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)

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”

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.

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)

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)

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)

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)

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)

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”

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)

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.

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)

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)