Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial

Abstract

BackgroundDalazatide 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.ObjectiveThe 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.MethodsPatients (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.ResultsThe 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.LimitationsThe study was small and drug treatment was for a short duration (4 weeks).ConclusionThis 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.

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…Toxicity studies with PAP‐1 and the peptidic K V 1.3 blocker ShK‐186 have so far not revealed any toxicity despite 6 months or 28 days of continuous administration in rats or rhesus macaques 4, 8. PAP‐1 has further completed IND‐enabling toxicity studies, while ShK‐186 has passed both IND toxicity studies and Phase‐1 safety studies without any adverse findings 6, 9…”

“…4,8 PAP-1 has further completed INDenabling toxicity studies, while ShK-186 has passed both IND toxicity studies and Phase-1 safety studies without any adverse findings. 6,9 In conclusion, we are proposing Kv1.3 inhibitors as novel potential therapeutics for reducing secondary inflammatory damage in ischemic stroke by preferentially targeting "M1-like" microglia functions. Following this first pharmacological proof-of-concept study, PAP-1 and other small molecule Kv1.3 blockers should be further explored in alternative stroke models, that for example establish reperfusion with alteplase to increase translatability to human stroke, and also be studied in females and animals with comorbidities.…”

“…Based on these encouraging target validation studies, ShK-186, now called Dalazatide, was moved into clinical trials, where it exhibited no major safety findings in Phase-1a and showed efficacy in Phase-1b studies in plaque psoriasis and is now being developed further. 9 In addition to T-cells, Kv1.3 is also expressed in microglia, where in vitro experiments with rodent microglia have shown the channel to be involved in inflammatory cytokine and nitric oxide production and in microgliamediated neuronal killing. [10][11][12][13][14] Electrophysiological experiments on slices 15 or acutely isolated microglia 16 have further demonstrated Kv1.3 currents on activated microglia following MCAO.…”

Immune drug discovery from venoms

“…The Dalazatide peptide recently underwent clinical trials in psoriasis and the patients showed an improvement of this condition. The clinical trial data has now been published (Tarcha et al, 2017)…”

“…For example, the ShK peptide from the venom of sea anemone inhibits the Kv1.3 ion channel in T effector memory (TEM) cells, producing decreased cell proliferation and suppression of IL-2 production ( Beeton et al, 2005) . Furthermore, a derivative of ShK (dalazatide) recently completed a successful Phase I clinical trial in psoriasis patients (Tarcha et al, 2017) The systematic study of the venom components and their interaction with the immune system may reveal novel therapeutics for a plethora of human diseases and therapeutics against envenomation symptoms. Venoms are engaged by the immune system and a response is generated to counterbalance their effects.…”