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

<div><p>Background</p><p>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.</p><p>Objective</p><p>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.</p><p>Methods</p><p>Patients (<i>n</i> = 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.</p><p>Results</p><p>The most common adverse events were temporary mild (Grade 1) hypoesthesia (<i>n</i> = 20; 75% placebo, 85% dalazatide) and paresthesia (<i>n</i> = 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 (<i>P</i> < 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.</p><p>Limitations</p><p>The study was small and drug treatment was for a short duration (4 weeks).</p><p>Conclusion</p><p>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.</p></div

Individual TLIGA scores over time.

<p>Placebo group (A), 30 mcg/dose group (B), and 60 mcg/dose group (C). Dalazatide clinical activity shown as improvement in target lesion for a patient after 4 weeks of treatment from the 60 mcg/dose group (D). Individual TLIGA responses by baseline body weight in the 60 mcg/dose group at Day 32 (E). R = improvement in target lesion; NR = no improvement. Bars indicate mean body weight for each subgroup.</p

Consort flow diagram.

<p>Graphical outline of the design and conduct of the study.</p

Dalazatide treatment reduces the expression of activation markers HLA-DR, Ki67 and CD40L by memory T cells from psoriasis patients.

<p>(A, B) The proportion of CD2+ memory T cells from the peripheral blood from placebo (PAL) and dalazatide (DAL, 60 μχγ/dose) treated patient samples were analyzed for the proportion of the indicated subpopulation and the % change from Day 29 relative to Day 1 calculated. A) HLA-DR expression, B) Ki67 expression, C) CD40L expression after PMA/ionomycin treatment. Samples were collected on Day 1 pre-dose and Day 29 post-dose. The CD40L+ populations as a percentage of CD4+ or CD8+ memory T cells were measured following an <i>ex vivo</i> culture of PBMC with 0.2 nM PMA and ionomycin (250 ng/mL) or media alone for 6 hours. The percentage of cells expressing CD40L in response to PMA/ionomycin was calculated as: Í40L+(stimulated) = Í40L+(PMA+Ionomycin)-Í40L+(Media alone). Data represent the mean ± SEM of the % change from Day 29 relative to Day 1. Statistical analysis between placebo and dalazatide groups was performed using one-tailed Student’s t-test. *<i>P</i> < 0.05. **P<0.01</p

Individual PASI scores at baseline and Day 32.

<p>Placebo group (A), 30 mcg/dose group (B), and 60 mcg/dose group (C). <b>*<i>P</i> < 0.01, two-tailed student’s t-test.</b></p

Dalazatide inhibits multiple soluble mediators of inflammation associated with psoriasis.

<p>PL = placebo group; R = improvement in target lesion, NR = no improvement in target lesion 60 mcg/dose dalazatide group. Data represent mean ± SEM of the % change from Day 32 relative to baseline (Day 1). **<i>P</i> < 0.01, two-tailed student’s t-test.</p

Pharmacokinetic analyses.

<p>Individual values for total drug exposure based on mean C_max (A) and AUC_last (B) for both the 30mcg/dose group (closed circles) and the 60mcg/dose group (open squares). Individual drug exposure levels correlated with body weight for C_max (C) and AUC_last (D). Individual drug exposure levels from the 60 mcg/dose group separated by those who had an improvement in target lesion response, responders (open square), vs those who did not yet show improvement, nonresponders (hatched square) based on C_max (E) and AUC_last (F).</p

Percent change in PASI score.

<p>Change in PASI score for 60 mcg/dose group based on body weight above the median or below the median. Bars indicated mean % change in PASI.</p

Patient demographics and baseline disease characteristics.

<p>Patient demographics and baseline disease characteristics.</p

Body weight and percent change in PASI score of TLIGA responders and non-responders.

<p>Body weight and percent change in PASI score of TLIGA responders and non-responders.</p