FDA acceptance of the New Drug Application with Priority Review

“The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for dersimelagon for filing and granted it Priority Review, with a Prescription Drug User Fee Act (PDUFA) date expected by the end of February 2027.” (opens the source at this quote in a new tab)
“LEO Pharma, a global leader in medical dermatology, today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing and granted Priority Review to the New Drug Application (NDA) for dersimelagon, a potential first-in-class oral therapy for EPP and XLP. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date by the end of February 2027.” (opens the source at this quote in a new tab)

Regulatory submission: NDA submitted June 2026

“On June 30, 2026, Tanabe Pharma America submitted a New Drug Application (NDA) to the FDA for dersimelagon for the treatment of EPP and XLP. Tanabe Pharma will continue its efforts toward obtaining approval in the U.S.” (opens the source at this quote in a new tab)

“Tanabe Pharma has initiated preparations for a New Drug Application (NDA) rolling submission.” (opens the source at this quote in a new tab)

Launch: Potential launch in 2027

“The acquisition is expected to increase LEO Pharma’s investments in 2026 for pre-launch activities and in 2027 for a potential launch.” (opens the source at this quote in a new tab)

Sponsor statement of the review acceptance and decision timing

“the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for an investigational oral selective melanocortin 1 receptor (MC1R) agonist, MT-7117 (dersimelagon), for the treatment of erythropoietic protoporphyria (EPP) and X-Linked Protoporphyria (XLP).” (opens the source at this quote in a new tab)
“The FDA has granted Priority Review, with a decision expected by the end of February 2027.” (opens the source at this quote in a new tab)

Fast Track and Orphan Drug designations

“Dersimelagon received Fast Track Designation from the U.S. FDA in June 2018 and was granted Orphan Drug Designation in June 2020.” (opens the source at this quote in a new tab)

“Dersimelagon has been granted both U.S. FDA Fast Track Designation and Orphan Drug Designation, and an NDA for the treatment of EPP and XLP was submitted to the U.S. FDA for regulatory review in June 2026, but has not yet been approved by the FDA or any other regulatory agency.” (opens the source at this quote in a new tab)

“Tanabe Pharma received Fast Track Designation for dersimelagon by the U.S. Food and Drug Administration in June 2018.” (opens the source at this quote in a new tab)

European Union orphan designation

“This medicine was designated as an orphan medicine for the treatment of erythropoietic protoporphyria in the European Union on 16 March 2022.” (opens the source at this quote in a new tab)

Designation field	Quoted record
Active substance	“dersimelagon”
Intended use	“Treatment of erythropoietic protoporphyria”
Orphan designation status	“Positive”
EU designation number	“EU/3/22/2585”
Date of designation	“16/03/2022”
Sponsor	“Tanabe Pharma GmbH”

European Union submission route and expected registration

Horizon-scan field	Quoted record
Registration route	“Centralised (EMA)”
Submission date	“July 2026”
Expected Registration	“August 2027”
Orphan drug	“Yes”

Approval status

“If approved, dersimelagon could become the first oral treatment for EPP and XLP, helping to address a significant unmet medical need. Dersimelagon has not yet been approved by the FDA or any other regulatory authority, and its safety and efficacy have not been established by any regulatory authority.” (opens the source at this quote in a new tab)

Development activity in China

“A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Pharmacokinetics, Safety, Tolerability and Pharmacodynamics of Single and Multiple Doses of MT-7117 in Chinese Healthy Subjects” (opens the source at this quote in a new tab)

Regulatory submission in Japan

No evidence found.

Manufacturer: LEO Pharma

“LEO Pharma also announced that it has successfully closed the acquisition of worldwide rights to dersimelagon from Tanabe Pharma, following the fulfilment of customary closing conditions.” (opens the source at this quote in a new tab)

“LEO Pharma has acquired worldwide rights to dersimelagon for up to USD 435 million in upfront and near-term milestone payments, plus potential downstream milestones and double-digit up to mid-teens tiered royalties on net sales.” (opens the source at this quote in a new tab)

Applicant of record and responsibility for United States approval

“The NDA was submitted by Tanabe Pharma America, Inc. (TPA, President: Yasutoshi Kawakami), its U.S. subsidiary.” (opens the source at this quote in a new tab)
“Under the agreement, Tanabe Pharma will remain responsible for obtaining U.S. regulatory approval for dersimelagon. Ongoing clinical trials will also continue as planned and are expected to be transferred to LEO Pharma in accordance with the agreement.” (opens the source at this quote in a new tab)

Transfer of worldwide rights from Tanabe Pharma to LEO Pharma

“it has entered into an agreement to transfer all rights, including global development and commercialization rights, of the oral agent MT-7117 (generic name: dersimelagon, a selective melanocortin 1 receptor agonist) being developed by our U.S. subsidiary, Tanabe Pharma America, Inc., for the indication of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) with a history of photosensitivity (including severe pain caused by sunlight exposure), to LEO Pharma (Head Office: Ballerup, Denmark; CEO: Christophe Bourdon).” (opens the source at this quote in a new tab)
“Under the terms of the agreement, Tanabe Pharma will receive up to USD 435 million in upfront and near-term milestone payments together with downstream milestones and tiered royalties on sales.” (opens the source at this quote in a new tab)

Generic name and therapeutic class

“Dersimelagon is an investigational, once-daily oral melanocortin 1 receptor (MC1R) agonist for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), two rare genetic skin diseases with significant unmet medical need.” (opens the source at this quote in a new tab)

“Dersimelagon is a novel synthetic, orally-administered, non-peptide small molecule, which acts as a selective agonist of MC1R” (opens the source at this quote in a new tab)

“Dersimelagon (formerly MT‐7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X‐linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc).” (opens the source at this quote in a new tab)

Development code and salt form of the active substance

“By exploring the structure of previously reported compound 5, we discovered compound 11 (MT-7117: dersimelagon phosphoric acid).” (opens the source at this quote in a new tab)

Proposed brand name

No evidence found.

Originator and change of corporate name

“Dersimelagon was internally discovered and developed by Tanabe Pharma, a Bain Capital portfolio company.” (opens the source at this quote in a new tab)

“Mitsubishi Tanabe Pharma to Begin a New Chapter under Bain Capital Ownership -Company Name Change to “Tanabe Pharma Corporation” Effective December 1, 2025-” (opens the source at this quote in a new tab)

Route of administration and formulation

Product field	Quoted record
Route of administration	“Oral”
Therapeutical formulation	“Tablet”

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

Relative bioavailability of the tablet strengths studied

“Both tablet formulations demonstrated rapid absorption, and the 100-mg tablets showed a 97% relative oral bioavailability versus 50-mg tablets.” (opens the source at this quote in a new tab)

Excipients of the film-coated tablet

“History of any hypersensitivity to the active ingredient and/or excipients (lactose monohydrate, hydroxypropylcellulose, carmellose calcium, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol, iron oxide yellow, iron oxide red, and iron oxide black). (EU ONLY)” (opens the source at this quote in a new tab)

Commercial tablet strengths

No evidence found.

United States wholesale acquisition cost and average sales price

No evidence found.

Expected annual cost per patient in the Dutch horizon scan

“Cost” (opens the source at this quote in a new tab)
“€ 71,000.00” (opens the source at this quote in a new tab)
“This amount gives an indication of the total cost. It is the result of the average expected patient volume times the average cost per patient. both per year” (opens the source at this quote in a new tab)

American Hospital Formulary Service classification and WHO Anatomical Therapeutic Chemical code

No evidence found.

Drug class used as the cost analogue in the Dutch horizon scan

“Kosten op basis van IHSI-inschatting, afgeleid van de mediane kosten van dezelfde ATC-klasse (D02BB - systemisch werkende UV‑protectiva) geneesmiddelen in Nederland.” (opens the source at this quote in a new tab)

Indication stated in the United States filing announcement

“the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for an investigational oral selective melanocortin 1 receptor (MC1R) agonist, MT-7117 (dersimelagon), for the treatment of erythropoietic protoporphyria (EPP) and X-Linked Protoporphyria (XLP).” (opens the source at this quote in a new tab)

Indication wording in the rights transfer announcement

“for the indication of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) with a history of photosensitivity (including severe pain caused by sunlight exposure)” (opens the source at this quote in a new tab)

Age range of the population studied in the phase 3 trial

“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)

Intended use and age scope recorded in European sources

“Intended use” (opens the source at this quote in a new tab)
“Treatment of erythropoietic protoporphyria” (opens the source at this quote in a new tab)

“Dersimelagon monotherapy for treatment of X-linked or erythropoietic protoporphyria in adolescents, adults and elderly.” (opens the source at this quote in a new tab)

Receptor target and the eumelanin barrier

“This medicine, also known as MT-7117, activates a receptor called melanocortin-1 receptor (MC1R). Activation of MC1R improves the production of melanin, specifically by increasing the protective brown/black type of pigmentation (called eumelanin) in the skin. This results in a physical barrier that blocks ultraviolet (UV) and visible light, which can cause cellular damage and phototoxicity in patients with erythropoietic protoporphyria (EPP). In addition to establishing a physical barrier, MC1R activation can also minimise cellular damage and pain experienced by patients with EPP through increased gene repair and anti-inflammatory mechanisms.” (opens the source at this quote in a new tab)

Induction of melanogenesis without sun exposure

“Dersimelagon (MT‐7117) is a novel synthetic, orally administered, nonpeptide small molecule that acts as a selective agonist of the melanocortin‐1 receptor, inducing melanogenesis in the absence of sun exposure.” (opens the source at this quote in a new tab)

“Dersimelagon is designed to increase skin melanin, helping reduce sunlight penetration and protect against phototoxic reactions.” (opens the source at this quote in a new tab)

Preclinical melanogenesis in cell culture and animals

“The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin.” (opens the source at this quote in a new tab)
“In B16F1 cells, MT‐7117 increased melanin production in a concentration‐dependent manner. In vivo, MT‐7117 (≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in mice. MT‐7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation in monkeys and complete reversibility was observed after cessation of its administration.” (opens the source at this quote in a new tab)
“MT‐7117 is a novel oral MC1R agonist that induces melanogenesis in vitro and in vivo, suggesting its potential application for the prevention of phototoxic reactions in patients with photodermatoses, such as erythropoietic protoporphyria and X‐linked protoporphyria.” (opens the source at this quote in a new tab)

Melanin density after single and multiple doses in healthy participants

“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)
“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)

Absorption and dose proportionality in 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)
“In the clinical trial, dersimelagon was rapidly absorbed following single oral doses, with exposure appearing to increase in a slightly more than dose-proportional manner, similar to that observed in rats following oral administration of dersimelagon.” (opens the source at this quote in a new tab)
“Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing.” (opens the source at this quote in a new tab)

Nonlinearity and effect of sex on exposure

“These studies showed that dersimelagon has a slightly nonlinear PK profile, with more than dose-proportional increases following single- or multiple-dose administration.” (opens the source at this quote in a new tab)
“Plasma concentrations were higher in females than in males and overall exposure was not significantly impacted by food intake.” (opens the source at this quote in a new tab)

Metabolism and route of excretion

“In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose.” (opens the source at this quote in a new tab)
“Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut.” (opens the source at this quote in a new tab)

Effect of food and of an acidic beverage on exposure

“No effect was observed on overall exposure (area under the plasma concentration versus time curve [AUC]) following consumption of a high-fat meal, and Cmax was higher (22%, 90% confidence interval [CI] 1.05-1.42) in a fed state compared with fasted conditions.” (opens the source at this quote in a new tab)
“In general, the consumption of an acidic beverage increased time to Cmax regardless of fed or fasted status and decreased overall exposure AUC and Cmax of dersimelagon.” (opens the source at this quote in a new tab)

Effect of age and race on exposure

“There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide.” (opens the source at this quote in a new tab)

Approved labeling

No evidence found.

Dermatologic conditions excluded from the phase 3 trial

“History of melanoma.” (opens the source at this quote in a new tab)
“Presence of squamous cell carcinoma, basal cell carcinoma, or other malignant skin lesions. Any suspicious lesions or nevi will be evaluated. If the suspicious lesion or nevi cannot be resolved through biopsy or excision, the subject will be excluded from the study.” (opens the source at this quote in a new tab)

Adverse events reported in the phase 3 trial

“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 events reported in the phase 2 trial

“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)

Adverse events reported 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)
“These TEAEs related to changes in skin pigmentation may be attributable to the study drug based on the pharmacological effects of dersimelagon by virtue of its mechanism of action as a selective MC1R agonist.” (opens the source at this quote in a new tab)

Contraindications

No evidence found.

Hepatic impairment

“Participants with mild (n = 7) or moderate (n = 8) hepatic impairment or normal hepatic function (n = 8) received a single oral 100-mg dersimelagon dose. Participants with mild (n = 8), moderate (n = 8), or severe (n = 8) renal impairment or normal renal function (n = 8) received a single 300-mg dose.” (opens the source at this quote in a new tab)
“Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function.” (opens the source at this quote in a new tab)

Renal impairment

“Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.” (opens the source at this quote in a new tab)

Adolescents aged 12 to 17 years

“Subjects aged 12 years to 75 years, inclusive, at Screening.” (opens the source at this quote in a new tab)

“First Oral Therapy to achieve Phase 3 Primary endpoint in EPP and XLP for adults and adolescents” (opens the source at this quote in a new tab)
“Treatment options remain limited for adults, and there are no approved therapies for adolescents.” (opens the source at this quote in a new tab)

Children younger than 12 years

No evidence found.

Sex

“Plasma concentrations were higher in females than in males and overall exposure was not significantly impacted by food intake.” (opens the source at this quote in a new tab)

Verapamil and esomeprazole

“Dersimelagon exposure increased ~25% when co‐administered with verapamil, an effect not considered clinically relevant.” (opens the source at this quote in a new tab)

“Similarly, overall exposure AUC of dersimelagon was comparable following administration alone or in combination with esomeprazole; however, coadministration of esomeprazole led to a slight decrease in Cmax (fasted: 9%, 90%CI 0.77-1.07; fed: 24%, 90%CI 0.66-0.88) compared with administration of dersimelagon alone.” (opens the source at this quote in a new tab)

Clinical drug interaction study with probe substrates

“Relatively potent in vitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P‐gp, and OATPs by dersimelagon was observed.” (opens the source at this quote in a new tab)
“Midazolam (CYP3A substrate), digoxin (P‐gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co‐administered with dersimelagon.” (opens the source at this quote in a new tab)
“Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co‐administering 300‐mg dersimelagon with these statin drugs.” (opens the source at this quote in a new tab)

Predicted statin exposure at the clinical doses

“In vitro studies showed that dersimelagon is a weak, reversible, competitive and time‐dependent inhibitor of cytochrome P450 3A4 (CYP3A4), as well as a potential inhibitor of efflux and uptake transporter proteins, such as P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3), organic anion transporters 1 (OAT1) and 3 (OAT3), and multidrug and toxin extrusion 1” (opens the source at this quote in a new tab)
“The systemic exposure of atorvastatin based on the maximum plasma concentration and area under the plasma concentration–time curve was predicted to increase 1.21‐fold and 1.25‐fold, respectively, if coadministered with dersimelagon 100 mg, and 1.42‐fold and 1.45‐fold with dersimelagon 200 mg.” (opens the source at this quote in a new tab)
“Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended.” (opens the source at this quote in a new tab)

Dose studied in the phase 3 trial

“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)

“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)

Doses studied in the phase 2 trial

“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)

Doses carried into late-stage evaluation

“dersimelagon 100 and 200 mg (doses currently being evaluated for the treatment of erythropoietic protoporphyria and X‐linked protoporphyria)” (opens the source at this quote in a new tab)

Dose used in the long-term extension study

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

Oral once-daily administration

“Dersimelagon is an investigational, once-daily oral small-molecule MC1R agonist being developed for EPP and XLP.” (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)

Administration with respect to food

“No effect was observed on overall exposure (area under the plasma concentration versus time curve [AUC]) following consumption of a high-fat meal, and Cmax was higher (22%, 90% confidence interval [CI] 1.05-1.42) in a fed state compared with fasted conditions.” (opens the source at this quote in a new tab)

Concomitant therapies restricted in the phase 3 trial

“Afamelanotide within 3 months” (opens the source at this quote in a new tab)
“Chronic treatment with any scheduled analgesic agents including, but not limited to, opioids and opioid derivatives such as morphine, hydrocodone, oxycodone, fentanyl, or their combination with other unscheduled analgesics or non-steroidal anti-inflammatory drug (Percocet and Vicodin-like prescription drugs) within 4 weeks.” (opens the source at this quote in a new tab)
“Antioxidant agents within 4 weeks, 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)

Sunscreen use permitted alongside 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)

Background preventive measures that continue during treatment

“Current approaches to the management of EPP and XLP are primarily limited to preventive measures, including sun avoidance and use of protective clothing and sunscreens, posing a substantial burden to patients by requiring significant lifestyle adjustments” (opens the source at this quote in a new tab)

Summary: products approved or in late-stage development for these disorders

Afamelanotide is the only approved product. It shares dersimelagon's target, the melanocortin 1 receptor, but is given as a 16 mg fixed-dose subcutaneous implant every 2 months by a trained and accredited implanter, is indicated for adults with erythropoietic protoporphyria only, and has no established safety or effectiveness in patients under 18 years. Two investigational products act on protoporphyrin IX rather than on pigmentation. Bitopertin, a glycine transporter 1 inhibitor taken orally, lowers whole-blood metal-free protoporphyrin IX; its application for accelerated approval received a complete response letter in February 2026 after the Food and Drug Administration concluded that the phase 2 trials did not show an association between the change in protoporphyrin IX and sunlight-exposure endpoints, and its phase 3 APOLLO trial is ongoing. PORT-77, an oral ABCG2 inhibitor, reduced plasma protoporphyrin IX in a phase 2a study and entered phase 2b/3 in September 2026. No head-to-head trial, network meta-analysis, or indirect treatment comparison exists across these products, and each program uses a different primary endpoint, so relative efficacy cannot be estimated from the published evidence.

Mechanistic distinction between symptomatic and protoporphyrin-lowering products

“While afamelanotide and dersimelagon are symptomatic treatments, bitopertin and cimetidine aim to decrease blood PPIX concentration which makes them potentially causative treatment options” (opens the source at this quote in a new tab)
“Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared.” (opens the source at this quote in a new tab)

Regulatory status of bitopertin

“We initiated the APOLLO trial in May 2025 and in September 2025 we submitted a New Drug Application, or NDA, for accelerated approval of bitopertin in EPP and XLP in the United States based on our existing data. In October 2025, we were awarded a Commissioner's National Priority Voucher, or CNPV, from the FDA for bitopertin in EPP and XLP.” (opens the source at this quote in a new tab)
“The FDA accepted our NDA for review in November 2025 and in February 2026 issued a complete response letter, or CRL.” (opens the source at this quote in a new tab)

Basis for the complete response letter issued for bitopertin

“On the first point, the FDA agreed that AURORA and BEACON provided sufficient evidence that bitopertin significantly lowers whole blood metal-free PPIX. On the second, based on review of AURORA and BEACON results, the FDA concluded that the trials did not show evidence of association between percent change in PPIX and sunlight exposure-based endpoints, as measured in the trials, despite the strong mechanistic and biological plausibility supporting the use of the PPIX biomarker in protoporphyria. The FDA indicated results of the APOLLO study could serve as evidence to support traditional approval.” (opens the source at this quote in a new tab)

Phase 3 trial of bitopertin

“The goal of this clinical trial is to learn if bitopertin works and is safe to treat EPP or XLP in participants 12 years or older.” (opens the source at this quote in a new tab)
“Average monthly total time in sunlight on days without pain from a phototoxic reaction between 10:00 to 18:00 (10:00 AM to 6:00 PM) after 6 months (24 weeks) of treatment” (opens the source at this quote in a new tab)
“Percent change from baseline in whole-blood metal-free PPIX levels at 6 months” (opens the source at this quote in a new tab)

Phase 2 results for bitopertin

“Patients received bitopertin 20 mg (n = 26), 60 mg (n = 25), or placebo (n = 24). At day 121, the percentage change from baseline in whole-blood metal-free protoporphyrin-IX versus placebo was -29.6% (P = .004) with bitopertin 20 mg and -49.8% (P < .001) with bitopertin 60 mg. Bitopertin was associated with a reduced incidence of phototoxic reactions.” (opens the source at this quote in a new tab)

Development status of PORT-77

“PORT-77 is an oral, small molecule ABCG2 inhibitor currently in Phase 2 development for EPP and XLP. PORT-77 is designed to modify efflux of PPIX from the red blood cell to the plasma and from hepatocytes to the biliary tract, representing a potentially disease-modifying, leading treatment that addresses the root cause of EPP and XLP.” (opens the source at this quote in a new tab)
“PORT-77 resulted in rapid, dose-dependent reductions in plasma PPIX with a mean decrease of 79% for participants receiving 300 mg BID and 63% for those receiving 180 mg QD.” (opens the source at this quote in a new tab)

Expedited designations granted for PORT-77

“the United States (U.S.) Food and Drug Administration (FDA) has granted Orphan Drug Designation and Fast Track Designation to its affiliate, Portal Therapeutics, for PORT-77, an investigational oral, small molecule ABCG2 inhibitor, for the treatment of EPP and XLP.” (opens the source at this quote in a new tab)

Absence of comparative evidence

“The currently available trial data on dersimelagon and bitopertin suggests treatment effects in EPP as compared to placebo control groups. However, safety and efficacy of dersimelagon and bitopertin need to be further characterized. Moreover, to ensure benefit for patients and access to therapy after regulatory approval, it also would be important to generate data on the relative safety and efficacy as compared to afamelanotide.” (opens the source at this quote in a new tab)

Definition of erythropoietic protoporphyria

“Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness.” (opens the source at this quote in a new tab)

Definition of X-linked protoporphyria and expression in heterozygous females

“X-linked protoporphyria (XLP) is characterized in affected males by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness.” (opens the source at this quote in a new tab)
“The phenotype in heterozygous females ranges from asymptomatic to as severe as in affected males.” (opens the source at this quote in a new tab)

Enzymatic basis: ferrochelatase deficiency and ALAS2 gain of function

“In EPP, autosomal recessive pathogenic variants in ferrochelatase (FECH) result in deficient activity of FECH, the last enzyme in the heme-biosynthetic pathway, leading to the accumulation of metal-free protoporphyrin in erythroid cells” (opens the source at this quote in a new tab)
“In XLP, gain-of-function variants in 5′-aminolevulinate synthase 2 (ALAS2) lead to overproduction and accumulation of metal-free and zinc protoporphyrin.” (opens the source at this quote in a new tab)

Autosomal recessive inheritance and the low-expression FECH allele

“EPP is inherited in an autosomal recessive manner. In about 96% of cases an affected individual inherits a loss-of-function FECH allele from one parent and a low-expression FECH allele from the other parent.” (opens the source at this quote in a new tab)
“About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C) resulting in residual ferrochelatase activity.” (opens the source at this quote in a new tab)

Population frequency of the low-expression allele

“Approximately 5%–10% of the European Caucasians population is a carrier for the low expression allele, which is even more prevalent in Japan (43%), and southeast Asia (31%), and practically absent in populations of sub‐Saharan origin.” (opens the source at this quote in a new tab)

Homozygosity for the low-expression allele does not cause disease

“Homozygosity for FECH c.315-48T>C does not cause EPP.” (opens the source at this quote in a new tab)

Genetic basis and inheritance of X-linked protoporphyria

“XLP accounts for 2–10% of protoporphyria cases and is caused by gain-of-function variants in exon 11 of ALAS2 and follows an X-linked inheritance pattern.” (opens the source at this quote in a new tab)

“Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women with an ALAS2 pathogenic variant have a 50% chance of transmitting the variant to each child.” (opens the source at this quote in a new tab)

Penetrance

“EPP appears to be 100% penetrant when there are biallelic FECH loss-of-function variants” (opens the source at this quote in a new tab)

“XLP appears to be 100% penetrant in males.” (opens the source at this quote in a new tab)

Estimated incidence and rank among the porphyrias

“EPP is the third most common porphyria, with an estimated incidence of two to five in 1,000,000; it is the most common porphyria in children.” (opens the source at this quote in a new tab)

Incidence in the Italian national porphyria network, 1996 to 2017

“revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year” (opens the source at this quote in a new tab)

Incidence of X-linked protoporphyria

No evidence found.

Reported prevalence range and sex distribution

“EPP is equally common in women and men. The prevalence ranges from 1:75,000 in the Netherlands (as the result of a founder effect) to 1:200,000 reported in Wales” (opens the source at this quote in a new tab)
“The prevalence of EPP may vary based on the population allele frequency of the low-expression c.315-48T>C allele, which ranges from approximately 1%-3% in Africans to approximately 43% in Japanese.” (opens the source at this quote in a new tab)

Prevalence of the protoporphyria group and the X-linked share

“The protoporphyrias are a group of three ultra‐rare genetic disorders of the erythroid heme biosynthesis (prevalence between 1:75000 and 1:100000), all leading to the accumulation of protoporphyrin IX (PPIX) in erythrocytes.” (opens the source at this quote in a new tab)
“About 4%–10% of protoporphyria patients suffer from XLEPP, which shows an X‐linked dominant inheritance.” (opens the source at this quote in a new tab)

United States patient count and X-linked share of cases

“It is estimated that the disorder occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe. The number of patients affected by these disorders in the US is unknown. XLP accounts for about 10% of cases in the United States.” (opens the source at this quote in a new tab)

Genetic prevalence in the UK Biobank exceeds diagnosed prevalence

“Based on the incidence of EPP in Europe, the prevalence of EPP was estimated to be 0.00092%.” (opens the source at this quote in a new tab)
“Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% CI: 0.0042%−0.0076%), 1.7–3.0 times more common than previously thought in the UK.” (opens the source at this quote in a new tab)

Diagnosed compared with exome-based prevalence

“The disease prevalence of EPP was estimated to be 1:109,000 in Europe, but more recent data using exome databases show a prevalence approximating 1:17,000 in Caucasians.” (opens the source at this quote in a new tab)

Heterogeneity of prevalence between European countries

“The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates.” (opens the source at this quote in a new tab)
“the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity” (opens the source at this quote in a new tab)

X-linked protoporphyria as a proportion of the protoporphyria phenotype in the United Kingdom and the United States

“Based on studies from the UK, XLP appears to account for about 2% of individuals with the erythropoietic protoporphyria phenotype” (opens the source at this quote in a new tab)
“In the US, XLP accounts for about 10% of individuals with the erythropoietic protoporphyria phenotype” (opens the source at this quote in a new tab)

Observed diagnosis distribution in the United States natural history study

“A total of 322 patients, 294 (91.3%) with EPP (132 men, 152 women) and 28 (8.7%) with XLP (12 men, 15 women, 1 unknown), were enrolled in the LS at the time of analysis.” (opens the source at this quote in a new tab)

Genotype distribution in the Italian national cohort

“most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP)” (opens the source at this quote in a new tab)

Age at symptom onset and lifelong persistence of photosensitivity

“Onset of photosensitivity is typically in infancy or childhood (with the first exposure to sun) and the photosensitivity remains for life.” (opens the source at this quote in a new tab)

“Patients’ mean (SD) age at symptom onset was 4.4 (4.4) years.” (opens the source at this quote in a new tab)

Frequency of hepatic dysfunction and progression to liver failure

“Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.)” (opens the source at this quote in a new tab)
“However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure.” (opens the source at this quote in a new tab)

“About 2–5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation.” (opens the source at this quote in a new tab)

Life expectancy outside advanced liver disease

“An unknown proportion of individuals with XLP develop liver disease. Except for those with advanced liver disease, life expectancy is not reduced.” (opens the source at this quote in a new tab)

Transplantation, mortality, and cause of death in the United States longitudinal study

“In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died.” (opens the source at this quote in a new tab)
“Eight (6 with EPP and 2 men with XLP) patients died; 4 due to liver failure, 2 (both with EPP) from complications related to BMT, and 1 due to HCC” (opens the source at this quote in a new tab)
“Of the total, 3.4% of enrolled patients had histologic evidence of protoporphyric hepatopathy and 2.5% required liver transplantation.” (opens the source at this quote in a new tab)
“Notably, at least 50% of the deaths that occurred in this cohort were attributable to liver involvement by these protoporphyrias.” (opens the source at this quote in a new tab)

Advanced hepatopathy by diagnosis

“A higher proportion of patients with XLP (1 male, 2 females) had advanced hepatopathy (3/27, 11.1%) compared with patients with EPP (8/294, 2.7%).” (opens the source at this quote in a new tab)
“Protoporphyric hepatopathy is rarely recognized at an early stage, and much of its natural history remains poorly understood.” (opens the source at this quote in a new tab)

Liver transplantation is not curative

“Liver transplantation can be lifesaving but is not curative and may be followed by allogeneic hematopoietic stem cell transplantation, which restores marrow FECH activity to ameliorate injury to the transplanted liver.” (opens the source at this quote in a new tab)

“However, the incidence of recurrent cholestatic liver disease in transplant recipients is substantial, reaching 65%.” (opens the source at this quote in a new tab)

Protoporphyrin IX accumulation and photoactivation in dermal vasculature

“Protoporphyrin is believed to be taken up from plasma by vascular endothelial cells in the skin where photoactivation by visible light leads to the formation of reactive oxygen species that cause cellular damage, inflammation, and cutaneous phototoxicity.” (opens the source at this quote in a new tab)

“The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain.” (opens the source at this quote in a new tab)

Action spectrum: the Soret band near 400 nm

“The skin of persons with EPP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called Soret band (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state.” (opens the source at this quote in a new tab)
“Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region.” (opens the source at this quote in a new tab)

Complement activation and mast cell degranulation

“Thunell et al., in 2000, first hypothesized that PPIX excitated at 410 nm leads to singlet oxygen (1O2*) mediated damage of endothelial cells” (opens the source at this quote in a new tab)
“The photodamage leads to the stimulation of an inflammatory response, occurring via complement system (CS) activation and mast cell degranulation, with exocytosis of vasoactive mediators.” (opens the source at this quote in a new tab)

“Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage.” (opens the source at this quote in a new tab)

Histologic substrate of the phototoxic reaction

“Histologically, the subpapillary vascular endothelial cells and the basal membranes are most harmed, resulting in an activation of the complement system,” (opens the source at this quote in a new tab)

“Histological examination of acute lesions shows epidermal vacuolization and intercellular edema in addition to endothelial vacuolization and cytolysis in the superficial blood vessels of the skin” (opens the source at this quote in a new tab)

Dissociation between pain and visible skin change

“although the skin typically exhibits no visible alterations within the first few minutes to hours. Instead, these alterations become apparent hours to days after the onset of pain, if at all.” (opens the source at this quote in a new tab)

“Symptoms may seem out of proportion to the visible skin lesions.” (opens the source at this quote in a new tab)

Biliary excretion of protoporphyrin and hepatobiliary injury

“Accumulated protoporphyrin in the bile can form stones, reduce bile flow, and damage the liver.” (opens the source at this quote in a new tab)

Erythrocyte protoporphyrin with metal-free and zinc fractionation as the recommended test

“Total erythrocyte protoporphyrin concentration, including proportions of metal-free and zinc-bound protoporphyrin, is the recommended test for the diagnosis of protoporphyria” (opens the source at this quote in a new tab)
“The percentage of metal-free protoporphyrin is typically >90% in EPP and ~50–85% in XLP.” (opens the source at this quote in a new tab)

“Detection of markedly increased free erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP” (opens the source at this quote in a new tab)
“It is important to evaluate by using an assay that distinguishes free protoporphyrin from zinc-chelated protoporphyrin” (opens the source at this quote in a new tab)

Diagnostic threshold and biochemical discrimination of the two disorders

“A metal‐free PPIX ≥3 times the upper limit of normal (ULN) establishes the diagnosis of protoporphyrias.” (opens the source at this quote in a new tab)
“Therefore, XLEPP can usually be distinguished biochemically from EPP1 by the higher proportion of ZnPP.” (opens the source at this quote in a new tab)

Commercial assays that measure zinc protoporphyrin can miss the diagnosis

“Some major commercial labs, such as Quest and LabCorp, provide a “free erythrocyte protoporphyrin” test, which is actually a zinc protoporphyrin test.” (opens the source at this quote in a new tab)
“Because zinc protoporphyrin is often normal in EPP, the diagnosis may be missed.” (opens the source at this quote in a new tab)

Genetic testing to distinguish the two disorders

“If a diagnosis of protoporphyria is established based on significantly elevated protoporphyrin, genetic testing of the FECH and ALAS2 genes is recommended to distinguish between EPP and XLP.” (opens the source at this quote in a new tab)

Diagnostic delay

“The mean diagnostic delay is over a decade, and evidence supports significant underdiagnosis.” (opens the source at this quote in a new tab)

“The mean number of years between initial symptoms and diagnosis of EPP was 13 years” (opens the source at this quote in a new tab)
“The majority (76%) presented with symptoms of EPP before four years of age” (opens the source at this quote in a new tab)
“Holme et al identified 389 patients with EPP in the UK; the median ages at symptom onset and diagnosis were one and 12 years, respectively.” (opens the source at this quote in a new tab)
“Wahlin et al identified 51 patients with EPP in Sweden; the median ages at onset and diagnosis were one and 22 years.” (opens the source at this quote in a new tab)

“The median delay in diagnosis from the onset of symptoms was 4.0 years (range 0-36), and 28 patients (80%) experienced a delay of 1 or more years” (opens the source at this quote in a new tab)

“Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old.” (opens the source at this quote in a new tab)

Misattribution of symptoms before diagnosis

“Thirty eight percent of patients saw five or more physicians prior to being diagnosed with EPP; of those, 22% saw more than 10 physicians.” (opens the source at this quote in a new tab)
“Prior to diagnosis, the majority of individuals were thought to have a sun allergy (50%), or another type of allergic reaction (16%); 15% of individuals were thought to have a psychological issue.” (opens the source at this quote in a new tab)

Cutaneous symptoms: prodromal tingling, burning, and phototoxic pain

“Patients typically present in childhood with prodromal symptoms, including tingling, itching, and burning on sun exposure, which is followed by severe, prolonged phototoxic pain and swelling unless exposure is interrupted. Symptom onset is typically within 10–30 minutes of exposure to visible light.” (opens the source at this quote in a new tab)
“the most commonly reported EPP symptoms after sun exposure were cutaneous burning (289, 89.8%), swelling (273, 84.8%), and tingling (252, 78.3%), and 176 (54.7%) reported a time-to-first symptom of <30 minutes” (opens the source at this quote in a new tab)

“Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31)” (opens the source at this quote in a new tab)

“Prodromal (early warning) symptoms after sunlight exposure, reported by > 50% of participants, included tingling, warmth, itching, sensitivity to touch, and burning; symptoms occurred in ≤ 10 min in 48.8% of adults and 15.2% of adolescents.” (opens the source at this quote in a new tab)
“67.1% of adults and 87.9% of adolescents experienced ≥ 1 phototoxic reaction in the previous 12 months” (opens the source at this quote in a new tab)

Cutaneous symptoms: escalation with continued exposure and the priming phenomenon

“Early symptoms often manifest within a few minutes of light exposure as tingling, itching or burning, which intensify with prolonged light exposure.” (opens the source at this quote in a new tab)
“Repeated light exposure can increase light sensitivity, the so‐called ‘priming phenomenon’.” (opens the source at this quote in a new tab)

Cutaneous symptoms: delayed and often absent visible skin change

“Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.” (opens the source at this quote in a new tab)

Cutaneous symptoms: chronic changes of sun-exposed skin

“Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails.” (opens the source at this quote in a new tab)
“Blistering was reported in 26% of individuals in one large series” (opens the source at this quote in a new tab)

Hepatobiliary symptoms: aminotransferase elevation and gallstones

“Previous studies in cohorts from the United States and Europe have shown elevated serum aminotransferases in 25%–27% of patients with EPP and XLP, and an increased prevalence of cholelithiasis.” (opens the source at this quote in a new tab)
“At the time of enrollment, 49 patients (15.2%) had a history of cholecystectomy” (opens the source at this quote in a new tab)
“Gallstones were commonly reported in patients with EPP or XLP (13.0%).” (opens the source at this quote in a new tab)

“In one series, approximately 22% of individuals with EPP had a known history of gallstones” (opens the source at this quote in a new tab)

“Approximately 20% of patients with EPP develop gallstones, with up to 5% of patients progressing to liver failure” (opens the source at this quote in a new tab)

Hepatobiliary symptoms: liver enzyme, steatosis, and fibrosis findings in a Dutch cohort

“Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients.” (opens the source at this quote in a new tab)

Hepatobiliary symptoms: higher frequency of abnormal liver enzymes in X-linked protoporphyria

“A natural history study in the US showed that 40% of males with XLP had a history of abnormal liver enzymes compared to 33% of persons with EPP-AR.” (opens the source at this quote in a new tab)

“Recent natural history studies showed that 37.5% of males with XLP and 22.2% of females with XLP had abnormal serum aminotransferases compared to 13.7% of individuals with EPP” (opens the source at this quote in a new tab)

Hematologic symptoms: microcytic anemia and iron deficiency

“A mild hypochromic, microcytic anemia is present in ~30–60% of patients with protoporphyria.” (opens the source at this quote in a new tab)

“Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported.” (opens the source at this quote in a new tab)

“Anemia was present on self-reported medical history in 145 (45.0%)” (opens the source at this quote in a new tab)

“it is estimated that 20%–60% of EPP patients develop mild microcytic anemia whose pathogenesis is unclear” (opens the source at this quote in a new tab)
“In addition, all microcytic patients showed PPIX mean levels significantly higher than normocytic patients” (opens the source at this quote in a new tab)

“Mild anemia with microcytosis and hypochromia or occasionally reticulocytosis can be seen; however, hemolysis is absent or mild.” (opens the source at this quote in a new tab)

Metabolic and bone symptoms: vitamin D deficiency from lifelong sunlight avoidance

“There is an increased recognition of prevalence of vitamin D deficiency in protoporphyria patients due to lifelong sunlight avoidance.” (opens the source at this quote in a new tab)

“All protoporphyria patients are at risk for vitamin D deficiency as a result of their lifelong sun‐avoiding behaviour.” (opens the source at this quote in a new tab)

“Persons with EPP who avoid sun/light are at risk for vitamin D deficiency” (opens the source at this quote in a new tab)

Multisystem course requiring longitudinal monitoring

“EPP and XLP are multi-systemic disorders presenting with severe, acute phototoxicity leading to a conditioned behavior of sun avoidance, decreased quality of life, and, in rare cases, liver failure.” (opens the source at this quote in a new tab)

Range of long-term complications

“The complications associated with the protoporphyrias are diverse and include protoporphyria‐related liver failure, gallstones, iron deficiency and vitamin D deficiency, with related reduced bone mineral density and fracture risk.” (opens the source at this quote in a new tab)

Reduced bone mineral density and fracture burden

“BMD is low in EPP patients, with 82.7% of the 139 patients having a Z-score below 0 SD at baseline. Low BMD classified as osteopenia was found in 39.5%, and osteoporosis in 15.3%.” (opens the source at this quote in a new tab)
“There were 50 osteoporosis-related fractures in 34.2% of patients.” (opens the source at this quote in a new tab)
“Among individuals aged 50 years and older, the prevalence of osteoporosis in EPP patients was much higher at 33.3% compared with 6.3% to 14.3% in the general European population” (opens the source at this quote in a new tab)

“In a Dutch cohort study, 36% of patients with EPP were diagnosed with osteopenia and 23% with osteoporosis, while the expected prevalence was 15% and 1%, respectively.” (opens the source at this quote in a new tab)

Chronic cutaneous sequelae

“Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. The dorsum of the hands is most notably affected.” (opens the source at this quote in a new tab)

Greater burden among those with liver disease

“The significant burden imposed by EPP appears to be greater among those with self‐reported liver disease.” (opens the source at this quote in a new tab)
“Among a total of 164 adult participants, 25 (15.2%) self‐reported liver disease and 139 did not.” (opens the source at this quote in a new tab)

Tolerated sunlight exposure before symptom onset

“Severity is variable, but most patients can only tolerate <30 minutes of sun exposure.” (opens the source at this quote in a new tab)

“Median times for onset of symptoms after sun exposure, onset of signs (oedema, erythema) and resolution of symptoms were 20 min, 6 h and 3 days, respectively.” (opens the source at this quote in a new tab)

“Before treatment, the PBTT was median 10 min (IQR 5-20). Under treatment, PBTT increased to median 180 min (IQR 120-240). Individual PBPF increased 1.8- to 180-fold (full range, median 15).” (opens the source at this quote in a new tab)

Interference with daily activities, school, and work

“Prodromal (early warning) symptoms after sunlight exposure, reported by > 50% of participants, included tingling, warmth, itching, sensitivity to touch, and burning; symptoms occurred in ≤ 10 min in 48.8% of adults and 15.2% of adolescents. Symptoms hindered daily activities at least "somewhat" for 62.8% of adults and 87.9% of adolescents, and 23.4% - 41.7% reported school/work absenteeism in past month; 67.1% of adults and 87.9% of adolescents experienced ≥ 1 phototoxic reaction in the previous 12 months” (opens the source at this quote in a new tab)
“Fifty-four percent (53.7%; adults) and 16.7% (adolescents) reported work productivity was affected by their EPP at least "a little bit” (opens the source at this quote in a new tab)

Emotional and psychological effects

“Most adults and adolescents reported feeling depressed (75.0%, 45.5%), anxious (79.9%, 60.6%), isolated (82.9%, 57.6%), frustrated (90.2%, 93.9%), and lonely (75.6%, 39.4%).” (opens the source at this quote in a new tab)

“The HADS was completed by 103 patients (95 EPP, 8 XLP), and mean scores for anxiety and depression were within the normal range (Table 3 ); however, 20% (21/103) of patients had borderline or abnormal anxiety levels, and 9.7% (10/103) had borderline or abnormal depression levels.” (opens the source at this quote in a new tab)

“Anxiety and depression due to disease-related symptoms have been reported. However, the rates of these conditions in adults are similar to the general population.” (opens the source at this quote in a new tab)

Employment and social functioning

“The educational level of EPP patients seemed higher compared to the Dutch population (36% vs. 30% high-education, 42% vs. 37% middle-education). At baseline 5% of the EPP patients were unemployed, none were unemployed during afamelanotide treatment.” (opens the source at this quote in a new tab)
“EPP patients scored low on the social functioning domain (SF-36) compared to the Dutch population (74.4 ± 27.3 vs. 84.0 ± 22.4; respectively), and improved during afamelanotide treatment (84.3 ± 20.9, p = 0.001). EPP has a significant negative impact on social aspects, with less employment despite a higher education level.” (opens the source at this quote in a new tab)

Performance of quality-of-life instruments in this disease

“Impaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.” (opens the source at this quote in a new tab)
“The percentage of scores indicating >1 SD of impairment, which can be considered clinically significant, are shown in Table 2 ; notably 21.8% (42/193) of patients have clinically significant pain interference.” (opens the source at this quote in a new tab)

“QoL was markedly impaired, with scores similar to those in severe dermatological disease (mean DLQI score 14.0, n = 176; mean CDLQI score 12.8, n = 44), indicating a large effect on patients' lives.” (opens the source at this quote in a new tab)

“The 3 factors from the EPIQ demonstrated acceptable to strong psychometric properties in terms of reliability (internal consistency, test-retest), validity (construct, known groups), and responsiveness. Ranges for meaningful change, using anchor- and distribution-based approaches, were established.” (opens the source at this quote in a new tab)

Adaptation confounds measurement of quality of life

“Patients with EPP are highly adapted to their condition which makes the quantification of their health-related quality of life (QoL) challenging.” (opens the source at this quote in a new tab)
“QoL under treatment was comparable to the age-matched population norm, and retrospective results for a treatment interruption and phototoxic reaction time point were comparable to the QoL of patients with chronic neuropathic pain and acute burn injuries, respectively.” (opens the source at this quote in a new tab)

Quality of life in children

“Children with EPP exhibited lower median scores in the PedsQL in both physical (cases: 87.5 (interquartile range [IQR] 77.7-96.1), controls: 99.2 [IQR 94.9-100.0], p = 0.03) and social (cases: 77.5 [IQR 69.4-86.3], controls: 97.5 [IQR 78.8-100.0], p = 0.04) domains compared to healthy children” (opens the source at this quote in a new tab)
“In conclusion, children with EPP experience a reduced QoL compared to both healthy children and adults with EPP. Ensuring treatment availability for this patient group is crucial for improving their QoL.” (opens the source at this quote in a new tab)

Resource use and total cost compared with matched comparators

“Over a mean follow-up of 30 months, patients with EPP/XLP had significantly higher all-cause HRU compared with comparators, with a mean PPPY number of inpatient stays of 0.8 vs 0.2 (RR = 3.4; P < 0.001), emergency department visits of 1.5 vs 0.9 (RR = 1.7; P = 0.002), and outpatient visits of 35.2 vs 17.5 (RR = 2.0; P < 0.001). All-cause costs were also significantly higher among patients with EPP/XLP compared with comparators with a mean PPPY total cost of $71,714 vs $18,646 (ratio = 3.9; P < 0.001), driven by inpatient costs (mean = $30,909 vs $6,318; ratio = 4.9; P < 0.001) and outpatient costs (mean = $33,416 vs $7,573; ratio = 4.4; P < 0.001).” (opens the source at this quote in a new tab)

Disease-specific and comorbidity-related cost components

“Medical costs related to EPP/XLP-associated comorbidities PPPY among patients with EPP/XLP were nearly 6 times those among matched comparator patients (mean = $25,611 [SD = $173,731] vs $4,298 [SD = $30,562]; cost ratio = 5.96; P < 0.001)” (opens the source at this quote in a new tab)
“and represented almost 40% of the total all-cause medical costs.” (opens the source at this quote in a new tab)
“Among patients with EPP/XLP, the mean total EPP/XLP-specific medical costs PPPY were $17,448 (SD = $90,366), approximately one-fourth of total all-cause health care costs, and were mainly driven by EPP/XLP-specific OP costs (mean = $14,534 [$83,836” (opens the source at this quote in a new tab)

Medication use in the absence of disease-directed therapy

“Although only 7.6% of patients with EPP/XLP received treatment for EPP/XLP, most commonly afamelanotide (3.9%), most (68.4%) used medication related to EPP/XLP-associated comorbidities, including narcotics (46.3%), nonsteroidal anti-inflammatory drugs (38.2%), and antidepressants (35.1%).” (opens the source at this quote in a new tab)

Concentration of burden among adolescents

“This study found that patients with EPP/XLP have significantly higher health care use and costs compared with those without the condition. Few patients received treatment for EPP/XLP, and the economic burden was particularly high among adolescents, who currently have no approved therapies.” (opens the source at this quote in a new tab)
“The adolescent subgroup included 28 patients with EPP/XLP and 112 matched comparator patients. Descriptive results in this subgroup (not compared statistically because of the low sample size) show that these patients also incurred numerically higher HRU and costs compared with the matched comparator cohort with relative rates and cost ratios even higher than those observed in the overall sample (all-cause IP stays: RR = 14.72; days hospitalized: RR = 28.86; ED visits: RR = 1.48; OP visits: RR = 3.19; and total all-cause health care costs: cost ratio = 16.36 in the adolescent subgroup” (opens the source at this quote in a new tab)

Patient-reported visit frequency

“Adults had a mean number of eight physician visits related to EPP in the previous 12 months, and adolescents had a mean number of 3.2 visits. Adults averaged 5.5 emergency room visits annually.” (opens the source at this quote in a new tab)

Higher resource use among those with liver disease

“EPP-related HCU in the previous 12 months was higher for those with liver disease than those without liver disease, including more physician visits (mean of 16.5 versus 6.0) and emergency room visits (mean of 9.0 versus 1.9).” (opens the source at this quote in a new tab)

Encounter counts and cost in a medical-record cohort

“Within 12 months of diagnosis, the mean (SD; median) number of office visits, emergency department visits, and inpatient hospitalizations related to EPP or XLP were 4.0 (3.5; 3.0), 0.8 (1.6; 0), and 0.4 (1.3; 0), respectively.” (opens the source at this quote in a new tab)
“Inpatient hospitalizations and ED encounters specifically related to EPP or XLP were seen in fewer than 40% of patients. However, these encounters were costly, resulting in a mean cost of approximately USD2700 per patient.” (opens the source at this quote in a new tab)

Monetized indirect costs and productivity loss

No evidence found.

Quantified family out-of-pocket costs and caregiver productivity loss

No evidence found.

Family adjustments described by parents of affected children

“All parents described a frustrating diagnostic odyssey before their child was finally diagnosed with EPP. They all agreed they felt relief following the diagnosis of EPP in their children, as well as validation that their child's symptoms were real.” (opens the source at this quote in a new tab)
“Parents had to make adjustments to their family's lives to accommodate for EPP such as driving to places in two separate cars, one with window tints and one without, and planning family activities outdoors in the evening.” (opens the source at this quote in a new tab)
“Most parents thought that their children initially struggled with fitting in socially, specifically at school, as they were physically isolated during activities such as recess, which resulted in social isolation.” (opens the source at this quote in a new tab)

Time lost from work and school in households affected by liver disease

“The mean number of hours missed from work and school in the past month was higher for those with liver disease (work: 10.9 h; school: 7.7 h) than those without liver disease (3.6 h for both).” (opens the source at this quote in a new tab)

Education of the family and school environment as a component of care

“It is crucial and complex for protoporphyria patients and their families to inform and educate their social network, to raise awareness and understanding of the limitations and the necessary support.” (opens the source at this quote in a new tab)
“Supporting the patients and their families in educating them about their social, school and work environments is an important part of care.” (opens the source at this quote in a new tab)

Measured cost of the diagnostic pathway

“Average costs from symptom onset to diagnosis of EPP or XLP were approximately USD600 per patient. Once diagnosed, average costs of referrals and tests in the first year were approximately USD400 across all patients.” (opens the source at this quote in a new tab)
“The mean (SD) number of specialist referrals before diagnosis was 2.8 (3.6) with a median of 2.0. Referrals were primarily to dermatologists (48%) and hematologists (22%).” (opens the source at this quote in a new tab)
“Data on the number of pre-diagnostic tests were not collected; thus, the analysis assumed only 1 test per patient.” (opens the source at this quote in a new tab)

Testing that guidelines recommend against

“Clinicians should avoid laboratories that measure protoporphyrin only by hematofluorometry, which can lead to falsely normal levels of erythrocyte protoporphyrins, and these results are often incorrectly labeled as “free erythrocyte protoporphyrin” (opens the source at this quote in a new tab)
“In patients with protoporphyria, plasma porphyrin levels may be normal or increased” (opens the source at this quote in a new tab)
“Elevated plasma porphyrins are not diagnostic of EPP and are therefore not recommended as first-line testing” (opens the source at this quote in a new tab)
“Urinary and fecal porphyrins are typically normal in protoporphyria, and testing is not recommended” (opens the source at this quote in a new tab)
“Skin biopsies are not indicated for the diagnosis of protoporphyria” (opens the source at this quote in a new tab)
“Genetic testing in the absence of biochemical testing is not recommended given the possibility of identifying variants of uncertain significance and the small percentage of patients in whom the genetic variant remains undefined” (opens the source at this quote in a new tab)

Specialized laboratory required for confirmatory testing

“In general, the biochemical analyses should be performed in a laboratory acknowledged as a specialized centre for porphyrin diagnostics, such as the laboratories certified by the International Porphyria Network (Ipnet, formerly known as European Porphyria Network; porphyrianet.org.).” (opens the source at this quote in a new tab)

Cost of genetic testing and of misdiagnosis

No evidence found.

Guideline recommendation for avoidance, clothing, and tinted sunscreens

“Sunlight avoidance and opaque clothing are recommended for the prevention of phototoxic symptoms in protoporphyria ( Table 2” (opens the source at this quote in a new tab)
“Window tinting for cars can be useful” (opens the source at this quote in a new tab)
“Because some patients report a small benefit with broad-spectrum and/or tinted sunscreens such as zinc oxide and titanium dioxide and because these agents block a portion of the far UVA wavelengths (350–399 nm) of light that activate protoporphyrin, it is reasonable for patients to use these agents for the prevention of phototoxic symptoms” (opens the source at this quote in a new tab)
“However, non-broad-spectrum or non-tinted sunscreens are not useful for prevention of phototoxic symptoms in protoporphyria” (opens the source at this quote in a new tab)
“Depending on symptom severity, workplace/school accommodations and educating teachers about protoporphyria can be useful, as well as educating children regarding how to explain their disease and to advocate for themselves” (opens the source at this quote in a new tab)

Behavioral adaptation as the default in the absence of treatment

“Without access to specific treatment options that prevent or treat phototoxic reactions, patients can only adapt their behaviour by avoiding activities outdoors in sunlight and by using light filters and photo-protective clothing consisting of opaque clothing with long sleeves, headwear, gloves, enclosed footwear and shields, even during the winter months. Given the early onset of the protoporphyrias and the diagnostic delay, most patients are already conditioned to avoid (sun)light before their diagnosis.” (opens the source at this quote in a new tab)

Advice recorded in a United States medical-record cohort

“Patients were advised to use sunscreen (85%) or modify their lifestyle (83%).” (opens the source at this quote in a new tab)

Approved indication and administration of afamelanotide

“SCENESSE is a melanocortin 1 receptor (MC1-R) agonist indicated to increase pain free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria (EPP). (1)” (opens the source at this quote in a new tab)
“SCENESSE should be administered by a healthcare professional who is proficient in the subcutaneous implantation procedure and has completed training prior to administration. (2.1)” (opens the source at this quote in a new tab)
“A single SCENESSE implant is inserted subcutaneously above the anterior supra-iliac crest every 2 months.” (opens the source at this quote in a new tab)
“The safety and effectiveness of SCENESSE have not been established in pediatric patients.” (opens the source at this quote in a new tab)
“The most common adverse reactions (incidence > 2%) are implant site reaction, nausea, oropharyngeal pain, cough, fatigue, dizziness, skin hyperpigmentation, somnolence, melanocytic nevus, respiratory tract infection, non-acute porphyria, and skin irritation (6).” (opens the source at this quote in a new tab)

European prescribing restrictions and authorisation basis for afamelanotide

“SCENESSE should only be prescribed by specialist physicians in recognised porphyria centres and administration should be performed by a physician trained and accredited by the marketing authorisation holder to administer the implant.” (opens the source at this quote in a new tab)
“The safety and efficacy of afamelanotide in children and adolescents aged to 17 years have not yet been established. No data are available.” (opens the source at this quote in a new tab)
“This medicinal product has been authorised under ‘exceptional circumstances’.” (opens the source at this quote in a new tab)

Randomized trial results for afamelanotide

“In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04).” (opens the source at this quote in a new tab)

Observational effectiveness of afamelanotide

“A total of 117 patients with EPP (59 women [50.4%]; mean [SD] age, 43.0 [15.5] years) were treated with afamelanotide. Nearly all patients continued treatment (115 [98%]) with a median (interquartile range) follow-up of 2.0 (1.3-2.1) years. Compared with baseline, mean time spent outside during treatment increased significantly by an added 6.1 hours per week (95% CI, 3.62-8.67; P < .001). Mean quality of life score improved significantly by 14.01% (95% CI, 4.53%-23.50%; P < .001). Phototoxic reactions were less painful (β, -0.85; 95% CI, -1.43 to -0.26; P < .001), but there was no significant difference in number or duration of reactions.” (opens the source at this quote in a new tab)

“The quality of life (QoL) scores, measured by an EPP-specific questionnaire, were 31 ± 24% of maximum prior to afamelanotide treatment, rose to 74% after starting afamelanotide and remained at this level during the entire observation period. Only minor adverse events attributable to afamelanotide, predominantly nausea, were recorded.” (opens the source at this quote in a new tab)

Guideline position on afamelanotide

“Therefore, afamelanotide is recommended for the prevention of phototoxic symptoms in EPP ( Table 2” (opens the source at this quote in a new tab)
“For patients using afamelanotide, total body skin examinations by a dermatologist are recommended every 6 months” (opens the source at this quote in a new tab)
“The drug is available in the US and Europe, however access is limited in the US due to the high cost and restricted sites for administration” (opens the source at this quote in a new tab)
“There is no data on the safety of afamelanotide during pregnancy so this cannot be recommended for pregnant women” (opens the source at this quote in a new tab)

Observed treatment duration and adherence in United States claims data

“Among the 27 patients with EPP/XLP who used afamelanotide during the follow-up period, the median duration of treatment was 5.68 months” (opens the source at this quote in a new tab)
“The mean PDC was 0.74 (SD = 0.23) at 6 months, 0.68 (SD = 0.21) at 12 months, and 0.63 (SD = 0.29) at 24 months, and only 39%-50% of patients had PDC greater than or equal to 0.8 in these periods” (opens the source at this quote in a new tab)

Cumulative global exposure to afamelanotide

“Over 18,500 SCENESSE® implants have been administered to EPP patients globally, demonstrating the sustained success and safety of the program, which commercially has achieved a compound annual growth rate (“CAGR”) of 35% since fiscal year 2016” (opens the source at this quote in a new tab)

Agents that guidelines do not recommend

“Due to insufficient data related to efficacy, the following therapies are not recommended for the prevention of phototoxic symptoms: beta-carotene, cysteine, cimetidine, isoniazid, warfarin, quinacrine, oral zinc, N-acetylcysteine, vitamin C, omega-3 fatty acids, oral adenosine monophosphate, canthaxanthine, terfenadine, inosine, dithiothreitol (DTT) and glycerol, pyridoxine, and hydroxyethylrutosides ( Table 2” (opens the source at this quote in a new tab)
“Although several previous studies have investigated beta carotene in EPP, the evidence shows unclear or no benefit” (opens the source at this quote in a new tab)

“There is an extensive and complete review on previous drugs such as beta‐carotene and cimetidine;” (opens the source at this quote in a new tab)
“however, none of these have any significant effect on protoporphyrias.” (opens the source at this quote in a new tab)

Continued use despite the absence of supporting evidence

“Following diagnosis, most patients were advised to prevent phototoxic reactions by avoidance of sun exposure and use of sunscreen; 40% were prescribed beta-carotene despite insufficient data regarding its efficacy. Further, despite studies showing that non-steroidal anti-inflammatory drugs provide little symptom relief, a third of the sample received recommendations for these drugs for EPP or XLP.” (opens the source at this quote in a new tab)

“Most patients used protective clothing and a sunscreen; 28% were taking beta-carotene and a further 56% had taken it; 29% were not under regular medical care.” (opens the source at this quote in a new tab)

Guideline position on narrowband ultraviolet B phototherapy

“For patients without access to afamelanotide, limited natural sunlight exposure or low-dose hardening phototherapy with narrowband UVB increased slowly over time to induce a gradual increase in endogenous melanin production may be considered for prevention of phototoxic symptoms” (opens the source at this quote in a new tab)
“However the effectiveness of this therapy is unclear and not well established” (opens the source at this quote in a new tab)
“For patients who are sensitive to indoor lighting, utilizing indoor lights that minimize the amount of blue light may be considered” (opens the source at this quote in a new tab)

Absence of an effective treatment for an established reaction

“No studies evaluating treatments for acute phototoxicity could be found” (opens the source at this quote in a new tab)
“Anecdotally, many patients choose to self-treat with ice, cold water, or cold compresses, resulting in minor relief, although others report that both cold and heat worsen symptoms” (opens the source at this quote in a new tab)
“Cold compresses or cooling devices may be considered for the treatment of phototoxic symptoms ( Table 2” (opens the source at this quote in a new tab)
“There is no evidence of benefit with narcotic analgesics, oral or topical corticosteroids, antihistamines, acetaminophen and non-steroidal anti-inflammatory drugs” (opens the source at this quote in a new tab)
“There are insufficient data to recommend these therapies” (opens the source at this quote in a new tab)
“The development of novel therapies to treat pain in protoporphyria patients is a large unmet need” (opens the source at this quote in a new tab)

Course of protoporphyric hepatopathy and monitoring recommendation

“Approximately 1–5% of patients with protoporphyria develop rapid and severe hepatobiliary disease characterized by an acute cholestatic hepatitis with liver failure (often called “EPP hepatic crisis”), or a slowly progressive biliary cirrhosis and end stage liver disease; these more advanced manifestations of liver disease due to protoporphyria are collectively referred to as “protoporphyric hepatopathy” (opens the source at this quote in a new tab)
“These patients almost invariably require liver transplantation” (opens the source at this quote in a new tab)
“Therefore, it is recommended that liver chemistries should be monitored at least yearly in patients with protoporphyria to detect early stages of liver dysfunction starting at the time of diagnosis of protoporphyria ( Figure 4” (opens the source at this quote in a new tab)
“We recommend TPE for patients with advanced protoporphyric hepatopathy to decrease plasma porphyrin levels and thereby reduce liver damage in order to bridge patients to liver transplant and/or hematopoietic stem cell transplant (see below” (opens the source at this quote in a new tab)
“Recurrent protoporphyric hepatopathy in the transplanted liver has been reported in 65 to 80% of patients in case series from the US, Australia, and Europe, with 43% showing evidence of recurrence by one year post-transplant” (opens the source at this quote in a new tab)

Escalating interventions for hepatic decompensation

“As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory.” (opens the source at this quote in a new tab)

Genotype-dependent effect of iron supplementation

“In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage.” (opens the source at this quote in a new tab)

Summary: constraints on the current standard of care

No therapy is approved for patients younger than 18 years, and afamelanotide, the only approved product, is indicated for adults with erythropoietic protoporphyria and not for X-linked protoporphyria. Afamelanotide is a fixed-dose subcutaneous implant administered every 2 months by a trained and accredited implanter at a recognized porphyria center, which limits dose adjustment and restricts the sites able to provide it. In a United States claims analysis of 696 patients with either disorder, 7.6% received any treatment for the condition and 3.9% received afamelanotide, with a median treatment duration of 5.68 months. Clinical practice guidelines recommend against beta-carotene, cysteine, cimetidine, and other systemic agents for prevention of phototoxic symptoms, and identify no effective treatment for an established phototoxic reaction. Sunlight avoidance remains necessary during treatment and is associated with vitamin D deficiency.

Absence of any approved pediatric therapy

“There are no approved therapies for pediatric patients.” (opens the source at this quote in a new tab)

“because of its mode of administration as a 16 mg fixed dose slow-release subcutaneous implant, dose-adjustments of the currently approved formulation of afamelanotide are not possible, which makes it unsuitable for the treatment of children. Afamelanotide is also not sufficiently effective or suitable for all adult patients, and, being a symptomatic treatment, does not address the increased risk for EPP-related liver failure. Moreover, because of lack of reimbursement, afamelanotide is not yet available to patients in many countries, despite being the only approved treatment for EPP” (opens the source at this quote in a new tab)

“The European Medicines Agency has deferred the obligation to submit the results of studies with SCENESSE in one or more subsets of the paediatric population in erythropoietic protoporphyria” (opens the source at this quote in a new tab)

Administration site and coverage restrictions

“The low number of afamelanotide users observed in this study, and the low duration of treatment and adherence, likely reflect both the restricted patient access limited to specific treatment centers authorized to administer afamelanotide as well as the strict insurance coverage criteria, including prior authorization, time-limited approvals for initial use, and requirements for evidence of clinical benefit to support continued treatment.” (opens the source at this quote in a new tab)

“Guideline-recommended pharmacological management of EPP symptoms among adults is currently restricted to afamelanotide; however, this therapy is not indicated for pediatric patients or patients with XLP, and there are limitations to access to this drug because administration is restricted to specific centers. There is a clear need for additional efficacious and accessible treatment options.” (opens the source at this quote in a new tab)

Residual burden during treatment

“A recent study in the Dutch cohort shows that, despite receiving treatment with afamelanotide, which normalizes the time patients can spend outdoors, many patients remain deficient in vitamin D.” (opens the source at this quote in a new tab)

“Maintain sun and light protection measures during treatment with SCENESSE to prevent phototoxic reactions related to EPP.” (opens the source at this quote in a new tab)

Summary: anticipated position of an oral melanocortin 1 receptor agonist

Dersimelagon shares its mechanism with afamelanotide, the only approved therapy, but is taken as a once-daily oral tablet rather than a subcutaneous implant placed every 2 months by an accredited implanter. If approved on the submitted application, it would be the first therapy available to patients aged 12 to 17 years and the first approved specifically for X-linked protoporphyria as well as erythropoietic protoporphyria. The phase 3 INSPIRE population was treatment-naive for dersimelagon and excluded participants receiving other active treatment for either disorder, so no evidence describes use after or alongside afamelanotide. Care would remain specialist-led: clinical practice guidelines recommend annual liver chemistries, an annual complete blood count and iron panel, vitamin D screening, and total body skin examination every 6 months for patients receiving a melanocortin 1 receptor agonist.

Contrast in route of administration with the approved therapy

“Dersimelagon is a melanocortin receptor 1 (MC1R) agonist with a similar mode of action to afamelanotide. In contrast to afamelanotide, which has to be given as a subcutaneous implant, this drug is available in an oral form.” (opens the source at this quote in a new tab)

Protoporphyrin concentration as a marker of disease severity

“Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003).” (opens the source at this quote in a new tab)
“Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.” (opens the source at this quote in a new tab)

Greater effect in participants with higher baseline protoporphyrin in the phase 2 trial

“The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL. There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels <1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo.” (opens the source at this quote in a new tab)

Variability of severity in females with X-linked protoporphyria

“Because of the possibility of skewed X-inactivation, disease severity in females can vary from mild to as severe as XLP males.” (opens the source at this quote in a new tab)

Limits of protoporphyrin concentration for stratification

“blood PPIX concentrations also cannot be used to stratify EPP trial populations regarding disease severity and, vice versa, do not demonstrate a representative inclusion of trial participants.” (opens the source at this quote in a new tab)

Variability in response to the approved comparator

“Individual PBPF increased 1.8- to 180-fold (full range, median 15).” (opens the source at this quote in a new tab)

Recommended laboratory monitoring

“Liver chemistries should be performed at the time of diagnosis and at least yearly thereafter ( Table 1 ).” (opens the source at this quote in a new tab)
“Because of the risk of iron deficiency and anemia, it is reasonable for patients to have an annual CBC and iron panel ( Table 1 ).” (opens the source at this quote in a new tab)
“Routine screening for vitamin D deficiency and supplementation as per population guidelines are recommended ( Table 1 ).” (opens the source at this quote in a new tab)

Genotype-directed iron repletion

“Iron repletion is indicated for XLP patients with iron deficiency because the addition of iron in the context of normal FECH function is expected to improve erythrocyte protoporphyrin levels.” (opens the source at this quote in a new tab)

Hepatoprotective measures and immunization

“Avoidance of excessive alcohol intake is recommended for all patients. Furthermore, immunization against hepatitis A and B is recommended.” (opens the source at this quote in a new tab)

Skin surveillance during melanocortin 1 receptor agonist therapy

“A regular full body skin examination (twice yearly) is recommended to monitor all nevi and other skin abnormalities.” (opens the source at this quote in a new tab)

Perioperative light filtering

“In patients undergoing surgery of prolonged duration, such as liver transplantation, light filters that limit transmission of the wavelengths 340-470 nm (i.e., acrylate yellow filter) are recommended.” (opens the source at this quote in a new tab)

Documentation supporting school and workplace accommodation

“Supportive care can include a document and/or medical alert card from the porphyria centre describing the medical condition, as well as the consequences of light exposure and the need for light protection. With these documents, patients can inform not only their peers, teachers and colleagues but also their health care providers, enabling a better understanding of the required adaptations.” (opens the source at this quote in a new tab)

Summary: outcomes a melanocortin 1 receptor agonist is expected to change

Therapy with a melanocortin 1 receptor agonist is symptomatic. It is expected to increase the time a patient can spend in sunlight before symptoms begin, reduce the number of sunlight-induced pain events, and improve patient-reported global impression and quality of life. It is not expected to lower protoporphyrin concentrations or to alter the risk of protoporphyric hepatopathy, and sunlight protection measures continue during treatment. The regulatory precedent for the approved comparator used hours of direct sunlight exposure without pain as the primary endpoint; the dersimelagon program instead used minutes of daily sunlight exposure before the first prodromal symptom, so effect sizes are not directly comparable between the two products.

Endpoint accepted for the approved comparator

“The primary efficacy end point was the number of hours of direct exposure to sunlight without pain.” (opens the source at this quote in a new tab)

Pain as the clinically meaningful outcome in a symptomatic therapy

“Being a symptomatic treatment, afamelanotide does not affect quantifiable biomarkers or objectively quantifiable disease signs in EPP. However, a “reduction in pain” is clinically meaningful and the extend of the provided benefit can be assessed by the patients themselves, as opposed to, for example, surrogate endpoints that measure change in biomarker expression” (opens the source at this quote in a new tab)

Differences in endpoints prevent cross-product comparison

“The primary endpoints used in the clinical trials investigating dersimelagon, bitopertin and cimetidine differ from each other, and from the endpoint used in the pivotal trial investigating afamelanotide in EPP. While some of the secondary endpoints assess the same aspects, the exact methods how the results were obtained need to be considered when comparing efficacy outcomes between the different interventions.” (opens the source at this quote in a new tab)