DENVER — The prodrome symptoms are an ominous sign. For many people with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP), the tingling, burning, itching, and stinging can mean a severe phototoxic reaction to light exposure is imminent.

A new agent in development, dersimelagon or MT-7117, offers hope for forestalling the time to prodromal symptoms, phase 3 results of the INSPIRE trial indicate. If ultimately FDA approved, this oral agent could allow people with these rare genetic photodermatoses to spend more time outdoors.

Amy (Dickey) Yeung, MD, MSc, assistant professor of medicine at Harvard Medical School and a pulmonary and critical care physician at Massachusetts General Hospital, both in Boston, should know. “I actually have EPP myself,” she said during a late-breaking research session here at the American Academy of Dermatology (AAD) 2026 Annual Meeting.

“I can tell you that phototoxic reactions are very, very, severely painful,” added Yeung. Episodes can last 3-7 days, a time during which many people “can’t sleep, or think, or do anything but sit in a dark room until it goes away.” 

Increasing Melanin Is Key

EPP and XLP are two related protoporphyria conditions. Through different genetic mechanisms related to heme biosynthesis, each condition causes protoporphyrin IX levels to rise in red blood cells, bone marrow, the liver, and elsewhere in the body. Accumulation of this photosensitive molecule in dermal cells triggers the cutaneous photosensitivity often first identified in childhood and lasting a lifetime.

Skin often appears normal. Chronic skin changes, including blistering, are rare. However, some swelling and petechiae can occur while people are experiencing symptoms.

Dersimelagon is a selective agonist of the melanocortin-1 receptor that stimulates the production of eumelanin, increasing pigmentation. More melanin can protect against 405 nm blue light exposure, which is a bigger trigger than ultraviolet light. Because of this, Yeung said, “sunscreens generally have no effect in EPP.”

In 2019, the FDA approved the first and so far only treatment for EPP: afamelanotide (Scenesse). Afamelanotide is indicated for adults; it is a fixed-dose, subcutaneous implant so the dosage cannot be adjusted for adolescents or children. In contrast, dersimelagon is a tablet, offering the potential for lower dosing. Other agents in development include bitopertin and PORT-77. 

Study Design

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

“Because of how significant the phototoxic reactions are, we didn’t want to ask patients to try to have a phototoxic reaction,” Yeung said. “But we did ask patients to try to have prodromal symptoms at least once weekly.” Patients self-reported time outdoors, including time to onset of prodromal symptoms.

People with significant, laboratory-confirmed liver disease were excluded from the study, as were people on any other active treatments for EPP or XLP.

Time to Triggering Prodrome Tallied

The primary endpoint was the change from baseline in average daily sunlight exposure time to first prodromal symptom at week 16. The time to prodrome was similar in both groups, Yeung said.

During weeks 12-16, there was a statistically significant increase in the average daily time to first prodromal symptom, with a treatment difference of 23 minutes (P = .004). “The exposure was actually continuing to increase, and by week 16, it was almost a 30 minutes per day improvement in light exposure,” Yeung said.

In addition, a higher proportion of patients taking dersimelagon reported more than 33 minutes in time to prodrome (P = .04). 

There also was an improvement in the proportion of patients experiencing more than 66 minutes outdoors without prodromal symptoms (P = .12). Many patients with EPP already adjust their lives to minimize light exposure, which might explain the nonsignificant finding, Yeung said. “It was a little hard to ask patients to go outside more than 66 minutes above their typical [exposure] every single day for this study.”

Secondary Outcomes

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

The study also met a secondary endpoint for the rate of sunlight-induced pain events, which was 39% lower with treatment than with placebo. These were mild pain symptoms that occurred during the prodromal period rather than a severe reaction, Yeung said.

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

Treatment-Emergent Adverse Events (TEAEs)

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

In the placebo group, TEAEs that led to discontinuation included brain fog and diarrhea.

In the dersimelagon group, in addition to the malignant melanoma in situ, skin hyperpigmentation, urticaria, and hepatic adverse events were observed. Headache occurred in 22.0% vs 12.0% among those on placebo, and nausea in 18.3% vs 10.8% among those on placebo, for example.

The melanocytic nevi rate was 20.7% in the dersimelagon group vs 1.2% in the placebo cohort. This difference “should be closely monitored,” Jasmin Barman-Aksözen, PhD, researcher and postdoctoral scientific associate at the University of Zurich, Zurich, Switzerland, said when asked to comment on the study.

“Besides being a scientist, I am also a patient with EPP, and since 2012, under treatment with afamelanotide,” Barman-Aksözen said.

Like afamelanotide, dersimelagon binds to receptors on melanocytes and increases skin pigmentation. In the study, s kin hyperpigmentation occurred in 23.2% of the dersimelagon group vs 4.8% of the placebo group.

The afamelanotide implant, replaced every 2 months, induces a moderate increase in skin pigmentation and has strong anti-inflammatory effects, said Barman-Aksözen, lead author of a March 2026 review article on new and developing EPP treatments. An increase in skin pigmentation can help to prevent visible light from entering the skin and reaching the blood vessels, where the phototoxic reactions take place.

An increase in pigmentation could have unintentionally unblinded the INSPIRE study. “It can be assumed that most patients in the INSPIRE trial did know to which treatment arm they had been randomized to, which might have influenced their sun exposure behavior,” Barman-Aksözen told Medscape Medical News. Also, because participants intentionally exposed themselves to light, it is possible that there was a selection bias toward people with less severe disease.

During regulatory approval of afamelanotide in Europe, members of the European Medicines Agency (EMA) voiced concerns regarding an increased risk for melanoma and other skin cancers. For this reason, patients in Europe are required to see a dermatologist every 6 months. To date, no increase in the risk for skin cancer has been detected, Barman-Aksözen noted.

Ideally, she said, he ad-to-head studies directly assessing dersimelagon against afamelanotide instead of a placebo control arm would avoid unblinding of the trials and would produce more comparable efficacy and safety results. All trial participants could be treated with both an oral formulation and an implant, one of which is a sham treatment.

Questions and Answers

The AAD late breaker session co-moderator Amy S. Paller, MD, chair in the Department of Dermatology at Northwestern University Feinberg School of Medicine, Chicago, asked about hyperpigmentation.

“There was actually one discontinuation in the placebo group and one in the dersimelagon group for hyperpigmentation,” Yeung replied. “Generally, patients didn’t mind the hyperpigmentation. It was well tolerated.”

Paller also asked about seasonality. “Some patients do say they only have symptoms in the summertime, but there are a lot of patients who continue to have symptoms in the wintertime too. So it could be a bit patient-specific,” Yeung said. “But I would imagine it could benefit patients all year.”

In response to a question about possible use of dersimelagon in hypopigmentation disorders such as vitiligo, Yeung replied, “Yes. I think it would be very good to try it in vitiligo as well.”

The study was funded by Tanabe Pharma America. Yeung disclosed being a consultant and investigator for Disc Medicine; a consultant for Guidepoint Global, LLC; an investigator and speaker for Mitsubishi Tanabe Pharma America (which is developing dersimelagon); an investigator for Portal Therapeutics; a consultant for Pierre Fabre; and a consultant for Recordati Rare Diseases. Barman-Aksözen reported having no relevant financial relationships.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health, and environmental reporting/journalism.