Remetinostat for the treatment of cutaneous T-cell lymphoma (CTCL)
Cutaneous T-cell lymphoma (CTCL) is an orphan disease. Remetinostat is expected to be an important additional treatment option for patients who suffer from this cancer, and the dermatologists who treat them.
Mechanism of Action
Remetinostat is a novel histone deacetylase inhibitor (HDAC) being developed for topical use for the treatment of CTCL. It was designed to be active in the skin in order to treat the disease, but to be rapidly broken down and inactivated in blood, in order to limit the adverse effects associated with systemic exposure to HDAC inhibitors.
CTCL is an orphan disease in both the US and Europe. The annual incidence is 1,000-3,000 and has an estimated prevalence in the US of ~20,000, with similar numbers of patients in EU5. Approximately 75% of CTCL patients have early stage (IA-IIA) disease. In the early stages of CTCL the disease is confined to the skin and is predominantly indolent, with most patients remaining in this stage of disease for many years. While disease progression is slow for most patients with early-stage CTCL, their tumours result in significant morbidity and quality of life issues, including clinically significant pruritus (itch). Since they remain in this stage for an extended period they usually require long-term treatment. The 1st line of treatment for these patients is topical steroids of increasing strength. 2nd line treatment options are limited once steroids become ineffective, or when their side effects become limiting. The second-line options lack sustained efficacy and/or tolerability and are often highly irritating. Consequently there is a substantial level of unmet need in patients whose lesions are not responding to current therapy or who continue to experience side effects like clinically significant pruritus, especially for continuous and extended treatment over large lesion areas. Remetinostat is expected to have the potential to capture a significant market share based on its clinical profile balancing efficacy, safety and tolerability.
Positive top line data from the phase II study in early-stage CTCL patients were reported in April 2017. Based on an intent-to-treat analysis, patients in the 1% remetinostat gel BID arm had highest proportion of confirmed responses (8/20, 40%), including 1 complete response. The response rates in the other two arms were 5/20 (25%) and 4/20 (20%) in the 0.5% BID arm and the 1% QD arm respectively, and did not include any complete responses. Across all three dose groups, topical remetinostat was well-tolerated without signs of systemic adverse effects, including those associated with systemic HDAC inhibitors.
Based on the data from the phase II study, Medivir expects to initiate discussions with regulatory authorities with the aim of initiating a phase III study later this year, and to present full phase II trial data at scientific meetings in the second half of 2017.
Facts and figures
- Gene expression can be regulated by non-heritable (epigenetic) modifications of DNA, including acetylation of histones. HDAC enzymes regulate this epigenetic process by removing these acetylations from histones, and causing subsequent changes in gene expression that lead to altered cellular differentiation and anti-tumour effects.
- HDAC inhibitors have been approved for the treatment of late-stage CTCL, demonstrating the proof of concept of this mechanism of action. However, they cause a range of systemic toxicities that mean they cannot be used in early-stage disease. Thus there is a clear opportunity for remetinostat to provide benefit to early stage CTCL patients who cannot be treated with these systemic HDAC inhibitors.
- In the US the expected addressable market for early-stage CTCL is $900 million
- The early stages of the disease is confined to the skin:
- Stage IA involves <10% of skin
- Stage IB involves >10% of skin
- Stage IIA has stage IA or B skin involvement with additional limited involvement of lymph nodes