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

NCT02156466 | Completed Phase 1 Results

• 2 other identifiers: 200574-0032013-005436-18
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

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).

Conditions

Psoriasis

Keywords

Psoriasis; MSB0010841; Anti-IL17A/F Nanobody; M1095

Outcome Measures

Primary Outcomes (38)

• Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

  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.

  Baseline up to Day 85

• Number of Subjects With Local Injection Site Reactions (ISRs)

  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.

  Day 1, 2,8, 15, 16, 22, 29, 30, 36, 43

• Amount of Pain at Injection Site Assessed By Visual Analog Scale (VAS)

  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.

  Day 1, 2, 8, 15, 16, 22, 29, 30, 36, 43

• Percentage of Subjects With Anti-MSB0010841 Binding Antibodies (Anti-Drug Antibodies [ADA])

  Data were presented for MSB0010841 combined group and placebo.

  Baseline up to Day 85

• 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)

• 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

  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).

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)

• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) Post Third Dose of MSB0010841

  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.

  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 Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) Post First Dose of MSB0010841

  Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).

  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 (AUCtau) Post Third Dose of MSB0010841

  Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).

  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 to Infinity (AUC 0-inf) Post Third Dose of MSB0010841

  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.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• Observed Serum Concentration Immediately Before First Dose (Cpre) of MSB0010841

  The observed serum concentration immediately before the first dose.

  Pre-dose (0 hours) on Day 1

• Observed Serum Concentration Immediately Before Third Dose (Cpre) of MSB0010841

  The observed serum concentration immediately before the third dose.

  Pre-dose (0 hours) on Day 29

• Minimum Concentration Observed (Cmin) During First Dosing Interval of MSB0010841

  The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)

• Minimum Concentration Observed (Cmin) During Third Dosing Interval of MSB0010841

  The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• 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)

• Average Concentration (Cav) Post First Dose of MSB0010841

  Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)

• Average Concentration (Cav) Post Third Dose of MSB0010841

  Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).

  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 (MRT0-t) Post First Dose of MSB0010841

  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).

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)

• Mean Residence Time (MRT0-t) Post Third Dose of MSB0010841

  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).

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-third dose (Day 29)

• Mean Residence Time of Drug in the Body From Time Zero Extrapolated to Infinity (MRT(0-inf) Post Third Dose of MSB0010841

  Mean residence time of drug in the body from time zero extrapolated to infinity, based on the last predicted concentration at tlast.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• 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)

• 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 Terminal Half-life (t1/2) Post Third Dose of MSB0010841

  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.

  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 (λz) Post Third Dose of MSB0010841

  Terminal rate constant was determined from the terminal slope of the logtransformed concentration curve using linear regression on terminal data points of the curve

  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

  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.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• Apparent Volume of Distribution During Terminal Phase (Vz/f) Post Third Dose of MSB0010841

  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.

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• Percentage Peak-Trough Fluctuation (PTF) Post First Dose of MSB0010841

  The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)

• Percentage Peak-Trough Fluctuation (PTF) Post Third Dose of MSB0010841

  The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100

  0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)

• Accumulation Ratio of Cmax (Racc (Cmax))

  Accumulation ratio for Cmax was calculated as Cmax, after third dose / Cmax, after first dose.

  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 of AUC (Racc(AUC))

  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.

  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)

• 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

  The observed serum concentration immediately before second dose.

  Pre-dose (0 hours) on Day 15

Secondary Outcomes (5)

• Percentage of Subjects With 50% or 75% Improvement From Baseline in Psoriasis Area and Severity Index (PASI) Score

  Baseline up to Day 85

• Mean Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Day 43

  Baseline, Day 43

• 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

• 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

• Percentage of Subjects With Exacerbation of Psoriasis

  Baseline up to Day 85

Study Arms (5)

MSB0010841 30 mg

EXPERIMENTAL

Drug: MSB0010841

MSB0010841 60 mg

EXPERIMENTAL

Drug: MSB0010841

MSB0010841 120 mg

EXPERIMENTAL

Drug: MSB0010841

MSB0010841 240 mg

EXPERIMENTAL

Drug: MSB0010841

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

MSB0010841 DRUG

MSB0010841(Anti- IL-17A/F Nanobody) will be administered at a dose of 30 mg as SC injection every other week (Day 1, Day 15 and Day 29) for a total duration of 6 weeks.

Also known as: Anti-IL-17A/F Nanobody, M1095

MSB0010841 30 mg

Placebo DRUG

Placebo matched to MSB0010841 will be administered as SC injection every other week (Day 1, Day 15 and Day 29) for a total duration of 6 weeks.

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Please contact the Merck KGaA Communication Center

Darmstadt, Germany

Location

MeSH Terms

Conditions

Psoriasis

Condition Hierarchy (Ancestors)

Skin Diseases, Papulosquamous; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

As AUCextra was more than 20% of AUC0-inf after first dose, AUCextra and all values derived from λz were regarded as implausible and "AUC0-inf", "MRT0-inf", "t1/2", "λz", "CL/f", and "Vz/f" were not calculated after first dose.

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2014
• First Posted: June 5, 2014
• Study Start: August 1, 2014
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: January 19, 2017
• Results First Posted: January 19, 2017

Record last verified: 2016-11

Locations

DE (1)