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.
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:
- systemic photoprotection to skin cells;
- optimisation of the response of skin cells to UV radiation;
- anti-oxidative capacity;
- elimination of photoproducts (chemical damage to DNA);
- increased activity of DNA repair genes (as part of NER and/or BER); and
- reduction of cell death (apoptosis) following UV exposure.
SCENESSE® (afamelanotide 16mg) 'DNA Repair' - Staged R&D to date
Short-term safety, repeat-dose toxicology
Proof of concept - human subjects
Long-term safety study in clinical trials (20 years)
Mid-term safety commercial use (4 years)
Scientific evidence DNA repair
Clinical evidence in
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.
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.
DNA Repair Communiqué I: The DNA Repair Communiqué series explores the world of the cell and provide key insights into the significance of DNA repair. This first Communiqué forms an introductory foundation, outlining fundamental aspects of cell biology and the significance of DNA repair to human survival. With this shared understanding, subsequent Communiqués will explore more detailed topics, including the role of DNA repair in oncogenesis and ageing.
DNA Repair Communiqué II: The second installation in the DNA Repair Communiqué series delves deeper into the topic of DNA synthesis and repair. It establishes the fundamentals of how DNA is synthesised, focusing on the role of DNA polymerases, and reviews how cells cope with damage to the DNA template, using translesion DNA synthesis (TLS).
Launch of novel DNA Repair Development Program to confirm the ability of SCENESSE® (afamelanotide 16mg) to repair damaged DNA and investigate its use as a treatment for xeroderma pigmentosum (XP). Read the announcement.
Update released on the use of SCENESSE® (afamelanotide 16mg) in the first XP-C patient receiving treatment as part of the Company’s DNA Repair Program. Read the announcement.
SCENESSE® DNA repair study in healthy volunteers (CUV151) approved. Read the announcement.
CLINUVEL announced on 5 October 2021 that it has received the necessary regulatory and ethics committee approvals to commence a new study in patients with the rare DNA repair disorder Xeroderma Pigmentosum (XP). The Phase II study (CUV156) will evaluate the safety of SCENESSE® (afamelanotide 16mg) in XP-C patients, as well as the drug’s ability to assist reparative processes following ultraviolet (UV) provoked DNA damage of the skin.
CLINUVEL announced the first XP patient treated in DNA Repair Study CUV156 on 22 October 2021.
CLINUVEL announced the expansion of the DNA Repair Program to the second group of xeroderma pigmentosum patients (XP-V) in the CUV156 study. Read the announcement.
CLINUVEL announced that the first disease-free subjects have received afamelanotide as part of the CUV151 mechanistic study to demonstrate the drug’s potency as a DNA reparative agent. Read the announcement.
The first xeroderma pigmentosum variant (XP-V) patient to receive afamelanotide treatment in the third active study in the Company’s DNA Repair Program (CUV152) was announced on 30 March 2022.
CINUVEL released the first results of the Phase II study (CUV156) evaluating afamelanotide in patients with XP. Analyses showed a decrease in ultraviolet (UV) light-induced DNA skin damage following treatment. Read the announcement here.
CINUVEL released the first positive results from a study evaluating the protective effects of afamelanotide on skin exposed to ultraviolet (UV) radiation (CUV151). Read the announcement here.
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