|
49
|
|
|
50
|
- Thymalfasin in chronic hepatitis B (CHB):
- HBeAg – disease
- Significant inhibition of HBV DNA maintained for 12-18 months
post-therapy, with 24-52 weeks Ta1 mono or combination therapy
- Possible role of Ta1 in maintaining long-term off treatment remission
|
|
51
|
|
|
52
|
- Rationale
- Decrease HBV DNA
- Decrease immune tolerance
- Induce immune clearance of HBV DNA
- Decrease HBV mutations
- Increase sustained response
- Chan, et al. Data on file, 1999
|
|
53
|
- Hong Kong trial
- 20 patients – vertically transmitted HBV
- High HBV DNA load, HBeAg negative
- Rx
- Lamivudine 100-150 mg/day for 12 months
- Thymalfasin 1.6 mg biw for 6 months
- 12 months post therapy:
- 70% HBV DNA negative
- Chan, et al. Data on file, 1999
|
|
54
|
|
|
55
|
|
|
56
|
|
|
57
|
|
|
58
|
- 8.22% HBsAg Carrier in China
- More than 25% with Chronic Hepatitis
- The thymic extracts from calf have been used in China for the treament
of chronic hepatitis B for more than 20 years
|
|
59
|
- Thymosin a -1: the first
synthetic polypeptide thymic hormone (ZADAXIN)
- Approved for use in China in 1996
- Thymosin a -1 is used in both
mono therapy and combination therapy with interferons or nucleoside
analogs in China
|
|
60
|
|
|
61
|
|
|
62
|
|
|
63
|
|
|
64
|
|
|
65
|
|
|
66
|
|
|
67
|
|
|
68
|
- 54 CHB: IFN + T a-1
- 49 CHB: IFN alone
- 6 months treatment and follow up 4 years
|
|
69
|
|
|
70
|
|
|
71
|
|
|
72
|
|
|
73
|
- 60 Patients, HBsAg Positive for
12 months prior
- Randomized Controlled trial
- Alt Elevated 2-10 X ULN
- Group One: lamivudine 100mg daily
- Group Two: Thymosin a -1
1.6mg biw
- Group Three: Thymosin a -1 +
lamivudine
- 6 months treatment with 12 months follow up
|
|
74
|
|
|
75
|
|
|
76
|
- Combination therapy (n=35): Ta1 1.6mg, Biw combined with
lamivudine 100mg, QD.
- Lamivudine alone (n=37) : 100mg, QD
- Duration: 1 year.
- Follow up: 1 year.
|
|
77
|
|
|
78
|
-
PreC Mutation YMDD
Mutation
- T+LAM 0/35 0/35
- LAM 1/37 (2.9%) 10/37（27.0%）
- χ2 7.840
- p value 0.006
|
|
79
|
|
|
80
|
|
|
81
|
|
|
82
|
|
Notes
