Afamelanotide (Scenesse)

Number: 0962

Policy

Aetna considers afamelanotide (Scenesse) medically necessary for the treatment of biochemically confirmed erythropoietic protoporphyria in adult members who have protoporphyrin above the lab reference range in peripheral red blood cells. 

Aetna considers continued treatment with afamelanotide medically necessary in adult members who are experiencing benefit from therapy while receiving afamelanotide.

Aetna considers afamelanotide experimental and investigational for all other indications.

Dosing Recommendations

Scenesse is available as a 16 mg implant.

Scenesse should be administered by a healthcare professional who is proficient in the subcutaneous implantation procedure and has completed training prior to administration.

A single implant, containing 16 mg of afamelanotide, is inserted subcutaneously above the anterior supra-iliac crest every 2 months using an SFM Implantation Cannula or other implantation devices that have been determined by the manufacturer to be suitable for implantation of Scenesse.

Source: Clinuvel, Inc. 2020.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• 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.

Erythropoietic protoporphyria (EPP) is an autosomal recessive inherited cutaneous porphyria characterized by severe burning pain in the skin within minutes of sun exposure, but leaving little residual skin damage. This photosensitivity is usually first noted in early childhood and may be misdiagnosed as an allergic reaction or primary angioedema. The predominant clinical manifestation in EPP and XLP is painful, non-blistering cutaneous photosensitivity that differs distinctly from the chronic, blistering skin manifestations of the other cutaneous porphyrias. Hepatobiliary complications include protoporphyrin-containing gallstones and, in less than 5 percent of cases, severe liver failure. The cutaneous phenotype can result from altered activity of one of two enzymes in the heme biosynthetic pathway, either a deficiency of ferrochelatase (FECH), which causes EPP; or a gain-of-function mutation of the erythroid-specific form of delta-aminolevulinic acid synthase (ALAS2), which causes X-linked protoporphyria (XLP). Impairment of the FECH enzyme results in the build-up of protoporphyrin in the bone marrow, red blood cells, blood plasma, skin, and eventually liver. Build up of protoporphyrin can cause extreme sensitivity to sunlight, liver damage, abdominal pain, gallstones, and enlargement of the spleen (Poh-Fitzpatrick 2016). An acquired, adult-onset form of EPP has also been described, in which a clone of cells with mutated FECH expands in the setting of a myeloproliferative or myelodysplastic syndrome. The term "protoporphyria" includes both EPP and XLP (Mittal 2019). All forms of Porphyria afflict fewer than 200,000 people in the United States (American Porphyria Association) .

Although the upper limit of normal can vary with age and among laboratories, the values in patients with EPP are markedly elevated, to approximately 300 to 8000 mcg/dL. If total erythrocyte protoporphyrin is elevated, the total should be fractionated, and so that the relative proportion (or amounts) of zinc protoporphyrin versus metal-free protoporphyrin can be derived. In EPP and most cases of XLP, the excess is predominantly metal-free protoporphyrin, whereas in other conditions, it is mostly zinc protoporphyrin.  The defining laboratory manifestation of EPP is a marked elevation of total erythrocyte protoporphyrin that is mostly metal-free (85 to 100 percent metal-free protoporphyrin); the defining finding in XLP is marked elevation of total erythrocyte protoporphyrin that is approximately 50 to 85 percent metal-free protoporphyrin (Mittal 2019).

Historically, the primary measures to manage EPP has been to avoid sunlight or fluorescent light, which can greatly impair daily activities and quality of life. Other forms of photoprotection and other interventions include protective clothing, hats, and protective tinted automobile window glass. Several small studies and case series also reported increased tolerance to sunlight with beta-carotene, especially in the summer. The proposed protective mechanism is quenching of oxygen free radicals by beta-carotene (Mittal 2019).

On October 08, 2019,  the Food and Drug Administration approved afamelanotide (Scenesse) to increase pain free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria (EPP). Afamelanotide is a synthetic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), a naturally occurring hormone that increases skin pigmentation by increasing melanin production, and reduces free radical formation and cytokine production. Afamelanotide, the first medication approved for the treatment of EPP, was granted priority review and orphan drug designation by the FDA and was approved for use in Europe in 2014 by the European Medicines Agency. The FDA approval of Scenesse was based upon the results from three vehicle-controlled, parallel-group clinical in subjects with EPP.

In 2010 CLINUVEL completed its first Phase III study of afamelanotide in patients with EPP (CUV017). A total of 91 patients completed the 12-month study, in which an 11-point Likert scale and physician assessments through case report forms (CRF) were used to evaluate pain as a principal symptom of phototoxicity. The duration of daily (sun)light exposure was used to assess the willingness of patients to expose themselves during all seasons. Melanin density (reflecting changes in skin pigmentation, measured by spectrophotometry) and quality of life (Short Form 36 surveys) were also evaluated. In an analysis of the total number of days (frequency distribution) on which patients experienced pain in the specific pain severity categories (severe, moderate, mild and none), a significant reduction of frequency was observed in patients on active drug [p=0.0023]. Characteristic to EPP, the majority of phototoxic reactions occurred during spring and summer. In analyzing the average pain severity experienced by the total number of patients, the assessment of all individual daily pain scores was significantly lower in patients receiving afamelanotide compared to those receiving placebo [p=0.0017]. An additional evaluation of the pain scores in patients willing to modify behavior by continuous exposure to daily (sun)light showed a positive trend toward a reduction in average pain score following active drug treatment [p=0.1654] (Scenesse prescribing information 2019; Langendonk 2015).

Two trials (U.S. study CUV039, NCT 01605136;  and the EU Study CUV029, NCT 00979745) were designed to assess exposure to direct sunlight on days with no phototoxic pain. The two trials differed in the number of days of follow-up, the time windows within a day in which time spent outdoors was recorded, and how the amount of time spent in direct sunlight on each day was characterized. The subjects enrolled in these trials were primarily Caucasian (98%), the mean age was 40 years (range 18 to 74 years), and 53% of subjects were male and 47% were female (Scenesse prescribing information 2019; Langendonk 2015).

Study CUV039 enrolled 93 subjects, of whom 48 received 16 mg of afamelanotide administered subcutaneously every 2 months and 45 received vehicle. Subjects received three implants and were followed for 180 days. On each study day, subjects recorded the number of hours spent in direct sunlight between 10 am and 6 pm, the number of hours spent in shade between 10 am and 6 pm, and whether they experienced any phototoxic pain that day. The primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 am and 6 pm on days with no pain. The median total number of hours over 180 days spent in direct sunlight between 10 am and 6 pm on days with no pain was 64.1 hours for subjects receiving afamelanotide and 40.5 hours for subjects receiving vehicle.

Study CUV029 enrolled 74 subjects, of whom 38 received afamelanotide (16 mg of afamelanotide administered subcutaneously every 2 months), 36 received vehicle. Subjects received five implants and were followed for 270 days. On each study day, subjects recorded the number of hours spent outdoors between 10 am and 3 pm, whether “most of the day” was spent in direct sunlight, shade, or a combination of both, and whether they experienced any phototoxic pain that day. The primary endpoint was the total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight. This analysis does not include sun exposure on days for which subjects reported spending time in a combination of both direct sunlight and shade. The median total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight was 6.0 hours for subjects in the afamelanotide group and 0.75 hours for subjects in the vehicle group.

In this review, Stölzel et al (2019) state physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development (Stölzel 2019).

In this review, Minder et al (2017) state afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone. Afamelanotide was the first α-MSH analogue to be applied to human volunteers. Ten daily doses of between 0.08 and 0.21 mg/kg in saline injected subcutaneously resulted in long-lasting skin pigmentation and enabled basic pharmacokinetics. Subcutaneous application had full bioavailability, but neither oral nor transdermal application resulted in measurable plasma concentrations or pigmentation response. Two trials in human volunteers showed that neither MC1R variants nor fair skin reduced the afamelanotide-induced increase in skin pigmentation. A controlled-release formulation optimizes administration in man and is effective at a lower dose than the daily saline injections. Promising therapeutic results were published in polymorphic light eruption, erythropoietic protoporphyria (EPP), solar urticaria, Hailey-Hailey disease and vitiligo. In 2014, afamelanotide was approved by the European Medicines Agency for the prevention of phototoxicity in adult patients with EPP. No late effects were reported in volunteers 25 years after the first exposure or after continuous long-term application of up to 8 years in EPP patients, and an immunogenic potential has been excluded. Generally, adverse effects were benign in all trials (Minder 2017).

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. Scenesse may induce darkening of pre-existing nevi and ephelides due to its pharmacological effect. A regular full body skin examination (twice yearly) is recommended to monitor all nevi and other skin abnormalities.  (Scenesse prescribing information 2019).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
HCPCS codes covered if selection criteria is met:
J7352	Afamelanotide implant, 1 mg
ICD-10 codes covered if selection criteria are met:
E80.0	Hereditary erythropoietic porphyria

The above policy is based on the following references: