Download RXI-109-1202 Effect of RXI-109 on CTGF mRNA Levels

#8225
RXI-109 Reduces a Key Component of
Dermal Scarring, Connective Tissue
Growth Factor (CTGF) mRNA, in a MultiDose Phase 1 Clinical Trial
1Lyn
Libertine MD, 1Pamela Pavco PhD, 1Karen Bulock PhD, Katherine Holton, 2Nelly
Paz MD, 1Geert Cauwenbergh Dr. Dr. Med. Sc.
1RXi
Pharmaceuticals, Corp., Westborough MA
2Hospital
y Clinica Bendana, Honduras
This work was supported entirely by RXi Pharmaceuticals.
Property of RXi Pharmaceuticals
72nd Annual Meeting of the American Academy of Dermatology
March 21-25, 2014, in Denver, CO
RXI-109 Background
 There are currently no drugs approved to prevent hypertrophic scar or keloid
formation
 RXI-109 targets and reduces CTGF, a key regulator of the dermal scarring pathway
 RXI-109 is an sd-rxRNA® that works through an RNA interference (RNAi) mechanism
 sd-rxRNAs are small interfering RNAs (siRNA) designed with RXi’s proprietary
technology
 sd-rxRNAs are efficiently taken up by cells
 RXI-109 is delivered locally to the incision/scar site
 Early treatment with RXI-109 may reduce hypertrophic scarring and keloid formation
 Two Phase 1 safety trials have been completed
 RXI-109-1201, an ascending dose, single dose study is presented in Poster #8214
 RXI-109-1202, an ascending dose, multi-dose study is presented here
 Phase 2 trials have initiated
 Additional related work presented at AAD 2104:

2
Preclinical data: Poster #8326
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Study RXI-109-1202: Overview
A Phase 1 Single Center, Randomized, Multi-Dose, Double-Blind,
Ascending Dose, Within-Subject Controlled Study of RXI-109 for the
Treatment of Incision Scars
Parameters evaluated:
-
Safety & side effect assessment versus placebo
-
Histological comparison of the scar sites versus placebo
-
Pharmacokinetic parameters after local intradermal injection
-
CTGF protein & mRNA levels
-
Photographic comparison versus placebo
3
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RXI-109-1202: Study Design and Abdominal
Incision Layout
RXI-109-1202
Multi-dose
5 dose cohorts (1 cohort w/ delayed dosing); 3 subjects each
Dose range 2.5 – 10 mg per incision site
Biopsies on Days 18 and 84
A
o
B
1
2
• Eight (8) injections and incisions (2 cm in length) were made on the abdomen of healthy
volunteers.
• Treatment at each incision site was made by intradermal injection according to a
predetermined randomization pattern for each subject.
• Randomized treatment to one side with RXI-109, one side with placebo.
• Each incision received 3 injections over a given time period.
• Incisions were spaced at least 4 cm apart.
• Safety assessments were made throughout the 3-month study.
4
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Study RXI-109-1202: Safety Results
Conclusions:
• No significant side effects nor toxicity were observed.
• Treatments did not reduce healing on the active or the placebo side, i.e. no
negative effect on wound healing/closure
• Maximum blood level of RXI-109 is only 5% of intradermally administered
dose
• No immunological reactions
• No changes noted in liver function tests, kidney or cardiovascular function,
complement, coagulation, urinalysis, hematology or blood chemistry
Monitored for side effects, safety and toxicity in the 7 days post injections, and
regularly afterwards for up to 3 months. Parameters monitored included:
• ECG
• Blood Biochemistry
• Blood Count
• Urinalysis and LFTs
• Complement and Coagulation
• Clinical Assessments of Incisions by Physician & Subjects
• RXI-109 in Systemic Circulation after Intradermal Injection
5
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Protocol RXI-109-1202: Pharmacokinetic
Parameters After Intradermal Dosing
Cohort Averages by Day
400
Dose 1 - 10 mg
Dose 3 - 10 mg
RXI-109 in whole blood (ng/mL
350
Dose 1 - 20 mg
300
Dose 3 - 20 mg
250
Dose 1 - 30 mg
200
Dose 3 - 30 mg
150
Dose 1 - 40 mg
100
Dose 3 - 40 mg
50
0
0
10
20
Cohort
Total Dose Per
Treatment Day (mg)
1
10
2
20
3
30
4
40
6
30
40
Hours
50
60
70
80
Day
Tmax (hr)
Cmax (ng/mL)
AUClast (hr*ng/mL)
1
14.7 ± 5.9
80.4 ± 14.7
3706 ± 624
15
13.4 ± 9.3
97.0 ± 19.6
4073 ± 815
1
15
1
15
1
15
20.0 ± 6.9
13.5 ± 9.4
20.0 ± 6.9
13.3 ± 9.3
20 ± 6.93
13.4 ± 10.1
161 ± 35
185 ± 23
239 ± 53
275 ± 55
172 ± 54
258 ± 110
7553 ± 1385
7293 ±1037
10695 ± 1835
11704 ± 119
8341 ± 2087
11044 ± 3493
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RXI-109-1202 Skin Assessments
Number of Incidences
RXI-109 Treatment
Placebo Treatment
7
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RXI-109-1202 Safety Conclusions
Local side effect profile more closely related to the
mechanics of incisions and injections than drug

Local effects were bilateral in nature

Most erythema was noted to be mild (Grade 1)

In 1201 local side effects presented unilaterally

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All sites with early side effects were dosed with RXI-109
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RXI-109-1202:
CTGF mRNA Silencing by Cohort
CTGF mRNA Three Days Post Third Dose
CTGF % Unwounded Expression
1200
Placebo
1000
RXI-109
800
600
43%
*
400
43%
50%
45%
**
200
0
(RXI-109 mg/incision
each treatment day)
Cohort 1
Cohort 2
Cohort 3
Cohort 4
(2.5 mg)
(5 mg)
(7.5 mg)
(10 mg)
Cohort 2,3,4
(5-10 mg)
p = 0.80
p = 0.046
p = 0.12
p = 0.14
p = 0.002

CTGF mRNA levels were upregulated in biopsies collected 3 days after the third dose compared to samples of
unwounded skin

Skin samples treated with the higher doses of RXI-109 (Cohorts 2-4 combined) had a statistically significant
reduction of CTGF mRNA compared to samples treated with placebo

No additional benefit was seen on CTGF mRNA reduction using a delayed dosing regimen, 10 mg per incision

Reduction of CTGF mRNA in RXI-109 treated sites is consistent with mechanism of action of the drug
Study RXI-109-1202: Conclusions

Safety and Pharmacokinetics

Safe and well tolerated at all dose levels tested (single and multi-dose)

No negative effect on healing in healthy volunteers with no predisposition for bad
scarring

Cmax and AUC increase proportionally with increased administered dose

Maximum blood level of RXI-109 is only 5% of intradermally administered dose

There is no evidence of significant accumulation of RXI-109 in the blood after repeat
administration with this dosing regimen

Biomarkers

Preclinical data demonstrate potent, dose dependent silencing of CTGF with RXI109 in vitro and in vivo with no delay in early wound healing

RXI-109-1202: Statistically significant reduction in CTGF mRNA three days after the
third dose in RXI-109 treated sites compared to placebo control. Dose dependent
silencing with more pronounced effect (average 45% silencing, p<0.002) with higher
doses tested.

Data consistent with the expected mechanism of action of RXI-109
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