Transcript Svecova_M1095 AAD e-poster_draft 3 v3_21 Dec_without

Safety and Efficacy of Multiple Ascending
Doses of Subcutaneous M1095, an
Anti-Interleukin-17A/F Bispecific
Nanobody®, in Patients with Moderate-toSevere Psoriasis
Danka Svecova,1 James G. Krueger,2 Oleksandr Sverdlov,3 Harald
Mackenzie,3 Daniela Willen,3 Evangelia Hatzis,3 Roland Grenningloh,3
Martin W Lubell3
1University
Hospital of Bratislava, Slovakia; 2Rockefeller University,
NY, USA; 3EMD Serono, Billerica, MA, USA
Background and Methods
• Targeting the interleukin (IL)-17 pathway is an effective treatment approach for patients with
plaque psoriasis1-2
• M1095 is an anti-interleukin (IL)-17A/F Nanobody®* that neutralizes the pro-inflammatory
cytokines IL-17A and IL-17F
• This multicenter, phase I, randomized, double-blind trial was conducted in adults with
moderate to severe, chronic plaque psoriasis (≥10% BSA affected, PASI ≥12 and sPGA ≥3)
–
–
Primary objective: safety, tolerability, immunogenicity and pharmacokinetics of multiple SC doses of M1095 vs
placebo (pharmacodynamics and efficacy were secondary objectives)
Patients (10 per cohort) were randomized (4:1) to receive M1095 (30, 60, 120, or 240 mg) or PBO SC every 2
weeks for 6 weeks
Treatment period
Site visits (day)
Treatment (day)
1, 2, 4 and 5
1
Follow up period
8 and 14 15, 16, 18 and 19 22 and 28 29, 30, 32, 33 36 43† 50
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1. Mease PJ, et al. N Engl J Med 2015;373:1329–39;
2. Papp KA, et al. Br J Dermatol 2013;168:412–21;
3. http://www.ablynx.com/technologyinnovation/understanding-nanobodies/
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73
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*Nanobodies® are a novel class of proprietary therapeutic protein based on single-domain
antibody fragments that contain the unique structural and functional properties of naturallyoccurring heavy chain only antibodies3; †Early termination according to protocol;
BSA, body surface area; PBO, placebo; PASI, Psoriasis Area and Severity Index; SC,
subcutaneous; sPGA, static Physician’s Global Assessment
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Patient Disposition and Demographics
Total
active dose
cohorts
(n=33)
Total
placebo
cohort
(n=8)
Total
(n=41)
Male/Female, n
29/4
6/2
35/6
Age (years), mean
44.8
46.1
45.1
BMI (kg/m2), mean
28.9
27.3
28.6
Screened (n=101)
Not randomized (n=57)
Randomized (n=44)
Analysis sets:
Safety
(n=41)*
PK
(n=32)†
PD/efficacy
(n=41)‡
Cohort
1
30mg
(n=8)
Withdrawals (n=6):
• By subject (n=1)
• Other (n=3)
• Adverse event (n=2)
Sensitivity
(n=38)§
Cohort
2
60mg
(n=8)
Cohort
3
120mg
(n=8)
Cohort
4
240mg
(n=9)
Cohort
PBO
(n=8)
Completed study
treatment (n=38)
*Received at least one dose of M1095 or PBO; †received active treatment without protocol deviations
affecting PK, and who provide evaluable PK data; ‡based on the safety analysis set; §based on the safety
analysis set, but excluding 3 subjects who were discontinued after treatment initiation
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Pharmacodynamics: Histological Response
• M1095 treatment led to complete reversal of disease pathology in skin biopsies of the majority
of patients in the higher dose groups*
• Dose-dependent reductions were observed in:
– Epidermal thickness
– Dermal and epidermal CD3+ T-cell counts
– Epidermal Ki67+ cell counts in psoriatic plaques
Placebo
60 mg
120 mg
b) Epidermal CD3+ T-cells (mean+SD)
300
400
300
200
200
100
100
0
0
0
L d-1
Sample
L d43
240 mg
c) Epidermal Ki67+ (mean+SD)
Ki67
(positive cells/mm)
500
CD3
(cells/mm)
Epidermal thickness
(µm)
a) Epidermal thickness (mean+SD)
30 mg
1000
800
600
400
200
0
N d-1
L d-1
Sample
L d43
N d-1
L d-1
Sample
L d43
*based on histological analysis of lesional and non-lesional skin on days -1 and 43
SEE BACK-UP SLIDES FOR GENE EXPRESSION PROFILES
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Efficacy: Mean Change from Baseline in
PASI Score over Time
• Marked dose-dependent decrease in PASI score vs placebo within 7 days of first M1095
dose in all 4 cohorts
PASI % change from
baseline
• Improvement in PASI score continued throughout the treatment period
0
-20
% PASI
30 mg (N=8)
60 mg (N=8)
120 mg (N=7)
240 mg (N=7)
Placebo (N=8)
-40
-60
-80
-100
1
8
15
Dosing
22
29
36
43
Days
50
57
64
71
78
85
92
PASI, Psoriasis Area and Severity Index
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Efficacy: Patients with PASI-75, PASI-90
and PASI-100 at Day 85 (Week 12)
• No patient in the PBO group achieved PASI-75, PASI-90 or PASI-100
• PASI-100 was achieved in ≥50% of patients receiving either 120 or 240mg M1095
PASI 75
PASI 90
PASI 100
Safety population (N=41)
Sensitivity analysis (N=38)
120
9/9
9/9
(100%) (100%)
8/8
(100%)
100
7/8
7/8
(88%) (88%)
7/8
(88%)
7/8
(88%)
80
60
40
5/9
(56%)
2/8
(25%)
1/8
(13%)
20
0
0
4/8
(50%)
4/8
(50%)
0
Proportion of patients (%)
Proportion of patients (%)
120
100
7/8
(88%)
60
M1095
120 mg
(N=8)
M1095
240 mg
(N=9)
3/7
(43%)
40
2/8
(25%)
1/8
(13%)
20
M1095
60 mg
(N=8)
6/7
(86%)
4/7
(57.1%)
4/8
(50%)
0
M1095
30 mg
(N=8)
7/8
7/8
(88%) (88%)
7/7
7/7
(100%) (100%)
80
0
Placebo
(N=8)
7/7
(100%)
0
0
0
Placebo
(N=8)
M1095
30 mg
(N=8)
M1095
60 mg
(N=8)
M1095
120 mg
(N=7)
M1095
240 mg
(N=7)
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PASI, Psoriasis Area and Severity Index
Efficacy: Patients with sPGA of Minimal or Clear
and with ≥2-Level Reduction from Baseline*
• Lesion severity improved in all M1095-treated patients
Patients with sPGA
of minimal/clear and
≥2-level reduction from
baseline (%)
• By Day 85, 30/33 (91%) M1095-treated patients had achieved a sPGA of minimal/clear with
≥2-level reduction from baseline, compared with 0/8 (0%) placebo-treated patients
100
80
30 mg (N=8)
60 mg (N=8)
120 mg (N=8)
240 mg (N=9)
Placebo (N=8)
60
40
20
0
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Day
*Safety population; sPGA, Static Physician’s Global Assessment
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Safety: Incidence of TEAEs by Treatment
and Severity
Relationship by Severity
Mild
Moderate
Severe
All TEAEs
Treatment
n
%
n
%
n
%
n
%
Placebo (N=8)
6
75
3
38
2
25
6
75
Cohort 1 30 mg (N=8)
4
50
4
50
0
0
6
75
Cohort 2 60 mg (N=8)
5
63
3
38
0
0
5
63
Cohort 3 120 mg (N=8)
5
63
2
25
0
0
5
63
Cohort 4 240 mg (N=9)
5
56
2
22
0
0
6
67
25
61
14
34
2
5
28
68
Total (N=41)
•
•
•
•
•
Multiple SC doses of M1095 were well tolerated up to a dose level of 240 mg
Most TEAEs were of mild severity, 4 events were graded ‘severe’, all occurred in the placebo group
Incidence of TEAEs did not appear to be dose dependent
Two subjects discontinued treatment: one due to an AE of injection site reaction and one to an AE of elevated
liver enzymes
One serious AE of acute vestibular syndrome was reported; the episode resolved in 7 days and was considered
unrelated to M1095 by the investigator
AE, adverse event; N, number of subjects exposed per treatment; n, number of subjects that experienced the AE per treatment;
%, percentage of subjects that experienced the AE per treatment; (n/N)*100%; TEAE, treatment emergent adverse event
SEE BACK-UP SLIDES FOR A SUMMARY OF MOST FREQUENT TEAEs AND IMMUNOGENICITY
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Safety: Summary of TEAEs Reported in
≥ 2 Subjects (Total)
TEAEs, n (%)
Cohort 1
30 mg
(N=8)
Cohort 2
60 mg
(N=8)
Cohort 3
120 mg
(N=8)
Cohort 4
240 mg
(N=9)
Total M1095
(N=33)
Placebo
(N=8)
2 (25)
1 (13)
0
1 (11)
4 (12)
1 (13)
Headache
0
2 (25)
0
1 (11)
3 (9)
0
Hypertension
0
1 (13)
1 (13)
0
2 (6)
1 (13)
Nasopharyngitis
0
0
1 (13)
1 (11)
2 (6)
1 (13)
Pruritus generalised
1 (13)
0
0
1 (11)
2 (6)
1 (13)
Somnolence
1 (13)
1 (13)
0
0
2 (6)
0
0
2 (25)
0
0
2 (6)
0
1 (13)
0
0
0
1 (3)
1 (13)
Arthralgia
0
1 (13)
0
0
1 (3)
1 (13)
Blood creatine
phosphokinase increased
0
1 (13)
0
0
1 (3)
1 (13)
1 (13)
0
0
0
1 (3)
1 (13)
0
0
0
0
0
2 (25)
Pruritus
Bronchitis
Fibrin D-dimer increased
Glucose urine
Psoriasis
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Summary
• Biopsy assessment of lesional skin showed complete reversal of disease pathology
in majority of patients in high dose groups
• All patients attained PASI-75 at the highest M1095 doses; half attained PASI-100
• Lesion severity by sPGA improved from moderate/severe at baseline to mostly
clear/minimal by end of study in >90% of patients
– No sPGA improvement observed in patients receiving PBO
• Multiple ascending doses of M1095 were well tolerated in patients with moderate
to severe plaque psoriasis
–
Similar incidence of TEAEs in M1095 and placebo groups
• No apparent dose dependency of the incidence or severity of TEAEs
– One subject withdrew due to an injection site reaction and one due to elevated liver enzymes
PASI, Psoriasis Area and Severity Index;
sPGA, Static Physician’s Global Assessment
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Conclusions
• M1095 is a novel anti-IL-17A/F Nanobody® with the promise of antidisease activity in psoriasis
• Multiple ascending doses of M1095 (up to 240 mg) were well
tolerated in patients with moderate-to-severe psoriasis
• Significant skin improvement was demonstrated by histological
analysis of skin biopsies
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Acknowledgments and Disclosures
• The authors would like to thank the patients and their families
• Study was funded by EMD Serono, a business of Merck KGaA,
Germany
• Medical writing assistance was provided by Bioscript Science,
Macclesfield, UK, and supported by Merck KGaA, Darmstadt,
Germany
• ML, HM, RG, DW and EH, are employees of EMD Serono, a business
of Merck KGaA, Germany. DS has no COIs to disclose
• OS was an employee of EMD Serono at the time of the study
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