Erythropoietic Protoporphyria
Conditions
Keywords
EPP, DISC-1459, RO4917838, porphyria
Brief summary
This is a Phase 2, multi-center, double-blind, placebo-controlled, parallel group study of bitopertin to evaluate the safety, tolerability, efficacy, and PPIX concentration change in participants with EPP. Participants may roll over to an open label extension portion after completing the double-blind treatment period.
Interventions
DRUGDISC-1459
Oral dose level 1, once a day for 120 days
DRUGPlacebo
Oral dose, once a day for 120 days
Sponsors
Disc Medicine, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged 18 years or older at the time of signing the informed consent form (ICF). 2. Diagnosis of EPP, based on medical history by ferrochelatase ( FECH) genotyping or by biochemical porphyrin analysis. 3. Body weight ≥50 kg. 4. Washout of at least 2 months prior to Screening of afamelanotide and dersimelagon, if applicable. 5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) \<2× upper limit of normal (ULN) and total bilirubin \<ULN (unless documented Gilbert syndrome) at Screening. Albumin \>lower limit of normal (LLN).
Exclusion criteria
Medical History: 1. Major surgery within 8 weeks before Screening or incomplete recovery from any previous surgery. 2. Other than EPP, an inherited or acquired red cell disease associated with anemia. 3. A history or known allergic reaction to any investigational product excipients or history of anaphylaxis to any food or drug. 4. History of liver transplantation. 5. History of alcohol dependence or excessive alcohol consumption, as assessed by the Investigator. 6. Human immunodeficiency virus (HIV), active Hepatitis B, or C. 7. Other medical or psychiatric condition or laboratory finding not specifically noted above that, in the judgment of the Investigator or Sponsor, would put the participant at unacceptable risk or otherwise preclude the participant from participating in the study 8. Condition or concomitant medication that would confound the ability to interpret clinical, clinical laboratory, or participant diary data, including a major psychiatric condition that has had an exacerbation or required hospitalization in the last 6 months. Treatment History: 9. Concurrent or planned treatment with afamelanotide or dersimelagon during the study period. 10. Treatment with opioids for any period \>7 days in the 2 months prior to screening or anticipated to require opioid use for \>7 days at any point during the study. 11. New treatment for anemia, including initiation of iron supplementation, in the 2 months prior to Screening. 12. Current or planned use of any drugs or herbal remedies known to be strong inhibitors or inducers of CYP3A4 enzymes for 28 days prior to the first dose and throughout the study. Laboratory Exclusions: 13. Hemoglobin \<10 g/dL at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Whole Blood Metal-free PPIX Levels | 121 days | Percent change from baseline in PPIX concentration was analyzed using a mixed model repeated measures analysis in the ITT population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Bitopertin Concentrations | Day 29 | Day 29 plasma bitopertin concentrations, 4 hours post-dose |
| Total Hours of Sunlight Exposure to Skin on Days With no Pain From 1000 to 1800 Hours (10:00am to 6:00pm) | 121 days | Cumulative total hours of sunlight exposure on days with no pain from 1000 to 1800 hours from baseline to Day 121 (EOS) was analyzed using analysis of variance in the ITT population. |
| Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post-sunrise and 1 Hour Pre-sunset | 121 days | Participants exposed their skin to sunlight once a week and measured the time it takes to experience a prodrome. The time (minutes) to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure was recorded in a diary. This sun exposure challenge was performed weekly. The average time (minutes) to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure was averaged over two-week intervals through Study Day 121. |
| Total Pain Intensity | Sum of Day 1 to Day 121 | The maximum total daily pain intensity scores of phototoxic reactions over the entire treatment period (D1-D121). The maximum pain score of a phototoxic reaction was measured on a Likert Scale (0-10). Total scores range from 0-1210. A score of 0 is the best outcome; and higher scores are a worse outcome. The maximum pain values on a scale of 0-10 in a day were summed across 121 days. |
| Incidence of Treatment-emergent Adverse Events | 121 days | Incidence of treatment-emergent adverse events |
| Erythrocyte Total PPIX Concentrations | 121 days | Percent change from baseline in erythrocyte total PPIX concentration was summarized by analysis visit in the ITT population. |
| Plasma Total PPIX Concentrations | 121 days | Percent change from baseline in plasma total PPIX concentration was summarized by analysis visit in the ITT population. |
| Whole Blood Total PPIX Concentrations | 121 days | Percent change from baseline in whole blood total PPIX concentration was summarized by analysis visit in the ITT population. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Oral dose, once a day for 120 days | 24 |
| DISC-1459 Oral Low Dose Level DISC-1459: Oral 20 mg dose, once a day for 120 days | 26 |
| DISC-1459 Oral High Dose Level DISC-1459: Oral 60 mg dose, once a day for 120 days | 25 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | DISC-1459 Oral Low Dose Level | DISC-1459 Oral High Dose Level | Total |
|---|---|---|---|---|
| Age, Customized Age | 42.3 years STANDARD_DEVIATION 12.24 | 45.0 years STANDARD_DEVIATION 14.31 | 47.8 years STANDARD_DEVIATION 14.02 | 45.1 years STANDARD_DEVIATION 13.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 26 Participants | 23 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 12 Participants | 38 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 13 Participants | 37 Participants |
| Whole Blood Metal-free PPIX | 8691.0 ng/mL STANDARD_DEVIATION 424.56 | 8154.6 ng/mL STANDARD_DEVIATION 6816.49 | 10597.0 ng/mL STANDARD_DEVIATION 4916.24 | 9140.4 ng/mL STANDARD_DEVIATION 5544.78 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 19 / 24 | 19 / 26 | 22 / 25 |
| serious Total, serious adverse events | 1 / 24 | 0 / 26 | 0 / 25 |
Outcome results
Primary
Percent Change From Baseline in Whole Blood Metal-free PPIX Levels
Percent change from baseline in PPIX concentration was analyzed using a mixed model repeated measures analysis in the ITT population.
Time frame: 121 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Whole Blood Metal-free PPIX Levels | 8.07 Percent Change |
| DISC-1459 Oral Low Dose | Percent Change From Baseline in Whole Blood Metal-free PPIX Levels | -21.48 Percent Change |
| DISC-1459 Oral High Dose l | Percent Change From Baseline in Whole Blood Metal-free PPIX Levels | -41.74 Percent Change |
Secondary
Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post-sunrise and 1 Hour Pre-sunset
Participants exposed their skin to sunlight once a week and measured the time it takes to experience a prodrome. The time (minutes) to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure was recorded in a diary. This sun exposure challenge was performed weekly. The average time (minutes) to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure was averaged over two-week intervals through Study Day 121.
Time frame: 121 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post-sunrise and 1 Hour Pre-sunset | 149.05 Minutes/Two Weeks | Standard Deviation 116.434 |
| DISC-1459 Oral Low Dose | Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post-sunrise and 1 Hour Pre-sunset | 155.51 Minutes/Two Weeks | Standard Deviation 99.903 |
| DISC-1459 Oral High Dose l | Daily Sunlight Exposure Time (Minutes) to First Prodromal Symptom (Burning, Tingling, Itching, or Stinging) Associated With Sunlight Exposure Between 1 Hour Post-sunrise and 1 Hour Pre-sunset | 176.14 Minutes/Two Weeks | Standard Deviation 134.952 |
Secondary
Erythrocyte Total PPIX Concentrations
Percent change from baseline in erythrocyte total PPIX concentration was summarized by analysis visit in the ITT population.
Time frame: 121 days
Population: Intention-to-treat population analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Erythrocyte Total PPIX Concentrations | 19.3 Percent Change | Standard Deviation 59.95 |
| DISC-1459 Oral Low Dose | Erythrocyte Total PPIX Concentrations | -20.5 Percent Change | Standard Deviation 29.73 |
| DISC-1459 Oral High Dose l | Erythrocyte Total PPIX Concentrations | -39.9 Percent Change | Standard Deviation 34.67 |
Secondary
Incidence of Treatment-emergent Adverse Events
Incidence of treatment-emergent adverse events
Time frame: 121 days
Population: Number and Proportion of Participants with at Least One TEAE
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Incidence of Treatment-emergent Adverse Events | 19 Participants |
| DISC-1459 Oral Low Dose | Incidence of Treatment-emergent Adverse Events | 19 Participants |
| DISC-1459 Oral High Dose l | Incidence of Treatment-emergent Adverse Events | 22 Participants |
Secondary
Plasma Bitopertin Concentrations
Day 29 plasma bitopertin concentrations, 4 hours post-dose
Time frame: Day 29
Population: Intention-to-treat population analyzed. There is no measurable bitopertin concentrations in placebo patients, since they did not receive drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Bitopertin Concentrations | 207.3 ng/mL | Standard Deviation 83.5 |
| DISC-1459 Oral Low Dose | Plasma Bitopertin Concentrations | 683.4 ng/mL | Standard Deviation 308.8 |
Secondary
Plasma Total PPIX Concentrations
Percent change from baseline in plasma total PPIX concentration was summarized by analysis visit in the ITT population.
Time frame: 121 days
Population: Intention-to-treat population analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Total PPIX Concentrations | 11.7 Percent Change | Standard Deviation 56.76 |
| DISC-1459 Oral Low Dose | Plasma Total PPIX Concentrations | -45.4 Percent Change | Standard Deviation 23.86 |
| DISC-1459 Oral High Dose l | Plasma Total PPIX Concentrations | -53.9 Percent Change | Standard Deviation 31.55 |
Secondary
Total Hours of Sunlight Exposure to Skin on Days With no Pain From 1000 to 1800 Hours (10:00am to 6:00pm)
Cumulative total hours of sunlight exposure on days with no pain from 1000 to 1800 hours from baseline to Day 121 (EOS) was analyzed using analysis of variance in the ITT population.
Time frame: 121 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Total Hours of Sunlight Exposure to Skin on Days With no Pain From 1000 to 1800 Hours (10:00am to 6:00pm) | 133.91 Hours |
| DISC-1459 Oral Low Dose | Total Hours of Sunlight Exposure to Skin on Days With no Pain From 1000 to 1800 Hours (10:00am to 6:00pm) | 175.11 Hours |
| DISC-1459 Oral High Dose l | Total Hours of Sunlight Exposure to Skin on Days With no Pain From 1000 to 1800 Hours (10:00am to 6:00pm) | 153.14 Hours |
Secondary
Total Pain Intensity
The maximum total daily pain intensity scores of phototoxic reactions over the entire treatment period (D1-D121). The maximum pain score of a phototoxic reaction was measured on a Likert Scale (0-10). Total scores range from 0-1210. A score of 0 is the best outcome; and higher scores are a worse outcome. The maximum pain values on a scale of 0-10 in a day were summed across 121 days.
Time frame: Sum of Day 1 to Day 121
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Pain Intensity | 13.0 Scores on a scale | Standard Deviation 9.38 |
| DISC-1459 Oral Low Dose | Total Pain Intensity | 15.0 Scores on a scale | Standard Deviation 13.95 |
| DISC-1459 Oral High Dose l | Total Pain Intensity | 6.3 Scores on a scale | Standard Deviation 2.5 |
Secondary
Whole Blood Total PPIX Concentrations
Percent change from baseline in whole blood total PPIX concentration was summarized by analysis visit in the ITT population.
Time frame: 121 days
Population: Intention-to-treat population analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Whole Blood Total PPIX Concentrations | 8.2 Percent Change | Standard Deviation 41.19 |
| DISC-1459 Oral Low Dose | Whole Blood Total PPIX Concentrations | -19.7 Percent Change | Standard Deviation 31.71 |
| DISC-1459 Oral High Dose l | Whole Blood Total PPIX Concentrations | -40.1 Percent Change | Standard Deviation 28.89 |