Date Published: July 19, 2017
Publisher: Public Library of Science
Author(s): Eric J. Tarcha, Chelsea M. Olsen, Peter Probst, David Peckham, Ernesto J. Muñoz-Elías, James G. Kruger, Shawn P. Iadonato, Heinz Wiendl.
Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis.
The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations.
Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires.
The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. The study was small and drug treatment was for a short duration (4 weeks). This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.
Dalazatide (previously referred to as ShK-186 and SL5) is a 37-amino acid synthetic peptide that is a specific inhibitor of the voltage-gated Kv1.3 potassium channel . It is a derivative of ShK, which was originally isolated from the venom of the sea anemone Stichodactyla helianthus . Human T cells rely on two potassium channels, Kv1.3 and KCa3.1 to maintain the calcium signaling required for their activation and differentiation, by maintaining a balance between calcium influx and potassium efflux. Chronically activated memory T cells that rely on upregulation of Kv1.3 expression for their effector function are sensitive to blockade by Kv1.3 inhibitors. These chronically activated memory T cells are key mediators of numerous autoimmune diseases, including psoriasis [3,4]. Other T cell subsets that upregulate the calcium-activated KCa3.1 channel upon activation are insensitive to blockade by Kv1.3 inhibitors . It has been demonstrated that in the effector memory T (TEM) cell population, the degree of Kv1.3 expression is a measure of cell activation, with greater Kv1.3 numbers/cell following repeated stimulation and that the channel is required for the maintenance of the TEM cell phenotype . These properties make Kv1.3 channels on T lymphocytes an attractive therapeutic target for autoimmune diseases (reviewed recently in ). Recent data suggest that the degree of Kv1.3 dependence is mediated by antigen exposure history, that chronically activated autoreactive T cells are primarily dependent on Kv1.3, and that conversion to Kv1.3 dependency is stable . Other lymphocytes, including class-switched memory B cells also depend upon Kv1.3 for activation, however their sensitivity to blockade by Kv1.3 inhibitors is still being explored . While various other cells of the immune system also express Kv1.3 channels, those cells express numerous K+ channels and are not sensitive to blockade by Kv1.3 inhibitors due to channel redundancy . In vivo studies with dalazatide in a delayed-type hypersensitivity model have shown that drug treatment inhibited the DTH response by suppressing TEM cells, but had no effect on naïve or central memory T cells . In addition, animals chronically treated with dalazatide are able to clear viral and bacterial infections similar to vehicle treated animals, while those treated with dexamethasone, which broadly suppresses the immune response have a significantly delayed clearance rate, further supporting the specific and immune sparing role of dalazatide .
Dalazatide has been evaluated for safety and tolerability in both healthy volunteers as well as patients with plaque psoriasis. No serious adverse events, discontinuations due to adverse events, or deaths occurred during this study and none have occurred during the clinical development program for dalazatide. Likewise, no drug-related trends in serum chemistry, hematology, urinalysis, or electrocardiography were noted in any clinical studies. The most common treatment-related adverse events for dalazatide were instances of paresthesia and hypoesthesia that were somewhat dose dependent. In a previous multiple-ascending-dose study (ClinicalTrials.gov NCT02446340), only a portion of patients in the 5 and 15 mcg/dose cohorts experienced paresthesia or hypoesthesia. Although highly variable within and between individuals, the median duration of paresthesia generally increased with increasing dose up to the 30 mcg/dose group, but not between the 30 and 60 mcg/dose groups. An evaluation of the number of individuals in each cohort that experienced paresthesia each week demonstrated that, in all but the 60 mcg/dose group, the fraction of individuals experiencing paresthesia and the maximum duration of paresthesia decreased over time within a group. Full neurological evaluations from the NCT02446340 trial, including mental status assessment, assessment of cranial nerves II‐XII (field of vision, extraocular movements, pupil function, facial sensation, masseter strength, facial movements, hearing, gag reflex, shoulder shrug, head turn against resistance and tongue movement), sensory examination including distal vibratory sensation, pronator drift, tendon reflexes, gait and coordination, were considered normal both in the presence of ongoing sensory‐related adverse events as well as once these events resolved.