麻豆传媒

When the FDA approved the first treatment specifically for erythropoietic protoporphyria (EPP) in 2019, it was "really the first ray of hope."

Before afamelanotide, "there was just a therapeutic desert," said Tasneem F. Mohammad, MD, who helped start the EPP program at the Henry Ford Health System in Detroit.

The rare genetic disorder causes overproduction of protoporphyrin by the bone marrow, which leads to painful burning and itching when the skin is exposed to light.

Diagnosis and Management

"During this pain reaction, really nothing helps," noted Manisha Balwani, MD, interim chief of medical genetics and genomics at the Icahn School of Medicine at Mount Sinai in New York City. "Patients can use cold compresses or antihistamines and steroids, but nothing is really helpful. Pain medications are not helpful."

Despite the distinctive symptoms, patients typically learn to adapt to avoid sun exposure early in life, so diagnosis of the disorder takes on average about 15 years, Balwani noted.

Diagnosis rests on total blood porphyrin (both metal-free protoporphyrin and zinc protoporphyrin) levels that are five to 50 times the upper limit of the normal range. Choosing a good laboratory is important, Balwani said. Some measure only zinc protoporphyrin "but label it, misleadingly, as 'free protoporphyrin,'" which isn't diagnostic, as a review in the noted.

Once the diagnosis is made, patients and their families can be advised to avoid the peak wavelength of light that excites porphyrin and triggers symptoms, which is in the blue range on the visible spectrum and can pass through window glass or even come from fluorescent bulbs.

Prevention

Physically blocking the light by covering the skin or using a zinc oxide type of sunblock (not a chemical sunscreen that blocks only ultraviolet light) can prevent symptoms.

Afamelanotide, a melanocortin-1 receptor agonist, is indicated to increase pain-free light exposure for adults with EPP. The subcutaneous implant increases production of photo-protective eumelanin.

In a , the pain-free time spent in direct sun was substantially longer with the drug (median 64 vs 40 hours over 180 days). In the parallel trial from the European Union, pain-free time outside during peak sun exposure hours was also significantly longer with afamelanotide (median 6.0 vs 0.75 hours over 9 months).

While the U.S. trial didn't show a significant impact on phototoxic reactions, the EU trial showed that getting an implant every 60 days roughly halved these reactions compared with placebo. Both trials showed improved quality of life.

Challenges

However, the drug hasn't been as widely adopted as it might have been, experts noted.

For one, "there has been a lot of controversy about afamelanotide because the initial clinical trials weren't as clear-cut that there was benefit for patients. So I think centers are hesitant to jump on board," said Jennifer Hand, MD, a geneticist and pediatric dermatologist at the Mayo Clinic in Rochester, Minnesota, an expert center for porphyrias. "Complicating that is that it is an implant. You have to have a doctor that is willing to do an invasive procedure for something that might not have as much evidence that it's helpful as you would like."

In addition, access has been limited to selected by drugmaker Clinuvel Pharmaceuticals to administer it.

For Hand, that means that patients must travel some 70 miles to the nearest site that can insert the subcutaneous implant.

Balwani was one of the lead investigators on the U.S. clinical trials at a center that sees perhaps the most patients with EPP in the country, yet neither her site nor any other in the New York metropolitan area was selected. The nearest site for her patients is hours away in Boston.

Afamelanotide is "not easily accessible for all patients," she noted, especially presenting challenges for out-of-town travel during the COVID-19 pandemic. "It can be really limiting."

Clinuvel responded that it has increased the number of centers dispersed across the country trained to administer the drug, which it noted is a "simple subcutaneous injection" typically performed by a nurse.

"In establishing its Specialty Center network for an ultra-rare disorder, Clinuvel has sought to ensure that no patient is more than five hours' drive away from accessing treatment, and consistently works to improve this," the company told 麻豆传媒. "To the Company's knowledge, no patient is currently unwilling or unable to access treatment due to their proximity to a Specialty Center."

Mohammad's center did get selected as one of the administration sites, after participating in the U.S. trial, and has treated some two dozen EPP patients with afamelanotide.

"It's been a really incredible learning experience and very gratifying to see what these patients have gone through before afamelanotide was approved and see the changes in their quality of life since they have been able to receive it," she told 麻豆传媒. "Everyone is getting some benefit from the medication, it's just the degree of that pain-free time in the sun varies by severity [of their EPP]."

Her experience has been that the benefits are greater than seen in the U.S. trial results.

When her patients were in the trial, they had told her they were very hesitant to expose their skin to the sun because of how bad their reactions usually were, she said. Now, her patients tell her they are pushing their boundaries on sun exposure further because they have experienced freedom from painful reactions while on the drug.

That clinical portrait fit the findings of a published last year in JAMA Dermatology. Among 117 patients in Europe on afamelanotide after market approval there, the increase in pain-free time in the sun averaged 1.41 hours per week more per year on treatment, rising to 6.14 hours more per week -- more than seen in the clinical trial.

"From a very young age, patients with EPP become conditioned to avoid direct sunlight owing to the painful attacks, and such conditioned behavior changes slowly over time if symptoms remain," the authors wrote.

Future Prospects

Another drug, dersimelagon, is in development as an orally administered agent with a mechanism of action similar to afemelanotide. A is underway in adults together with patients as young as 12.

An agent for pediatric use would be helpful, Hand noted. "In general in the pediatric age group, there is a tremendous amount of light exposure for most people compared to adults," she said. "For children, it's harder to cover them up entirely. It's harder to completely change their schedule ... as they are growing and developing."

While an oral agent would be appealing for patients, Balwani agreed, neither afemelanotide nor dersimelagon tackle the cause of EPP.

"Of course, it's great to have therapeutic options," she concluded. "What we really need for the porphyrias are disease-modifying therapies to change the course of the disease."

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