Multiple Ascending Dose Trial of MSB0010841 (Anti-IL17A/F Nanobody) in Psoriasis Subjects

Phase 1

Completed

Conditions: Psoriasis

Interventions: Drug: MSB0010841
Drug: Placebo

Registration Number: NCT02156466

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: This is a multicenter, Phase 1, randomized, double-blind, placebo-controlled trial in subjects with moderate to severe psoriasis to assess the safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of multiple subcutaneous ascending doses of MSB0010841 (Anti-interleukin-17A/F \[Anti-IL-17A/F\] Nanobody).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

Inclusion Criteria

Chronic plaque psoriasis for at least 6 months before screening
Greater than or equal to (>=) 10% of BSA with plaques
Psoriasis Area and Severity Index (PASI) >=12
Static Physician's Global Assessment (sPGA) >=3 (where scores range from 0 [clear of disease] to 5 [severe disease]) at the screening and baseline visits
Other protocol defined inclusion criteria could apply

Exclusion Criteria

Any condition, including protocol-specified laboratory findings and findings in the medical history or in the pre-trial assessments which in the Investigator's opinion constitutes a risk or a contraindication for the subject's participation in the trial or that could interfere with the trial objectives, conduct or evaluation
Currently having a form of non-plaque psoriasis as specified in the protocol
Drug induced psoriasis
Biological treatments as specified in the protocol, within 3 months prior to Day 1
Systemic immunosuppressants or phototherapy as specified in the protocol, within 1 month prior to Day 1
Use of anti-coagulant medications and/or antiplatelet medications as defined in the protocol
Use of aspirin as defined in the protocol
Topical corticosteroid treatments other than low-strength or lower-mid strength corticosteroids on the face, scalp, axillae, and/or groin within 1 month prior to Day 1
Any previous treatment with an agent targeting interleukin (IL)-17, IL-12 and/or IL-23 as specified in the protocol
Other protocol defined exclusion criteria could apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MSB0010841 240 mg	MSB0010841	-
MSB0010841 120 mg	MSB0010841	-
Placebo	Placebo	-
MSB0010841 30 mg	MSB0010841	-
MSB0010841 60 mg	MSB0010841	-

Primary Outcome Measures

Name	Time	Method
Levels of Anti-MSB0010841 Antibody Titers	Day 8, 15 (pre-dose), 22, 29 (pre-dose), 36, 43, 63 and 85
Levels of Pre-existing Anti-MSB0010841 Antibody Titers	Pre-dose on Day 1
MSB0010841 Serum Concentration Over Time After First Dose	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
MSB0010841 Serum Concentration Over Time After Second Dose	0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)	Baseline up to Day 85	An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. TEAEs were the AEs occurring or worsening after treatment administration.
Number of Subjects With Local Injection Site Reactions (ISRs)	Day 1, 2,8, 15, 16, 22, 29, 30, 36, 43	The injection site was assessed by the Principal Investigator (PI) or his/her designee for local reactions such as redness, swelling, indurations or bruising, and by the subject for itching. Redness and bruising were scaled as None (no visible redness or bruising present); Mild (less than or equal to \[\<=\] 2.0 centimeters \[cm\] redness or bruising area); Moderate (greater than \[\>\] 2 to \<=5.0 cm redness or bruising area); Severe (\>5.0 cm redness or bruising area). Swelling was scaled as None (no swelling detected); Mild (palpable 'firmness' only); Moderate (\<= 4 cm swelling); Severe (\>4 cm swelling). Induration was scaled as None (no induration); Mild (able to move skin parallel to plane (sliding) and perpendicular to skin (pinching up); Moderate (able to slide skin, unable to pinch skin); Severe (unable to slide or pinch skin). Itching was scaled as No itching; Mild itching; Moderate itching and Severe itching. Subjects who reported any of the local ISRs were reported.
Amount of Pain at Injection Site Assessed By Visual Analog Scale (VAS)	Day 1, 2, 8, 15, 16, 22, 29, 30, 36, 43	Subjects were asked to assess their severity of injection site pain on a 100 millimeter (mm) VAS, where 0 = no pain and 100 = worst possible pain. Mean of amount of pain was calculated for the subjects having a value \> 0. Maximum values per subjects (over injection site areas) are used for counting the amount of pain at injection site. Maximum pain scores recorded among all participants analysed in each arm are reported for each time point.
Percentage of Subjects With Anti-MSB0010841 Binding Antibodies (Anti-Drug Antibodies [ADA])	Baseline up to Day 85	Data were presented for MSB0010841 combined group and placebo.
Mean Residence Time (MRT0-t) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC(0-t)/AUC(0-t) where AUMC(0-t) is area under the plasma concentration-time first moment curve from time zero to time t (336 hours) and AUC(0-t) is the area under the plasma concentration-time curve from time zero to tome t (336 hours).
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above LLOQ.
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-third dose (Day 29)	Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).
Percentage Peak-Trough Fluctuation (PTF) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC 0-inf) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-infcalculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clast calc/λz, where Clast calc is the calculated concentration at the last sampling time point at which the measured concentration is at or above LLOQ and λz is the terminal rate constant determined from the terminal slope of the log transformed concentration curve using linear regression on terminal data points of the curve.
Observed Serum Concentration Immediately Before First Dose (Cpre) of MSB0010841	Pre-dose (0 hours) on Day 1	The observed serum concentration immediately before the first dose.
Observed Serum Concentration Immediately Before Third Dose (Cpre) of MSB0010841	Pre-dose (0 hours) on Day 29	The observed serum concentration immediately before the third dose.
MSB0010841 Serum Concentration Over Time After Third Dose	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).
Percentage Peak-Trough Fluctuation (PTF) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Minimum Concentration Observed (Cmin) During Third Dosing Interval of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.
Maximum Concentration Observed (Cmax) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Maximum Concentration Observed (Cmax) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Minimum Concentration Observed (Cmin) During First Dosing Interval of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.
Average Concentration (Cav) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)	Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).
Average Concentration (Cav) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).
Mean Residence Time (MRT0-t) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-third dose (Day 29)	MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC(0-t)/AUC(0-t) where AUMC(0-t) is area under the plasma concentration-time first moment curve from time zero to time t (336 hours) and AUC(0-t) is the area under the plasma concentration-time curve from time zero to tome t (336 hours).
Mean Residence Time of Drug in the Body From Time Zero Extrapolated to Infinity (MRT(0-inf) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Mean residence time of drug in the body from time zero extrapolated to infinity, based on the last predicted concentration at tlast.
Time to Reach Maximum Observed Concentration (Tmax) Post First Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Time to Maximum Observed Concentration (Tmax) Post Second Dose of MSB0010841	0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Apparent Terminal Half-life (t1/2) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/ λz, where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Terminal Rate Constant (λz) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Terminal rate constant was determined from the terminal slope of the logtransformed concentration curve using linear regression on terminal data points of the curve
Accumulation Ratio of Cmax (Racc (Cmax))	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1) and 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Accumulation ratio for Cmax was calculated as Cmax, after third dose / Cmax, after first dose.
Accumulation Ratio of AUC (Racc(AUC))	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1) and 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Accumulation ratio for AUC, calculated as area under the serum concentration-time curve within one complete dosing interval at third dose divided by area under the serum concentration-time curve within one complete dosing interval at first dose.
Maximum Observed Concentration (Cmax) Post Second Dose of MSB0010841	0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Observed Serum Concentration Immediately Before Second Dose (Cpre) of MSB0010841	Pre-dose (0 hours) on Day 15	The observed serum concentration immediately before second dose.
Time to Reach Maximum Observed Concentration (Tmax) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Apparent Clearance (CL/f) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Apparent Volume of Distribution During Terminal Phase (Vz/f) Post Third Dose of MSB0010841	0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following first dose and Dose/(AUCtau multiplied by λz) after third dose.

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects With 50% or 75% Improvement From Baseline in Psoriasis Area and Severity Index (PASI) Score	Baseline up to Day 85	PASI: a physician assessed index that measured psoriasis severity and evaluated erythema, infiltration, and desquamation (scaling) on different body areas including the head, upper extremities, the trunk, and lower extremities. T Erythema, infiltration, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) was multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score. PASI score ranged from 0 to 72, with higher scores reflecting greater disease severity. PASI 50% or 75% was defined as the percentage of participants who achieved \>=50 or 75% improvement in PASI score from Baseline.
Mean Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Day 43	Baseline, Day 43	PASI: a physician assessed index that measured psoriasis severity and evaluated erythema, infiltration, and desquamation (scaling) on different body areas including the head, upper extremities, the trunk, and lower extremities. T Erythema, infiltration, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) was multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score. PASI score ranged from 0 to 72, with higher scores reflecting greater disease severity. PASI 50% or 75% was defined as the percentage of subjects who achieved \>=50 or 75% improvement in PASI score from Baseline.
Percentage of Subjects With Static Physician's Global Assessment (sPGA) Score of Minimal or Clear and With at Least 2 Level Reduction From Baseline	Day 8, 15, 22, 29, 36, 43, 50, 85	The static Physician's Global Assessment (sPGA) scale rated the investigator's overall clinical assessment of a subjects plaque thickness, erythema, and scaling on a 6-point scale ranging from 0 (clear, except for residual discoloration) to 5 (majority of plaques have severe thickness, erythema, and scale). To assign a sPGA score, the investigator examined all psoriatic lesions and assigned a severity score ranging from 0 to 5 for thickness, erythema, and scaling. Scores for thickness, erythema, and scaling are summed and the mean of these 3 scores equals the overall sPGA score. Overall sPGA score ranged from 0 to 5, where lower scores indicate clinical improvement. Percentage of subjects who achieved a sPGA rating of 0 (clear) or 1 (minimal) and had at Least 2 level reduction from Baseline score were reported.
Mean Percent Change From Baseline in the Body Surface Area (BSA) Affected by Psoriasis at Day 8, 15, 22, 29, 36, 43, 50 and 85	Baseline, Day 8, 15, 22, 29, 36, 43, 50 and 85	The BSA is the physician's evaluation for the extent of disease. The entire body area is divided into 4 districts: head, upper limbs, trunk and lower limbs to which corresponds the 10%, 20%, 30% and 40% of the entire body surface respectively. The investigator assesses the percentage of the subjects' body surface area affected by psoriasis in each district. The final affected BSA value is the sum of the percentage of each district.
Percentage of Subjects With Exacerbation of Psoriasis	Baseline up to Day 85	Psoriasis exacerbation was defined as either a worsening of 25% over the baseline value of the PASI score (PASI score at any visit \>=125% of baseline PASI).