Pemphigus Foliaceus, Pemphigus Vulgaris
Conditions
Brief summary
This is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to investigate the efficacy, safety, patient outcome measures, tolerability, immunogenicity, PK, and PD of efgartigimod PH20 SC in adult participants aged from 18 years with PV or PF. The trial comprises a screening period of up to 3 weeks, a treatment period of up to 30 weeks, and an 8-week follow-up period for participants who do not enroll into the open-label extension (OLE) trial ARGX-113-1905. The primary objective of the ARGX-113-1904 trial is to demonstrate the efficacy of subcutaneous administration of efgartigimod co-formulated with recombinant human hyaluronidase PH20 (Efgartigimod PH20 SC) compared to placebo in the treatment of participants with Pemphigus Vulgaris (PV). Secondary objectives are to also demonstrate the efficacy of efgartigimod PH20 SC in the treatment of participants with Pemphigus Foliaceus (PF), and to demonstrate early onset of action and a prednisone-sparing effect. After confirmation of eligibility, participants will be randomized in a 2: 1 ratio to receive efgartigimod PH20 SC or placebo
Interventions
BIOLOGICALefgartigimod PH20 SC
Subcutaneous injection of efgartigimod using rHuPH20 (PH20) as a permeation enhancer
OTHERPlacebo
Subcutaneous injection of placebo
DRUGprednisone
Oral prednisone tablets
Sponsors
argenx
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability to understand the requirements of the trial, to provide written informed consent (including consent for the use and disclosure of research-related health information), willingness and ability to comply with the trial protocol procedures (including required trial visits). 2. The participant is male or female, and aged from 18 years at the time of signing the informed consent form (ICF). 3. The participant has a clinical diagnosis of PV (mucosal, cutaneous, mucocutaneous) or PF which has been confirmed by cutaneous histology, positive direct immunofluorescence (IF), and positive indirect IF and/or enzyme-linked immunosorbent assay (ELISA). 4. The participant meets one of the following profiles: 1. Newly diagnosed disease with PDAI ≥15 at baseline and naïve to treatment 2. Newly diagnosed disease with PDAI ≥15 while receiving a first course of oral prednisone (or equivalent). According to clinical judgment, the participant has shown no significant improvement of PV or PF signs for at least 2 weeks before baseline and is considered fit to start prednisone treatment at 0.5 mg/kg qd at baseline. 3. Experiencing flare with PDAI ≥15, a maximum of 4 years since diagnosis, and off prednisone therapy ± a conventional immunosuppressant (e.g., azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil) or dapsone. Note: conventional immunosuppressants and dapsone must be discontinued before baseline. 4. Experiencing flare with PDAI ≥15, a maximum of 4 years since diagnosis, and receiving a tapered dose of oral prednisone (or the equivalent), provided that prednisone has been given at stable dose ± a conventional immunosuppressant for at least 2 weeks and patients are fit to start prednisone treatment at 0.5 mg/kg qd at baseline. 5. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating clinical trials and: 1. Male participants: Male participants must agree to use acceptable method of contraception, and not donate sperm from signing the ICF until the end of the study. 2. Female participants: Women of childbearing potential must: * have a negative serum pregnancy test at screening and negative urine pregnancy test at baseline before the IMP can be administered. * agree to use a highly effective or acceptable contraception method, which should be maintained at minimum until after the last dose of IMP 6. For Japanese participants enrolled in sites in Japan only: A Japanese participant is defined as a participant whose parents and 4 grandparents are Japanese, and who has Japanese nationality, was born in Japan, has not lived outside of Japan for a total of \>10 years, and currently lives in Japan.
Exclusion criteria
1. Participant has a confirmed diagnosis of paraneoplastic pemphigus, drug-induced pemphigus, pemphigus vegetans, pemphigus erythematosus, or any other non-PV/non-PF autoimmune blistering disease. 2. Participants with mild disease severity as defined by PDAI \<15 at baseline. 3. Participants who show a significant improvement of PV or PF in the period from screening to baseline according to clinical judgment (eg, the patient has achieved DC or a substantial reduction in PDAI activity score during screening period). 4. The participant has been administered therapy(ies) other than oral prednisone or conventional immunosuppressants (e.g., azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil) or dapsone within 2 months before the baseline visit and that can affect clinical disease activity. For example, excluded medications are intravenous methylprednisolone, dapsone, sulfasalazine, tetracyclines, nicotinamide at doses above the recommended daily allowance (RDA)/dietary reference intake (DRI), plasmapheresis/ plasma exchange, immunoadsorption, and IVIg. 5. Use of any monoclonal antibody (including rituximab or another anti-CD20 biologic) within 6 months before the baseline visit. 6. Known hypersensitivity to any of the components of the administered treatments. 7. The participant has a known contraindication to oral prednisone. 8. The participant has a history of refractory disease, as defined by a failure to respond to first-line and second-line therapies 9. Participants who have a history of malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥3 years before first IMP administration. Participants with any of the following cancers can be included at any time, provided they are adequately treated prior to their participation in the study: * Basal cell or squamous cell skin cancer, * Carcinoma in situ of the cervix, * Carcinoma in situ of the breast, * Incidental histological finding of prostate cancer 10. Participants with clinical evidence of other significant serious disease or participants who recently underwent or have planned a major surgery during the period of the trial, or any other condition in the opinion of the investigator, that could confound the results of the trial or put the patient at undue risk. 11. Pregnant and lactating women and those intending to become pregnant during the trial. 12. Current or history (i.e. within 12 months of screening) of alcohol, drug, or medication abuse. 13. Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of PV or PF or put the participant at undue risk. 14. The participant has a Karnofsky Performance score \<60%. 15. Vaccination with live viral vaccines within 28 days prior to randomization. 16. The participant has clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection. 17. Positive serum test at screening for an active viral infection with any of the following conditions: Hepatitis B Virus, Hepatitis C Virus , HIV. 18. The participant has total immunoglobulin G (IgG) \<6 g/L at screening. 19. The participant has previously participated in a trial with efgartigimod and has received at least one administration of IMP. 20. Use of an investigational drug within 3 months or 5 half-lives of the drug (whichever is longer) prior to first IMP administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pemphigus Vulgaris (PV) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy | up to 30 weeks treatment period | Proportion of participants with pemphigus vulgaris who had CRmin within 30 weeks, defined as the absence of new lesions and complete healing of established lesions while the participant was receiving prednisone at ≤10 mg/day for at least 8 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris Participants | Up to 30 weeks | Normalized Cumulative prednisone dose (NCPD, mg/kg/day) is the average daily intake of all weight-adjusted prednisone doses received during the study, taking into account the number of days in study |
| Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris Participants | Up to 30 weeks | Time to complete remission (absence of new lesions and complete healing of established lesions) in participants with pemphigus vulgaris |
| Time to Disease Control (DC) in Pemphigus Vulgaris (PV) Participants | Up to 30 weeks | Time to disease control in participants with pemphigus vulgaris (Absence of new lesions and the start of healing of established lesions) |
| Number of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy Within 30 Weeks | up to 30 weeks treatment period | Proportion of participants with pemphigus vulgaris and pemphigus foliaceus who had CRmin within 30 weeks, defined as the absence of new lesions and complete healing of established lesions while the participant was receiving prednisone at ≤10 mg/day for at least 8 weeks. |
| Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | Up to 30 weeks | Time to complete remission (absence of new lesions and complete healing of established lesions) in participants with pemphigus vulgaris and pemphigus foliaceus |
| Time to Disease Control in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | Up to 30 weeks | Time to disease control in participants with pemphigus vulgaris and pemphigus foliaceus (Absence of new lesions and the start of healing of established lesions) |
| Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | Up to 30 weeks | Normalized Cumulative prednisone dose (NCPD, mg/kg/day) is the average daily intake of all weight-adjusted prednisone doses received during the study, taking into account the number of days in study |
Countries
Australia, Bulgaria, China, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Japan, Poland, Romania, Russia, Serbia, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Efgartigimod PH20 SC Patients randomized to receive weekly administrations of efgartigimod PH20 until CRmin (complete remission on minimal prednisone therapy) or end of treatment period or early roll-over to the open-label extension study ARGX-113-1905. All participants received concurrent oral prednisone (or equivalent) at a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted according to recommendations as per protocol | 147 |
| Placebo PH20 SC Patients randomized to receive weekly administrations of placebo PH20 SC until CRmin (complete remission on minimal prednisone therapy) or end of treatment period or early roll-over to the open-label extension study ARGX-113-1905. All participants received concurrent oral prednisone (or equivalent) at a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted according to recommendations as per protocol | 75 |
| Total | 222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | lack of efficacy, geopolitical situation in Ukraine, flares after CRmin, SAE due to prednisone, etc | 30 | 19 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 4 | 1 |
| Overall Study | Requires Prohibited Medication | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Efgartigimod PH20 SC | Placebo PH20 SC | Total |
|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 12.55 | 52.3 years STANDARD_DEVIATION 13.37 | 50.1 years STANDARD_DEVIATION 12.9 |
| Pemphigus Foliaceus (PF) | 23 Participants | 9 Participants | 32 Participants |
| Pemphigus Vulgaris (PV) | 124 Participants | 66 Participants | 190 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 144 Participants | 70 Participants | 214 Participants |
| Race/Ethnicity, Customized Race Asian | 49 Participants | 16 Participants | 65 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Race White | 96 Participants | 53 Participants | 149 Participants |
| Sex: Female, Male Female | 73 Participants | 42 Participants | 115 Participants |
| Sex: Female, Male Male | 74 Participants | 33 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 147 | 0 / 75 |
| other Total, other adverse events | 113 / 147 | 47 / 75 |
| serious Total, serious adverse events | 18 / 147 | 10 / 75 |
Outcome results
Primary
Number of Pemphigus Vulgaris (PV) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy
Proportion of participants with pemphigus vulgaris who had CRmin within 30 weeks, defined as the absence of new lesions and complete healing of established lesions while the participant was receiving prednisone at ≤10 mg/day for at least 8 weeks.
Time frame: up to 30 weeks treatment period
Population: Randomized participants with pemphigus vulgaris (PV) who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Efgartigimod PH20 SC | Number of Pemphigus Vulgaris (PV) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy | 44 Participants |
| Placebo PH20 SC | Number of Pemphigus Vulgaris (PV) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy | 20 Participants |
Secondary
Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris and Pemphigus Foliaceus Participants
Normalized Cumulative prednisone dose (NCPD, mg/kg/day) is the average daily intake of all weight-adjusted prednisone doses received during the study, taking into account the number of days in study
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris or pemphigus foliaceus who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efgartigimod PH20 SC | Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 0.403 mg/kg/day | Standard Deviation 0.21 |
| Placebo PH20 SC | Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 0.431 mg/kg/day | Standard Deviation 0.225 |
Secondary
Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris Participants
Normalized Cumulative prednisone dose (NCPD, mg/kg/day) is the average daily intake of all weight-adjusted prednisone doses received during the study, taking into account the number of days in study
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris (PV) who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efgartigimod PH20 SC | Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris Participants | 0.416 mg/kg/day | Standard Deviation 0.215 |
| Placebo PH20 SC | Normalized Cumulative Prednisone Dose During the Treatment Period in Pemphigus Vulgaris Participants | 0.444 mg/kg/day | Standard Deviation 0.232 |
Secondary
Number of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy Within 30 Weeks
Proportion of participants with pemphigus vulgaris and pemphigus foliaceus who had CRmin within 30 weeks, defined as the absence of new lesions and complete healing of established lesions while the participant was receiving prednisone at ≤10 mg/day for at least 8 weeks.
Time frame: up to 30 weeks treatment period
Population: Randomized participants with pemphigus vulgaris or pemphigus foliaceus who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Efgartigimod PH20 SC | Number of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy Within 30 Weeks | 55 Participants |
| Placebo PH20 SC | Number of Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF) Participants Who Achieve Complete Clinical Remission (CR) on Minimal Prednisone Therapy Within 30 Weeks | 24 Participants |
Secondary
Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris and Pemphigus Foliaceus Participants
Time to complete remission (absence of new lesions and complete healing of established lesions) in participants with pemphigus vulgaris and pemphigus foliaceus
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris or pemphigus foliaceus who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efgartigimod PH20 SC | Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 106 days |
| Placebo PH20 SC | Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 113 days |
Secondary
Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris Participants
Time to complete remission (absence of new lesions and complete healing of established lesions) in participants with pemphigus vulgaris
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris (PV) who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efgartigimod PH20 SC | Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris Participants | 106 days |
| Placebo PH20 SC | Time to Complete Clinical Remission (CR) in Pemphigus Vulgaris Participants | 120 days |
Secondary
Time to Disease Control (DC) in Pemphigus Vulgaris (PV) Participants
Time to disease control in participants with pemphigus vulgaris (Absence of new lesions and the start of healing of established lesions)
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris (PV) who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efgartigimod PH20 SC | Time to Disease Control (DC) in Pemphigus Vulgaris (PV) Participants | 16 days |
| Placebo PH20 SC | Time to Disease Control (DC) in Pemphigus Vulgaris (PV) Participants | 15 days |
Secondary
Time to Disease Control in Pemphigus Vulgaris and Pemphigus Foliaceus Participants
Time to disease control in participants with pemphigus vulgaris and pemphigus foliaceus (Absence of new lesions and the start of healing of established lesions)
Time frame: Up to 30 weeks
Population: Randomized participants with pemphigus vulgaris or pemphigus foliaceus who received at least part of a dose of efgartigimod PH20 SC or placebo PH20 SC. These participants also received prednisone with a starting dosage of 0.5 mg/kg/day. The dose of prednisone was adjusted per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efgartigimod PH20 SC | Time to Disease Control in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 15 days |
| Placebo PH20 SC | Time to Disease Control in Pemphigus Vulgaris and Pemphigus Foliaceus Participants | 15 days |