DNA Repair

About DNA Repair​

As part of a staged clinical program, CLINUVEL has worked with global experts to identify and design clinical objectives which focus on clinically meaningful and relevant study endpoints, including assessment of DNA photoproducts (chemical reactions within DNA strands), repair of DNA damage, and evaluation of the treatment impact on patients’ quality of life.

Following treatment of the first patient with xeroderma pigmentosum (XP-C) under a Special Access Program, the DNA Repair Program will proceed with an open label Phase II study involving six XP-C patients (CUV150) and a control study enrolling 10 healthy volunteers (CUV151), whereby clinical and histological (skin biopsies) evaluation of afamelanotide treatment will be undertaken in both groups.

Details of the sponsored studies CUV156 and CUV151 will be released as they are finalised.

DNA Damage
and Repair​

Ultraviolet (UVB of wavelengths 290-320 nm and UVA of 320-400 nm) and high energy visible (HEV, 380-500 nm) light penetrate human skin leading to cellular oxidative stress and damage to DNA within the nucleus of skin cells. This damage consists of changes to the DNA structure (photoproducts) which, if left unrepaired, can replicate and increase the risk of skin cancers, such as melanoma.

Under normal conditions, human biology is capable of repairing DNA damage through nucleotide excision repair and/or base excision repair (NER and BER, respectively), in which defective strands of DNA are “snipped” and removed, and replaced by the correct DNA sequences. XP patients, organ transplant recipients and people of Anglo-Saxon origin with red hair, blue eyes and fair skin are at the highest risk of developing skin cancers because they have either insufficient or defective NER and BER, i.e. a reduced capacity to repair damaged DNA.

Scientific evidence supports the use of afamelanotide, the active ingredient in SCENESSE®, for photoprotection and repair of UV-induced DNA damage.

During the development of SCENESSE®, a number of categories of scientific evidence have been accumulated:

  1. systemic photoprotection to skin cells;
  2. optimisation of the response of skin cells to UV radiation;
  3. anti-oxidative capacity;
  4. elimination of photoproducts (chemical damage to DNA);
  5. increased activity of DNA repair genes (as part of NER and/or BER); and
  6. reduction of cell death (apoptosis) following UV exposure.

Figure 1:
SCENESSE® (afamelanotide 16mg) 'DNA Repair' - Staged R&D to date

Stage R&D Description

1

Short-term safety, repeat-dose toxicology

2

Proof of concept - human subjects

  • reduction in apoptosis (cell death) following UV radiation

3

Long-term safety study in clinical trials (20 years)

4

Mid-term safety commercial use (4 years)

5

Scientific evidence DNA repair

  • in vitro, ex-vivo data
  • reduction in apoptosis in humans

6

Clinical evidence in

  • XP (clinical evaluation)
  • healthy volunteers (clinical evaluation)

Figure 1 illustrates how the DNA Repair Program has placed emphasis on the safety of patients and volunteers exposed to afamelanotide – more than 10,000 doses in over 1,400 subjects – during 20 years of clinical use, a requisite to being able to complete the clinical use of the hormone as a DNA restorative drug in patients at the highest risk of contracting skin cancers.

Stages S1 to S5 have been evaluated by the Company and regulatory authorities as satisfactory and complete, enabling Stage 6 of clinical investigation in the scope of SCENESSE® as a DNA-regenerative pharmaceutical therapy. Clinical stage S6 consists first of a Special Access Program in XP to confirm the safety of the drug in this highest-risk population, followed by a pilot study in XP-C (CUV150), and a parallel control study in healthy volunteers (CUV151) who are exposed to UV radiation under standardised conditions.

The exact biochemical and cellular mechanisms of UV-induced cellular damage and repair by SCENESSE® are explained in technical terms in Figure 2, attached below.

Click to enlarge the image

Additional
resources

SCIENTIFIC COMMUNIQUÉ X: Photoprotection and The Significance of the Minimal Erythema Dose (MED) Testing. Developing new and effective photoprotectants are paramount to curbing the ever-rising rates of skin cancer and lowering mortality rates worldwide. Yet we must have effective methods in place which can accurately assess the benefit of these therapies. This communiqué, examines the application of one of these assessment methods, Minimal Erythema Dose (MED).

SCIENTIFIC COMMUNIQUÉ IX: Beyond Pigment; The Melanocortin 1 Receptor (MC1R) in DNA Repair, details the role of the MC1R in DNA repair following light damage to our skin. It references how molecules such as afamelanotide can be used to manipulate the MC1R system and, in turn, act as one preventive strategy towards skin cancer.

SCIENTIFIC COMMUNIQUÉ VIII: DNA Repair Mechanisms, answers what human DNA repair mechanisms and why are they relevant in maintaining skin health.

SCIENTIFIC COMMUNIQUÉ VI: Understanding the mechanisms behind solar-radiation-induced DNA damage is a crucial step in reducing the rising incidence of skin cancer. In SCIENTIFIC COMMUNIQUÉ VI: Ultraviolet Radiation Damage and Oxidative Stress in Skin Cancer, CLINUVEL reviews the clinical significance of skin cancer as a disease and looks closely at the aetiology behind its formation.

References

  • Black JO. Xeroderma pigmentosum. Head and neck pathology. 2016 Jun;10(2):139-44.
  • Haddadeen C, Lai C, Cho SY, Healy E. Variants of the melanocortin‐1 receptor: do they matter clinically?. Experimental dermatology. 2015 Jan;24(1):5-9.
  • Green AC, Olsen CM. Increased risk of melanoma in organ transplant recipients: systematic review and meta-analysis of cohort studies. Acta dermato-venereologica. 2015 Nov 1;95(8):923-7.
  • Sinha RP, Häder DP. UV-induced DNA damage and repair: a review. Photochemical & Photobiological Sciences. 2002;1(4):225-36.
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