LM-030 for Netherton Syndrome
Disease and Prevalence
Netherton Syndrome was first described by Comel in 1949 (1) and Netherton in 1958 (2). It is a severe autosomal recessive disease characterized by erythema and scaling, “bamboo hair” and immune system abnormalities (3).
Netherton Syndrome in newborns can be life-threatening due to a compromised skin barrier that leads to severe dehydration, hypernatremia, hypothermia, weight loss and sepsis. Failure to thrive is common in childhood as a result of chronic erythroderma, persistent cutaneous infection, malnutrition and metabolic disorders (4,5). Mortality rate has been reported from 10% to 40% in infancy (6,7). The severity of the skin condition may lessen somewhat as patients grow into adulthood, however, it remains serious and debilitating condition. Most Netherton Syndrome patients are also inflicted with immune system-related disorders such as food allergies and asthma.
Though the prevalence of Netherton Syndrome is not well documented, there is a reported worldwide birth incidence of 1 in 200,000 (8). The estimated number of patients in the US could be around 2,000, and in Europe, the number is estimated to be more than 2,000.
Pathogenesis and LM-030 Mechanism of Action
Netherton Syndrome is caused by loss of function mutations in the SPINK5 gene that encodes a serine peptidase inhibitor, Lympho-epithelial Kazal-type-related inhibitor (LEKTI) (1). The loss of LEKTI leads to dysregulation of epidermal proteases and severe skin barrier impairment. Kallikrien-related peptidases, such as KLK7, and the epidermal elastase 2 (ELA2), which are inhibited by LEKTI, are reported to play major roles in Netherton Syndrome pathology (9-11).
LM-030 exerts its therapeutic effect through the inhibition of both KLK7 and ELA2 activities, leading to skin barrier restoration.
Figure 1. Mechanism of action of LM-030
Current Treatment & Unmet Need
There is no approved treatment for Netherton Syndrome. Current approaches are all limited to symptom relief or supportive care with marginal efficacy and undesirable side effects. There is an urgent need for a targeted, effective and well-tolerated therapy. LM-030 has the potential to become the first of such agents.
Ready to enter into a pivotal trial, LM-030 is the most advanced targeted therapy in development for this devastating disease. It is well-positioned to be the first approved treatment for Netherton Syndrome.
Comel M, Dermatology 1949; 98:133-136
Netherton EW, Arch. Dermatol. 1958; 78:483-487
Bitoun E et al., Journal of Investigative Dermatology 2002; 118(2):352-361
Jones SK et al., Br. J. Dermatol. 1986; 114:741-743
Judge MR et al., Br. J. Dermatol. 1994; 131:615-621
Hoeger PH and Harper JI, Arch. Dis. Child 1998; 79:186-191
Hovnanian A, Expert Rev. Dermatol. 2012; 7(1):81-92
Hovnanian A, Cell Tissue Res. 2013; 351(2):289-300
Kasparek P et al., PLOS Genetics 2017; 13(1):e1006566
Caubet C et al., Journal of Investigative Dermatology 2004; 122:1235-1244
Bonnart C et al., Med. Sci. (Paris) 2010; 26(8-9):681-685
The image is reproduced with permission from JAMA Dermatology, 1999, 135 (7): 823-832. Copyright©1999 American Medical Association. All rights reserved.
Licensed from Novartis, LM-030 is a topical treatment ready to enter into a pivotal trial for Netherton Syndrome, a rare and severe monogenic skin disease that has no approved treatment.
LM-030, an inhibitor of kallikrein-related peptidase 7 (KLK7) and epidermal elastase 2 (ELA2), targets the underlying cause of Netherton Syndrome and is well positioned to become the first approved treatment for this debilitating and potentially life-threatening disease.
It has completed extensive preclinical testing and demonstrated positive proof of concept in a Phase 2a study in Netherton Syndrome.
LM-030 has fast track designation, orphan drug designation and rare pediatric disease designation from the FDA for the treatment of Netherton Syndrome. It also has orphan drug designation from the European Commission. The rare pediatric disease designation may entitle Lifemax to receive a pediatric rare disease priority review voucher upon LM-030 approval.