Section 4 of 6

Clinical evidence

109 evidence topics · 27 sources

Study summaries

INSPIRE

Objective

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)

Location and study date

Study status and dates

Registry field	Quoted record
Overall status	“Completed”
Start date, actual	“2023-12-11”
Primary completion, actual	“2026-04-14”
Completion, actual	“2026-05-19”
Enrollment, actual	“165”

Sponsor and geographic scope

“The trial, mainly conducted by Tanabe Pharma America, Inc. (Jersey City, New Jersey, USA), enrolled 165 participants with EPP or XLP (aged 12 years and older and under 75 years).” (opens the source at this quote in a new tab)

Posted results

No evidence found.

Study design

Randomized, double-blind, placebo-controlled design with open-label extension

“The INSPIRE study is a global, randomized, double-blind, placebo-controlled phase 3 clinical trial in adult and adolescent participants with EPP or XLP. Participants were randomly assigned to either a placebo group or an active treatment group (dersimelagon 200 mg once daily) for a 16-week double-blind period, followed by a 36-week open-label extension period of active treatment.” (opens the source at this quote in a new tab)
“The double-blind treatment phase has been completed, while the open-label phase is ongoing.” (opens the source at this quote in a new tab)

Registry design fields

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

Eligibility criteria

Diagnosis and age

“Male and female subjects with a confirmed diagnosis of EPP or XLP based on medical history” (opens the source at this quote in a new tab)
“Subjects aged 12 years to 75 years, inclusive, at Screening” (opens the source at this quote in a new tab)
“In the Investigator's opinion, subject can understand the nature of the study and any risks involved in participation, and willing to cooperate and comply with the protocol restrictions and requirements (including travel and receiving direct sunlight exposure as much as possible” (opens the source at this quote in a new tab)

Hepatic and dermatologic exclusions

“Presence or history of any hepatobiliary disease, including druginduced liver injury at screening, determined as clinically significant by the Investigator after the discussion with the Sponsor Medical Monitor” (opens the source at this quote in a new tab)
“Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≥ 2.0 × 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)

Exclusion of prior dersimelagon and other investigational therapy

“Subjects who participated in any previous MT-7117 clinical studies” (opens the source at this quote in a new tab)
“Previous treatment with any investigational agent such as bitopertin, within 12 weeks before Screening or 5 half-lives of the investigational product (whichever is longer” (opens the source at this quote in a new tab)

Erythrocyte protoporphyrin threshold for entry

No evidence found.

Treatment

Dose, route, and frequency

“After screening, study participants (ranging from 12 to 75 years of age) received either dersimelagon 200 mg or placebo once daily.” (opens the source at this quote in a new tab)

“The study consists of a 16-week double-blind treatment period, in which participants are randomly assigned to either the placebo group or active treatment group (dersimelagon 200 mg once daily), followed by a 36-week open-label extension period of active treatment.” (opens the source at this quote in a new tab)

Restriction on zinc oxide sunscreen during treatment

“Use of sunscreens with zinc oxide. Note: Sunscreens without zinc oxide are allowed, however their use, in frequency, quantity and body surface area should be maintained relatively stable throughout the duration of the study” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using average daily sunlight exposure time to first prodromal symptom as the primary endpoint

Registered definition of the primary outcome measure

“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 16” (opens the source at this quote in a new tab)
“The comparison between MT-7117 treatment group and placebo group will be performed.” (opens the source at this quote in a new tab)

Registered secondary outcome measures

“Patient Global Impression of Change (PGIC) at Week 16.” (opens the source at this quote in a new tab)
“Total number of sunlight-induced pain events defined as prodromal symptoms (burning, tingling, itching, or stinging) with pain rating of 1-10 on the Likert scale during the 16-week double-blind treatment period.” (opens the source at this quote in a new tab)
“Total number of sunlight-induced non-prodrome, phototoxic reactions during the 16-week double-blind treatment period.” (opens the source at this quote in a new tab)

How participants were instructed to generate the endpoint

“Because of how significant the phototoxic reactions are, we didn't want to ask patients to try to have a phototoxic reaction,” (opens the source at this quote in a new tab)
“But we did ask patients to try to have prodromal symptoms at least once weekly.” (opens the source at this quote in a new tab)

Regulatory precedent for sunlight-exposure time as a clinically meaningful endpoint

“Accurately tracking sunlight exposure is important for evaluating new therapies and pain-free light exposure time is the precedented, clinically meaningful endpoint used to support afamelanotide's marketing authorization in the US and European Union.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Planned enrollment

“Up to 150 patients with a confirmed diagnosis of EPP or XLP from ages 12 to 75 years may qualify for enrollment.” (opens the source at this quote in a new tab)

Participants randomized per arm

“Yeung and other global INSPIRE trial investigators enrolled 165 patients with EPP or XLP aged 12 years or older. They randomly assigned 82 patients to 200 mg dersimelagon daily and another 83 to placebo. Baseline characteristics were well balanced between groups. Double-blind assessment at week 16 was followed by a 36-week open-label extension.” (opens the source at this quote in a new tab)

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

Balance of baseline characteristics between arms

“Baseline characteristics were well balanced between groups.” (opens the source at this quote in a new tab)

Tabulated baseline characteristics

No evidence found.

Efficacy results

Primary endpoint result

“Dersimelagon, a selective agonist of melanocortin 1 receptor (MC1R), met the primary endpoint, showing a statistically significant prolongation of average daily sunlight exposure time to first prodromal symptom during Weeks 12–16 versus placebo, with a placebo-adjusted least-squares mean difference of 23.19 minutes (p=0.004) in primary analysis. At Week 16, the effect increased to 29.64 minutes (p=0.004) in supplementary analysis.” (opens the source at this quote in a new tab)

Result at the registered Week 16 timepoint

“The primary endpoint was the change from baseline in average daily sunlight exposure time to first prodromal symptom at week 16. The time to prodrome was similar in both groups, Yeung said.” (opens the source at this quote in a new tab)
“During weeks 12-16, there was a statistically significant increase in the average daily time to first prodromal symptom, with a treatment difference of 23 minutes (P = .004).” (opens the source at this quote in a new tab)

Key secondary endpoint results

“Key secondary endpoints were also met, including statistically significant differences in Patient Global Impression of Change (PGIC) and reduction of total pain events compared to placebo (PGIC: -1.83, p<0.001; reduction of total pain events: 39%, p=0.004), supporting clinical meaningful outcome of primary endpoint.” (opens the source at this quote in a new tab)

Responder analyses reported at the congress presentation

“a higher proportion of patients taking dersimelagon reported more than 33 minutes in time to prodrome (P = .04” (opens the source at this quote in a new tab)
“There also was an improvement in the proportion of patients experiencing more than 66 minutes outdoors without prodromal symptoms (P = .12).” (opens the source at this quote in a new tab)
“The study also met a secondary endpoint for the rate of sunlight-induced pain events, which was 39% lower with treatment than with placebo.” (opens the source at this quote in a new tab)

Phototoxic reactions occurring without a preceding prodrome

“The investigators assessed the number of patients who skipped a prodrome and went directly to a full phototoxic reaction, “which is actually pretty rare in EPP,” she added. This outcome was underpowered and there was no statistically significant difference between groups.” (opens the source at this quote in a new tab)

Confidence intervals for the reported effect estimates

No evidence found.

Health-related quality of life and patient-reported outcomes

Patient Global Impression of Change

“A higher number of patients on dersimelagon reported “much better” and “moderately better” improvements in symptoms on the Patient Global Impression of Change (PGIC) tool. In the placebo group, patients typically reported “no change” or “a little bit better” symptoms, Yeung said. The difference in PGIC ratings was statistically significant between groups (P< .001).” (opens the source at this quote in a new tab)

Other patient-reported outcome instruments

No evidence found.

Safety results

Overall tolerability and most common adverse events

“The most common adverse events, occurring more frequently than placebo, were melanocytic nevi (benign moles), headache, nausea, diarrhea, and skin hyperpigmentation, with the mechanism of MC1R agonist.” (opens the source at this quote in a new tab)
“Dersimelagon was generally well-tolerated, with a safety profile consistent with its mechanism of action.” (opens the source at this quote in a new tab)

“In the INSPIRE study, dersimelagon demonstrated a favorable safety and tolerability profile, with most adverse events being mild or moderate in severity.” (opens the source at this quote in a new tab)

Adverse event rates by treatment arm reported at the congress presentation

Adverse event	Dersimelagon 200 mg	Placebo
Headache	“22.0%”	“12.0%”
Melanocytic nevi	“20.7%”	“1.2%”
Nausea	“18.3%”	“10.8%”

Serious adverse event of malignant melanoma in situ

“Safety and tolerability “were quite good,” Yeung said. There were no deaths. There was one serious TEAE in the dersimelagon group — a patient who developed a malignant melanoma in situ. This person had a family history of malignant melanoma and had a lesion at the beginning of the study; the malignant melanoma in situ was identified on day 36.” (opens the source at this quote in a new tab)
“It was determined by the investigator to be related but determined by the sponsor to be unrelated,” (opens the source at this quote in a new tab)

Discontinuations

“In the placebo group, TEAEs that led to discontinuation included brain fog and diarrhea.” (opens the source at this quote in a new tab)
“There was actually one discontinuation in the placebo group and one in the dersimelagon group for hyperpigmentation,” (opens the source at this quote in a new tab)

Cumulative exposure in the development program

“Dersimelagon has been studied in 410 participants with EPP or XLP to date” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the INSPIRE evidence base

No results have been posted to ClinicalTrials.gov, the EU Clinical Trials Information System, or the Japan Registry of Clinical Trials, and no peer-reviewed publication exists. No protocol, statistical analysis plan, analysis-set definition, sample-size calculation, or multiplicity strategy is public, and no confidence interval has been published for any endpoint. Disposition, baseline characteristics, and complete adverse event tables are not available, and no results are reported separately for erythropoietic protoporphyria compared with X-linked protoporphyria or for the adolescent subgroup. The company reports the primary analysis over Weeks 12 to 16, whereas the registered primary outcome measure is at Week 16; the presenter reported that time to prodrome was similar between groups at Week 16 alone. Skin pigmentation is a pharmacologic effect of the drug, and in the phase 2 trial most participants correctly identified their assigned treatment, so blinding was incomplete. Participants were required to expose themselves to sunlight until symptoms developed, which may select for less severely affected individuals.

Functional unblinding by treatment-induced pigmentation

“Likewise, in the phase II trial investigating dersimelagon, 97% of the patients in the low dose group, 100% of the patients in the high dose group and 59% of the patients in the placebo group correctly guessed their treatment allocation” (opens the source at this quote in a new tab)
“During the approval procedures of afamelanotide, the EMA assessed that the lack of complete blinding of the trials impaired the validity of the evidence for efficacy, but also acknowledged that there was no possibility of blinding the studies appropriately” (opens the source at this quote in a new tab)

Independent commentary on blinding and selection

“It can be assumed that most patients in the INSPIRE trial did know to which treatment arm they had been randomized to, which might have influenced their sun exposure behavior,” (opens the source at this quote in a new tab)
“The melanocytic nevi rate was 20.7% in the dersimelagon group vs 1.2% in the placebo cohort. This difference “should be closely monitored,” (opens the source at this quote in a new tab)

MT-7117-G01

Objective

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)

Location and study date

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)

Study design

Registry design fields

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

Eligibility criteria

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)

Treatment

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.

Study outcomes

Rationale for using average daily sunlight exposure time to first prodromal symptom as the primary endpoint

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)

Statistical analysis description

Number of participants (Planned and analyzed)

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”

Description of analysis sets

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)

Results

Participant disposition

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.

Baseline characteristics

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.

Efficacy results

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)

Health-related quality of life and patient-reported outcomes

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”

Safety results

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)

Study limitations

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)

ENDEAVOR

Objective

Purpose of the study

“The purpose of this study is to investigate the efficacy and safety of MT-7117 on sunlight exposure duration without symptoms and tolerance in subjects with EPP.” (opens the source at this quote in a new tab)

Trial name and registration

“(Funded by Mitsubishi Tanabe Pharma; Endeavor ClinicalTrials.gov number, NCT03520036.).” (opens the source at this quote in a new tab)

Location and study date

Study status and dates

Registry field	Quoted record
Overall status	“Completed”
Start date, actual	“2018-07-05”
Primary completion, actual	“2019-09-28”
Completion, actual	“2019-09-28”
Enrollment, actual	“102”

Study design

Period structure and total participation

“This is a Phase 2, randomized, double-blind, placebo controlled study to assess the efficacy, tolerability, and safety of MT-7117 in subjects with EPP. The study consists of a 2 week screening period, a 16 week double-blind treatment period, and a 6 week follow-up period at Week 22. The total participation period is approximately 24 weeks.” (opens the source at this quote in a new tab)

Absence of an open-label extension

No evidence found.

Eligibility criteria

Age and diagnosis

“2. Male and female subjects with a confirmed diagnosis of EPP based on medical history, aged 18 years to 75 years, inclusive, at Screening.” (opens the source at this quote in a new tab)

Hepatic, dermatologic, and renal exclusions

“3. Presence of clinically significant hepatobiliary disease based on LFT values at Screening.” (opens the source at this quote in a new tab)
“4. 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)
“6. History or presence of melanoma and/or atypical nevus at Screening.” (opens the source at this quote in a new tab)
“7. 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

“15. Treatment with afamelanotide within 3 months before Randomization (Visit 2).” (opens the source at this quote in a new tab)
“18. Chronic treatment with prescription-based analgesic agents including but not limited to opioids and opioid derivatives such as morphine, hydrocodone, oxycodone or their combination with other analgesics or non-steroidal anti-inflammatory drug (NSAID, as Percocet and Vicodin-like prescription drugs) within 4 weeks before Randomization (Visit 2).” (opens the source at this quote in a new tab)
“20. Previous exposure to MT 7117.” (opens the source at this quote in a new tab)

Treatment

Doses studied

“Patients 18 to 75 years of age were randomly assigned in a 1:1:1 ratio to receive placebo or dersimelagon at a dose of 100 or 300 mg once daily for 16 weeks.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using average daily time to first prodromal symptom as the primary endpoint

Clinical rationale for a prodromal-symptom endpoint

“Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153).” (opens the source at this quote in a new tab)

Pharmacodynamic outcome measure

“Pigmentation will be assessed in melanin density which are numeric scores measured by spectrophotometer on 6 skin segments (forehead, left cheek, right inside upper arm, left medial forearm, right-hand side of abdomen, and left-hand side of buttock).” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Participants randomized

“Of the 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) who underwent randomization, 90% completed the treatment period.” (opens the source at this quote in a new tab)

“A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP]), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]).” (opens the source at this quote in a new tab)

Description of analysis sets

Results

Participant disposition

Disposition over the whole study

Disposition	MT-7117 low dose	MT-7117 high dose	Placebo
Started	“33”	“34”	“35”
Completed	“31”	“30”	“31”
Not completed	“2”	“4”	“4”
Withdrawn for an adverse event	“1”	“2”	“0”
Withdrawn for a protocol violation	“1”	“0”	“0”
Withdrawn by subject	“0”	“1”	“4”

Dosing error affecting the safety population

“One subject who was randomized to Placebo received MT-7117 high Dose instead of placebo. Therefore, the subject was counted as MT-7117 high Dose Group in the Safety Population” (opens the source at this quote in a new tab)

Baseline characteristics

Demographics of the randomized population

Characteristic	MT-7117 low dose	MT-7117 high dose	Placebo	Total
Age in years, mean	“41.8”	“41.9”	“38.1”	“40.6”
Age in years, standard deviation	“12.8”	“14”	“12.6”	“13.1”
Female	“15”	“25”	“13”	“53”
Male	“18”	“9”	“22”	“49”
White	“33”	“33”	“32”	“98”
Asian	“0”	“0”	“1”	“1”
Black or African American	“0”	“0”	“0”	“0”

Efficacy results

Primary endpoint result

“The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon: the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group (P = 0.008) and 62.5 minutes in the 300-mg dersimelagon group (P = 0.003).” (opens the source at this quote in a new tab)

Unadjusted change from baseline by arm

Outcome measure, change from baseline to Week 16, minutes	MT-7117 low dose	MT-7117 high dose	Placebo
Average daily time to first prodromal symptom, mean	“74.7”	“92.4”	“21.0”
Average daily time to first prodromal symptom, standard deviation	“76.8”	“100”	“63.4”
Average daily duration of sunlight exposure without prodromal symptoms, mean	“72.6”	“86.1”	“19.9”

Secondary endpoint results

“There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo.” (opens the source at this quote in a new tab)

Consistency of effect across seasons and geographic regions

“Results: TTP at baseline was similar across seasons, and both subgroups observed an increase in TTP at week 16. This increase was statistically significant for subgroup 2 (LSMD [SE] = 48.4 [21.9], P = .032 for 100 mg dersimelagon and LSMD [SE] = 66.0 [22.1], P = .004 for 300 mg dersimelagon vs placebo).” (opens the source at this quote in a new tab)
“Conclusions: This post hoc analysis demonstrates that improvement in average daily TTP after treatment with dersimelagon is maintained regardless of season and geographic region in individuals with EPP.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Quality of life reported in the primary publication

“The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo.” (opens the source at this quote in a new tab)

Exit questionnaire responses

“Additionally, an online questionnaire assessing quality of life was completed by 75 of the 102 patients enrolled. Of those taking dersimelagon 100 mg, 57.6% rated their EPP as “very much better” and 69.7% rated they were “much more often” able to be outside at the end of the study. Likewise, among those who used dersimelagon 300 mg, positive ratings were given by 48.6%.” (opens the source at this quote in a new tab)

Posted PROMIS-57 and Patient Global Impression of Change results

No evidence found.

Safety results

Most common adverse events

“The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation.” (opens the source at this quote in a new tab)

“MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%).” (opens the source at this quote in a new tab)

Deaths and serious adverse events

Safety summary	MT-7117 low dose	MT-7117 high dose	Placebo
Deaths	“0”	“0”	“0”
Serious adverse events	“1”	“0”	“0”
Other non-serious adverse events	“31”	“34”	“31”

Non-serious adverse events reported at the 3% threshold

MedDRA preferred term	MT-7117 low dose	MT-7117 high dose	Placebo
Nausea	“5”	“16”	“4”
Ephelides	“5”	“11”	“0”
Skin hyperpigmentation	“3”	“11”	“0”
Headache	“6”	“10”	“6”
Diarrhoea	“4”	“8”	“4”
Melanocytic naevus	“4”	“7”	“3”
Fatigue	“1”	“6”	“1”
Photosensitivity reaction	“5”	“5”	“3”
Skin discolouration	“1”	“3”	“0”
Urticaria	“0”	“2”	“0”
Hepatic enzyme increased	“1”	“0”	“0”
Anaphylactic reaction	“1”	“0”	“0”

Discontinuations and the serious adverse event causality assessment

“Participation in the trial was discontinued by four patients in the placebo group (voluntary withdrawal), two patients in the 100 mg dersimelagon group (one for nonadherence and one for a serious adverse event), and four patients in the 300 mg dersimelagon group (one voluntary withdrawal, two withdrawals for adverse events, and one withdrawal for clinically significant lichen planus found during nevi assessment). The serious adverse event that led to discontinuation by one patient in the 100 mg dersimelagon group was an anaphylactic reaction that was deemed by the investigators to be unrelated to dersimelagon” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the phase 2 trial

The trial enrolled adults only, was conducted entirely in the United States, and 98 of 102 participants were White with no Black participants. There was no formal power calculation and no multiplicity adjustment across three registered primary outcome measures and seven secondary endpoints, and the registry posts no confidence intervals or P values for any outcome. Sex was unevenly distributed, with 25 of 34 participants female in the high-dose arm compared with 13 of 35 in the placebo arm. Blinding was incomplete because the drug increases skin pigmentation. The erythrocyte protoporphyrin and seasonal subgroup analyses were post hoc. The larger phase 3 trial that followed, using the same primary endpoint at Week 26, did not reproduce the effect size observed here.

Incomplete blinding and absence of a power analysis

“Additionally, there was incomplete blinding in this trial due to increases in skin pigmentation when taking dersimelagon, which allowed many subjects to correctly guess if they were assigned to the active drug group.” (opens the source at this quote in a new tab)
“In the phase 2 trial, limitations included a lack of formal statistical power analysis, although such limitations are common in studies of rare diseases such as EPP/XLP” (opens the source at this quote in a new tab)

Critique of the prodromal-symptom endpoint and of placebo control

“Recognizing the seriously harmful consequences of daylight exposure for EPP patients, investigators in the dersimelagon trial specified endpoints in terms of minutes of exposure before the appearance of prodromal symptoms.” (opens the source at this quote in a new tab)
“Further, the tingling and itching is not always present. At times, the phototoxic reaction directly starts with the pain, or with a combination of milder symptoms and pain.” (opens the source at this quote in a new tab)
“Further, being melanocortin receptor agonists, afamelanotide and dersimelagon both increase skin pigmentation and cause partial unblinding of the trial participants in the active treatment group – thus undermining the rationale for the use of placebo controls.” (opens the source at this quote in a new tab)

MT-7117-A-301

Objective

Primary objective

“To evaluate the long-term safety and tolerability of oral dersimelagon.” (opens the source at this quote in a new tab)

Location and study date

Study title, status, and dates

Registry field	Quoted record
Official title	“A Phase 3, Multicenter, Open-label, Long-term, Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)”
Overall status	“Active, not recruiting”
Start date, actual	“2021-08-10”
Primary completion, estimated	“2027-12”
Enrollment, actual	“286”

Study design

Open-label single-group design

Design field	Quoted record
Allocation	“na”
Intervention model	“Single group”
Masking	“None”
Phase	“Phase 3”

Relationship to the other trials in the program

“Another open-label extension study will continue to evaluate the long-term safety and tolerability of dersimelagon and enroll participants from the INSPIRE study and participants who have completed the study MT-7117-G01, if interested.” (opens the source at this quote in a new tab)

Eligibility criteria

Rollover eligibility from the phase 3 trials

“2. Subjects who have completed: MT-7117-G01 (completed through Week 58 [Visit 12]) or, MT-7117-A-302 (completed through Week 58 [Visit 10]) or, MT-7117-A-301 (completed EOT - Week 104 or Week 130) according to protocol amendment 1 or 2.” (opens the source at this quote in a new tab)

Hepatic and dermatologic exclusions

“3. Subjects with AST, ALT, ALP ≥ 3.0 × upper limit of normal (ULN) or TB > 1.5 × ULN at Screening. The TB level of > 1.5 × ULN listed in this exclusion criteria may not be applicable to subjects with a documented medical history of Gilbert's syndrome.” (opens the source at this quote in a new tab)
“5. History of melanoma.” (opens the source at this quote in a new tab)

Treatment

Dose and route

“Dersimelagon 200mg” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using treatment-emergent adverse events as the primary endpoint

Safety outcome measures and observation period

“Number of patients with Treatment emergent adverse events (TEAEs) (including serious adverse events [SAEs] and adverse events of special interest [AESIs]).” (opens the source at this quote in a new tab)
“Number of patients with Nevi appearance” (opens the source at this quote in a new tab)
“up to 66 further months” (opens the source at this quote in a new tab)

Absence of efficacy endpoints

“E.6.4 Safety Yes E.6.5 Efficacy No” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Participants enrolled

Registry field	Quoted record
Enrollment, actual	“286”

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

Not applicable.

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

No evidence found.

Study limitations

Summary: status of the long-term extension

The study is open-label and single-group, so it provides no controlled comparison. It remains ongoing with estimated completion in December 2027, and no results have been posted to ClinicalTrials.gov or the EU Clinical Trials Register. Enrollment is restricted to participants who completed one of the two phase 3 trials or a previous period of the extension itself, which excludes participants from the phase 2 trial and selects for people who tolerated and continued earlier treatment.

MT-7117-E01

Objective

Purpose of the first-in-human study

“In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated.” (opens the source at this quote in a new tab)

Location and study date

No evidence found.

Study design

Single and multiple ascending dose design

“In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated.” (opens the source at this quote in a new tab)

Eligibility criteria

No evidence found.

Treatment

Doses administered

“No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using melanin density as a pharmacodynamic endpoint

Melanin density as the pharmacodynamic measure of target engagement

“Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

No evidence found.

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

Not applicable.

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

Treatment-emergent adverse events in healthy participants

“Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses.” (opens the source at this quote in a new tab)
“Overall, the incidence of TEAEs was relatively low, with most events occurring during Part A (SAD) and Part E (MAD) and the majority being mild to moderate in severity. No deaths or serious AEs were reported during any part of the study.” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the first-in-human study

The study enrolled healthy participants rather than people with either disorder, so it does not describe clinical efficacy. Melanin density is a pharmacodynamic measure of target engagement and not a clinical outcome. The study was not designed to detect uncommon adverse events, and the transaminase elevations observed over 14 days of dosing were the basis for the intensified liver monitoring built into the later trials.