The translational safety intelligence portal

The FDA has updated the product information of Xofluza (baloxavir marboxil; polymerase acidic protein inhibitor), adding hypersensitivity as an adverse reaction reported postmarketing. Regulatory Agency Communication

The FDA has updated the product information of Nplate (romiplostim; thrombopoietin receptor agonist) to include anaphylaxis as an adverse reaction reported postmarketing. Regulatory Agency Communication

Analysis of two phase I studies of GSK2982772 (RIPK1 inhibitor) in healthy volunteers. Adverse events (AEs) included abnormal dreams, catheter-site bruise, fatigue, contact dermatitis, flatulence, ventricular tachycardia and headache. Other AEs are listed.

Study of how TYMS polymorphisms affect methotrexate toxicity in children with acute lymphoblastic leukemia. A significant association was found between TYMS 1494del6 genotypes and neutropenia, infection and leukopenia, and between 28 bp VNTR and thrombocytopenia. Carriers of the dominant allele were 9.2 times more likely to develop grade 3 and 4 leukopenia.

Pharmacovigilance study using data from the FAERS database assessing the association of H1-antihistamines with torsade de pointes. Positive disproportionality signals were identified for astemizole, cetirizine, chlorpheniramine, clemastine, desloratadine, diphenhydramine, hydroxyzine, loratadine, meclizine, promethazine, terfenadine and trimeprazine. 6 new signals were included, which were strongly associated with QT prolongation, cardiac reactions and electrolyte abnormalities.

Phase I study of the siRNA olpasiran (AMG 890; apolipoprotein A expression inhibitor) in healthy subjects and subjects with elevated plasma lipoprotein(a). Treatment-emergent adverse events (TEAEs) more frequent with olpasiran than with placebo were upper respiratory tract infection (URTI; 4/30 [13.3%] patients on olpasiran vs 1/10 [10%] on placebo), viral URTI, contusion, skin abrasion and arthralgia (1 [3.3%] vs 0 each) among healthy subjects; and back pain (3/18 [16.7%] vs 0/6), viral URTI (2 [11.1%] vs 0), contusion, skin abrasion, fatigue and arthralgia (1 [5.6%] vs 0 each) among subjects with elevated lipoprotein(a). AEs of special interest were injection-site reactions, which were reported in 1 (3.3%) healthy subject treated with olpasiran. Congress Alert

First-in-human phase I study of Org 48775-0 (MAPK 11/14 inhibitor) in healthy male subjects. In the single-ascending dose study (n = 23), adverse events (AEs) possibly related to treatment were dizziness (3 patients at 600 mg), diarrhea (1 at 3 mg), headache (1 at 100 mg) and catheter-related phlebitis (1 at 200 mg). In the multiple-ascending dose study (n = 30), AEs possibly related to Org 48775-0 were dizziness (8), somnolence (6), headache, nasopharyngitis (5 each), cough (4), fatigue, oropharyngeal pain (3 each), upper abdominal pain (2), nasal congestion, nausea, skin irritation, ocular hyperemia, dry eye, sleep disorder and diarrhea (1 each).

Article discussing potential postmarketing strategies to reduce ibrutinib-related cardiotoxicity. Ibrutinib-related cardiotoxicity may be caused by off-target inhibition of other kinases. An analysis of the World Health Organization’s VigiBase identified 303 ibrutinib-related deaths, including 103 deaths due to arrhythmias and 90 due to central nervous system hemorrhage. Other toxicities are listed.

Danyelza carries a black box for serious infusion-related reactions including cardiac arrest, anaphylaxis, hypotension, bronchospasm and stridor; and severe neurotoxicity including neuropathic pain, transverse myelitis, reversible posterior leukoencephalopathy syndrome and pain. [Data from FDA approved drug report for Danyelza (naxitamab-gqgk; ganglioside GD2 inhibitor)] Regulatory Agency Communication

The special warnings and precautions for use section of the EMA EPAR for Phelinun indicates that it may cause local tissue damage; increased bone marrow toxicity in patients who have recently received radiotherapy or chemotherapy; hepatic veno-occlusive disease; excessive myelosuppression resulting in irreversible bone marrow aplasia or failure; cytopenia including fall in leukocyte and severe thrombocytopenia; diarrhea, vomiting and stomatitis; mutagenicity in animals and chromosome aberrations in patients; acute leukemia and myelodysplastic syndrome; and second primary malignancy with alkylating agents. Other adverse events reported with drug combinations are listed. [Data from EMA European public assessment report for Phelinun (melphalan; DNA alkylating agent)] Regulatory Agency Communication

The special warnings and precautions for use section of the EMA EPAR for Oxlumo (lumasiran) indicates that it increases plasma glycolate levels, which may increase the risk of metabolic acidosis or worsening of pre-existing metabolic acidosis in patients with severe or end-stage renal disease. [Data from EMA European public assessment report for Oxlumo (lumasiran; hydroxyacid oxidase 1 expression inhibitor)] Regulatory Agency Communication

First-in-human phase I study of XmAb20717 (PD-1/CTLA-4 inhibitor; 0.15-20 mg/kg q2w) in 123 patients with advanced solid tumors. The most common treatment-related adverse events (AEs) were immune-related AEs (irAEs). The most common irAEs were rash (25.9% patients at <10 mg/kg; 36.5% at 10 mg/kg), pruritus (18.5%; 25%) and transaminases increase (7.4%; 17.7%). Grade ≥3 irAEs reported in >3 patients were rash and transaminase increase. Fatal AEs were immune-mediated pancreatitis in a patient with pancreatic metastases at baseline, and myocarditis and respiratory failure in a patient with a pacemaker and a history of atrial fibrillation. Other irAEs are listed. Congress Alert

The warnings and precautions section of the FDA approved drug report for Zokinvy indicates that it causes laboratory abnormalities, including electrolyte abnormalities (such as hyperkalemia), myelosuppression (such as reductions in absolute neutrophil count) and increased liver enzymes (such as increased AST/ALT); nephrotoxicity in preclinical studies with rats; retinal toxicity and low-light vision decline in monkeys; impaired fertility in both male and female rats, and toxicity in the male reproductive tract in monkeys; and may cause embryo-fetal toxicity (including fetal harm) based on findings from animal reproduction studies (embryo-fetal toxicity in pregnant rats and skeletal malformations in pregnant rabbits). Other warnings and precautions of lonafarnib are listed. [Data from FDA approved drug report for Zokinvy (lonafarnib; protein farnesyltransferase inhibitor)] Regulatory Agency Communication

Phase II study of cilofexor (C;30 mg qd), firsocostat (F;20 mg qd) and selonsertib (S;18 mg qd) alone or in combination in patients with bridging fibrosis and cirrhosis. The most common adverse events (AEs) in the monotherapy groups were pruritus (8/40 patients [20%] in the cilofexor group vs. 8/40 [20%] in the firsocostat group vs. 7/39 [18%] in selonsertib group), urinary tract infection (5 [13%] vs. 3 [8%] vs. 6 [15%]) and headache (4 [10%] vs. 7 [18%] vs. 4 [10%]). The most common AEs in the combination groups were pruritus (22/77 [29%] in C+S group vs. 22/78 [28%] in C+F group vs. 14/79 [18%] in F+S group), nausea (10 [13%] vs. 10 [13%] vs. 20 [25%]) and fatigue (9 [12%] vs. 8 [10%] vs. 14 [18%]). Serious AEs were cellulitis in the cilofexor monotherapy and F+S groups (3 [8%] and 1 [1%] respectively) and acute myocardial infarction in the firsocostat monotherapy and C+F groups (1 [3%] and 1 [1%] respectively). Other AEs are listed.

First-in-human phase I clinical study of AMG 404 (PD-1 inhibitor) in 62 patients with advanced solid tumors. The most common treatment-related adverse events (TRAEs) were fatigue (7 patients), hypothyroidism (6), increased blood thyroid stimulating hormone, nausea (4 each), increased aspartate aminotransferase, decreased appetite and pyrexia (3 each). Other TRAEs are listed. Congress Alert

Phase I study of CMP-001 alone or in combination with pembrolizumab in patients with advanced melanoma. The most common treatment-related adverse events (TRAEs) reported in the CMP-001 monotherapy group were flu-like symptoms. In the CMP-001/pembrolizumab group, the most common TRAEs were flu-like symptoms and injection-site reactions. The most common grade 3/4 TRAE reported in both treatment groups was hypotension. Congress Alert

Phase I clinical trial of ARO-ANG3 (angiopoietin like 3 expression inhibitor; 100, 200 or 300 mg) in patients with dyslipidemia. Common treatment-emergent adverse events (TEAEs) included contusion, oropharyngeal pain, vascular access site bruising/hematoma (4/29 patients [14%] with ARO-ANG3 vs 0/3 with placebo, each), muscle spasm and presyncope/syncope (3 [10%] vs 0, each). A serious TEAE of ketosis related to dapagliflozin and dehydration was observed. 1 TEAE of contusion was related to concomitant NSAID treatment. Other TEAEs are listed. Congress Alert

The special warnings and precautions for use section of the EMA EPAR for Adakveo (crizanlizumab) indicates that it causes infusion-related reactions, including possible signs and symptoms of fever, chills, nausea, vomiting, fatigue, dizziness, pruritus, urticaria, sweating, shortness of breath or wheezing; and laboratory test interference, including automated platelet counts (platelet clumping). [Data from EMA European public assessment report for Adakveo (crizanlizumab; P-selectin inhibitor)] Regulatory Agency Communication

Study reporting that beta-cell-specific Pak1 knockout in mice led to glucose intolerance and elevated beta-cell apoptosis. Human PAK1-deficient beta-cells showed reduced glucose-stimulated insulin secretion and mitochondrial function.

Phase II study of combined bemcentinib (first-in-class selective AXL inhibitor) and pembrolizumab (PD-1 inhibitor) in 73 patients with non-small cell lung cancer. The most common treatment-related adverse events (TRAEs) were increased alanine aminotransferase (24 [33%]), diarrhea (23 [32%]) and increased aspartate aminotransferase (22 [30%]). Grade ≥3 TRAEs included increased alanine aminotransferase (8 [11%]), increased aspartate aminotransferase (5 [7%]), asthenia (4 [5%]), anemia (2 [3%]), fatigue, QT interval prolongation and diarrhea (1 [1%] each). Other TRAEs observed in ≥10% patients are listed. Congress Alert

Phase I/II study of GB1275 (integrin, alpha M subunit modulator) in 36 patients with advanced solid tumors. 19 patients (52.8%) experienced GB1275-related adverse events, the most common being dysesthesia (13.9%) and photosensitivity reaction (11.1%). Congress Alert

The FDA has updated the product information of Erleada (apalutamide; androgen receptor antagonist), adding the risk of cerebrovascular disorders to the “Warnings and Precautions” section. Regulatory Agency Communication

The PRAC has recommended updating the product information of Imbruvica (ibrutinib; BTK inhibitor) to include a warning on hepatitis E. Regulatory Agency Communication

The FDA has updated the product information of Trokendi XR (topiramate; carbonic anhydrase inhibitor/sodium channel blocker) to include a warning about serious skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis). Nephrocalcinosis has also been added as an adverse reaction reported postmarketing. Regulatory Agency Communication

The FDA has updated the product information of Haldol (haloperidol lactate; 5-HT2A/D2/D3/D4 receptor antagonist) to include a warning about cerebrovascular adverse reactions (including stroke, transient ischemic attack and fatalities). Regulatory Agency Communication

The FDA has updated the product information of Forteo (teriparatide recombinant human; PTH1/2 receptor agonist), adding a warning about cutaneous calcification (including calciphylaxis). The risk of anti-drug antibody formation has been added to the “Adverse Reactions” section. Regulatory Agency Communication

Phase II clinical trial of Tesomet (metoprolol/tesofensine; 0.5 mg) in patients with hypothalamic obesity. Common adverse events (AEs) included sleep disorders (8/13 patients [62%] with Tesomet vs 1/8 [13%] with placebo), dry mouth (6 [46%] vs 0), dizziness (6 [46%] vs 3 [38%]) and headache (5 [38%] vs 0). Other AEs are listed. [Data from a Saniona corporate presentation] Company Communication

Phase I clinical trial of IMC-001 (PD-L1 inhibitor; 2-20 mg/kg q2w) in 15 patients with metastatic or locally advanced solid tumors. The most common adverse events were general weakness, decreased appetite, fever and cough. 1 patient in the 2 mg/kg cohort experienced grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be treatment-related. Congress Alert

Phase I clinical study of retifanlimab (PD-1 inhibitor; 500 mg q4w) in 44 patients with advanced solid tumors. The most common grade 3/4 adverse event (AE) was anemia (3 [6.8%]). Immune-related AEs included grade 3 dry mouth and grade 3 myositis (1 each). Congress Alert

First-in-human phase I study of NKTR-255 (interleukin-15 receptor agonist; 1.5 or 3 mcg/kg) in 4 patients with relapsed/refractory hematologic malignancies. In the dose-escalation period, 3 patients experienced flu-like symptoms (1 at each dose) including pyrexia (3 patients; 1 grade 3), chills (2) and influenza-like illness (1). Other treatment-related adverse events (TRAEs) were muscle tightness, myalgia (1 patient at 1.5 mcg/kg each), headache, hypercalcemia, hypotension, abnormal liver function test, platelet count decrease, grade 3 lymphocyte count decrease and grade 3 white blood cell count decrease (1 at 3 mcg/kg each). Other TRAEs are listed. Congress Alert

Two registration studies of clazosentan (ETA receptor antagonist; 10 mg qh) for reducing vasospasm-related morbidity and all-cause mortality in 442 Japanese patients following aneurysmal subarachnoid hemorrhage. Treatment-emergent adverse events occurring >5% with clazosentan and with a difference >2% compared to placebo were vomiting and signs of hemodilution or fluid retention (including hyponatremia, hypoalbuminemia, anemia, pleural effusion, and brain and pulmonary edema). [Data from an Idorsia communication announcing positive results of two Japanese registration studies of clazosentan] Company Communication

Adverse reactions reported in clinical trials of casirivimab/imdevimab in patients with mild to moderate COVID-19 are listed. [Data from FDA emergency use fact sheet for casirivimab and imdevimab] Regulatory Agency Communication

First-in-human phase I dose escalation study of the bispecific antibody ATOR-1015 (CTLA-4 inhibitor/OX40 agonist) in 23 patients with advanced and/or refractory solid malignancies. 9 patients experienced infusion-related reactions, symptoms of which included chills, rash and pain. Potentially immune-related adverse events were reported in 3 patients and consisted of rash, vitiligo and exanthema/eczema (1 patient each). Congress Alert

First-in-human, phase I study of CUE-101 in 19 patients with recurrent/metastatic HPV16+ head and neck cancer. Adverse events included fatigue (3 patients), decreased appetite, arthralgia, muscular weakness, paresthesia, bullous pemphigoid and infusion-related reaction (1 each). Congress Alert

First-in-human study of KHK2455 (indoleamine 2,3-dioxygenase 1 inhibitor) in combination with mogamulizumab (CCR4 antagonist) in 36 patients with advanced solid tumors. Serious KHK2455-related adverse events included grade 3 gastrointestinal necrosis (observed in the KHK2455 monotherapy group), nausea and drug eruption (combination group). Other treatment-emergent adverse events (TEAEs) observed either in the combination or monotherapy groups are listed. 5 drug-related TEAEs observed with the combination therapy led to discontinuation of the treatment. Congress Alert

The EMA has updated the product information of Mysimba (naltrexone/bupropion) to include a new warning on the interaction between Mysimba and digoxin. Drug-induced lupus erythematosus was added to the “undesirable effects” section with frequency “not known”. Lupus erythematosus may occur with Mysimba or with naltrexone and bupropion as monotherapies. Regulatory Agency Communication

The EMA has updated the product information of Myalepta (metreleptin; leptin receptor agonist) to include a new warning on the risk of autoimmune disease (including severe autoimmune hepatitis). A clear causal relationship between Myalepta and autoimmune disease has not been established yet. Regulatory Agency Communication

Phase III clinical trial assessing the safety and efficacy of rilonacept (IL-1beta inhibitor) in 86 patients with recurrent pericarditis. During the run-in period, the most common treatment-emergent adverse events (TEAEs) were injection-site erythema (18 patients [20.9%]), myalgia (9 [10.5%]), arthralgia (8 [9.3%]), headache (7 [8.1%]), nasopharyngitis (6 [7%]), injection-site pruritus, cough, injection-site swelling and diarrhea (5 [5.8%] each). Other TEAEs reported during the run-in period or in the randomized-withdrawal period, and more frequent with rilonacept than with placebo before bailout are listed.

Phase I study of ARO-APOC3 (apolipoprotein C3 expression inhibitor) in patients with hypertriglyceridemia and chylomicronemia. Treatment-emergent adverse events (TEAEs) included injection-site reactions (8/41 patients [19.5%] with ARO-APOC3 vs 0/8 with placebo), increased transaminases (including ALT) and liver function test (7 [17%] vs 0), headache (6 [15%] vs 0) and upper respiratory tract infection (4 [10%] vs 0). Other TEAEs are listed. [Data from an Arrowhead presentation on the clinical development of ARO-APOC3] Company Communication

Phase III study comparing lorlatinib to crizotinib in 296 patients with advanced ALK-positive non-small-cell lung cancer. The most common adverse events (AEs) in the lorlatinib group were hypercholesterolemia (105/149 [70%] patients with lorlatinib; 5/142 [4%] with crizotinib), hypertriglyceridemia (95 [64%]; 8 [6%]), edema (82 [55%]; 56 [39%]), increased weight (57 [38%]; 18 [13%]) and peripheral neuropathy (50 [34%]; 21 [15%]). In the lorlatinib group, 2 deaths were considered possibly related to treatment: 1 from acute cardiac failure and 1 from respiratory failure in the setting of infectious pneumonia. Other AEs of lorlatinib and crizotinib are listed.

Phase II/III study of the ChAdOx1-nCoV19 (AZD1222) vaccine against SARS-CoV-2 and comparison with MenACWY in healthy young and old adults. The most common local adverse reactions (ARs) reported after ChAdOx1-nCoV19 vaccination were injection-site pain and tenderness and the most common systemic ARs were fatigue, headache, malaise and muscle ache. Severe ARs included warmth, chills, fever, joint pain and nausea. Other ARs of ChAdOx1-nCoV19 and MenACWY are listed.

Phase II study of SHR0302 (JAK1 inhibitor) in 194 Chinese patients with rheumatoid arthritis. During weeks 1-12, infection (including 4 cases of herpes zoster and 1 opportunistic infection (cryptococcal pneumonia)) was more common in patients receiving SHR0302 than in those on placebo. Congress Alert

Phase I study of AMV564 (CD3/CD33 interacting agent; 15, 50 or 75 mcg) in patients with advanced solid tumors. The most common adverse events (AEs; grade >1) included injection site reactions (12/16 patients), pyrexia (11) and anemia (8). Other AEs are listed. Congress Alert

First-in-human trial of ACTolog IMA101 (adoptive T-cell therapy) for relapsed/refractory solid tumors. The most common treatment-emergent adverse events (TEAEs) included anemia, neutrophil count decrease (93.3% patients each), platelet count decrease, white blood cell count decrease (80.0% each), nausea (73.3%) and cytokine release syndrome (66.7%). Other TEAEs are listed. Congress Alert

Phase I study of AGEN1181 (CTLA-4 inhibitor) in immunogenic and non-immunogenic tumors. 28.5% patients experienced grade ≥3 immune-related adverse events, consistent with CTLA-4 therapies. Congress Alert

The FDA has updated the product information of Yervoy (ipilimumab; CTLA-4 inhibitor) to include a warning about drug rash with eosinophilia and systemic symptoms. Regulatory Agency Communication

The FDA has updated the product information of Trintellix (vortioxetine hydrobromide; 5-HT1A receptor agonist/5-HT3 receptor antagonist/SERT inhibitor) to include aggression, agitation, anger, hostility and irritability as adverse reactions reported postmarketing. Regulatory Agency Communication

The NMPA has approved the use of Xgeva (denosumab; RANKL inhibitor) for preventing bone metastases in patients with solid tumors or multiple myeloma. The most common adverse events (AEs) reported in patient with solid tumors were fatigue, asthenia, hypophosphatemia and nausea. Dyspnea was the most common serious AE, whilst osteonecrosis and hypocalcemia were the main AE leading to discontinuation. In patients with multiple myeloma, the most common AEs were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash and headache. Pneumonia was the most frequent serious AE, and osteonecrosis of the jaw was the main AE leading to discontinuation. [Data from a BeiGene communication announcing the approval of Xgeva for the prevention of bone metastasis in China] Company Communication

Initial results from a first-in-human phase I study of the monoclonal antibody BMS-986218 (CTLA-4 inhibitor; 2-70 mg q4w) in 65 patients with advanced cancer. The most common treatment-related adverse events were pruritus (12% patients) and diarrhea (11%; 3% grade 3). 1 patient receiving BMS-986218 at 2 mg died due to treatment-related pneumonitis. Congress Alert

The special warnings and precautions for use section of the EMA EPAR for Arikayce liposomal (amikacin) indicates that it causes serious and life-threatening hypersensitivity reactions (including anaphylaxis); allergic alveolitis and pneumonitis; bronchospasm; exacerbation of underlying pulmonary disease (such as chronic obstructive pulmonary disease); ototoxicity (including deafness, dizziness, presyncope, tinnitus and vertigo); nephrotoxicity; and neuromuscular disorders. Other warnings and precautions of amikacin are listed. [Data from EMA European public assessment report for Arikayce liposomal (amikacin; 16S/30S ribosomal protein inhibitor)] Regulatory Agency Communication

Interim results from an ongoing phase Ib study of a combination of the bispecific antibodies KN026 and KN046 in 24 patients with advanced HER2-positive solid tumors. The most common (≥10%) treatment-related adverse events (AEs) were anemia (5 [23.8%] patients), increased AST, rash, diarrhea (4 [19%] each), increased blood bilirubin and infusion-related reaction (3 [14.3%] each). 7 patients experienced immune-related AEs. Congress Alert

First-in-human phase I study of the monoclonal antibody IBI188 (CD47 inhibitor) in 20 patients with advanced/refractory solid tumors and lymphoma. The most common treatment-related adverse events (TRAEs) were nausea, back pain (7 patients each), fatigue (6), vomiting and increased blood bilirubin (4 each). 3 patients had grade ≥3 TRAEs: grade 3 blood bilirubin increase, grade 4 platelet count decrease and grade 3 anemia (1 each). Treatment-related anemia was reported in 3 (15%) patients, which was expected and associated with the mechanism of IBI188. 65% patients had infusion-related reactions. Congress Alert

Phase II/III study of lenacapavir (Gag polyprotein inhibitor) in 24 subjects with HIV-1 Infection. The most common adverse events were injection-site swelling (21%) and injection-site nodules (17%). [Data from a Gilead communication announcing topline results from a phase II/III study of lenacapavir for HIV-1 infection] Company Communication

First-in-human phase I/II study of VT1021 (thrombospondin-1 expression enhancer; 0.5-15.6 mg/kg biw) in 46 patients with advanced solid tumors. 1 patient dosed at 1.0 mg/kg had a grade 3 infusion reaction, and 3 patients had grade 2 infusion reactions (dosed at 1.0, 6.6 and 8.8 mg/kg, respectively). Other VT1021-related adverse events were fatigue (7 patients), nausea (4), constipation, increased aspartate aminotransferase, increased blood bilirubin, hypomagnesaemia and dizziness (2 each). Congress Alert

Phase III clinical trial of the vaccine candidate BNT162b2 for the prevention of COVID-19 in 43,661 participants. Grade 3 solicited adverse events observed in ≥2% patients after the second dose were fatigue (3.8%) and headache (2%). [Data from a Pfizer and BioNTech communication announcing that the phase III study of BNT162b2 has met all its primary efficacy endpoints and the vaccine has shown an efficacy of 95% against COVID-19] Company Communication

Retrospective study assessing the incidence and risk factors of cardiovascular adverse events associated with carfilzomib (20-S proteasome inhibitor) in 7,330 patients with multiple myeloma. Carfilzomib was significantly associated with an increased risk of heart failure (hazard ratio 1.47 [95% CI: 1.20-1.81], p = 0.0002), ischemic heart disease (1.45 [1.19-1.75], p = 0.0002), and hypertension (3.33 [2.83-3.92], p < 0.0001). No association was found between carfilzomib and cardiac conduction disorders (arrhythmia and heart blocks; 0.95 [0.82-1.12], p = 0.5498). Carfilzomib users had a higher risk of symptoms such as edema (5.09 [4.13-6.27], p < 0.0001), syncope (4.27 [3.09-5.89], p < 0.0001), dyspnea (1.33 [1.18-1.48], p < 0.0001) and chest pain (1.18 [1.04-1.35], p < 0.0001).

Preliminary results from a phase I study of RP2 (CTLA-4 inhibitor) in 9 patients with solid tumors. Common grade 1-2 treatment-related adverse events (TRAEs) included pyrexia (6 patients [66.7%]), fatigue, hypotension (3 each [33.3%]) and chills (2 [22.2%]). Grade 3 TRAEs were cytokine release syndrome and hypocalcemia (1 each [11.1%]). Other TRAEs are listed. Congress Alert

Phase II clinical study of penpulimab (PD-1 inhibitor; 200 mg q2w) in 73 patients with relapsed or refractory classic Hodgkin lymphoma. The most common treatment-related adverse events (TRAEs) were fever (24.5%), hypothyroidism (21.3%), upper respiratory tract infection (18.1%) and ALT elevations (17%). Grade ≥3 decreased platelet count was reported in 2.1% patients. 42.6% patients reported immune-related adverse events including grade 3 psoriasis and IgA nephropathy (1 each). Congress Alert

Phase II clinical study of zalifrelimab (CTLA-4 inhibitor; 1 mg/kg q3w) in 44 patients with solid tumors. The most common treatment-related adverse events were fatigue, nausea, anemia, diarrhea and vomiting, all of which are consistent with the drug class. Congress Alert

Phase IIa study of vixarelimab (oncostatin M-specific receptor, beta subunit antagonist) in 49 patients with prurigo nodularis. Treatment-emergent adverse events included upper respiratory tract infection (4/23 [17.4%] patients with vixarelimab vs 1/26 [3.8%] with placebo), viral gastroenteritis, influenza, postoperative wound infection, subcutaneous abscess, allergic dermatitis, idiopathic angioedema, night sweats and urticaria (1 [4.3%] vs 0 each). [Data from a Kiniksa corporate presentation, November 2020] Company Communication

Phase I clinical study of propranolol (10-30 mg bid) in combination with pembrolizumab (200 mg q3w) in 9 patients with locally advanced or metastatic melanoma. The most common treatment-related adverse events (TRAEs) were fatigue, rash, vitiligo (4 [44.4%] each), nausea (3 [33.3%]), chills, edema, diarrhea and pruritus (2 [22.2%]). Grade ≥3 TRAEs were hemophagocytic lymphohistiocytosis and elevated alanine aminotransferase (1 [11.1%] each). Other TRAEs are listed.

The FDA has updated the product information of Motegrity (prucalopride succinate; 5-HT4 receptor agonist) to include suicide, suicide attempts, suicidal ideation, self-injurious ideation, depression, anxiety, insomnia, nightmares and visual hallucinations as adverse reactions reported postmarketing. The “Warnings and Precautions” section has been updated accordingly. Regulatory Agency Communication

The FDA has updated the product information of Bavencio (avelumab; PD-L1 inhibitor), adding novel severe immune-mediated adverse events (listed) to the “Warnings and Precautions” section. Regulatory Agency Communication

Phase IIb clinical trial of UGN-102 (mitomycin; DNA alkylating agent) in patients with non-muscle invasive bladder cancer. The most common adverse events (≥10%) were dysuria, urinary frequency, hematuria, urinary urgency, urinary tract infection and fatigue. [Data from an UroGen communication announcing final results from the OPTIMA II trial] Company Communication

The UK MHRA has issued safety advice on the link between Esbriet (pirfenidone; TGFbeta inhibitor) and the risk of serious liver injury. A European review identified severe postmarketing cases of drug-induced liver injury (DILI), including hepatitis and liver failure. 2 fatal cases of DILI have been reported: in the first case, the patient presented with acute liver failure, grade 3 hepatic encephalopathy, elevated liver function tests, jaundice and altered mental state, and subsequently died from organ failure; in the second case, which was associated with a drug-drug interaction between pirfenidone and concomitant esomeprazole (a substrate for cytochrome P450 enzymes), the patient was hospitalized with jaundice, pruritus, nausea, fatigue and increased transaminases, and died from sepsis, lactic acidosis and multiorgan failure. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Ferinject (ferric carboxymaltose; iron donor) and risk of hypophosphatemia leading to osteomalacia and fractures. A European review found 36 spontaneous cases of osteomalacia in patients with concurrent hypophosphatemia associated with ferric carboxymaltose, including 6 cases of hypophosphatemic osteomalacia. 19 (53%) patients developed fractures, including femoral neck and pelvic or hip fractures. Cases of hypophosphatemia, including serious cases, have also been reported with Monofer (ferric derisomaltose). Regulatory Agency Communication

The UK MHRA has issued safety advice on the risk of serotonin syndrome associated with Zyban (bupropion; DAT/NET inhibitor) when used with other serotonergic drugs such as selective serotonin reuptake inhibitors and serotonin norepinephrine re-uptake inhibitors. Cases of serotonin syndrome have also been reported in association with bupropion overdose, the majority of which were intentional. Regulatory Agency Communication

The UK MHRA has requested contributions to a review undertaken by an Expert Working Group assessing the possible association between Roaccutane (isotretinoin; retinoid acid receptor agonist) and suspected psychiatric and sexual disorders. Isotretinoin has also been linked to a significant risk of teratogenic effects. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Provigil (modafinil; DAT inhibitor) and the risk of congenital malformations. A review using data from a prospective US registry and spontaneous reports found that Provigil is causally associated with a possible increased risk of major congenital malformations if used during pregnancy, including congenital heart defects, hypospadias and orofacial clefts. Regulatory Agency Communication

Phase I study of the virus-like particle vaccine candidate for COVID-19 CoVLP (3.75, 7.5 and 15 mcg), alone or adjuvated with either CpG 1018 or AS03, in 180 healthy subjects. The most common local reaction was pain at the injection site (66.5% after the first dose; 61.2% after the second dose). Other adverse events (AEs) were headache (25.7%; 33.1%) and fatigue (20.7%; 33.1%). After the first dose, a case of grade 3 fatigue was reported. Grade 3 AEs were reported in 6 patients after the second dose: fatigue, redness at injection site, swelling at injection site and feeling of general discomfort or uneasiness. Other solicited and unsolicited AEs are listed.

Phase II study of an inactivated SARS-CoV-2 vaccine in 742 healthy subjects. Subjects received a medium (MD) or a high dose (HD) at an interval of 14 or 28 days. Solicited injection-site and systemic adverse reactions more frequent with the vaccine than placebo were injection-site pain with both procedures; injection-site itch, injection-site redness and fever in the 14-day interval procedure; and diarrhea and hypersensitivity/urticaria in the 28-day interval procedure.

Phase I clinical study of cosibelimab (PD-L1 inhibitor; 800 mg q2w or 1,200 mg q3w) in 123 patients with advanced cancers. The most common treatment-related adverse events (TRAEs) were fatigue (19 [15.4%]; 2 [1.6%] grade ≥3), rash (17 [13.8%]), hypothyroidism, infusion-related reaction (10 [8.1%] each), anemia (7 [5.7%]; 2 [1.6%]), diarrhea and nausea (7 [5.7%] each). 2 patients (1.6%) experienced grade 2 pneumonitis. Congress Alert

Interim analysis of a phase III trial evaluating the efficacy of mRNA-1273 vaccine (SARS-CoV-2 proteins-directed immunity inducer; 100 mcg) for COVID-19 prevention in 30,000 healthy participants. Grade 3 adverse events included fatigue (9.7% patients), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%), injection-site pain (2.7%) and injection-site erythema/redness (2%). [Data from a Moderna communication announcing that mRNA-1273 vaccine had an efficacy of 94.5% in the COVE study] Company Communication

The NMPA has decided to update the product information of cetirizine hydrochloride (H1 receptor antagonist). Data from clinical studies indicated the following adverse events: drowsiness, rhinitis, diarrhea, headache, dizziness, pharyngitis, dry mouth, nausea, abdominal pain and fatigue. Postmarketing data indicated that abnormal feeling, diarrhea, pruritus, skin rash, weakness, discomfort and excitement have been observed occasionally (≥1/1,000 - <1/100). Other safety issues are listed. Regulatory Agency Communication

Hypersensitivity reactions such as anaphylaxis, urticaria and angioedema have been observed in the postmarketing setting of Xofluza (baloxavir marboxil; polymerase acidic protein/viral RNA polymerase inhibitor). [Data from EMA summary of opinion for Xofluza] Regulatory Agency Communication

The most common side effects of Elzonris (tagraxofusp; interleukin 3 receptor, alpha subunit antagonist) are hypoalbuminemia, increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia. The most common serious adverse reaction is capillary leak syndrome (17% patients). [Data from EMA summary of opinion for Elzonris] Regulatory Agency Communication

The EMA has recommended restricting the use of ulipristal acetate (progesterone receptor modulator) for uterine fibroids only to premenopausal women for whom surgical procedures are not appropriate or have not worked. This follows serious cases of liver injury (requiring liver transplantation). Information about the risk of liver failure will be added to the drug's product information. Regulatory Agency Communication

The most common side effect of Roclanda (latanoprost/netarsudil) is conjunctival hyperemia. [Data from EMA summary of opinion for Roclanda] Regulatory Agency Communication

The most common side effects of Phesgo (pertuzumab/trastuzumab) are alopecia, diarrhea, nausea, anemia, asthenia and arthralgia. [Data from EMA summary of opinion for Phesgo] Regulatory Agency Communication

Study identifying genetic risk factors associated with isoniazid-induced liver injury. The NAT2*6 and NAT2*7 alleles were frequently found in patients with isoniazid-induced liver injury but only the HLA-B*52:01 allele was significantly associated (OR = 2.67 [95% CI: 1.63-4.37]).

Phase II study of SNG001 (inhaled interferon beta-1a; interferon-alpha/beta receptor agonist) in patients with Covid-19. The most common treatment-emergent adverse event (TEAE) was headache (7/48 patients [14.6%] with SNG001 vs 5/50 [10%] with placebo). TEAEs related to SNG001 included cough (2 [4.2%]), decreased oxygen saturation, diarrhea, dry throat, oral pain, night sweats and tremor (1 [2.1%] each). Other TEAEs are listed.

Placebo-controlled trial evaluating the efficacy of fluvoxamine (SERT inhibitor; 100 mg) for preventing clinical deterioration in outpatients with symptomatic COVID-19. Adverse events included headache/head pain (2/80 patients [2.5%] with fluvoxamine vs 1/72 [1.4%] with placebo), muscle aches, bacterial infection, vasovagal syncope, teeth chattering and dehydration (1 [1.3%] vs 0 each).

The FDA has updated the product information of Xifaxan (rifaximin; RNAP inhibitor), adding rhabdomyolysis as an adverse reaction reported postmarketing. Regulatory Agency Communication

The special warnings and precautions for use section of the EMA EPAR for Calquence (acalabrutinib) as monotherapy or in combination with obinutuzumab indicates that it may cause major hemorrhagic events (including central nervous system and gastrointestinal hemorrhage, some with fatal outcome); hepatitis B reactivation and serious infections (including bacterial, viral or fungal infections, some with fatal outcomes); cytopenias (including grade 3-4 neutropenia, anemia and thrombocytopenia); second primary malignancies (including skin and non-skin cancers); atrial fibrillation/flutter; and drug interactions with CYP3A inhibitors/inducers. Other warnings and precautions of acalabrutinib are listed, including those of drug combinations. [Data from EMA European public assessment report for Calquence (acalabrutinib; BTK inhibitor)] Regulatory Agency Communication

Study assessing the impact of gadolinium-based contrast agents on the liver of mice. Treatment with Omniscan (gadodiamide; 2.5 mmol/kg) led to ballooning of hepatocytes, increased lipid accumulation in the liver and altered liver metabolome. These findings may be suggestive of non-alcoholic fatty liver disease. Congress Alert

Phase I study of ASN007 (ERK1/2 inhibitor) in cancer patients. Treatment-related adverse events (TRAEs) were diarrhea, nausea, vomiting, acneiform dermatitis, maculo-papular rash, rash, chorioretinopathy and blurred vision. Grade ≥3 TRAEs included diarrhea, vomiting, maculo-papular rash, rash and chorioretinopathy. Dose-limiting toxicities were fatigue, retinal detachment, vitreous floaters and retinopathy. Congress Alert

Preliminary results from a first-in-human phase I/IIa study of GEN1046 (4-1BB activator/PD-L1 inhibitor; 25-1,200 mg q3w) in 61 patients with advanced solid malignancies. The most common treatment-related adverse events were increased transaminases (24.6% patients; 9.8% grade 3-4), hypothyroidism (16.4%; 1.6%) and fatigue (13.1%; 1.6%). Congress Alert

First-in-human phase I study of SAR441000 (mRNAs encoding IL-12, IL-15, interferon alpha 2 and GM-CSF), alone or combined with cemiplimab, in patients with advanced solid tumors. Treatment-related adverse event (TRAEs) observed with SAR441000 monotherapy included fatigue (5/17 patients [29.4%]), chills, vomiting and injection site reactions (2 each [11.7%]). Common TRAEs reported with combined therapy included fatigue (5/6 [83.3%]), diarrhea, nausea and vomiting (2 each [33.3%]). Other TRAEs are listed. Congress Alert

The PMDA is currently reviewing the precautions regarding co-administration of venetoclax (Bcl-2 inhibitor) and posaconazole (lanosterol 14-alpha demethylase [fungal] inhibitor). Regulatory Agency Communication

The PMDA is currently reviewing the association between eculizumab (complement C5 inhibitor) and the risk of infection. Regulatory Agency Communication

First case report of a 54-year-old man who developed organizing pneumonia and diffuse alveolar injury with profound hypotension and ischemia induced by an overdose of amlodipine (calcium channel blocker; 70 tablets). Congress Alert

Study assessing the mechanism underlying neurodegeneration induced by olanzapine (5-HT2A/5-HT2C/5-HT3/D2 receptor antagonist) in murine hypothalamic neurons. Results show that olanzapine may cause neurotoxicity by aberrant autophagy as a result of oxidative stress, mitochondrial dysfunction and inhibition of mitophagy. The study also reports that these effects could be reversed by N-acetylcysteine.

First-in-human phase I study evaluating the safety, efficacy and pharmacokinetics of VIR-2482 (hemagglutinin inhibitor; 60-1,800 mg) for preventing influenza A in 100 healthy subjects. 6 subjects reported mild injection-site reactions, including bruising, redness, swelling, pain and tenderness. Congress Alert

Interim analysis of an ongoing first-in-human phase I study of the SARS-CoV-2 vaccine candidate CVnCoV (2-12 mcg) in 245 healthy volunteers. The most common solicited local adverse event (AE) was injection-site pain, including severe cases. Other local AEs were injection-site swelling and itching. The most frequent solicited systemic AEs were mild or moderate headache, fatigue, myalgia and chills. Other systemic AEs are listed.

Phase III study comparing venetoclax (800 mg) plus bortezomib (1-3 mg/m2) and dexamethasone (20 mg) to combined bortezomib and dexamethasone in patients with multiple myeloma. The most common adverse events (AEs) were diarrhea (43% with venetoclax/bortezomib/dexamethasone vs. 36% with bortezomib/dexamethasone), constipation (34% vs. 30%), nausea (33% vs. 21%), upper respiratory tract infection (27% vs. 23%), insomnia (26% vs. 27%), fatigue (25% vs. 28%) and peripheral neuropathy (25% vs. 21%). Common grade 3 AEs included diarrhea (15% vs. 11%), anemia (14% vs. 14%), pneumonia (11% vs. 7%), decreased platelet count (8% vs. 8%) and thrombocytopenia (7% vs. 10%). 3 treatment-related deaths occurred in the venetoclax/bortezomib/dexamethasone group: 2 due to pneumonia and 1 due to septic shock. Other AEs are listed.

The FDA has updated the product information of Aubagio (teriflunomide; DHODH inhibitor) to include drug-induced liver injury and drug reaction with eosinophilia and systemic symptoms as adverse reactions reported postmarketing. Regulatory Agency Communication

The FDA has updated the product information of Ocrevus (ocrelizumab; CD20 inhibitor), adding a warning about reduced immunoglobulin levels (including IgG). This information has also been included in the “Adverse Reactions” section. Regulatory Agency Communication

The EMA will update the product information of products containing bendamustine hydrochloride to include a warning of progressive multifocal encephalopathy (including fatal cases and with combination) and non-melanoma skin cancer (such as basal cell carcinoma and squamous cell carcinoma) based on clinical experience. Regulatory Agency Communication

First-in-human phase I clinical study of SPR720 (DNA gyrase B inhibitor; 100-2,000 mg single dose or 500-1,000 mg qw) in patients with mycobacterial infections. The most common treatment-emergent adverse events (TEAEs) reported in single ascending-dose cohorts were nausea (9/42 patients [21.4%] with SPR720 vs 0/14 patients with placebo), vomiting (8 [19%] vs 0), headache (7 [16.7%] vs 1 [7.1%]) and diarrhea (3 [7.1%] vs 0). The most common TEAEs reported in multiple ascending-dose (MAD) cohorts were diarrhea (13/30 [43.3%] vs 1/10 [10%]), headache (8 [26.7%] vs 0), nausea (7 [23.3%] vs 0), vomiting (4 [13.3%] vs 0), abdominal pain (3 [10%] vs 0) and back pain (2 [6.7%] vs 0). Slight elevations in ALT were observed in patients in the MAD cohorts; and 1 patient discontinued due to increased pancreatic enzymes attributed to high plasma drug concentration. Congress Alert

The FDA has issued an emergency use authorization for bamlanivimab (SARS-CoV-2 Spike protein inhibitor) for the treatment of mild-to-moderate COVID-19. Side effects observed in clinical trials of bamlanivimab included anaphylaxis, infusion-related reactions, nausea, diarrhea, dizziness, headache, itching and vomiting. Regulatory Agency Communication

Pooled analysis of 2 phase III trials of aducanumab (beta-amyloid aggregation inhibitor; 3, 6 or 10 mg/kg) in 2,757 patients with Alzheimer’s disease. The most common adverse events (AEs) were amyloid related imaging abnormality-edema/effusion (30.4% patients with aducanumab vs 2.7% patients with placebo), headache (19.6% vs 15.2%), amyloid related imaging abnormality-microhemorrhages and hemosiderin deposits (17.7% vs 6.5%), fall (14.1% vs 11.8%), superficial siderosis of central nervous system (12.1% vs 2.2%) and diarrhea (8.2% vs 6.8%). Other AEs are listed. [Data from FDA and Biogen Briefing Information (aducanumab) for the November 6, 2020 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee] Regulatory Agency Communication

Phase II study of daxibotulinumtoxinA (synaptosomal-associated protein 25 inhibitor; 80 or 120 Units [U]) in 155 patients with plantar fasciitis. The most common treatment-related adverse events were injection-site pain (6.1% with daxibotulinumtoxinA 80 U, 5.6% with 120 U vs 5.8% with placebo) and injection-site erythema (2%; 1.9% vs 1.9%). [Data from a Revance communication announcing results from a phase II clinical trial of daxibotulinumtoxinA for the management of plantar fasciitis] Company Communication

Phase III trial of bardoxolone methyl (Nrf2 activator and NF-kappaB/STAT3 inhibitor) in patients with Alport syndrome. Common adverse events occurring more frequently than with placebo included muscle spasms and increased aminotransferases. [Data from a Reata communication announcing new results from a phase III study of bardoxolone methyl] Company Communication

In a pivotal phase III study of INP104 (dihydroergotamine mesylate; 5-HT1B/D receptor agonist) in patients with migraine, the most frequent (≥5%) treatment-emergent adverse events were nasal congestion (16.7%), nausea (7.9%), nasal discomfort (5.4%) and abnormal taste (5.1%). [Data from an Impel communication announcing FDA submission of New Drug Application for INP104 for the acute treatment of migraine] Company Communication

Phase III study comparing cabotegravir (HIV integrase inhibitor) and combined emtricitabine and tenofovir disoproxil (FTC/TDF) for HIV prevention in women. Injection-site reactions were reported in 32% participants receiving cabotegravir and in 9% receiving FTC/TDF. Gastrointestinal disorders and nausea were more common in the FTC/TDF arm than in the cabotegravir arm. [Data from a GSK and ViiV Healthcare communication announcing results from a phase III study of cabotegravir for HIV prevention] Company Communication

Phase III study of lenabasum (CB2 receptor agonist; 20 mg bid) for the treatment of systemic sclerosis. Common adverse events included dizziness (18.3% patients with lenabasum vs 4.9% with placebo) and dry mouth (5.0% vs 1.6%). [Data from a Corbus communication announcing new data from the RESOLVE-1 trial] Company Communication

First case report of a 19-year-old man with history of hidradenitis suppurutiva treated with adalimumab (TNF-alpha Inhibitor) who developed pauci-immune crescentic glomerulonephritis. Congress Alert

First case report of a 65-year-old man who suffered acute interstitial nephritis and severe acute kidney injury whilst receiving furosemide (NKCC2 inhibitor; 20 mg qd). Congress Alert

Phase I study of vorinostat (300 mg) in combination with sirolimus (4 mg) or everolimus (10 mg) in patients with Hodgkin lymphoma. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (18/22 patients [82%] with vorinostat/sirolimus vs 17/18 [94%] with vorinostat/everolimus), neutropenia (12 [55%] vs 5 [28%]), anemia (10 [45%] vs 9 [50%]), transaminitis (10 [45%] vs 4 [22%]) and mucositis (9 [41%] vs 6 [33%]). Common grade 3 TRAEs were anemia (5 [23%] vs 3 [17%]), thrombocytopenia (4 [18%] vs 10 [55%]), neutropenia (4 [18%] vs 4 [22%]), increased triglycerides (1 [5%] vs 2 [11%]), transaminitis (1 [5%] vs 1 [6%]), neuropathy and febrile neutropenia (1 [5%] vs 0 each). Other TRAEs are listed.

Phase II trial of neratinib (pan-HER inhibitor) in patients with metastatic non-small cell lung cancer. Diarrhea was reported (4 patients [36%] grade 1 and 1 [9%] grade 2). [Data from a Puma Biotechnology communication announcing interim results from a phase II trial of neratinib] Company Communication

Conclusions from a Periodic Safety Update Report of iopamidol. The CMDh has recommended updating the product information to include acute generalized exanthematous pustulosis, hemiplegia and Kounis syndrome as adverse reactions with frequency “not known". The “warnings and precautions” section should be updated to include the risk of severe cutaneous adverse reactions (listed). Regulatory Agency Communication

Phase II study of LY-CoV555 (SARS-CoV-2 spike protein inhibitor) in patients with Covid-19. Common adverse events (AEs) included nausea (12/309 patients [3.9%] with LY-CoV555 vs 5/143 [3.5%] with placebo), dizziness (10 [3.2%] vs 3 [2.1%]), infusion-related reactions (7 [2.3%] vs 2 [1.4%]), pruritus (5 [1.6%] vs 1 [0.7%]), chills (4 [1.3%] vs 0), pyrexia (4 [1.3%] vs 1 [0.7%]) and chest discomfort (3 [1%] vs 1 [0.7%]). Other AEs are listed.

The EMA has updated the product information of Kisqali (ribociclib; CDK4/CDK6 inhibitor) to include that it may increase blood creatinine by inhibiting OCT2 and MATE1. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of levonorgestrel/ethinylestradiol. A causal relationship between levonorgestrel/ethinylestradiol and acquired angioedema, and between concomitant use of glecaprevir/pibrentasvir with ethinylestradiol and transaminase elevation are at least a reasonable possibility. The PRAC has proposed that the product information of products containing levonorgestrel/ethinylestradiol should be updated accordingly. Regulatory Agency Communication

First case report of a 58-year-old woman with ulcerative colitis who developed acute interstitial nephritis and acute tubular necrosis induced by vedolizumab (integrin alpha4beta7 antagonist; 300 mg q8w). Congress Alert

The FDA has updated the product information of Lynparza (olaparib; PARP-1/2 inhibitor) to include angioedema as an adverse reaction reported postmarketing. Regulatory Agency Communication

The PMDA has updated the package insert of Opdivo (nivolumab; PD-1 inhibitor) to include the risk of fulminant hepatitis. Regulatory Agency Communication

The PMDA has updated the package insert of Copaxone (glatiramer acetate; BDNF expression enhancer) to include the risk of hepatic impairment in the “Clinically Significant Adverse Reactions” section. Regulatory Agency Communication

Phase Ib study of BXCL701 (talabostat; 0.4 or 0.6 mg qd) in combination with pembrolizumab (200 mg) in 13 patients with metastatic castration-resistant prostate cancer. Grade ≥3 treatment-related adverse events included anemia (3 patients), fatigue (2), thrombocytopenia, syncope, increased hemoglobin, white blood cell count elevation, pneumonitis, sinusoidal obstruction syndrome, hyponatremia and increased lactic acid (1 each). 1 patient died from treatment-related acidosis. BXCL701 on-target adverse events consistent with cytokine activation are listed. Congress Alert

First-in-human phase I study of the human monoclonal antibody MAU868 (major capsid protein VP1 ligand; 1-100 mg/kg) in 33 healthy subjects. The most common adverse events were nasal congestion, oropharyngeal pain (3 patients each [9.1%]) and injection site hemorrhage (2 [6.1%]). Congress Alert

Review of the use of therapies targeting CXCR4 in hematologic and solid malignancies. Specific targeting of CXCR4 on hematopoietic stem cells impaired their proliferative capacity. In a phase I study of ulocuplumab, leukocytosis was present during the 4 weeks of monotherapy.

Phase Ib clinical trial of RBT-9 (stannous protoporphyrin; heme oxygenase 1 inhibitor; 9, 27 or 90 mg) in 42 subjects with or without chronic kidney disease. The most common treatment-emergent adverse event was photosensitivity. Congress Alert

Study characterizing a novel in vitro assay in human induced pluripotent stem cell-derived cardiomyocytes to predict cardiotoxicity. Results suggested that the negative inotropic effects of itraconazole are caused by Cav1 blockade.

First-in-human phase I/Ib study of GSK2831781 (lymphocyte activating 3 inhibitor; up to 5 mg/kg) in 40 healthy subjects (part A) and 27 patients with psoriasis (part B). In part A, adverse events (AEs) more frequent with GSK2831781 than with placebo were headache (5/24 [19%] with GSK2831781 vs 2/14 [14%] with placebo), abdominal pain and oropharyngeal pain (3 [12%] vs 0 each). In part B, AEs included oral herpes (3/18 [17%] vs 1/9 [11%]), oropharyngeal pain and post-procedural inflammation (2 [11%] vs 0 each). Minor and transient reductions in NK cells were reported within 6 hours of dosing. 7/44 participants treated with GSK2831781 developed treatment-induced anti-drug antibodies.

Phase I trial of osimertinib plus ramucirumab in 25 patients with T790M-positive EGFR-mutant non-small cell lung cancer. The most common treatment-related adverse events (TRAEs) were hypertension (12 [48%]), diarrhea (9 [36%]), stomatitis and platelet count decrease (6 [24%] each). Grade ≥3 TRAEs were platelet count decrease (16%), hypertension (8%) and neutrophil count decrease (1 [4%]). 1 patient died due to a TRAE of subdural hemorrhage. Other TRAEs are listed.

Phase II study of BPN14770 (PDE4D negative allosteric modulator; 25 mg bid) in 30 patients with fragile X syndrome. The most common adverse event was vomiting (3 patients [10%]). [Data from a Shionogi communication announcing positive topline results from a phase II study of BPN14770 in patients with fragile X syndrome] Company Communication

Open-label extension of a phase II clinical study of ozanimod (S1P1/S1P5 receptor agonist; 0.92 mg qd) in 170 patients with ulcerative colitis. The most common treatment-emergent adverse events (TEAEs) were hypertension, upper respiratory tract infection (10 [5.9%] each) and increased gamma-glutamyltransferase (9 [5.2%]). The most common serious TEAEs were anemia and ischemic stroke (2 [1.2%] each). 2 (1.2%) patients discontinued treatment due to ischemic stroke. Other serious TEAEs and TEAEs leading to discontinuation are listed. Congress Alert

The most common adverse events reported in a clinical study of MK-6482 (HIF-2alpha inhibitor) in 55 patients with metastatic renal cell carcinoma were anemia (49% grade 1-2; 26% grade 3; caused by an on-target decrease in erythropoietin) and hypoxia (11%; 15%). [Data from review evaluating VHL/HIF and VEGF inhibitors in patients with clear-cell renal cell carcinoma] Congress Alert

The Summary of Product Characteristics for Orfadin (nitisinone; 4-hydroxyphenylpyruvate dioxygenase inhibitor) has been updated to reflect new safety and efficacy information following an extension of the indication. New adverse events reported with nitisinone included infections, particularly respiratory tract infections such as bronchitis and pneumonia. Regulatory Agency Communication

Phase Ib results from a phase Ib/II clinical study of RMC-4630 in combination with intermittent or daily cobimetinib in 49 patients with advanced solid tumors. The most common treatment-related adverse events (TRAEs) were diarrhea (21/33 patients [63.6%]; 3 [9.1%] grade ≥3 with RMC-4603 plus daily cobimetinib vs 7/16 patients [43.8%]; 1 [6.3%] grade ≥3 with RMC-4603 plus intermittent cobimetinib), thrombocytopenia (12 [36.4%]; 3 [9.1%] vs 5 [31.3%]; 1 [6.3%]), edema (12 [36.4%] vs 2 [12.5%]), rash (8 [24.2%]; 3 [9.1%] vs 4 [25%]) and anemia (7 [21.2%]; 1 [3%] vs 3 [18.8%]; 0). Other TRAEs are listed. Congress Alert

List of adverse events reported in phase III trials of Hydexor (acetaminophen/hydrocodone/promethazine), including those of the active comparator Norco (acetaminophen/hydrocodone). [Data from FDA Briefing Information (Hydexor) for the November 2, 2020 Joint Meeting of the Anesthetic and Analgesic Drug Products and the Drug Safety and Risk Management Advisory Committees] Regulatory Agency Communication

The FDA has updated the product information of zoledronic acid (farnesyl pyrophosphate synthase inhibitor) to include a warning about embryo-fetal toxicity based on results from reproduction studies in rats (i.e. fetal malformations and embryo-fetal lethality) and the drug’s mechanism of action. Acquired Fanconi syndrome has been also added as an adverse reaction reported postmarketing. Regulatory Agency Communication

The PMDA has issued an alert for proper use of eldecalcitol (vitamin D receptor agonist) due to its known risk of hypercalcemia. Regulatory Agency Communication

Phase I study of LOXO-305 (BTK inhibitor; 25-200 mg qd) in 28 patients with B-cell malignancies. Treatment-related adverse events (TRAEs) included maculo-papular rash (4 patients [14%]), diarrhea, anemia (3 each [11%]), fatigue, arthralgia (2 each [7%]), hyperbilirubinemia and contusion (1 each [4%]). Grade 3 TRAEs were leukocytosis and neutropenia (1 each). Congress Alert

First-in-human phase I study of milademetan (Mdm2 inhibitor; 15-340 mg qd) in 78 patients with solid tumors or lymphomas. Common drug-related adverse events (DRAEs) observed with continuous dosing regimens included nausea (57 patients [73.1%]; 2 [2.6%] grade ≥3), thrombocytopenia (55 [66.7%]; 21 [34.6%]), fatigue (36 [46.2%]; 3 [3.8%]), anemia (33 [42.3%]; 14 [17.9%]), diarrhea (26 [33.3%]), vomiting (22 [28.2%]; 2 [2.6%]) and neutropenia (10 [12.8%]; 8 [10.3%]). These DRAEs were also reported with intermittent dosing regimen. Congress Alert

Phase I study of the SARS-CoV-2 vaccine candidate CVnCoV (2-12 mcg) in healthy individuals. At 12 mcg, most grade 3 adverse events were reported after administration of the second dose and included fatigue, headache, chills, muscle pain and fever. [Data from a CureVac communication announcing positive interim data from an ongoing phase I study of its COVID-19 vaccine candidate, CVnCoV] Company Communication

Regeneron communication announcing that the independent data monitoring committee for the clinical trials of the antibody cocktail REGN-COV2 in hospitalized patients with COVID-19 has recommended that enrollment of patients requiring high-flow oxygen or mechanical ventilation should be placed on hold based on a potential safety signal and an unfavorable risk/benefit profile. Company Communication

The NMPA has decided to update the product information of ornithine aspartate injection. Postmarketing experience reports of gastrointestinal, systemic, nervous, skin, respiratory, immune and vascular events (listed) should be amended in the “Adverse Reactions” section. The “Precautions” section was also updated to warn about a case of anaphylactic shock, and that the ability of driving or operating machinery could be affected. Regulatory Agency Communication

First-in-human phase I study of TPX-0022 (CSF-1R/Met/Src inhibitor; 20-120 mg qd) in 22 patients with advanced solid tumors. Treatment-related adverse events included dizziness (10 patients [45.5%]), increased lipase (5 [22.7%]), increased amylase (4 [18.2%]), fatigue, nausea, vomiting (3 [13.6%] each) and anemia (2 [9.1%]). Dizziness was likely due to off target inhibition of TRK. Grade 1-2 peripheral edema was reported in 9.1% patients. Congress Alert

Health Canada will update the product information of benzodiazepines and benzodiazepine-like drugs (listed) to include the risk of problematic use and substance use disorder, severe withdrawal symptoms, and falls and fractures in specified populations. Regulatory Agency Communication

The dosing of garetosmab (REGN2477; inhibin beta A chain inhibitor) in an ongoing phase II study in patients with fibrodysplasia ossificans progressiva has been paused following reports of fatal serious adverse events during the open-label extension, in which all patients received active treatment. [Data from a Regeneron communication providing an update on the garetosmab phase II LUMINA-1 trial in fibrodysplasia ossificans progressiva] Company Communication

Study evaluating pregnancy and fetal outcomes after exposure to modafinil or armodafinil (DAT inhibitors) during pregnancy. The prevalence of major congenital malformations was 13% in patients receiving either drug, which is higher than the general prevalence in the general population (3%).

Results from preclinical studies of the probody-drug conjugate CX-2043 (epithelial cell adhesion molecule interacting agent/tubulin polymerization inhibitor). Cynomolgus monkeys receiving CX-2043 at 9 mg/kg developed dry skin, slight abrasion and mild dehydration. An antibody-drug conjugate sharing the same mechanism of action was not well tolerated when administered to monkeys at 3 or 6 mg/kg, and was associated with weight loss, liquid feces, decreased levels of albumin, sodium, chloride and red blood cells, and increased AST, blood urea nitrogen and creatine levels. Congress Alert

Gilead has stopped screening and enrollment for its clinical trials of filgotinib (JAK1 inhibitor) in psoriatic arthritis, ankylosing spondylitis and uveitis. This follows the FDA’s rejection of Gilead’s application for approval of filgotinib in rheumatoid arthritis due to toxicity concerns.

Roche, together with the EMA, has issued a Direct Healthcare Professional Communication warning about drug-induced liver injury (including fatal cases) when using Esbriet (pirfenidone; TGFbeta inhibitor). The drug’s product information will be updated accordingly. Regulatory Agency Communication

Phase I study of BPX-601 (5E6 cells/kg) in combination with rimiducid in 4 patients with pancreatic cancer. Adverse events included confusion (2 events), hematuria, neurotoxicity and dysgraphia (1 each). 1 patient experienced grade 4 cytokine release syndrome considered related to treatment. [Data from a Bellicum Pharmaceuticals communication announcing interim results from a phase I study of BPX-601 in combination with rimiducid] Company Communication

Health Canada has issued a safety review evaluating the risk of central sleep apnea in patients receiving Brilinta (ticagrelor; P2Y12 receptor antagonist). 9 cases of central sleep apnea after treatment with Brilinta were identified, and 8 cases were considered probably or possibly related. Health Canada has requested an update of Brilinta’s product information to include a warning about this potential safety issue. Regulatory Agency Communication

Phase I/II clinical study of adagrasib (MRTX849; KRAS G12C inhibitor; 600 mg bid), alone or in combination with other antineoplastic agents, in patients with KRAS G12C-mutated cancer. The most common treatment-related adverse events (TRAEs) observed in the pooled results were nausea (54%; 2% grade 3-4), diarrhea (51%), vomiting (35%; 2%), fatigue (32%; 6%), increased ALT (20%; 5%) and increased AST (17%; 5%). Grade 5 TRAEs included pneumonitis and cardiac failure (1 patient each). Other TRAEs are listed. Congress Alert