Dystrophic Epidermolysis Bullosa
Conditions
Keywords
bullosa, DEB, RDEB, Krystal, epidermolysis, Beremagene, Geperpavec, KB103, HSV-COL7A1
Brief summary
This study was conducted to assess the safety and efficacy of topical Beremagene Geperpavec (KB103, HSV1-COL7) on DEB patients.
Detailed description
The primary objectives were the evaluation of safety, through incidence of adverse events associated with the administration of B-VEC as compared to placebo, as well as the demonstration of molecular correction of the disease by establishing the presence of functional COL7 expression and anchoring fibrils (AF) formation post administration of B-VEC. Additional primary objectives were to assess the proportion of wounds with complete wound closure (≥90% reduction from baseline wound surface area) at Week 8, 10, and 12, the duration of wound closure, and the time to wound closure of B-VEC treated wounds as compared with placebo treated wounds.
Interventions
BIOLOGICALTopical beremagene geperpavec
Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein
BIOLOGICALPlacebo gel
Placebo gel
Sponsors
Krystal Biotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Intrasubject treatment assignment/randomization
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of the recessive form of dystrophic epidermolysis bullosa (RDEB). * Age 1. Phase 1: 18 years old or older, 2. Phase 2a: 5 years old or older, 3. Phase 2b: 2 years old or older, 4. Phase 2c: 2 years old or older. * Willing and able to give consent/assent * Confirmation of RDEB diagnosis by genetic testing, IF, and IEM * LH24 antibody negative (non-collagenous \[NC\] 2domain \[NC2-\]) and NC1 domain \[NC1+\]). (This criterion is applicable to the first 2 adults on the study (Phase 1). Subsequent subjects can be NC1+ or NC1-) * Confirmed RDEB COL7A1 mutations in subject * Wound that meets the wound size/surface area entry criteria: 1. Phase 1: Two wounds up to 10 cm2; 1 randomized to B-VEC and 1 randomized to placebo 2. Phase 2a and 2b: At least 3 wounds up to 20 cm2; 2 wounds randomized to B-VEC and 1 randomized to placebo 3. Phase 2c: At least 2 wounds up to 50 cm2; at least 1 randomized to B-VEC and 1 randomized to placebo * Subjects, who are, in the opinion of the investigator, able to understand the study, cooperate with the study procedures, and are willing to return to the clinic for all the required follow-up visits.
Exclusion criteria
* Medical instability limiting ability to travel to the investigative center * The presence of medical illness expected to complicate participation and/or compromise the safety of this technique, such as active infection with human immunodeficiency virus (HIV), hepatitis B (as determined by hepatitis B surface antigen screening), or hepatitis C (as determined by detection of hepatitis C antibodies, or positive result of hepatitis C polymerase chain reaction \[PCR\] analysis) * Serum antibodies to COL7 demonstrated on enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence microscopy, Western blot, or cell-mediated immunity to enzyme-lined ImmunoSpot® (subjects with negative results within 12 months of screening are eligible) * Active infection in the area that will undergo administration * Evidence of systemic infection * Known allergy to any of the constituents of the product * Current evidence or a history of squamous cell carcinoma in the area that will undergo treatment * Active drug or alcohol addiction * Hypersensitivity to local anesthesia (lidocaine/prilocaine cream) * Receipt of chemical or biological study product for the specific treatment of RDEB in the past 3 months * Specific wounds that have previously been administered investigational gene or cell therapy * Subjects who have taken systemic antibiotics within 7 days * Positive pregnancy test or breast-feeding * Clinically significant abnormalities as determined by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Wound Closure Responder, ITT Population | from baseline at Weeks 8, 10, and 12 | One wound is a responder if the reduction from baseline in wound surface is ≥90%. |
| Number of Subjects Reported at Least One Adverse Event, Safety Population | baseline to 12 weeks | Safety assessments included evaluation of medical and medication history, physical / skin examination, vital signs, adverse events, and laboratory evaluations. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention. |
| Number of Adverse Events Reported, Safety Population | baseline to 12 weeks | Safety assessments included evaluation of medical and medication history, physical / skin examination, vital signs, adverse events, and laboratory evaluations. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention. |
| Time to Wound Closure Analysis, ITT Population | baseline to complete wound closure | Time to wound closure was defined as the time from the first treatment to Complete Wound Closure (≥90% reduction in wound surface area from baseline) |
| Duration of Wound Closure, ITT Population | Time from the complete closure to the first reopening of the same wound | Duration of wound closure |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) The randomization scheme and subject-specific randomization envelopes were created for each phase of the study. At the baseline visit, subjects were assigned a randomization number and the investigator selected either 2 (Phase 1, B-VEC: Placebo = 1:1), 3 (Phase 2a and 2b, B-VEC: Placebo = 2:1), or 2 (Phase 2c, B-VEC: Placebo = 1:1) similar sized wounds, as applicable. Using the randomization scheme with the subject-specific envelope, the wounds were assigned to either B-VEC or placebo. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Early termination, Sponsor decision | 1 |
Baseline characteristics
| Characteristic | All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) |
|---|---|
| Age, Continuous | 20.3 years STANDARD_DEVIATION 8.05 |
| Race/Ethnicity, Customized Ethnicity : Hispanic or Latino | 3 Participants |
| Race/Ethnicity, Customized Ethnicity : Not Hispanic or Latino | 9 Participants |
| Race/Ethnicity, Customized Race : White | 12 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 9 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Complete Wound Closure Responder, ITT Population
One wound is a responder if the reduction from baseline in wound surface is ≥90%.
Time frame: from baseline at Weeks 8, 10, and 12
Population: The intent-to-treat (ITT) population: subjects who were administered KB103 who have had at least one paired assessment of the target wound area post-administration, i.e., at least one KB103 target wound and one placebo target wound.~The Safety population: all subjects who were administered IP. The per-protocol (PP) population: all subjects in the ITT population who have had at least one paired assessment of the target wound area post-administration and completed the protocol as planned.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Complete Wound Closure Responder, ITT Population | Week 8 | 14 number of responder |
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Complete Wound Closure Responder, ITT Population | Week 10 | 12 number of responder |
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Complete Wound Closure Responder, ITT Population | Week 12 | 12 number of responder |
| Placebo | Complete Wound Closure Responder, ITT Population | Week 8 | 0 number of responder |
| Placebo | Complete Wound Closure Responder, ITT Population | Week 10 | 2 number of responder |
| Placebo | Complete Wound Closure Responder, ITT Population | Week 12 | 1 number of responder |
Primary
Duration of Wound Closure, ITT Population
Duration of wound closure
Time frame: Time from the complete closure to the first reopening of the same wound
Population: ITT population included all subjects who were administered IP and had at least 1 post dose paired wound assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Duration of Wound Closure, ITT Population | 103.0 days |
| Placebo | Duration of Wound Closure, ITT Population | 16.5 days |
p-value: 0.0009Log Rank
Primary
Number of Adverse Events Reported, Safety Population
Safety assessments included evaluation of medical and medication history, physical / skin examination, vital signs, adverse events, and laboratory evaluations. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention.
Time frame: baseline to 12 weeks
Population: Safety population included all subjects administered B-VEC or Placebo. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Number of Adverse Events Reported, Safety Population | 35 number of adverse events |
Primary
Number of Subjects Reported at Least One Adverse Event, Safety Population
Safety assessments included evaluation of medical and medication history, physical / skin examination, vital signs, adverse events, and laboratory evaluations. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention.
Time frame: baseline to 12 weeks
Population: Safety population included all subjects administered B-VEC or Placebo. Due to the 'split-person' intrasubject design, the safety assessments were reported at subject level, but not per intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Number of Subjects Reported at Least One Adverse Event, Safety Population | 9 Participants |
Primary
Time to Wound Closure Analysis, ITT Population
Time to wound closure was defined as the time from the first treatment to Complete Wound Closure (≥90% reduction in wound surface area from baseline)
Time frame: baseline to complete wound closure
Population: Intent to treat (ITT) included all subjects who were administered IP and had at least 1 post dose paired wound assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) | Time to Wound Closure Analysis, ITT Population | 13.5 days |
| Placebo | Time to Wound Closure Analysis, ITT Population | 22.5 days |
p-value: 0.0216Log Rank