Product Candidate: QRX003

QRX003 is under development as a potential therapy for the treatment of Netherton Syndrome (NS). The product is a once-daily topical lotion comprised of a broad-spectrum serine protease inhibitor, formulated with the proprietary Invisicare® delivery technology.

Netherton Syndrome (NS)

Netherton Syndrome – a rare, hereditary skin disorder – is an autosomal recessive genetic disease caused by a mutation in the SPINK5 gene (serine protease inhibitor, Kazal Type 5) leading to severe skin barrier defects and recurring infections, as well as a pronounced predisposition to allergies, asthma and eczema. Patients also often suffer from severe dehydration, chronic skin inflammation and stunted growth.

The SPINK5 gene, when behaving normally, encodes a protein, called Lympho-Epithelial Kazal Type Related Inhibitor or LEKTI, that serves to regulate the activity of certain skin proteases, called Kallikreins, that are responsible for the normal everyday process of skin shedding. For patients with NS, the LEKTI protein is absent due to the mutation of the SPINK5 gene. The effect of this absence of the LEKTI protein is unregulated hyperactivity of the Kallikreins which in turn results in uncontrolled desquamation and leads to a highly porous and defective skin barrier.

People with Netherton Syndrome have too few layers of their outer skin (stratum corneum) so the skin does not perform its primary function as a protective barrier. This leads to the increased risk of infections, warts, skin cancer and irritation by allergens and other environmental microorganisms. The skin is prone to scaling and is accompanied by hair anomalies, along with increased susceptibility to atopic eczema. Pruritus (itching) is a major problem as well as elevated IgE antibody levels. Furthermore, because the skin is so compromised, patients experience trans-epidermal water loss (TEWL), and adults can lose up to 2 quarts of water a day. In infants and children, TEWL can result in a failure to thrive and delayed or stunted growth.

Currently, there is no cure for Netherton Syndrome, nor are there any approved therapeutic treatments. What is available, such as skin moisturizers, are currently limited to providing symptomatic relief. Due to the highly compromised skin, even the selection of an appropriate moisturizer can be challenging. For example, moisturizers typically used for skin barrier repair, such as those containing lanolin and petrolatum, can cause further skin damage to NS patients due to friction or high shear forces upon application or removal. Topical steroids may have harmful rather than helpful effects and can further reduce the thickness of the skin barrier. Incidences of Cushing’s Syndrome have also been reported from the use of topical steroids. Other standard topical treatments, such as calcineurin inhibitors, can lead to dangerously high systemic blood levels due to the defective skin barrier.

QRX003: Tailored Treatment

QRX003, a topical lotion, offers a combination of a broad-spectrum serine protease inhibitor formulated with the proprietary Invisicare® technology.

When applied daily to the skin, the active ingredient in QRX003 performs the function of the missing LEKTI protein and down regulates, but does not completely stop, the activity of the Kallikreins, leading to a more normalized skin shedding process and the formation of a stronger and more effective skin barrier. The serine protease inhibitor in QRX003 also acts as a potent anti-inflammatory and antioxidant. The Invisicare® delivery technology offers immediate protection against TEWL and environmental agents. Uniquely this technology both moisturizes the skin while providing a protective barrier.

In addition to Netherton Syndrome, QRX003 is being developed for the following additional rare disease indications:

Peeling Skin Syndrome

Due to mutations in the TGM5 gene, inherited in an autosomal recessive pattern, this disorder is characterized by the continuous painless peeling of the top layer of skin. It can appear as abnormal blistering of the skin anywhere on the body, but most often presents on the hands and feet. Symptoms can include pruritus (itching), hyperpigmentation, and redness. Incidence is less than one in one million.

SAM Syndrome

Presents with severe skin dermatitis, multiple allergies and metabolic wasting (SAM). This is a rare life-threatening inherited condition caused by mutations in the desmoglein1 gene.

Palmoplantar Keratoderma

This condition causes thickening of the skin on the hands and feet and can be either inherited or acquired. Patients may experience pain when walking, excessive foot odor and/or sweating, along with reduced sensation of fingers or toes. Incidence is 4.4 cases per 100,000.

Product Candidate: QRX008

VLA-4 inhibition for treatment of Scleroderma

Systemic sclerosis (Scleroderma) is a multisystem, autoimmune disorder defined by progressive vascular, inflammatory, and fibrotic dysfunction. It is characterised by an early inflammatory phase, which is followed by progressive fibrosis of varying extent and distribution, resulting in severe dysfunction of involved organs. Interaction of vascular cell adhesion molecule 1 (VCAM-1) with its ligand, very late antigen 4 (VLA-4), is a key process in inflammatory disease. There is an established genetic and clinical link for VCAM-1 in Scleroderma, with VCAM-1 having a genome-wide association with Scleroderma, and Scleroderma patients having elevated VCAM-1 serum levels. VLA-4, an α1β4 integrin, plays a pivotal role in controlling immune cell migration into inflamed tissue as it directly participates in cell arrest under flow. The VCAM-1:VLA-4 interaction therefore makes an attractive target for therapeutic intervention in Scleroderma. A lead series of small molecule inhibitors has been developed to disrupt the VCAM-1:VLA-4 interaction. Proof of concept has been demonstrated with VLA-4 inhibition in the Tsk1/+ mouse model of Scleroderma. Further preclinical assessment is underway for the selection of a lead compound for entry into the clinic in 2023.

Product Candidate: QRX007

QRX007 is a bi-functional protein designed to be highly selective and potent inhibitor of the KLK5 and KLK7 kallikreins at nanomolar concentrations as a potential treatment for Netherton Syndrome.

Netherton syndrome (NS) is an autosomal recessive skin disorder with severe skin inflammation, scaling, constant allergy and specific hair defection. NS is caused by dysfunctional mutations in the LEKTI-encoding SPINK5 gene resulted in complete loss or reduction of LEKTI activity. As LEKTI is a key regulator of epidermal proteolytic activity, loss or reduction of LEKTI activity leads to hyperactivity of serine proteases, including KLK5, KLK7 and KLK14, and subsequent over-degradation of corneodesmosomes by these proteases. Therefore, skin sections of NS patients show thinning and detachment of the stratum corneum and partial or complete loss of the stratum granulosum. Further, KLK5 is postulated to activate phospholipase A2, possibly via the PAR-2 pathway, leading to release of inflammation-mediating prostaglandins. KLK7 is also postulated to stimulate inflammatory effects in NS by activation of pro-inflammatory cytokine interleukin-1β (IL-1β). It has been demonstrated that KLK5/KLK7 double knock-out mice are protected from developing NS, potentially validating KLK5/KLK7 dual inhibition as an important therapeutic goal.

Product Candidate: QRX004

Epidermolysis Bullosa

Epidermolysis Bullosa (EB) is a group of rare and genetic skin disorders in which the skin is so fragile, even minor trauma or friction can have devastating results, causing severe pain, blistering, scarring, infections, chronic wounds and immobility. Patients can experience agonizing, traumatic and time-consuming daily dressing changes. Severe forms of EB cause disfigurement, disability and early death. Recessive Dystrophic (RDEB) is a form of dystrophic EB. RDEB is a monogenic disease resulting in chronic skin blistering and wounding. Marked by devastating, progressive, painful blistering, RDEB is diagnosed at infancy and accompanied by a high mortality rate – 76% do not live beyond their 30s. The cost of bandaging alone can exceed $10,000 per month. The cause of RDEB is a mutation in the COL7A1 gene that encodes for COL7. There is no cure or approved treatment for EB

Also formulated with the Invisicare® technology, QRX004 is a topical lotion initially under development as a potential treatment for Recessive Dystrophic Epidermolysis Bullosa (RDEB).

QRX004 contains two active ingredients. The primary ingredient induces a read-through of nonsense mutations and leads to creation of robust and sustained type VII collagen. The result is improved wound closure, reduced blistering and stronger skin.