December Horizon Scanning Research & 2016 Intelligence Centre

Afamelanotide 16mg Implant (SCENESSE) for generalised – first line in combination with narrow-band ultraviolet B light (NB-UVB)

NIHR HSRIC ID: 6667

Lay summary Afamelanotide is a new drug to treat generalised vitiligo. Vitiligo is a long-term condition where white patches develop on the skin, because of a lack of pigment in the skin. This condition may cause significant psychological distress. Afamelanotide is administered as an implant once every 28 days with NB-UVB light therapy administered 2-3 times per week. If licensed, afamelanotide may offer an additional treatment option for patients with this condition.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Generalised vitiligo: adults; stable or slowly progressing; with 10-50% of total body surface involvement – first line; in combination with narrow-band ultraviolet B light (NB- UVB).

TECHNOLOGY

DESCRIPTION

Afamelanotide (SCENESSE; [Nle4,D-Phe7]-alpha-MSH; CUV-1647; EPT-1647; melanotan I; melanotan) is a structural analogue of endogenous alpha--stimulating hormone (α-MSH), which is formulated as a bioresorbable implant. Afamelanotide acts as an agonist at the 1 receptor, activating the synthesis and transport of eumelanin. Afamelanotide may facilitate repigmentation and proliferation of from melanocyte reservoirs and is also believed to have antioxidant and immunomodulatory properties.

In a phase II clinical trial, afamelanotide 16mg implant was administered subcutaneously (SC) once every 28 days for a total of 6 implants in combination with NB-UVB light administered 3 times per week, for a total of 72 treatments1.

Afamelanotide implant (as SCENESSE) has Marketing Authorisation in the EU for the prevention of phototoxicity in adult patients with erythropoietic protoporphyria2. The most common adverse events with SCENESSE are nausea, headache, and mild reactions at the implant site, such as discoloration, pain and redness, which affects around 1 in 5 patients. SCENESSE must not be used in patients with reduced liver or kidney functions2.

INNOVATION and/or ADVANTAGES

If licensed, afamelanotide may offer an additional treatment option for patients with generalised vitiligo.

DEVELOPER

Clinuvel Pharmaceuticals Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase II clinical trials.

PATIENT GROUP

BACKGROUND

Vitiligo is an acquired, chronic depigmentation disorder that manifests as white macules on the skin, which increase in size over time, and may cause significant psychological stress3. Vitiligo is classified into segmental vitiligo and vitiligo (referred to in the past as nonsegmental vitiligo), which includes the most common form of the condition, generalised vitiligo, that accounts for 85-90% of people with this condition4. Vitiligo can affect any area of Horizon Scanning Research & Intelligence Centre

the skin, but most commonly occurs on the face, neck, extremities and in the skin creases5. Generalised vitiligo presents with a widespread distribution of macules, and is usually symmetrical4. Depigmentation mainly occurs due to the loss of functioning melanocytes in the skin. The cause is not clearly understood, but the aetiology includes genetic, environmental, autoimmune, and viral factors6,5.

CLINICAL NEED and BURDEN OF DISEASE

Vitiligo indiscriminately affects 1-2% of the general population, and is more commonly diagnosed in women and people with darker skin pigmentation4. In the UK, about 1 in 100 people develop vitiligo, and while around half of people are affected before the age of 20, it can occur at any age3,5. Vitiligo is a disease that significantly impairs quality of life, but the degree of impact at the population level depends to some extent on the ethnic make-up of the population7. In Western Europe, the proportion of people who have diagnosable psychiatric morbidity associated with the condition is estimated to be between 25-30%; however in India, the proportion of people with vitiligo and an associated psychiatric morbidity is estimated to be between 56-75%8.

The population likely to be eligible to receive afamelanotide could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE medical technology guidance. The ReCell spray-on skin system for treating skin loss, scarring and depigmentation after burn injury (MTG21). November 2014.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for Specialised Dermatology Services (All Ages). A12/S/a.

Other Guidance

• Primary Care Dermatology Society. Vitiligo. 20169. • NICE Clinical Knowledge Summary. Vitiligo. 20164. • European Dermatology Forum. Guidelines for Vitiligo. 20148. • British Association of Dermatologists. Guidelines for the management and diagnosis of vitiligo. 200810.

CURRENT TREATMENT OPTIONS

Currently there is no cure for vitiligo and no effective treatments that promote repigmentation and/or halt its progression with lasting effects3.Therapies currently used in adults include:3,4,8,9 • Topical treatment – potent or highly potent corticosteroids, vitamin D analogues, and calcineurin inhibitors (e.g. or , used mainly for the face and neck area as an alternative to topical steroids). These should be taken for a period no longer than 3 months.

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• Phototherapy – NB-UVB phototherapy for adults whose disease cannot be managed with topical treatments, have widespread vitiligo, or have localised vitiligo associated with a significant impact on their quality of life. NB-UVB should be used in preference to oral psoralen combined with ultraviolet A light (PUVA). However, no consensus exists as to the optimum duration of phototherapy, and practice varies widely. • Psychological support and counselling. • Surgical treatments for sites where there have been no new lesions, no extension of the lesion in the past year, and no Koebner phenomenon.

Treatment results vary between individuals4. NB-UVB phototherapy is the most effective treatment for patients with moderate to severe condition, however none are optimal and more therapeutic interventions for vitiligo are needed10.

EFFICACY and SAFETY

Trial NCT01382589, CUV101, NCT01430195, CUV102; CUV103; afamelanotide or EudraCT:2011-000169-10; afamelanotide and NB- placebo, both with NB-UVB afamelanotide with NB- UVB light therapy vs NB- light therapy; phase II. UVB light therapy vs NB- UVB light therapy only; UVB light therapy only; phase II. phase II. Sponsor Clinuvel Pharmaceuticals Clinuvel Pharmaceuticals Clinuvel Pharmaceuticals Status Completed. Completed. Ongoing.

Source of Trial registry1. Publication11, trial Press release13. information registry12, and manufacturer. Location France, Italy and USA. Singapore. Switzerland. Design Randomised, active- Randomised, active- Randomised, placebo- controlled. controlled. controlled. Participants n=15; aged ≥18 yrs; n=56; aged ≥18 yrs; n=21 (planned); aged ≥21 confirmed diagnosis of confirmed diagnosis of yrs; Fitzpatrick skin types III generalised vitiligo with 15- generalised vitiligo with and VI; confirmed diagnosis 50% of total body surface 15-50% of total body generalised vitiligo with 15- involvement; stable or surface involvement; 50% of total body surface slowly progressive vitiligo stable or slowly involvement; stable or over a 3-month period; progressive vitiligo over a slowly progressive vitiligo Fitzpatrick skin types III-VI; 3-month period; over a 3-month period; no vitiligo involving the Fitzpatrick skin types III- vitiligo involving head and hands and feet only; no VI; no vitiligo involving the neck; no vitiligo involving extensive leukotrichia; no hands and feet only; no the hands and feet only; no vitiligo of ≥5 yrs duration; extensive leukotrichia; no extensive leukotrichia; no no treatment with NB-UVB vitiligo of ≥5 yrs duration; treatment with NB-UVB within 6 mths; no allergy to no treatment with NB- within 6 weeks; no allergy afamelanotide, the polymer UVB within 6 mths; no to afamelanotide, or contained in the implant, or allergy to afamelanotide, lignocaine/lidocaine or lignocaine or lignocaine/lidocaine or other local anaesthetic /lidocaine or other local other local anaesthetic used during administration; anaesthetic used during used during no treatment with topical administration; no administration; no immunomodulators treatment with topical treatment with topical (corticosteroids, calcineurin immunomodulators immunomodulators inhibitors) within 4 wks. (corticosteroids, calcineurin (corticosteroids, inhibitors) within 4 wks. calcineurin inhibitors) within 4 wks.

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Schedule Randomised to Randomised to Randomised to afamelanotide16mg implant afamelanotide 16mg afamelanotide 16mg administered (SC) once implant administered SC implant administered SC every 28 days for a total of once every 28 days for a once every 28 days for a 6 implants in combination total of 4 implants in total of 6 implants in with NB-UVB light therapy combination with NB-UVB combination with NB-UVB administered 3 times per light therapy administered light therapy administered week for 6 mths; or NB- 3 times per week for 6 twice weekly; or placebo in UVB light therapy mths; or NB-UVB light combination with NB-UVB administered 3 times per therapy administered 3 light therapy administered week for 6 mths. times per week for 6 twice weekly. mths. Follow-up 6 mths follow-up after the 6 mths follow-up after the 3 month follow-up after the treatment period. treatment period. treatment period. Primary Time to onset of Pigmentation of full body, Pigmentation of full body, outcome/s repigmentation of full body, face, trunk and face, trunk and extremities face, trunk and extremities. extremities using the using the VASI and VETF VASI and VETF scores. scores. Secondary Pigmentation measured by Time to onset of Time to onset of outcome/s Vitiligo Area Scoring Index repigmentation of full repigmentation of full body, (VASI) and Vitiligo body, face, trunk and face, trunk and extremities; European Task Force extremities; maintenance maintenance of (VETF) scores; of pigmentation using the pigmentation measured by maintenance of VASI and VETF scores. VASI and VETF scores; pigmentation measured by DLQI; safety; vitiligo quality of life measured by VASI and VETF scores; biopsies (at selected the Vitiligo Quality of Life quality of life using the study sites). (VitiQoL); safety. Dermatology Life Quality Index (DLQI); safety. Key results Not reported. The extent of Preliminary results repigmentation in the available only for combination therapy combination therapy n=4 group was significantly and NB-UVB monotherapy greater than observed in n=3. Results to date show the NB-UVB monotherapy increased repigmentation in group (VASI, p=0.025); the combination treatment; pts who received change in VASI score combination therapy indicate a positive trend in achieved earlier favour of combination repigmentation than those treatment (p=0.052 at day receiving NB-UVB 168); improvement in monotherapy (overall average VASI score was median time 43 days vs greater for the combination 68 days, p=0.086; 95% group after the second CI; time to repigmentation afamelanotide dose for the of the face 41.0 vs 61.0 trunk, lower and upper days, p=0.001; time to extremities; pts with repigmentation of the Fitzpatrick skin types V and upper extremities, 46.0 vs VI showed a good clinical 69.0 days, p=0.003; a response to the subset analysis of the combination treatment. VASI scores showed significantly better, more complete and deeper repigmentation in patients with the darkest skin complexion (phototype IV- VI, n=24) who had received the combination

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therapy compared to those on monotherapy (p=0.046; 95% CI).

Repigmentation following treatment with combination therapy remained higher than with NB-UVB monotherapy at 11 mths (p=0.032; 95% CI); repigmentation for the combination group was maintained at the 11 mth follow-up, vitiligo did not reoccur. Adverse Not reported. The most common No serious AEs were effects (AEs) treatment emergent AEs reported in the preliminary reported were cutaneous analysis. All reported AEs including: erythema in 19 to date have been in line pts in the combination with previous clinical therapy group (68%) and experience. 22 pts in the NB-UVB monotherapy group (82%). The most common adverse drug reactions (ADRs) in the combination group consisted of nausea (18%) and fatigue (11%). Other events included: hyperpigmentation (7%) and pruritus (7%). Expected Study completion date Study completion date Study completion date reporting reported as Sept 2016. reported as Apr 2016. reported as Q1 2017. date

ESTIMATED COST and IMPACT

COST

The cost of afamelanotide 16mg implant (SCENESSE) is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: improved quality of life for patients or  No impact identified carers.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other: staff or training needs.  None identified

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Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Clinical.Trials.gov. A phase II randomised pilot study to compare the efficacy and safety of subcutaneous, bioresorbable afamelanotide implants and narrow-band ultraviolet B (NB-UVB) light in the treatment of nonsegmental vitiligo. www.clinicaltrials.gov/ct2/show/NCT01382589 Accessed 7 November 2016. 2 European Medicines Agency. Afamelanotide (SCENESSE). www.ema.europa.eu Accessed 7 November 2016. 3 Manga P, Elbuluk N and Orlow SJ. Recent advances in understanding vitiligo. September F1000 Research 2016;5(F1000 Faculty Rev):2234. 4 NICE Clinical Knowledge Summary. Vitiligo. February 2016. 5 NHS Choices. Vitiligo. www.nhs.uk/conditions/vitiligo/Pages/Introduction.aspx Accessed 7 November 2016. 6 Vitiligo Society UK. What is vitiligo? - The causes. www.vitiligosociety.org.uk/index.php/what-is- vitiligo/the-causes.html Accessed 15 November 2016. 7 Krishna GS, Ramam M, Mehta M et al. Vitiligo impact scale: an instrument to assess the psychosocial burden of vitiligo. Indian Journal of Dermatology Venereology and Leprology 2013 Mar-Apr;79(2):205-210. 8 Taieb A, Alomar A, Böhm M et al. Guidelines for vitiligo. Vitiligo European Task Force (VETF) in cooperation with the European Academy of Dermatology and Venereology (EADV) and the Union Européenne des Médecins Spécialistes (UEMS). December 2014. 9 Primary Care Dermatology Society. Vitiligo. July 2016. www.pcds.org.uk/clinical-guidance/vitiligo Accessed 15 November 2016. 10 Gawkrodger DJ, Ormerod AD, Shaw L et al. Guidelines for the management and diagnosis of vitiligo. British Journal of Dermatology 2008;159:1051-1076. 11 Lim HW, Grimes PE, Agbai O et al. Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo. A randomised multicentre trial. JAMA Dermatology 2015;151(1):42-50. 12 Clinical.Trials.gov. Afamelanotide and narrow-band ultraviolet B (NB-UVB) light in the treatment of nonsegmental vitiligo (CUV102). https://clinicaltrials.gov/ct2/show/NCT01430195 Accessed 10 November 2016. 13 Clinuvel Pharmaceuticals press release. Preliminary results of Singaporean phase II study CUV103 in patients with naturally darker skin are consistent with results from previous US phase II trial CUV102. December 3, 2015. http://www.clinuvel.com Accessed 10 November 2016.

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