Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody‐mediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complement‐mediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase I, first‐in‐human, double‐blind, randomized, placebo‐controlled, dose‐escalation trial of single and multiple doses of sutimlimab or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of sutimlimab were well tolerated without any safety concerns. sutimlimab exhibited a steep concentration–effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 μg/mL. This study establishes the foundation for using sutimlimab as a highly selective inhibitor of the classical complement pathway in different diseases.

3D printers enable designers and makers to rapidly produce physical models of future products. Today these physical prototypes are mostly passive. Our research goal is to enable users to turn models produced on commodity 3D printers into interactive objects with a minimum of required assembly or instrumentation. We present Sauron, an embedded machine vision-based system for sensing human input on physical controls like buttons, sliders, and joysticks. With Sauron, designers attach a single camera with integrated ring light to a printed prototype. This camera observes the interior portions of input components to determine their state. In many prototypes, input components may be occluded or outside the viewing frustum of a single camera. We introduce algorithms that generate internal geometry and calculate mirror placements to redirect input motion into the visible camera area. To investigate the space of designs that can be built with Sauron along with its limitations, we built prototype devices, evaluated the suitability of existing models for vision sensing, and performed an informal study with three CAD users. While our approach imposes some constraints on device design, results suggest that it is expressive and accessible enough to enable constructing a useful variety of devices.

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Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially lifethreatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one-compartment model with first-order rate of absorption and linear clearance, showing slow absorption and a long half-life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect-response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti-inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady-state minimum concentration (C min,ss ; 25.4 μg/mL) that was ~ 4.5-fold higher than the half-maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure-response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE. Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease with an estimated prevalence of 1 in 50,000. 1 It manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Swelling may last several days, and most patients have multiple attacks per year. 2 Symptoms usually begin during childhood, sometimes as young as age 2 years, and persist throughout life. 2 HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1-INH), resulting in deficiency of C1-INH protein or function. 3 C1-INH is involved in regulating the contact, complement, and coagulation

RATIONALE: Efficacy of lanadelumab in preventing HAE attacks was demonstrated in the phase 3 HELP Study (NCT02586805) and ongoing OLE (NCT02741596). Findings from an exploratory analysis evaluating efficacy by baseline HAE attack rate are presented, reflecting cumulative results through 31August18.. METHODS: Patients with ≥1 attack/4 weeks at baseline who continued from the HELP Study (rollovers) received a single 300mg lanadelumab dose on Day 0, then 300mg every 2 weeks (Q2W) after their first attack (regular dosing stage). Patients who were not HELP Study participants (nonrollovers) with ≥1 historical attack/12 weeks received 300mg Q2W from Day 0. Monthly HAE attack rate (regular dosing stage for rollovers; from Day 0 for nonrollovers) was evaluated by baseline rates of <1, 1 to <2, 2 to <3, or ≥3 attacks/month. RESULTS: In 212 patients (rollover, n5109; nonrollover, n5103), baseline HAE attack rate was <1 for 11.8% (0 rollovers, 25 nonrollovers); 1 to < 2 for 34.9% (35 rollovers, 39 nonrollovers); 2 to <3 for 14.2% (19 rollovers, 11 nonrollovers); and ≥3 for 39.2% (55 rollovers, 28 nonrollovers) of patients. With lanadelumab treatment, median (range) reductions in HAE attack rate from baseline were-92.2% (-100.0%, 852.8%) for baseline attack rate <1;-100.0% (-100.0%,-32.4%) for baseline attack rate 1 to <2;-98.1% (-100.0%,-21.7%) for baseline attack rate 2 to <3; and-96.5% (-100.0%,-32.4%) for baseline attack rate ≥3. CONCLUSIONS: Treatment with lanadelumab produced marked reductions in monthly HAE attack rates regardless of baseline attack frequency, consistent with the results of the pivotal study.