For patients with erythropoietic protoporphyria (EPP), a rare blood disorder, exposure to sunlight, even indoor lighting, can be extremely painful. With the European Medicines Agency's (EMA's) recommendation in November to approve Clinuvel's Scenesse (afamelanotide), synthetic peptide analog of α-melanocyte-stimulating hormone (α-MSH), EPP patients may no longer be forced to choose between painful photosensitivity and social isolation. The fact that the drug works “is one of the biggest surprises of my career,” says Robert Sarkany, a dermatologist and EPP expert at Guy's and St. Thomas's in London. “I was so skeptical [of the drug] that I was very reluctant for my patients to take part in the trial, and they didn't take part in the trial. I was wrong, and they'll sure enough get it now,” he says. The European Commission has yet to finalize the approval of the drug but usually does so within months of a recommendation from the EMA. Once approved, adult patients with the most severe disease will be first in line, because of lingering risks of long-term effects.

Clinuvel's new drug stimulates pigment production in melanocytes. Credit: Jacopin/BSIP/Science Source

In EPP, a deficiency in the ferrochelatase enzyme involved in the heme biosynthesis pathway leads to abnormal tissue build-up of protoporphyrin, a key component of heme. When accumulated protoporphyrin is exposed to light, it releases free oxygen radicals that degrade lipids, cross-link membrane proteins, and induce erythrocyte hemolysis and endothelial cell damage and inflammation. This phototoxic reaction in skin exposed to light can be severe and painful.

Clinuvel, based in Melbourne, Australia, tested Scenesse in three phase 3 placebo-controlled trials in a total of 258 EPP patients. Clinuvel CEO Philippe Wolgen says Scenesse-treated patients were able to experience significantly more pain-free sun exposure than placebo-treated patients (over 180 days, a median of 116 hours versus 61 hours). The most common adverse events were headache and nausea. Results from two of the trials have been submitted for peer review and will be published in 2015.

Scenesse is delivered through a rice-grain-sized bioabsorbable implant placed under the skin. The drug interacts with the melanocortin 1 receptor (MC1R) to stimulate melanin production, which protects from UV radiation and prevents protoporphyrin excitation. MC1R also modulates the expression of various antioxidants that may be able to mop up the harmful free radicals. Pigment production also gives individuals a tan. But Sarkany attributes most of the effect to this antioxidant activity. The tanning effect could be a red herring, he says, mainly because people with dark skin can also have EPP. Clinuvel thinks both pathways are important.

But Sarkany, who reviewed the clinical data for the EMA, notes that although the EPP trials were properly conducted, they are susceptible to bias. Not only are EPP endpoints like sun exposure and pain measurements prone to bias, but because Scenesse is a tanning agent, it unblinds the trials.

In this case, however, the biases may under-represent the benefit of the drug. “The trial data look okay, but what we are hearing from patients is so much more clear-cut,” says Sarkany. Some patients, he says, report a “mind blowing” increase in how long they can spend in the sun, with the benefit persisting for years in some patients who stayed on treatment after the trials completed. “I don't like anecdotal stuff normally, but it is striking because it is entirely different to anything else I've experienced in my life,” he says. Patients have spent their whole lives developing lifestyles that let them avoid the sun, he adds, and because old habits die hard short-term trials with behavioral endpoints might not best capture the full magnitude of benefit of the drug.

Clinuvel plans to file for approval in the US in 2015. The company estimates that there are 5,000 to 10,000 EPP patients worldwide. The company has yet to issue market expectations, but says that the drug will be priced in line with other orphan drugs. The biotech is also developing Scenesse as a re-pigmentary agent for vitiligo, a much more common condition.