Pharmaceutical
Division

DNA Repair Program

Every day we are exposed to wavelengths of light – both ultraviolet (UV) and High Energy Visible (HEV) light – which damage the DNA located within the nucleus of our skin cells. The human body has developed protective and reparative responses to photodamage, yet there are many groups of individuals within our societies who exhibit defective and inefficient DNA repair responses.

It is estimated that, globally, two billion individuals are susceptible to accelerated photodamage, leading to premature ageing and, ultimately, chronic skin damage with an increased risk to various forms of skin cancer. UV (including HEV) exposure is, worldwide, the external factor commonly acknowledged as the leading cause for developing skin cancers; three forms of carcinogenesis (basal cell, squamous cell and melanoma) dominate, and it is estimated in the western world that between 2 to 5 million new cases are diagnosed every year, although numbers for Asia, Latin America and Africa remain less accurate.

CLINUVEL has uniquely identified several untreated and unserved groups at the highest risk of skin cancers and photodamage, and is developing products and solutions for these populations, divided into three categories:

Group A

Immune-suppressed and -compromised patients

i. Immune-suppressed patients (receiving long term immune-suppressive drugs, cancer patients, auto-immune diseased, etc)

iii.Organ transplant recipients (also receiving a mix of immune-suppressing therapies)

iii. Patients receiving immune-modulatory drugs (new class of therapies for auto-immune disorders and specific cancers)

Group B

Genetically disadvantaged populations

iv. Red-hair-blue-eyes-freckled individuals of Anglo-Saxon descent (MC1R defective)

v. Individuals with a history of, and propensity to, frequent sunburns

vi. Individuals with a family history of skin cancers (Gorlin Syndrome, Actinic Neoplasia Syndrome, melanoma, actinosis, Dubreuilh Syndrome and others)

Group C

General Populations at Extreme Risk

vii. Outdoor workers living near the equator or under the ozone hole (AU-NZ-Pacific)

viii.Professional sportswomen and -men, extreme sporters exposed to reflective surfaces: water, desert, snow/ice.

There are more eligible patient populations, but the distinction provided generally covers CLINUVEL’s addressable segments of the populations.

CLINUVEL intends to address these three groups and subsegments, dividing these further in distinct therapeutic opportunities and commercial markets. CLINUVEL is the first company to focus and dedicate its resources to these segments to serve the various populations. With a methodological, planned and staged approach to address unserved need in these three populations, the Group is releasing communication and educational campaigns to reach the populations at risk, while raising awareness.

CLINUVEL’s communications and marketing output are aimed at providing information on specific physical and behavioural risks, needs and prospective solutions for the categorised populations. Online news will be disseminated through frequent and periodic educational campaigns to reach the widest possible relevant audiences. The Company’s competitive advantage is based on its technological and scientific expertise and knowhow established over four decades of devotion.

The Company has established a leading position in the medical and scientific community, and its standing in the field is expected to facilitate the launch of prescriptive and healthcare (non-prescriptive) products for the benefit of the three categories.

In comparison, few companies globally have established this particular footprint, and it is expected that CLINUVEL will be able to obtain a leading position in specialised care.

CLINUVEL’s DNA Repair Program is focussed on confirming the pharmacological properties of melanocortins, including its drug SCENESSE® (afamelanotide 16mg) to assist in the reparative process of UV-induced DNA damage.

Melanocortins, including afamelanotide, have been shown to maximise the biological function of skin cells following UV-radiation and exposure, as well as to repair subsequent DNA damage. CLINUVEL is publishing in its step wise approach the progress of its DNA Repair Program including the instruments, measures and methodologies to evaluate DNA damage, repair, and regeneration. Naturally, in protecting CLINUVEL’s knowhow and intellectual property, not all details of the programs are discussed.

Some of the methodologies rely on in-vitro data, others on preclinical and clinical data following standardised testing and simulated UV irradiation and exposure under environmental conditions.
CLINUVEL has explored and published many of its methodologies during the Scientific Communiqué series. The reader is referred to these series.

A significant focus of the DNA Repair Program is on patients with the most acute and highest need, born with the genetic condition xeroderma pigmentosum (XP), with healthy volunteers of fair skin complexion serving as control groups.

XP is a group of eight rare disorders causing extreme UV intolerance leading to skin cancers, defects in development and neural disease. Compared to the general population, XP patients have been shown to have a 1,000 to 10,000-fold increased risk of developing skin cancer(s). Some of the XP populations have a limited life span (median 30 years) due to metastasis of cancerous cells. Thus far, there is no remedy, prevention or cure for XP.

In March 2021, CLINUVEL announced an expansion to its DNA Repair Program focussing on treating patients with XP variant (XP-V), as well as those with XP-C.

XP-V and XP-C comprise an estimated 20% and 40%, respectively, of the global XP patient population.
In XP-C patients the defect in a DNA repair mechanism (nucleotide excision repair or NER) is the cause of phototoxicity, UV intolerance and development of skin cancers. XP-V patients have a genetic defect leading to an inability to replicate damaged DNA (POLH gene), ultimately causing skin carcinogenesis. Both populations are in extremis prone to developing skin cancers following UV exposure.

Four studies have been announced in XP-C, XP-V and healthy volunteers, conducted by expert academics and physicians worldwide.

CUV150 and CUV151 are conducted simultaneously. CUV152 and CUV153 are planned to start in Q1 2022 and Q2 2022, respectively.

Clinical trials forming CLINUVEL’s current DNA Repair Program. The Program has been expanded to evaluate afamelanotide in XP-V patients.
Table 1: Clinical trials forming CLINUVEL’s current DNA Repair Program. The Program has been expanded to evaluate afamelanotide in XP-V patients.

Treated groups will receive afamelanotide in various frequencies and doses for a duration of up to four months. Skin samples (biopsies) of UV-exposed skin areas will be taken for laboratory analyses of DNA damage before and after drug administration. Patients will be frequently monitored, including complete skin examinations before and during treatment. Quality of life questionnaires will assist in evaluating the possible impact of the treatment on patients’ wellbeing and daily functioning.

To date, the COVID pandemic has had an impact on the recruitment of XP patients in Europe, the United States and Latin America, since hospitals wish to minimise the risk to patients. It is expected that treatment will start as the COVID numbers decrease.

The map below shows the known populations and clusters of XP patients.

Known population clusters

If demonstrated to be safe and effective for XP, SCENESSE® would be the first drug worldwide for this group of unserved patients, and the first pharmaceutical therapy with proven evidence of impact on DNA regeneration.

CLINUVEL’s DNA Repair Program evaluates the widest range of populations at risk. Populations at highest risk of photodamage and skin cancers are XP patients, followed by EPP and immune-compromised patients. Healthy individuals at highest risk are those with a fair-skin complexion, Fitzpatrick skin type I and II, prone to burn and who prove melano-incompetent. CLINUVEL’s programs aim to launch complementary products (prescriptive and OTC) aiming to address all populations identified as high risk to photodamage and carcinogenesis.

Clinuvel
strategic update II
April 2021

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