Treatment-related Safety Research Articles

Superselective ablative chemo-ethanol embolization for recurrent single hepatocellular carcinoma: a 6-month outcome analysis.

To evaluate the safety and effectiveness of superselective ablative chemo-ethanol embolization (SACE) for the treatment of patients with recurrent single hepatocellular carcinoma (rHCC). This retrospective study included 22 patients (19 men; median age, 63 years [range, 38-86]) with Child-Pugh class of A/ B/C (16/3/3) that underwent SACE between January and June 2023 for recurrent single HCCs measuring ≤5 cm in diameter using a mixture of 99% ethanol and ethiodized oil/doxorubicin emulsion. The primary endpoint was the 6-month tumor response, and the secondary endpoints were the 1-month tumor response and treatment-related safety. This study was approved by our institutional review board, and the requirement for informed consent was waived. SACE was successfully performed in 22 patients (95.2%). The complete response rates at 1-month and 6-month after treatment were 100.0% and 83.3%, respectively. At 6-month, local tumor progression occurred in one patient and intrahepatic distant metastasis was found in six patients (30.0%). No 6-month mortalities were reported. No adverse events greater than grade 2 or laboratory deteriorations were observed. Biliary complications or liver abscesses were not observed. SACE for a single rHCC was highly effective in achieving a favorable 6-month tumor response and showed acceptable adverse events. However, further prospective studies are required to verify these findings.

Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC): Preliminary findings.

LBA4132 Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and PD-1 blockade, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells, macrophages and NK cells, with induction of host-protective immunity. Methods: This is a phase II trial of BXCL701 in patients with metastatic PDAC (mPDAC) following progression on 1 line of treatment for advanced disease and amenable to serial biopsies. BXCL701 is administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all other cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks). We estimate that historical 2nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% if the true rate is 50%, we will need 19 patients in stage 1 and 20 in stage 2 (39 total). There is a safety lead-in phase of 6 patients. We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Correlative pharmacodynamic studies include imaging mass cytometry to examine 36 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q3 2023 (NCT05558982). Results: Six patients have enrolled, 3 women and 3 men, median age 57.5 (range 37-80). One patient was progression-free at 18 weeks and 1 patient had stable disease (SD) at 9 weeks, not yet evaluable for the 18-week landmark. Objective response rate is 16% and disease control rate is 50% (RECIST: 1 partial response, -41%, and 2 patients with SD, -18% and 0%). Three patients had significant reductions in CA19-9 from baseline (-100%, -73%, and -97%). Median PFS and overall survival have not been reached (NR, 95% CI 1.45 months-NR and 0.92 months-NR, respectively). There have been no serious treatment-related safety events. The safety lead-in will complete after the next patient completes the 6-week safety window (1 patient was unevaluable). Conclusions: BXCL701 plus pembrolizumab is well-tolerated and shows early signs of potential clinical activity in patients with mPDAC refractory to chemotherapy. Clinical trial information: NCT05558982 .

#1118 Direct delivery of novel gene therapy to podocytes enables pathway to clinical translation for the treatment of glomerular diseases

Abstract Background and Aims Adeno associated vector (AAV) gene therapy has the potential to treat a wide range of kidney diseases via the targeted delivery of genes to kidney cells to repair cellular and renal function. Despite the potential to impact many kidney conditions, kidney AAV gene therapy has proven challenging due to technical and physiological hurdles limiting the ability of AAV to be effectively delivered to podocytes. We have developed a novel AAV gene therapy, PS-001, and local method of administration, to effectively and safely deliver the podocin gene NPHS2 to podocytes. Biallelic NPHS2 mutations are the most common cause of monogenic childhood nephrotic syndrome. Curative efficacy and resolution of disease phenotype was demonstrated in transgenic murine models following PS-001 gene therapy treatment. The potential for translation of this approach to NPHS2 nephropathy patients in the clinic was also demonstrated in pre-clinical studies in Gottingen Minipigs. Method Transgenic murine models representative of NPHS2-driven nephropathy were treated with an AAV gene therapy encoding NPHS2, including a knock in mouse model (Nphs2R140Q/−) which introduces a R140Q mutation in the podocin gene. Mice were assessed for improvement in disease phenotype via analysis of proteinuria, serum albumin, renal histopathology and survival. Mice were treated with an analogue of PS-001, as the PS-001 capsid is not permissive in rodents. Gottingen minipigs were treated with PS-001 and followed for 4 weeks. Clinically relevant doses and a procedure for local administration specifically to the kidney were established. In-life safety assessments from blood and urine were monitored and at study end pig tissues were assessed for podocin biodistribution using multiple assays (qPCR, RT-qPCR, ELISA, RNAScope and IF) and for toxicological effects via histopathological analysis. Results Using our AAV gene therapy platform, which includes a capsid that is highly effective at transducing human podocytes and promoter that drives gene expression specifically in the podocyte, the gene therapy product PS-001 encoding NPHS2 was generated. Using a murine analogue of PS-001, in vivo proof of concept studies in a translationally relevant murine disease model (Nphs2R140Q/−) showed NPHS2 delivery and podocin expression in glomeruli and efficacy in terms of renal function rescue. This was demonstrated by resolution of severe proteinuria (mean ACR ug/mg 6049 ± 2803 vs 192 ± 51 in PS-001 treated animals, n = 11), improved serum albumin (g/L 27.50 ± 3.33 g/L vs 30.75 ± 2.46 in PS-001 treated animals, P = .021) and reduction in glomerulosclerosis (mean sclerosed glomeruli 81% ± 19 vs 18.75% ± 12 in PS-001 treated animals, P < .0001). The methods to translate the approach to the clinical setting using a local administration were established in pigs. Administration of PS-001 resulted in transgene mRNA expression across 89% ± 11% of kidney glomeruli as assessed by RNAScope (n = 3 pigs), and transgene derived podocin could be specifically detected in podocytes as assessed by IF analysis. Using qPCR, RT-PCR and ELISA it was shown that using local administration, podocin gene expression was restricted exclusively to the kidney glomerulus, with gene expression undetectable in off-target organs including the liver. Additional toxicological assessments of renal and other organ function from urine and blood, and post-study histopathological assessments revealed no pre-clinical treatment-related safety concerns. Conclusion We present data showing development of an AAV gene therapy and method of administration for the delivery of transgenes specifically to podocytes. We have shown transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate glomerular biology. This technology therefore provides an important novel modality for potentially treating a broad range of glomerular disease. PS-001 is being developed as a novel approach to treat steroid resistant nephrotic syndrome caused by mutated NPHS2, and may become the first podocyte targeted gene therapy to enter clinical development.

Risdiplam for the treatment of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a devastating disease that is the leading genetic cause of death in infants and young children. It includes a broad spectrum of phenotypes that are classified into clinical groups based on the age of onset and maximum motor function achieved. The most common form of SMA is due to a defect in the survival motor neuron 1 gene (SMN1) localized to 5q11.2-q13.3. The development of clinical symptoms and disease progression is thought to be due to decreased levels of survival motor neuron (SMN) protein. SMA type 1 results in almost inevitable mortality within the first 2 years of life. The first two drugs approved globally for the treatment of SMA were the antisense oligonucleotide nusinersen (Spinraza), and the gene therapy onasemnogene abeparvovec-xioi (Zolgensma). Both interventions have approval and restrictions on use in different countries around the world. Despite these approved therapies, the medical unmet need in SMA (the majority of patients with SMA are not on a disease-modifying therapy) remains high with therapies in the pipeline to address some of the remaining limitations. The third and more recently approved drug for SMA is risdiplam (Evrysdi), an orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing toward the production of full-length SMN2 mRNA to increase functional SMN protein levels. In Russia the drug risdiplam was approved for use on November 26, 2020 with indications for the treatment of SMA in patients aged 2 months and older, and in 2023 the indications were expanded - use is allowed starting from the birth. Risdiplam is widely distributed into the CNS and peripheral tissues including muscles. Following risdiplam administration, SMN protein levels compared with baseline levels increase between 2- and 6-fold depending on the SMA phenotype treated. The risdiplam clinical development program currently has four ongoing clinical trials assessing its safety and efficacy. Clinical trials included more than 450 patients receiving risdiplam to date, has been well tolerated and no treatment-related safety findings leading to study withdrawal have been observed. Data from real clinical practice - more than 11.000 patients worldwide receive therapy with risdiplam, also confirm the safety and good tolerability of the drug.

Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity

ObjectiveGlucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. MethodsOur focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 μg) or placebo, and a drug–drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-μg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. ResultsFor the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. ConclusionAlthough treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

A retrospective study of the efficacy and safety of donafenib combined with TACE as adjuvant therapy in patients with high-risk recurrence factors after hepatocellular carcinoma surgery.

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.

SUNFISH Parts 1 and 2: 4-year Efficacy and Safety Data of Risdiplam in Types 2 and 3 Spinal Muscular Atrophy (SMA) (S34.009)

SUNFISH Parts 1 and 2: 4-year Efficacy and Safety Data of Risdiplam in Types 2 and 3 Spinal Muscular Atrophy (SMA) (S34.009)

Evaluation of standard-of-care intravitreal aflibercept treatment practices in patients with diabetic macular oedema in the UK: DRAKO study outcomes

Background/ObjectivesDRAKO (NCT02850263) was a 24-month, prospective, non-interventional, multi-centre cohort study enrolling patients with diabetic macular oedema (DMO) including central involvement. The study evaluated UK standard-of-care intravitreal aflibercept (IVT-AFL) treatment. This analysis describes the treatment pathway and service provision for the anti–vascular endothelial growth factor (VEGF) treatment-naïve (C1) and non-naïve patients (C2) who received prior anti-VEGF treatment for DMO other than IVT-AFL.MethodsMean changes in best-corrected visual acuity and central subfield thickness were measured and stratified by baseline factors, including ethnicity and administration of five initial monthly injections within predefined windows. Clinic visits were classified as treatment only (T1), monitoring assessment only (T2), combined visits (T3) or post-injection visits with no treatment or assessment (T4).ResultsMedian time from decision to treat to treatment was 6 days. As a percentage of total visits, T1, T2, T3 and T4 were 7%, 42%, 48% and 3% for C1 and 11%, 39%, 48% and 2% for C2. Most IVT-AFL injections were administered by healthcare professionals (HCPs) other than doctors (C1, 57.4%; C2, 58.5%). The percentage of treatments associated with a procedure-related adverse event where at least 75% of injections were completed by the same injector role were similar for doctors and other HCPs (C1, 1.1% and 0.8%; C2, 0.7%, and 1.0%).ConclusionsResults indicate that upon DMO diagnosis, patients were treated promptly, and most visits were combined (treatment and assessment) or monitoring only. Most IVT-AFL was administered by non-physicians with a similar treatment-related safety profile as IVT-AFL administered by physicians.

Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial

BackgroundSelective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength...

P.113 Safety update: Risdiplam clinical trial development program

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. Safety data were analyzed from four studies within the risdiplam clinical development trial program: FIREFISH (NCT02913482) assesses efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of risdiplam in infants with type 1 SMA (aged 1–7 months at enrollment). SUNFISH (NCT02908685) assesses efficacy, safety, tolerability, PK and PD of risdiplam in patients with types 2/3 SMA (aged 2–25 years at enrollment). JEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®). RAINBOWFISH (NCT03779334) assesses efficacy, safety, PK and PD of risdiplam in infants (from birth–6 weeks of age at first dose) with genetically diagnosed and presymptomatic SMA. We have previously reported pooled safety analyses from FIREFISH, SUNFISH and JEWELFISH showing no treatment-related safety findings leading to withdrawal in 465 patients treated with risdiplam for up to 46.9 months (data-cuts: 12 November 2020, 30 September 2020 and 29 January 2021, respectively). The rate of adverse events (AEs) per 100 patient years was comparable across the type 1 and type 2/3 SMA populations. The overall rate of serious AEs was higher in the type 1 SMA population compared with the types 2/3 SMA population. With continued risdiplam treatment, there was a marked decline in SAE rates over time in type 1 SMA. Here we will present updated safety analyses from the risdiplam studies, including safety data from the RAINBOWFISH study. Safety data from across the risdiplam studies will add to the understanding of the long-term safety profile of risdiplam.

Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.

Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT-1014-6470 was well tolerated in a single-ascending dose study in healthy subjects. This double-blind, randomized, placebo-controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple-ascending doses of ACT-1014-6470. Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT-1014-6470 administered twice daily for 4.5days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60-mg dose level, PK samples were collected until 8weeks post last dose. The total adverse event number was 57 and no treatment-related safety pattern was apparent. At steady state, ACT-1014-6470 reached maximum plasma concentrations after 2-3h and the half-life estimated up to Day 10 was 115-146h across dose levels. Exposure parameters increased dose-proportionally, steady state was attained between Day 3-5, and ACT-1014-6470 accumulated 2-fold. At the 60-mg dose level, ACT-1014-6470 was quantifiable until 8weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT-1014-6470. The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.

Age and Outcomes of Early Rhythm Control in Patients With Atrial Fibrillation

This study sought to investigate whether the effects of early rhythm control differ according to age. Rhythm control, compared with usual care among patients recently diagnosed with atrial fibrillation (AF), was found to be associated with a lower risk of adverse cardiovascular outcomes. It is unclear whether the results can be generalized for older adults. This retrospective population-based cohort study included 31,220 patients with AF, from the Korean National Health Insurance Service database, undergoing rhythm control (antiarrhythmic drugs or ablation) or rate control therapy, initiated within 1 year of AF diagnosis. A composite outcome of cardiovascular death, ischemic stroke, hospitalization for heart failure, or myocardial infarction was compared in subgroups stratified by age. Compared with rate control, early rhythm control was associated with a lower risk of the primary composite outcome in patients<75 years of age (HR: 0.80; 95%CI: 0.72-0.88). The protective association between early rhythm control and cardiovascular outcomes exhibited a linear decrease with advancing age, with declined benefits in patients≥75 years of age (HR: 0.94; 95%CI: 0.87-1.03; Pinteraction=0.045). Trends toward lower risks of ischemic stroke (HR: 0.78; 95%CI: 0.67-0.90) and acute myocardial infarction (HR: 0.63; 95%CI: 0.41-0.97) were observed in the older adults. No significant differences in safety outcomes were found across different ages. The beneficial association of early rhythm control with cardiovascular outcomes was attenuated with increasing age, with the larger benefits in younger patients<75 years of age. No differences were found by age in treatment-related safety outcomes.

Abstract 12803: Human IPSC-Derived Committed Cardiac Progenitor Cells Engraft and Differentiate Following Transendocardial Injections in a Swine Ischemic Heart Failure Model

Introduction: A hallmark of human myocardium is the inability to regenerate functional myocardium following myocardial infarction (MI) which can result in heart failure. In an effort to remuscularize infarcted myocardium, we tested a novel human iPSC-derived committed cardiac progenitor (CCP) cell population. Whether CCPs survive and differentiate to form grafts following transcatheter delivery in a clinically representative large animal model is unknown. Hypothesis: We hypothesized that transendocardial injection (TEI) of CCPs, combined with a cardiac fibroblast-derived matrix (CFM) particles as a cell retention agent leads to functional cardiac tissue grafts. Methods: Large MI following coronary artery balloon-occlusion reperfusion was induced in mini-swine that received a 4-drug immunosuppression regimen. 28 days later, TEI targeting the peri-infarct region was performed using combinations of 200 million CCPs with or without 50 mg CFM particles and Flexbumin control. 14 injections/pig were performed, and animals were followed for 4-8 weeks. Histopathology, continuous ECG recording and cardiac MRI were performed. Results: Human cell grafts were identified using Ku80+ human cell specific antibody in the initial n=11 evaluable CCP treated swine after 1 month (see representative image, Ku80+ human cells=green). The CCPs largely differentiate into TnI positive cardiomyocytes (red) in grafts observed at one month. Immunolabeling for a panel of cardiomyocyte markers confirmed the presence of human cardiomyocytes. Of n=29 initial pigs, no treatment-related safety issues were identified, such as post TEI pericardial effusion, ventricular tachyarrhythmias or tumors. Conclusions: TEI of CCPs, with and without CFM, resulted in grafts of human cardiomyocytes in the myocardium of immunosuppressed pigs, after 1 month post MI. Ongoing cardiac MRI analyses will determine the impact of CCP therapy on cardiac structure and function.

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis

ObjectiveTumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This...

A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19

ABSTRACT Objective: Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study. Methods: Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment. Results: Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = −0.3 [−0.61, −0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events. Conclusion: Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.

Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis.

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

SMA – THERAPY: P.263 SUNFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with Type 2 or 3 spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a severe, progressive neuromuscular disease caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second gene, SMN2, produces only low levels of functional SMN protein. Risdiplam (RG7916) is a centrally and peripherally distributed oral SMN2 pre-mRNA splicing modifier that increases the levels of functional SMN protein. SUNFISH (NCT02908685) is a multicenter, two-part, randomized, placebo-controlled, double-blind study (randomized 2:1, risdiplam:placebo) in a broad population of patients with Type 2 or 3 SMA, aged 2–25 years. Part 1 (n=51) assesses the safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD) of different risdiplam dose levels in patients with Type 2/3 SMA (ambulant and non-ambulant); confirmatory Part 2 (n=180) assesses the safety and efficacy of the Part 1-selected dose of risdiplam in patients with Type 2/non-ambulant Type 3 SMA. There have been no treatment-related safety findings leading to withdrawal in any risdiplam trial (data-cut: 28th June 2019). In SUNFISH Part 1 (data-cut: 9th Jan 2019) risdiplam treatment led to a median >2-fold increase in blood SMN protein levels after 4 weeks, which was sustained for ≥12 months. Treatment with the pivotal dose of risdiplam for ≥12 months also led to improvements in motor function versus natural history (data-cut: 9th Jan 2019). Safety, tolerability and PK/PD data will be reported from patients in Part 1 who have received risdiplam treatment for ≥24 months (data-cut: 15th Jan 2020). Updated Part 1 exploratory efficacy data, including motor outcome measures, will also be presented. The clinical benefit of risdiplam is being assessed in Part 2, which met its primary endpoint of change from baseline in the 32-item Motor Function Measure after 1 year of risdiplam treatment, compared to placebo (data-cut: 6th Sept 2019). SUNFISH Parts 1 and 2 are ongoing globally.

Clinical outcomes of laparoscopic-based renal denervation plus adrenalectomy vs adrenalectomy alone for treating resistant hypertension caused by unilateral aldosterone-producing adenoma.

Previous studies describing renal denervation (RDN) from the intima of the renal artery for the treatment of resistant hypertension have reported variable efficacies, and RDN triggers renal intimal injury and atherosclerosis. This study aimed to evaluate the efficacy and safety of RDN from the adventitia of renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone-producing adenoma (APA). A total of 60 consecutive patients with resistant hypertension caused by unilateral APA were enrolled in this study. Patients were randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n=30) or adrenalectomy alone (control group, n=30) and were followed up for 12months. The primary efficacy end point was the change in 24-hours mean ambulatory systolic blood pressure (SBP) from baseline to 12months. At the 12-month follow-up, the mean reduction of 24-hours average SBP and office SBP in the RDN group was 20.7±15.2 and 37.1±26.0mmHg, respectively, which was significantly higher than the mean reduction of 24-hours average SBP (11.9±11.1mmHg, P=.017) and the office SBP (25.9±16.8mmHg, P=.035) in the control group. Serum potassium levels returned to normal 12months post-procedure. Patients in the RDN group had higher proportion of cured clinical and biochemical outcomes than those in the control group (35.7% vs 17.9% in clinical outcome; 96.4% vs 89.3% in biochemical outcome, respectively). There were no procedural-, device-, or treatment-related safety events during the 12-month follow-up period between the groups. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy is more effective than adrenalectomy alone for treating resistant hypertension caused by unilateral APA.

IBD in the time of corona - vigilance for immune-mediated diseases.

The gastrointestinal tract represents a target organ for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), warranting a thorough discussion on the consequences, particularly regarding inflammatory bowel diseases. Here, aspects of gastrointestinal involvement with SARS-CoV-2, the role of viruses as modulators of mucosal immunity and as treatment-related safety hazards, and the current clinical evidence will be discussed.

Evaluation of the Human Factor IX Gene Therapy Vector TAK-748 in Hemophilia: Results from Non-Clinical Studies in Factor IX Knockout Mice and Rhesus Monkeys

Introduction: Adeno-associated virus (AAV)-based factor IX (FIX) gene therapy has the potential to provide clinical benefit in patients with hemophilia B. TAK-748 is a novel next-generation AAV vector for FIX gene therapy. The vector design includes the insertion of 3 hepatocyte-specific cis-regulatory elements to increase the strength of the liver-specific transthyretin promoter driving expression of a human FIX transgene. Aims: The objectives of this study were to investigate the TAK-748 dose-response relationship for FIX activity, and evaluate its efficacy, in FIX knockout (KO) mice and rhesus monkeys. Methods: Male FIX KO mice (N=12/group) received single intravenous doses of TAK-748 (7.4×1010, 1.5×1011, 7.4×1011, or 1.5×1012 vector genomes [vg]/kg) or buffer. Blood samples were taken on days 7, 14, 28, 42, and 56 for the analysis of plasma FIX activity. At the end of the observation period, the bleeding phenotype was assessed by a tail-tip bleeding assay. The viral transduction efficiency of TAK-748 in liver tissue was analyzed by quantitative real-time polymerase chain reaction. Safety assessments included monitoring for clinical signs, and histopathological analysis of selected organs (liver, spleen, kidney, and heart). Male rhesus monkeys (N=3/group) were administered single TAK-748 intravenous bolus injections (3.8×1011, 9.5×1011, or 1.9×1012 vg/kg). Blood samples were collected before dosing and weekly after dosing up to week 18. Plasma FIX activity, human (hu)FIX antigen, and anti-hu-Padua FIX neutralizing antibodies were analyzed. Results: No clinical signs or deaths were recorded in animals treated with TAK-748, and there were no TAK-748-related histopathological findings in the tissues collected from the mice. FIX activity levels in plasma from FIX KO mice treated with buffer were below the lower limit of quantification. Administration of TAK-748 resulted in a dose-dependent increase in mean plasma FIX activity, and supraphysiologic mean FIX levels up to 41.0 IU/mL (1.5×1012 vg/kg). In the tail-tip bleeding assay, blood loss was significantly reduced in the TAK-748 groups at dose levels above 7.4×1010 vg/kg (P&lt;0.05 vs. buffer control). Administration of TAK-748 to rhesus monkeys resulted in a dose-dependent increase in mean plasma FIX activity and antigen, and peak levels of huFIX expression were detected 2-4 weeks after treatment. Mean huFIX activity was 0.3, 0.6, and 1.9 IU/mL after treatment with 3.8×1011 vg/kg, 9.5×1011 vg/kg, and 1.9×1012 vg/kg TAK-748, respectively. A significant reduction in FIX activity and huFIX protein was observed in most of the animals starting about 4 weeks after dosing with TAK-748. In most animals, anti-huFIX Padua neutralizing antibody titers were detected at about week 6 of the study and correlated with the preceding reductions in huFIX expression. Conclusions: Treatment with TAK-748 resulted in dose-dependent increases in plasma FIX activity and was efficacious in FIX KO mice and rhesus monkeys. There were no treatment-related safety findings. Disclosures Weiller: Baxalta Innovations GmbH, a Takeda company: Employment. Wang:Shire US Inc., a Takeda company: Employment, Equity Ownership. Coulibaly:Baxalta Innovations GmbH, a Takeda company: Employment. Schuster:Baxalta Innovations GmbH, a Takeda company: Employment. Rottensteiner:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. Sun:Shire US Inc., a Takeda company: Employment. Chuah:Shire, a Takeda company: Consultancy, Research Funding; Catalyst Bio: Consultancy, Research Funding; Pfizer: Research Funding. Vandendriessche:Shire, a Takeda company: Consultancy, Honoraria, Research Funding; Catalyst Bio: Consultancy, Research Funding; Pfizer: Research Funding; Biotest: Honoraria. Scheiflinger:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. Höllriegl:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership.