Pharmaceutical
Division

Strategy and Planning: DNA Repair Program

PHOTOPROTECTION FIRST

The need to photoprotect patients and individuals at highest risk had been considered for decades, however until 2014 no prior therapeutic solution was found. With the introduction of SCENESSE^® as a systemic photoprotective drug in Europe in 2014, in the United States in 2019, and Australia in 2020, the basis of CLINUVEL’s long-term strategy was laid.

Systemic photoprotection by using afamelanotide indicates, the:

1.formation of a temporary physical skin barrier

2.attenuation of UVA, UVB and HEV exposure (radiation)

3.protection of the nucleus of cells (“supra-nuclear cap”)

4.reduction of UV damage (radical oxygen species)

5.optimisation of the cellular response (MC1R signalling)

6.switch of the eumelanin:pheomelanin ratio in favour of protective eumelanin

7.increase of detoxifying properties (chelative function)

8.reduction of tissue-water following damage (extravasation, oedema)

9.optimisation of tissue response (NFκB)

10.optimisation of vascular (capillary) response in damaged tissues (MC1R-MC4R)

The first clinical and pharmacological focus has been to demonstrate the benefits of afamelanotide and melanocortins in photodermatoses (light-induced diseases) such as polymorphic light eruption and solar urticaria.

CLINUVEL successfully evaluated and validated systemic photoprotection as a medicinal therapy in the most severe group of patients suffering from light emitted along the visible (HEV) and invisible spectrum, those diagnosed with a genetic haem defect expressed as erythropoietic protoporphyria (EPP).

DNA REPAIR AS SECOND FOLLOW-ON

By identifying the most severely affected group of patients diagnosed with a defect in cellular DNA repair mechanisms, CLINUVEL set out to provide the final piece of evidence on the properties of afamelanotide as a hormonal therapy to photoprotect and assist the repair of single strand DNA defects caused by UV exposure (UVB induced DNA damage). The group of patients evaluated is diagnosed with the genetic disease xeroderma pigmentosum (XP).

Patients suffering from two variants – XP-C and XP-V – have been identified as potentially benefiting most from the systemically administered (through the blood circulation) afamelanotide therapy.

In administering afamelanotide to XP patients, the DNA-reparative objectives are not only to achieve the 10 criteria as defined above under systemic photoprotection, but also to demonstrate

1.reduction of photoproducts (chemical bonds within a single DNA strand)

2.reduction in cell death (apoptosis of epidermal cells)

3.increase in cellular response to initiate and accelerate repair (proteins, complementation factors)

4.increase in enzymatic activity

5.increase in melanogenic response (skin pigmentation)

6.decrease in UV-intolerance, and burn(s)

The strategy has been to first focus on those most severely affected patients who express insufficient DNA repair. In parallel, CLINUVEL is expanding the use of melanocortins and associated technological knowhow and expertise in pharmaceuticals serving the groups at risk of photodamage (see three categories of populations in the DNA Repair Program section).