New EPP drug candidates hard to compare with Scenesse, analysis finds
Differences in trial design make head-to-head conclusions difficult
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New drug candidates being tested for erythropoietic protoporphyria (EPP) cannot yet be reliably compared with Scenesse (afamelanotide), the only approved treatment for adults with the disease, because their clinical trials are designed in very different ways, according to a new analysis.
“Efficacy and safety of currently investigated treatments for EPP are not directly comparable,” the researchers wrote, adding that “trials directly assessing new pharmacotherapies against [Scenesse] would be the more informative, and methodologically and ethically sounder trial design.”
The study, “New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective,” was published in the Orphanet Journal of Rare Diseases by a team of researchers in Switzerland and Italy.
How Scenesse works, and its limits
Scenesse, an implant administered under the skin every two months, is approved in the U.S., Europe, and Australia to restore light tolerance in adults with EPP. The therapy works by boosting the body’s production of eumelanin, a natural brown pigment that helps protect the skin from visible light, thereby reducing painful skin reactions triggered by light exposure.
In EPP, this extreme light sensitivity is largely caused by the toxic accumulation of a light-sensitive molecule called protoporphyrin IX (PPIX). Symptoms often begin in childhood, though the age at which they appear can vary.
Despite its benefits, Scenesse is not approved for children and adolescents, “is … not sufficiently effective or suitable for all adult patients,” and “is not yet available to patients in many countries,” the researchers wrote.
As a result, the researchers said there is a clear need for new treatment options for EPP, particularly for children and adolescents, who are often among the most severely affected.
In recent years, several new treatment candidates for EPP have been developed, and some are now being tested in clinical trials. “However, until now, a detailed analysis on how well [Scenesse] and currently investigated drug candidates for EPP can be compared is lacking,” the researchers wrote.
To address this gap, the team reviewed and compared the clinical trial protocols of EPP drugs currently in development. By searching public trial registries between August and November 2024, and again in February 2025, they identified 29 studies.
From these, 16 studies were selected for detailed analysis, covering three experimental drugs — MT-7117 (dersimelagon), bitopertin, and cimetidine — as well as trials used or being used to evaluate Scenesse.
MT-7117, like Scenesse, is designed to improve light tolerance by stimulating eumelanin production, while bitopertin and cimetidine aim to lower blood levels of PPIX, targeting the underlying cause of disease symptoms.
Why trial differences make comparisons difficult
After reviewing these trials, the researchers found major differences in study design that make meaningful comparisons between treatments very difficult.
The most serious concern was that none of the experimental therapies were tested directly against Scenesse. Instead, all drugs were evaluated only against a placebo or against patients’ initial disease state, or baseline, “which means that their relative efficacies and safeties remain unknown,” the researchers wrote.
“In ultra-rare diseases, understanding the potential benefits and risks of new treatments and how they compare to existing treatments before their potential approval is crucial,” they added.
Because of the very small market size, the team explained, new drugs might replace existing therapies rather than expand treatment options, potentially causing approved treatments such as Scenesse to disappear from the market due to reduced profitability. Without direct comparisons before approval, patients could ultimately be left with treatments that are less safe or less effective than those already available, according to the researchers.
Such trial designs also raised ethical concerns. The researchers noted that international ethical guidelines, including the Declaration of Helsinki, recommend testing new drugs against the best available existing treatment, which in EPP is Scenesse, rather than relying on placebo alone.
Beyond the lack of appropriate comparators, the team found that trials often enrolled different types of patients and assessed very different outcomes. For example, Scenesse trials focused on how long patients could remain in sunlight without pain, while MT-7117 studies measured the time to early warning symptoms after light exposure, and bitopertin and cimetidine trials assessed reductions in PPIX levels.
A major unmet need for children and adolescents
Another major gap was the lack of pediatric studies. Many trials focused primarily on adults, despite the urgent unmet need in younger patients. The researchers noted that MT-7117, bitopertin, and cimetidine are oral drugs that can be dose-adjusted based on body weight, making trials in children more feasible.
Based on their findings, the researchers proposed several specific changes to how EPP trials are designed.
For therapies that act through the same biological pathway, such as Scenesse and MT-7117, the authors argued that head-to-head trials would be both scientifically and ethically preferable to placebo-controlled studies.
The researchers also highlighted innovative trial designs, including adaptive trials that allow an early switch from placebo to active treatment. These approaches, they wrote, could reduce patient burden while still generating meaningful comparative data. They also proposed master protocol trials, which test several drugs for the same disease within a single, shared study framework.
“We wrote this manuscript as a call to action,” the researchers wrote, urging that “improving the design of trials assessing new pharmacotherapies for EPP is necessary and possible.”
