Primary objective

“to investigate the efficacy of MT-7117 on time to onset and severity of first prodromal symptoms (burning, tingling, itching, or stinging) associated with sunlight exposure in adults and adolescents with EPP or XLP” (opens the source at this quote in a new tab)

Study status and dates

Registry field	Quoted record
Overall status	“Completed”
Start date, actual	“2020-06-01”
Primary completion, actual	“2021-12-14”
Completion, actual	“2022-07-26”
Enrollment, actual	“184”

Participants enrolled by country

“Number of subjects enrolled per country Country: Number of subjects enrolled Norway: 3 Country: Number of subjects enrolled Spain: 11 Country: Number of subjects enrolled Sweden: 5 Country: Number of subjects enrolled United Kingdom: 14 Country: Number of subjects enrolled Germany: 6 Country: Number of subjects enrolled Italy: 21 Country: Number of subjects enrolled United States: 93 Country: Number of subjects enrolled Japan: 11 Country: Number of subjects enrolled Australia: 12 Country: Number of subjects enrolled Canada: 8 Worldwide total number of subjects 184 EEA total number of subjects 46” (opens the source at this quote in a new tab)
“Global end of trial date 26 Jul 2022” (opens the source at this quote in a new tab)

Registry design fields

Design field	Quoted record
Allocation	“Randomized”
Intervention model	“Parallel”
Masking	“Triple”
Primary purpose	“treatment”
Phase	“Phase 3”

Age, diagnosis, and body weight

“Male and female subjects with a confirmed diagnosis of EPP or XLP based on medical history, aged 12 years to 75 years, inclusive, at Screening” (opens the source at this quote in a new tab)
“Subjects have a body weight of ≥30 kg” (opens the source at this quote in a new tab)

Hepatic, dermatologic, and renal exclusions

“History or presence of photodermatoses other than EPP or XLP” (opens the source at this quote in a new tab)
“Subjects with AST, ALT, ALP ≥3.0 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN at Screening” (opens the source at this quote in a new tab)
“History of melanoma” (opens the source at this quote in a new tab)
“History of familial melanoma (defined as having 2 or more first-degree relatives, such as parents, sibling and/or child” (opens the source at this quote in a new tab)

Prohibited prior and concomitant therapy

“Treatment with phototherapy within 3 months before Randomization (Visit 2” (opens the source at this quote in a new tab)
“Treatment with afamelanotide within 3 months before Randomization (Visit 2” (opens the source at this quote in a new tab)
“Treatment with antioxidant agents within 4 weeks before Randomization (Visit 2), at doses which, in the opinion of the Investigator, may affect study endpoints (including but not limited to beta-carotene, cysteine, pyridoxine” (opens the source at this quote in a new tab)

Registry arm descriptions

“Oral tablet of placebo once a day.” (opens the source at this quote in a new tab)
“Oral tablet of MT-7117 Low Dose once a day.” (opens the source at this quote in a new tab)
“Oral tablet of MT-7117 High Dose once a day.” (opens the source at this quote in a new tab)

Tablet strength and number of tablets per arm

“Arm title MT-7117 low dose” (opens the source at this quote in a new tab)
“Dosage and administration details Subjects self-administered 2 tablets of investigational medicinal product (IMP) with or without food each morning. Subjects received 1 tablet of MT-7117 and 1 tablet of matching placebo” (opens the source at this quote in a new tab)

Disclosed dose amounts

No evidence found.

Definition of the primary efficacy endpoint and its averaging window

“Change from baseline in average 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 at Week 26 (Visit 7” (opens the source at this quote in a new tab)

Secondary efficacy endpoints

“Patient Global Impression of Change (PGIC) at Week 26” (opens the source at this quote in a new tab)
“The percentage of subjects who are responders based on average daily sunlight exposure time to first prodromal symptom associated with sunlight exposure between 1 hour post-sunrise and 1 hour pre-sunset defined by within-subject meaningful change of 66 minutes increase from baseline to Week 26” (opens the source at this quote in a new tab)

Participants analyzed by population

Population	Placebo	MT-7117 low dose	MT-7117 high dose
Randomized and started double-blind treatment	“61”	“63”	“60”
Primary endpoint analysis set	“60”	“63”	“60”
PROMIS-57 analyses	“49”	“59”	“56”
Patient Global Impression of Change analysis	“56”	“59”	“56”

Definition of the efficacy analysis set

“Included all randomized subjects who received at least 1 dose of study medication with Baseline and post randomization- sunlight exposure diary assessments during the double-blind treatment period” (opens the source at this quote in a new tab)

Point at which sequential testing stopped

“Because MT-7117 High Dose did not demonstrate statistically significant differences compared to placebo, the prespecified sequential testing was stopped before formally statistically testing the next hypothesis of the primary endpoint of Low Dose and the secondary endpoints. Therefore, Nominal p values presented for these endpoints are for descriptive purposes only. Consequently, the subsequent primary endpoint of the MT-7117 Low Dose group and the secondary endpoints were not formally tested.” (opens the source at this quote in a new tab)

Disposition during the 26-week double-blind treatment period

Disposition	Placebo	MT-7117 low dose	MT-7117 high dose
Started	“61”	“63”	“60”
Completed	“57”	“60”	“58”
Not completed	“4”	“3”	“2”
Adverse event	“0”	“1”	“0”
Physician decision	“1”	“0”	“0”
Withdrawal by subject	“3”	“2”	“2”

Entry into the double-blind extension

“Of 57 participants randomized to placebo in 26 weeks double-blind period, 28 were re-randomized to MT-7117 low dose, and 28 were re-randomized to MT-7117 high dose” (opens the source at this quote in a new tab)

Number screened and screen failures

No evidence found.

Age distribution and sex

Characteristic	Placebo	MT-7117 low dose	MT-7117 high dose	Total
Adolescents aged 12 to 17 years	“12”	“13”	“12”	“37”
Adults aged 18 to 65 years	“47”	“45”	“46”	“138”
Older than 65 years	“2”	“5”	“2”	“9”
Age in years, arithmetic mean (standard deviation)	“34.1 ( 15.6”	“33.5 ( 17.1”	“34.4 ( 15.3”	“184”
Female	“30”	“30”	“33”	“93”
Male	“31”	“33”	“27”	“91”

Race and ethnicity

Category	Placebo	MT-7117 low dose	MT-7117 high dose
Hispanic or Latino	“7”	“7”	“2”
Not Hispanic or Latino	“53”	“52”	“58”
White	“52”	“60”	“55”
Asian	“9”	“1”	“2”
Black or African American	“0”	“0”	“0”

Baseline disease characteristics, including diagnosis split and protoporphyrin concentrations

No evidence found.

Primary endpoint: change from baseline in average daily sunlight exposure time to first prodromal symptom at Week 26

Arm	Least-squares mean change, minutes	Standard error
Placebo	“20.59”	“10.29”
MT-7117 low dose	“30.39”	“10.04”
MT-7117 high dose	“43.29”	“10.13”

Comparison with placebo	Least-squares mean difference, minutes	95% confidence interval	P value
MT-7117 low dose	“9.8”	“-18.52”to “38.12”	“0.496”
MT-7117 high dose	“22.7”	“-5.68”to “51.09”	“0.116”

Sponsor description of the primary endpoint outcome

“For the primary efficacy endpoint, change from baseline in average 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 at Week 26 (Visit 7), MT-7117 High Dose did not demonstrate statistically significant improvement over placebo (LSMD = 22.70 minutes, p = 0.116).” (opens the source at this quote in a new tab)

Secondary endpoint: Patient Global Impression of Change at Week 26

Arm	Least-squares mean, points	Least-squares mean difference from placebo	95% confidence interval	Nominal P value
Placebo	“3.25”
MT-7117 low dose	“2.41”	“-0.84”	“-1.23”to “-0.44”	“< 0.001”
MT-7117 high dose	“1.82”	“-1.43”	“-1.83”to “-1.03”	“< 0.001”

Secondary endpoint: total number of sunlight-induced pain events over 26 weeks

Arm	Geometric mean number of events	Incident rate ratio compared with placebo	95% confidence interval	Nominal P value
Placebo	“23.9”
MT-7117 low dose	“15.87”	“0.76”	“0.49”to “1.16”	“0.199”
MT-7117 high dose	“13.78”	“0.55”	“0.36”to “0.84”	“0.006”

Secondary endpoint: responder rate using the 66-minute within-subject meaningful change

Arm	Responders, percentage of participants	Odds ratio compared with placebo	95% confidence interval	Nominal P value
Placebo	“12”
MT-7117 low dose	“11”	“0.805”	“0.323”to “2.007”	“0.642”
MT-7117 high dose	“16”	“1.412”	“0.598”to “3.336”	“0.431”

Independent characterization of the trial outcome

“The first published phase II trial results demonstrated effectiveness,” (opens the source at this quote in a new tab)
“while the phase III trial did not meet its primary efficacy endpoint” (opens the source at this quote in a new tab)

PROMIS-57 pain intensity domain, change from baseline at Week 26

Arm	Least-squares mean change	Least-squares mean difference from placebo	95% confidence interval	Nominal P value
Placebo	“-1.42”
MT-7117 low dose	“-1.56”	“-0.15”	“-0.62”to “0.33”	“0.55”
MT-7117 high dose	“-1.65”	“-0.23”	“-0.72”to “0.25”	“0.343”

PROMIS-57 physical function domain, change from baseline at Week 26

Arm	Least-squares mean change	Least-squares mean difference from placebo	95% confidence interval	Nominal P value
Placebo	“0.67”
MT-7117 low dose	“1.54”	“0.87”	“-0.08”to “1.82”	“0.072”
MT-7117 high dose	“1.22”	“0.56”	“-0.4”to “1.51”	“0.252”

Deaths and serious adverse events by period and arm

Group	Deaths, affected of at risk	Serious adverse events, affected of at risk
Double-blind treatment, placebo	“0”	“0”
Double-blind treatment, MT-7117 low dose	“0”	“2”
Double-blind treatment, MT-7117 high dose	“1”	“2”
Double-blind extension, placebo to low dose	“0”	“2”
Double-blind extension, placebo to high dose	“0”	“1”
Double-blind extension, MT-7117 low dose	“0”	“1”
Double-blind extension, MT-7117 high dose	“0”	“2”

Non-serious adverse events reported at the 5% threshold during double-blind treatment

MedDRA preferred term	Placebo	MT-7117 low dose	MT-7117 high dose
Nausea	“4”	“4”	“17”
Headache	“3”	“8”	“9”
Diarrhoea	“1”	“5”	“8”
Melanocytic naevus	“1”	“6”	“8”
Skin hyperpigmentation	“1”	“3”	“8”
Skin discolouration	“0”	“5”	“6”
Ephelides	“1”	“3”	“4”
Photosensitivity reaction	“6”	“1”	“2”
Porphyria non-acute	“5”	“1”	“1”
Alanine aminotransferase increased	“1”	“3”	“0”
Aspartate aminotransferase increased	“1”	“4”	“0”
Gamma-glutamyltransferase increased	“5”	“3”	“1”

Overall burden of non-serious adverse events

“Total subjects affected by non serious adverse events subjects affected / exposed 40 / 61 (65.57%) 44 / 63 (69.84%) 44 / 60 (73.33” (opens the source at this quote in a new tab)

Serious adverse events by term

“There were 4 subjects (3.3%) who experienced serious TEAEs, 2 subjects in the MT-7117 Low Dose group, 2 subjects in the MT-7117 High Dose group, and no subjects in the placebo group. In the MT-7117 Low Dose group, 1 subject experienced myocarditis, and 1 subject experienced meningitis viral. In the MT-7117 High Dose group, 1 subject experienced asthma that was considered moderate. One subject in the MT-7117 High Dose group experienced a severe event of cholestasis with a fatal outcome.” (opens the source at this quote in a new tab)
“Six subjects (3.6%) experienced serious TEAEs in the MT-7117 combined group: hepatic enzyme increased (2 [7.1%]) placebo to MT-7117 Low Dose; porphyria non acute (1 [3.6%]) placebo to MT-7117 High Dose; pericarditis (1 [1.8%]) MT-7117 Low Dose; esophagitis (1 [1.9%]) and fibula fracture (1 [1.9%]) in MT-7117 High Dose.” (opens the source at this quote in a new tab)

Independent safety oversight

“An external independent Data Monitoring Committee was established to perform regular review of safety data to ensure the ongoing safety of participating subjects until the last subject completed the Double blind extension period.” (opens the source at this quote in a new tab)

Summary: interpretation of the first phase 3 trial

The trial did not meet its primary endpoint at either dose. Type I error was controlled by a fixed-sequence procedure in which the high dose was tested first; because that comparison was not statistically significant, testing stopped, and every subsequent P value, including those for the low dose, the Patient Global Impression of Change, and the pain-event count, is nominal and descriptive rather than confirmatory. The pre-specified 66-minute responder analysis was negative at both doses, and the placebo group improved by 20.59 minutes, a change of similar magnitude to the treatment differences observed. The sample size was calculated to detect a treatment difference of 52 to 57 minutes, and the observed differences were 9.8 minutes at the low dose and 22.7 minutes at the high dose. One death occurred, from cholestasis in the high-dose arm, the only death reported anywhere in the dersimelagon program in these disorders; the investigator assessed it as probably related to study drug and the sponsor as unlikely or unrelated, and an institutional review board suspended dosing at United States sites from July 14 to July 20, 2021. Two further serious hepatic enzyme elevations occurred in participants switching from placebo to active drug in the extension period. The actual dose amounts are redacted in every public document, no peer-reviewed publication exists, and no baseline disease characteristics, diagnosis subgroup, adolescent subgroup, or exploratory endpoint results have been posted. The sponsor reported no limitations in its results summary.

Limitations declared by the sponsor

“Limitations and caveats” (opens the source at this quote in a new tab)
“None reported” (opens the source at this quote in a new tab)

Independent critique of the prodromal-symptom endpoint

“The trials investigating dersimelagon use “time to prodrome” as their primary efficacy outcome measure. Prodromal symptoms are a newly introduced concept of early warning signals for a phototoxic reaction such as itching, tingling, burning and stinging.” (opens the source at this quote in a new tab)
“However, in their study, 76% of the participants reported having recovery times of one up to five days after experiencing a prodrome, and 46% experienced pain despite immediately exiting the sun.” (opens the source at this quote in a new tab)
“Consistent with our assessment, phototoxic pain events were observed in all treatment arms in the phase II trial investigating dersimelagon, i.e., in the placebo, low dose and high dose treatment groups [ 52 ]. Therefore, the endpoint “time to prodrome” does not prevent participants from developing severe reactions.” (opens the source at this quote in a new tab)