Giamarellos-Bourboulis, Evangelos J

Abstract Background The results of a previous phase IIa trial suggested efficacy of the anti-C5a compound vilobelimab in a small number of patients with severe hidradenitis suppurativa (HS) refractory to adalimumab treatment. Objectives To study the efficacy of vilobelimab in a larger-scale randomized phase IIb trial (SHINE) of patients with moderate-to-severe HS. Methods In total, 177 patients with moderate-to-severe HS were treated either with placebo or one of four doses of vilobelimab, a monoclonal antibody that targets the complement split product C5a. Hidradenitis Suppurativa Clinical Response (HiSCR) at 16 weeks was the primary endpoint. Those who achieved HiSCR switched to open-label low-dose vilobelimab; those who did not were switched to medium-dose vilobelimab. The trial was registered with the EU Clinical Trials Register (EudraCT number 2017-004501-40) and ClinicalTrials.gov (NCT03487276). Results The study did not meet the primary endpoint, perhaps due, in part, to an unexpectedly high HiSCR placebo response rate of 47.1%. HS flares decreased and post hoc analysis showed that high-dose vilobelimab significantly decreased the median draining tunnel counts and IHS4 score by 63%. Following the switch to medium-dose vilobelimab at week 16, 45.5% of those who did not respond to treatment achieved HiSCR at week 40. Conclusions Compared with placebo, vilobelimab treatment did not result in significant HiSCR improvements in patients with moderate-to-severe HS. Post hoc analysis revealed significant effects for the highest tested dose on draining tunnel reduction and IHS4 score, which captures reductions in draining tunnels. These findings warrant further investigation.

Abstract Background The SUNSHINE and SUNRISE phase III trials demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. Patients completing the core trials could enter a 4-year extension trial. Objectives To evaluate the long-term efficacy, safety/tolerability and maintenance of clinical response to secukinumab through week 104 in the extension trial. Methods Patients with a hidradenitis suppurativa (HS) clinical response (HiSCR) at week 52 of the core trials (extension trial baseline visit) entered a randomized withdrawal period. HiSCR responders receiving subcutaneous secukinumab 300 mg every 2 or 4 weeks (SECQ2W/SECQ4W) through week 52 in the core trials were randomized 2 : 1 to continue secukinumab (SECQ2W-R-Q2W or SECQ4W-R-Q4W) or receive placebo (SECQ2W-R-PBO or SECQ4W-R-PBO) through week 104. The primary endpoint was time to loss of response (LOR; newly defined for this trial) through week 104 in week 52 HiSCR responders (SECQ2W-R-Q2W vs. SECQ2W-R-PBO and SECQ4W-R-Q4W vs. SECQ4W-R-PBO). Time to LOR was tested at 1.25% (one-sided) for each comparison (one-sided familywise alpha of 2.5%) through week 104. If LOR was met, patients could remain in the trial on open-label secukinumab treatment. Additional endpoints included safety and HiSCR. The trial was registered with ClinicalTrials.gov (NCT04179175). Results Overall, 84.3% of patients who completed the core trials entered the extension trial; 55.9% were week 52 HiSCR responders. The primary endpoint was not met for either secukinumab dosing regimen. The estimated risk reduction for LOR was 13% (SECQ2W-R-Q2W vs. SECQ2W-R-PBO; one-sided P = 0.25) and 30% (SECQ4W-R-Q4W vs. SECQ4W-R-PBO; one-sided P = 0.04). The median time to LOR was numerically longer in the secukinumab arms vs. placebo {SECQ2W-R-Q2W [283 days; 95% confidence interval (CI) 176, –] vs. SECQ2W-R-PBO [239 days; 95% CI 120, –]; SECQ4W-R-Q4W [365 days 95% CI 225, –] vs. SECQ4W-R-PBO [171 days; 95% CI 113–337]}. In week 52 HiSCR responders reporting LOR, 44% (SECQ2W-R-Q2W), 58% (SECQ2W-R-PBO), 40% (SECQ4W-R-Q4W) and 34% (SECQ4W-R-PBO) were achieving HiSCR at the time of LOR. Overall, the safety of secukinumab was consistent with the core trials. Conclusions The primary endpoint of this trial was not met. HiSCR was maintained in many patients at the time of LOR. The safety of secukinumab was consistent with the previously characterized safety profile in the core trials.

Abstract Many patients in the emergency department present with signs and symptoms that arouse concern for sepsis; however, other explanations are also possible. There are currently no rapid tests used in clinical practice that reliably distinguish the presence of a bacterial or viral infection vs. a non-infectious etiology and can predict a patient’s likelihood to decompensate. The diagnostic and prognostic uncertainty in “gray zone” patients complicates the decision to begin therapy as clinicians need to balance the risk of withholding therapy vs. the risk of the therapy itself (e.g., overtreatment with antibiotics and hospitalization, which is costly, potentially harmful, and contributes to antibiotic resistance). The TriVerity™ Test uses isothermal amplification and machine-learning algorithms to quantify and interpret mRNA expression levels to determine both likelihood of bacterial infection, viral infection, or no infection, and whether the patient will likely require one or more critical interventions within 7 days. The three scores each fall into one of five interpretation bands ranging from Very high to Very low. Testing takes approximately 30 minutes using the proprietary Myrna™ Instrument with an operator hands-on-time of under one minute. We enrolled 1,222 patients from 22 emergency departments (ED) to validate the performance of the TriVerity Test. Patients were treated as per local standard of care and were followed for 28 days. Bacterial and viral TriVerity results were validated against clinically adjudicated infection status; the illness severity TriVerity result was validated against the need for at least one critical interventions within 7 days. The bacterial TriVerity result had high AUROC for the diagnosis of bacterial infection (0.83; 80% CI 0.81–0.85) and divided bacterial infection likelihood scores into five interpretation bands with increasing likelihood ratios of infection ranging from Very low (LR- 0.08, 80% CI 0.06–0.11) to Very high (LR + 8.04, 80% CI 5.72–11.78). The AUROC for the bacterial TriVerity result was significantly higher compared to AUROCs for C-reactive protein, procalcitonin or white blood cell count. Similarly, the viral TriVerity score showed high AUROC for the diagnosis of viral infection (0.91; 80% CI 0.90–0.93) and likelihood ratios from Very low (LR- 0.09, 80% CI 0.05–0.14) to Very high (LR + 40.93; 80% CI 29.11–79.23). The TriVerity Illness Severity score showed a high AUROC for the prediction of illness severity (0.77; 80% CI 0.77–0.81) with scores divided into five interpretation bands with increasing likelihood ratios ranging from Very low (LR- 0.22; 80% CI 0.14–0.33) to Very high (LR + 11.33; 80% CI 7.31–17.00). TriVerity illness severity results allowed marked re-classification of the risk for “ICU-level care” as compared to clinical assessment (qSOFA scores) alone. In conclusion, TriVerity provides rapid, highly accurate and actionable results for the diagnosis and prognosis of patients with suspected acute infection and/or sepsis, supporting a major unmet medical need. TriVerity may improve personalized management of patients with suspected acute infections and suspected sepsis for improved overall healthcare outcomes.