The translational safety intelligence portal

First case report of a 51-year-old woman with stage IIIc anal carcinoma who developed thrombotic thrombocytopenic purpura induced by nivolumab (PD-1 inhibitor).

First-in-human phase I study of intratumoral BO-112 (DExD/H-box helicase 58 / MDA5 activator and TLR3 agonist; 0.6 or 1 mg), alone or combined with a PD-1 inhibitor, in patients with solid malignancies. Treatment-related adverse events (AEs) reported with BO-112 monotherapy were pyrexia (3/16 patients [18.8%]), chills, headache (2 each [12.5%]), nausea, vomiting, injection site pain and myalgia (1 each [6.3%]). AEs observed in the combination group and considered related to BO-112 included pyrexia (18/28 patients [64.3%]), asthenia (9 [32.1%]), nausea (7 [25%]), chills, myalgia (6 each [21.4%]), vomiting and decreased appetite (4 each [14.3%]). Other AEs related to BO-112 are listed.

The FDA has updated the product information of Zydelig (idelalisib; PI3Kdelta inhibitor), adding the risk of drug reactions with eosinophilia and systemic symptoms (DRESS) to the “Warnings and Precautions” and “Adverse Reactions” sections. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between dolutegravir and the risk of neural tube defects. Preliminary results from an observational study suggested an increased risk of neural tube defects in children born to women who were taking dolutegravir during pregnancy (0.19% with dolutegravir vs 0.11% with other antiretrovirals). Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Zejula (niraparib; PARP-1/2 inhibitor) and the risk of severe hypertension and posterior reversible encephalopathy syndrome (PRES). A recent review identified several cases of severe hypertension in patients receiving Zejula, including rare cases of hypertensive crisis. 5 cases of PRES associated with Zejula have been identified worldwide. The product information of Zejula will be updated to include hypertensive crisis and PRES as adverse reactions with frequency “rare”. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between dihydropyrimidine dehydrogenase (DPD) deficiency and the risk of severe and fatal toxicities of fluoropyrimidines (5-fluorouracil, capecitabine and tegafur). Patients with complete or partial DPD deficiency are at increased risk of developing severe and fatal adverse reactions to fluoropyrimidines, including stomatitis, diarrhea, mucosal inflammation, neutropenia and neurotoxicity. The product information of these drugs will be updated to include a recommendation of testing for DPD deficiency before initiating treatment with fluoropyrimidines. Regulatory Agency Communication

The EMA has updated the product information of Beovu (brolucizumab; VEGF inhibitor) to add a new warning on retinal vasculitis and/or retinal vascular occlusion, endophthalmitis, intraocular inflammation, traumatic cataract and retinal detachment. Regulatory Agency Communication

The EMA has updated the product information of Azilect (rasagiline; MAO-B inhibitor) to include data from a retrospective study in patients with Parkinson’s disease that suggest an increased risk of melanoma. The “special warnings and precautions for use” section of the SmPC has been updated accordingly. Regulatory Agency Communication

Preclinical study evaluating the sensitivity of cancer cell lines to N-myristoyltransferase inhibition with PCLX-001. Some mice receiving PCLX-001 died, and most exhibited significant weight loss, low neutrophil and lymphocyte counts, decreased red blood cell counts and low monocyte and platelet counts. Mice bearing diffuse large B-cell lymphoma cell xenografts receiving PCLX-001 20, 50 or 60 mg/kg/day had rough and scruffy coats, piloerection and dehydration. Doxorubicin-treated mice caused weight loss and death in the majority of mice within the first 7 days of the experiment.

Phase I study of quavonlimab (25 or 75 mg q3w or q6w) plus pembrolizumab (200 mg q3w) in 134 patients with non-small-cell lung cancer. The most common grade ≥3 treatment-related adverse events were increased alanine aminotransferase, pneumonitis (8% each) and increased aspartate aminotransferase (6%). Congress Alert

Phase I study of TAK-788 (EGFR/HER2 inhibitor) in healthy volunteers. The most common adverse events were headache, nausea, diarrhea, upper abdominal pain, soft feces and flatulence. 1 grade 3 event of increased lipase was reported. Congress Alert

Study of the pharmacokinetics of NUC-3373 (thymidylate synthase inhibitor) in combination with leucovorin, in patients with metastatic colorectal cancer. Treatment-related adverse events included grade 4 bilirubin elevation and grade 3 fatigue, nausea, fever, elevated ALT and elevated ALP (1 patient each). Leucovorin did not affect the pharmacokinetics or safety profile of NUC-3373. Congress Alert

First-in-human phase I study of TAS-119 (aurora kinase A inhibitor) in patients with advanced solid tumors. Dose-limiting toxicities were serious corneal microcysts (2 patients; grade 3 in 1), grade 3 nausea, dry eyes and fatigue (1 each). Treatment-related adverse events (TRAEs) included ocular symptoms (10/34 [29.4%] in the escalation phase; 12/40 [30%] in the expansion phase), diarrhea (8 [23.5%]; 13 [32.5%]), nausea (5 [14.7%]; 5 [12.5%]) and decreased appetite (4 [11.8%]; 7 [17.5%]). Other TRAEs are listed.

Phase I trial of CTX110 (CD19-targeted CAR T-cell therapy) for relapsed/refractory CD19+ B-cell malignancies. Adverse events observed at dose levels 1-3 (3E7 - 3E8 CAR T-cells) included cytokine release syndrome (30%, all grade ≤2) and immune effector cell-associated neurotoxicity syndrome (10%, grade 2). 1 patient received dose level 4 (6E8 CAR T-cells) and was hospitalized with febrile neutropenia, short-term memory loss and confusion which progressed to obtundation; he was found to have reactivation of HHV-6 and HHV-6 encephalitis and died 52 days after CTX110 infusion. [Data from a CRISPR Therapeutics communication announcing results from a phase I trial of CTX110] Company Communication

BIIB089, an SMN1 gene therapy for the treatment of spinal muscular atrophy, has been put on clinical hold due to dorsal root ganglion toxicity. Consequently, Biogen has decided to discontinue development of BIIB089. [Data from a Biogen presentation announcing third quarter 2020 financial results and providing a business update] Company Communication

3-year postmarketing surveillance study of ipragliflozin (SGLT2 inhibitor; 50 mg qd) in 11,424 patients with type 2 diabetes mellitus. The most common adverse drug reactions (ADRs) were pollakiuria (470 [4.25%]) and polyuria (303 [2.74%]), genital pruritus (81 [0.73%]), cystitis (77 [0.70%]), urinary tract infection (74 [0.67%]). The most common ADRs leading to death were pancreatic carcinoma (3 cases), myocardial infarction and pneumonia (2 each). Other ADRs are listed.

Clinical trial supporting the approval of lenvatinib (tyrosine kinase inhibitor; 8 or 12 mg qd) as first-line treatment for patients with unresectable hepatocellular carcinoma. The most common adverse events (AEs) were hypertension (45% with lenvatinib vs 31% with sorafenib), fatigue (44% vs 36%), diarrhea (39% vs 46%), decreased appetite (34% vs 27%), decreased weight (31% vs 22%), arthralgia/myalgia (31% vs 20%) and abdominal pain (30% vs 28%). The most frequent serious AEs were hepatic encephalopathy (5%), ascites, hepatic failure (3% each) and decreased appetite (2%). The most frequent AEs leading to discontinuation of lenvatinib were hepatic encephalopathy (2%), fatigue, hyperbilirubinemia and hepatic failure (1% each). Other AEs are listed.

The EMA has updated the product information of Tecentriq (atezolizumab; PD-1 inhibitor) to include additional adverse drug reaction (ADRs) reported in a phase III study of atezolizumab given as monotherapy. These ADRs have been added to section 4.8 (“Undesirable effects”) of the SmPC and consist of headache (frequency “very common”), dry skin and increased blood creatinine (frequency “common”). Regulatory Agency Communication

The FDA has updated the product information of Lumigan (bimatoprost; FP receptor agonist) to include non-periocular skin discoloration as an adverse reaction reported postmarketing. Regulatory Agency Communication

The EMA has updated the product information of Obizur (susoctocog alfa; coagulation factor VIII analog) to include the risk of anamnestic reactions with rise in human factor VIII and/or porcine factor VIII inhibitors with frequency “very common”. Regulatory Agency Communication

First-in-human phase I study of JTX-4014 (PD-1 inhibitor) in 18 patients with advanced solid tumors. The most common adverse events (AEs) were fatigue (9), dizziness, increased aspartate aminotransferase (4 each), increased alanine aminotransferase, anemia and tumor pain (3 each). Grade 3 treatment-related AEs included increased blood alkaline phosphate, pneumonitis and maculo-papular rash (1 each). Other AEs are listed.

Clinical trial of hydroxychloroquine (TLR7/9 antagonist) in 1,561 patients with COVID-19. Adverse events included major cardiac arrhythmia (8.2%), supraventricular tachycardia (7.6%), atrial flutter/atrial fibrillation (6.3%), ventricular tachycardia (0.4%), ventricular fibrillation (0.3%) and atrioventricular block (0.1%). 1 serious case of torsades de pointes considered related to treatment was reported.

Study reporting that the neurotoxicity observed with CD19-targeted CAR T-cell therapies may be caused by an on-target, off-tumor effect due to expression of CD19 in brain mural cells.

The most common adverse reactions to Inmazeb (≥20%) were pyrexia, chills, tachycardia, tachypnea and vomiting. [Data from FDA approved drug report for Inmazeb (atoltivimab/maftivimab/odesivimab-ebgn)] Regulatory Agency Communication

Phase I/II trial of the BBIBP-CorV vaccine (SARS-CoV-2 proteins-directed immunity inducer; 2-8 mcg intramuscularly) in 640 healthy participants. The most common injection site adverse reaction was pain. Systemic reactions included fever, inappetence, nausea, constipation, joint pain, anaphylaxis, drowsiness and dizziness. No serious adverse events were reported. Laboratory abnormalities and other local and systemic adverse reactions are listed.

The most common side effects of Tecartus (brexucabtagene autoleucel; CD19-targeted CAR T-cell therapy) are cytokine release syndrome, infections and encephalopathy. [Data from EMA summary of opinion for Tecartus] Regulatory Agency Communication

The most common side effects of Oxlumo (lumasiran; hydroxyacid oxidase 1 expression inhibitor) are injection-site reaction and abdominal pain. [Data from EMA summary of opinion for Oxlumo] Regulatory Agency Communication

The most common side effect of Libmeldy (arylsulfatase A gene therapy) is the development of antibodies against arylsulfatase A. [Data from EMA summary of opinion for Libmeldy] Regulatory Agency Communication

The most common side effects of Trixeo Aerosphere (formoterol/glycopyrronium bromide/budesonide) are pneumonia (4.6%), headache and urinary tract infection (2.7% each). [Data from EMA summary of opinion for Trixeo Aerosphere] Regulatory Agency Communication

The most common side effects of Leqvio (inclisiran; PCSK9 synthesis inhibitor) are reactions at the injection site. [Data from EMA summary of opinion for Leqvio] Regulatory Agency Communication

The most common side effects of Fintepla (fenfluramine; 5-HT2B receptor agonist) are decreased appetite, diarrhea, pyrexia, fatigue, upper respiratory tract infection, lethargy, somnolence and bronchitis. Fenfluramine is associated with valvular heart disease and pulmonary arterial hypertension at high doses. [Data from EMA summary of opinion for Fintepla] Regulatory Agency Communication

The most common side effects of Vocabria (cabotegravir) in combination with Rekambys (rilpivirine) are injection site reactions, headache, pyrexia, nausea, fatigue, asthenia, myalgia and dizziness. [Data from EMA summary of opinion for Vocabria] Regulatory Agency Communication

Preliminary results from a first-in-human phase I study of tidutamab (CD3 interacting agent/sst2 receptor ligand; 0.1-2 mcg/kg) in 27 patients with advanced neuroendocrine tumors. Common grade 3-4 treatment-related adverse events included lymphopenia/decreased lymphocyte count (11 patients [41%]), increased GGT, vomiting, increased ALT/AST (5 each [19%]) and nausea (4 [15%]). Nausea and vomiting were dose-limiting toxicities at 2 mcg/kg, and were considered related to sst2 receptor engagement. Lymphopenia may be related to the anti-CD3 activity of tidutamab. Other adverse events are listed. Congress Alert

The EMA has updated the product information of Stocrin (efavirenz; reverse transcriptase inhibitor), adding a new warning on neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis and delirium). Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms, which may increase efavirenz levels. The SmPC and package leaflet have been updated accordingly. Regulatory Agency Communication

First-in-human phase I study of iadademstat (ORY-1001; lysine specific demethylase 1A inhibitor) in 41 patients with relapsed or refractory acute myeloid leukemia. The most common drug-related adverse events (DRAEs) were asthenia (8 events), fever of unknown origin or neutropenic fever (7), anorexia (6), thrombocytopenia, dysgeusia and diarrhea (5 each). Serious DRAEs included neutropenic fever or fever of unknown origin (4), pneumonia or respiratory infection, differentiation syndrome (2 each), cellulitis, thrombocytopenia and asthenia (1 each). 3 grade 5 DRAEs were reported: differentiation syndrome (2), pneumonia and cellulitis (1 each). Other DRAEs are listed.

The EMA has updated the product information of Vfend (voriconazole; lanosterol 14-alpha demethylase inhibitor) to include a warning on adrenal events and the risk of drug-drug interactions with naloxegol, ivacaftor and corticosteroids as voriconazole is a strong CYP3A4 inhibitor. Regulatory Agency Communication

Health Canada has issued a communication reminding not to use benzocaine-containing products in children under 2 years of age due to the risk of methemoglobinemia. Regulatory Agency Communication

The FDA has updated the product information of Lamictal (lamotrigine; sodium channel blocker) to include a warning about cardiac rhythm and conduction abnormalities after observing class IB antiarrhythmic activity in vitro, which could lead to reduced ventricular conduction, widen QRS interval, proarrhythmia and sudden death. Regulatory Agency Communication

The FDA has updated the product information of Keytruda (pembrolizumab; PD-1 inhibitor), adding the risk of chronic graft-versus-host disease in the “Warnings and Precautions“ section. The “Adverse Reactions” section has also been updated to include novel safety data from the KEYNOTE-204 study comparing Keytruda to brentuximab vedotin. Regulatory Agency Communication

The FDA has issued a drug safety communication advising against the use of nonsteroidal anti-inflammatory drugs (NSAIDS) around 20 weeks or later in pregnancy due to a serious risk of kidney problems in unborn babies, which can result in oligohydramnios and/or neonatal renal impairment. The product information of NSAIDS will be updated to warn about this risk. Regulatory Agency Communication

The EMA has updated the product information of Bavencio (avelumab; PD-L1 inhibitor) to include new adverse drug reactions (ADRs) regarding myasthenia gravis/myasthenic syndrome, with frequency “uncommon”. Other immune-related ADRs reported in <1% patients were myositis, hypopituitarism, uveitis and Guillain-Barré syndrome. Regulatory Agency Communication

Phase I clinical trial assessing the safety and immunogenicity of BNT162b1 and BNT162b2 (SARS-CoV-2 proteins-directed immunity inducers; 10-30 mcg) in 195 healthy subjects. Local reactions such as injection site pain occurred at similar proportions in patients aged 18-55 and patients aged 65-85 years, but redness and swelling were not reported in older patients with BNT162b2. Common systemic adverse events (AEs) were fatigue, headache, fever and chills. Other AEs are listed.

The development of VX-814 (alpha-1-antitrypsin modulator) will be discontinued due to the liver enzyme (AST/ALT) elevations observed in a phase II study in patients with alpha-1 antitrypsin deficiency. [Data from a Vertex Pharmaceuticals communication announcing an update on its clinical programs targeting alpha-1-antitrypsin] Company Communication

Phase III study assessing the safety and tolerability of zuranolone (GABAA positive allosteric modulator; 30 mg qd) in 725 patients with major depressive disorder. The most common (≥5%) adverse events (AEs) were somnolence (69 [9.5%] patients), headache (63 [8.7%]) and dizziness (39 [5.4%]). The most common AEs leading to discontinuation were dizziness, anxiety and nausea (2 each). [Data from a Sage Therapeutics communication announcing positive interim results from a phase III trial of zuranolone in patients with major depressive disorder] Company Communication

Phase II trial of bavituximab plus pembrolizumab in 40 patients with advanced gastric or gastroesophageal cancer. The most common treatment-related adverse events (TRAEs, occurring in ≥20% patients) included decreased appetite (16 patients [40%]), nausea (15 [37.5%]), fatigue (12 [30%]), constipation, vomiting (10 [25%] each), anemia and decreases in weight (8 [20%] each). 1 serious AE of pneumonitis was considered related to both bavituximab and pembrolizumab. Other TRAEs are listed. Congress Alert

Phase I study of sotorasib (KRAS inhibitor) in 129 patients with solid tumors harboring the KRAS p.G12C mutation. Grade 3 treatment-related adverse events (TRAEs) included increased ALT (4.7% patients), diarrhea (3.9%), increased AST (2.3%), increased blood alkaline phosphatase (1.6%), hepatitis, decreased lymphocyte count, increased gamma-glutamyltransferase and hyponatremia (0.8% each). There was 1 grade 4 TRAE of increased ALT (0.8%). Other TRAEs are listed.

First-in-human phase I study of BAY-1895344 (ATR inhibitor) in 22 patients with advanced solid tumors. The most common treatment-emergent adverse events (AEs) were anemia (81.8%; all grade 3), neutropenia (72.7%; 54.5% grade 3/4), fatigue (68.2%; 4.5%), nausea (50%; 9.1%) and thrombocytopenia (45.5%; 18.2%). Serious treatment-related AEs included grade 4 neutropenia, grade 3 diarrhea, hypotension and nausea, grade 2 fatigue and medication error (1 patient each). Other AEs are listed.

Pivotal phase III study of daxibotulinumtoxinA (synaptosomal-associated protein 25 inhibitor) in 301 patients with cervical dystonia. The most common treatment-related adverse events (TRAEs) were injection-site pain (7.9% with 125 Units; 4.7% with 250 Units), headache (4.7%; 4.7%) and injection-site erythema (4.7%; 2.3%). AEs of interest with botulinum toxin treatments for cervical dystonia were muscular weakness (4.7%; 2.3%) and dysphagia (1.6%; 3.9%). 1 TRAE of neck pain was reported as severe. [Data from a Revance communication announcing positive results from a phase III trial of daxibotulinumtoxinA for injection in cervical dystonia] Company Communication

Systematic review of 15 meta-analyses evaluating the association between maternal use of selective serotonin reuptake inhibitors (SSRIs; SERT inhibitors) and the risk of congenital anomalies. A positive association was found between maternal SSRI use and congenital anomalies, particularly with paroxetine and fluoxetine. Cardiovascular congenital defects were associated with general SSRI use and specifically with use of paroxetine, fluoxetine and sertraline.

First-in-human phase I/II study of casimersen (dystrophin interacting agent) in 12 patients with Duchenne muscular dystrophy. 1 patient experienced treatment-related iron deficiency and another had treatment-related flushing. Congress Alert

First-in-human phase I/II study of SRP-9003 (beta-sarcoglycan gene therapy; 5E13 or 2E14 vg/kg) in patients with limb girdle muscular dystrophy type 2E. Adverse events (AEs) reported in patients receiving SRP-9003 at 5E13 vg/kg included elevated liver enzymes (2/3 patients; including a serious event with bilirubin increase) and vomiting (1). AEs observed with SRP-9003 2E14 vg/kg included vomiting, pain in extremity, serious dehydration resulting from vomiting (considered treatment-related) and elevated GGT levels. Congress Alert

Preliminary results from the first-in-human study of scAAV9.U7-ACCA (dystrophin interacting agent; 3E13 vg/kg) in 2 patients with Duchenne muscular dystrophy. Adverse events included transient episodes of nausea and vomiting. Congress Alert

Eli Lilly’s clinical trial of its antibody treatment for COVID-19, consisting of Lilly’s monoclonal antibody LY-CoV555 in combination with the standard of care (remdesivir), in hospitalized COVID-19 patients has been paused due to a potential safety concern. The independent safety board found that the difference in clinical status between patients receiving the antibody and those who received placebo crossed a predetermined threshold for safety.

The FDA has updated the product information of Palynziq (pegvaliase-pqpz; bacterial phenylalanine ammonia lyase analog) to include novel adverse reactions reported in clinical trials (listed). Regulatory Agency Communication

The FDA has updated the product information of Dipentum (olsalazine sodium; 5-LOX/COX-1/COX-2 inhibitor and PPARgamma agonist), adding the risk of hepatic failure, photosensitivity, nephrolithiasis, renal impairment (including minimal change disease, acute/chronic interstitial nephritis, renal failure and kidney toxicity in animals), acute intolerance syndrome (leading to cramping, acute abdominal pain, bloody diarrhea, fever, headache and rash) and hypersensitivity reactions (which may lead to myocarditis, pericarditis, nephritis, hepatitis, pneumonitis or hematologic abnormalities) to the “Warnings and Precautions” section. All these adverse events have been reported with mesalamine, a product of olsalazine. Nephrolithiasis has also been included as an adverse reaction reported postmarketing. Regulatory Agency Communication

The most common adverse events (AEs; >5%) reported in clinical trials of ALKS 3831 (olanzapine/samidorphan fixed-dose combination) were increased weight, somnolence, dry mouth, headache, anxiety, increased appetite, fatigue, infections, increased waist circumference, upper respiratory tract infection and increased creatine kinase. Other AEs of ALKS 3831 and olanzapine are listed. [Data from the FDA Briefing Information for the October 9, 2020 Meeting of the Psychopharmacologic Drugs and Drug Safety and Risk Management Advisory Committees] Regulatory Agency Communication

Study reporting the discovery of CC-90011 (lysine-specific demethylase 1A inhibitor). In a patient-derived xenograft model of small cell lung cancer, mice treated with CC-90011 showed a mean body weight loss of <1%.

Adverse events reported in phase III trials comparing olanzapine/samidorphan with olanzapine and/or placebo are listed, including those of long-term extension analyses. [Data from the Alkermes Briefing Information for the October 9, 2020 Meeting of the Psychopharmacologic Drugs Advisory and Drug Safety and Risk Management Advisory Committees] Company Communication

Analysis of 2 phase II studies of GB001 (DP2 receptor antagonist; 20-60 mg qd) in patients with eosinophilic asthma and chronic rhinosinusitis. Liver chemistry elevations (including one serious case) were reported in asthmatic patients treated with GB001. [Data from a Gossamer Bio communication announcing phase II results of GB001 for asthma and chronic rhinosinusitis] Company Communication

Conclusions from a Periodic Safety Update Report of Revlimid (lenalidomide; cereblon/VEGF inhibitor). Based on a large number of cases reported in a cumulative review, a causal relationship between lenalidomide and pulmonary hypertension (as a possible class effect) is plausible. The product information of products containing lenalidomide will be updated accordingly. Regulatory Agency Communication

Phase III study of Dupixent (dupilumab; interleukin-4 receptor subunit alpha antagonist; 100 or 200 mg q2wk) in 408 children with uncontrolled moderate-to-severe asthma. The most common adverse events with Dupixent included injection-site reactions (18% for Dupixent vs 13% for placebo), viral upper respiratory tract infections (12% vs 10%) and eosinophilia (6% vs 1%). [Data from a Sanofi and Regeneron communication announcing that a pivotal phase III trial of Dupixent has met its primary and all key secondary endpoints in children with uncontrolled moderate-to-severe asthma] Company Communication

Johnson & Johnson has temporally paused all dosing in clinical trials of its COVID-19 vaccine JNJ-78436735 after a patient developed an unexplained illness in a phase III trial. Company Communication

Phase Ib clinical trial of derazantinib (300 mg qd) plus atezolizumab (1,200 mg q3w) in 26 patients with advanced urothelial cancer. The most common adverse events were asthenia, fatigue, nausea and diarrhea. [Data from a Basilea communication announcing interim results from the FIDES-02 study] Company Communication

Phase II study of the antibody-drug conjugate Padcev (enfortumab vedotin; nectin-4 inhibitor/tubulin polymerization inhibitor) in patients with urothelial cancer. The most common (>5% patients) grade ≥3 treatment-related adverse events were neutropenia, rash, fatigue, increased lipase, diarrhea, decreased appetite, anemia and hyperglycemia. [Data from an Astellas and Seagen communication announcing topline results from a phase II study of Padcev in patients with urothelial cancer] Company Communication

The FDA has updated the product information of Zytiga (abiraterone acetate; CYP17A1 inhibitor) to include a warning about severe hypoglycemia in diabetic patients treated with pioglitazone or repaglinide. Hypersensitivity and anaphylaxis (which may lead to difficulty swallowing or breathing, swollen face, lips, tongue or throat, and urticaria) have been included as adverse reactions reported postmarketing. Regulatory Agency Communication

Study of remdesivir (viral RNA polymerase inhibitor) in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection. Adverse events (AEs) more common with remdesivir than with placebo included arrhythmia, blood glucose increase, blood albumin decrease, platelet count decrease and delirium. Serious AEs more common with remdesivir included atrial fibrillation, cardiac arrest and glomerular filtration rate decrease. Other AEs are listed.

Results from preclinical studies of AT845 (lysosomal alpha-glucosidase gene therapy) for treating Pompe disease. Monkeys receiving AT845 at doses >10E14 vg/kg showed elevated ALT/AST levels, immune responses, increased cardiac biomarkers and echocardiogram abnormalities. These adverse events were considered related to a xenogeneic immune response rather than to the drug’s mechanism of action. Congress Alert

The FDA has updated the product information of Betaseron (interferon beta-1b; interferon alpha/beta receptor agonist), adding hemolytic anemia as an adverse reaction reported postmarketing. Regulatory Agency Communication

The PMDA is currently reviewing the potential association between nivolumab (PD-1 inhibitor) and fulminant hepatitis. Regulatory Agency Communication

The PMDA is currently reviewing the potential association between ixekizumab (IL-17A inhibitor) and interstitial pneumonia. Regulatory Agency Communication

The PMDA is currently reviewing the potential association between glatiramer acetate (BDNF expression enhancer) and hepatic impairment. Regulatory Agency Communication

First-in-human phase I study of DS-1205c (AXL inhibitor) in combination with gefitinib in 20 patients with EGFR-mutant non-small cell lung cancer. Common treatment-emergent adverse events (TEAEs) were increased AST (7 [35%] patients), increased ALT, maculopapular rash (6 [30%] each), diarrhea (5 [25%]) and decreased white blood cell count (4 [20%]). 2 dose-limiting toxicities were reported: decreased neutrophil count (1 event at 800 mg bid) and nausea (1 event at 1,200 mg bid). Other TEAEs are listed. Congress Alert

First-in-human phase Ib study of CS1001 (PD-L1 inhibitor) in combination with XELOX in 29 patients with gastric or gastro-esophageal junction carcinoma (GC/GEJ), or with cisplatin/5-fluorouracil in 39 patients with esophageal squamous cell carcinoma (ESCC). The most common grade ≥3 CS1001-related adverse events (AEs) in both cohorts included decreased platelet count (6 patients in the GC/GEJ cohort; 2 in the ESCC cohort), decreased WBC count, decreased neutrophil count (3; 3 each) and anemia (3; 6). In the ESCC cohort, there was 1 death of unknown cause attributed to CS1001. Other CS1001-related AEs are listed. Congress Alert

First-in-human phase I single-ascending-dose (SAD) and multiple-ascending-dose (MAD) studies of iberdomide (cereblon modulator) in healthy subjects. In the SAD study, 6/65 (9.2%) subjects had treatment-emergent adverse events suspected to be iberdomide-related: pruritus (2 subjects), diarrhea, urticaria, T-wave inversion on electrocardiogram and oropharyngeal pain (1 each). A dose-limiting toxicity of grade 3 neutropenia was reported with iberdomide 1 mg in the MAD study.

Study reporting that Mdr2-knockout mice exhibit some phenotypes of primary sclerosing cholangitis (including cholestatic liver injury and fibrosis). Deletion of Mdr2 also altered fecal bile acid composition and enhanced susceptibility to colitis.

Phase II study of ATL1102 (integrin, alpha 4 subunit expression inhibitor; 25 mg qwk) in 9 patients with Duchenne’s muscular dystrophy. The most common treatment-emergent adverse events were injection-site erythema (8 patients), skin discoloration (6), injection-site pain (5), injection-site bruising (4) and injection-site swelling (3). Congress Alert

Phase II trial of retifanlimab (PD-1 inhibitor; 500 mg qw4) in 94 patients with squamous carcinoma of the anal canal. Grade ≥3 immune-related adverse events were reported in 6 patients (6.4%), including skin reactions, pneumonitis (2 each), nephritis and adrenal insufficiency (1 each). Infusion reactions were observed in 4 (4.3%) patients, none were grade ≥3. Congress Alert

Phase II study of LY-CoV555 monotherapy or in combination with LY-CoV016 (SARS-CoV-2 spike protein inhibitors) in patients with mild-to-moderate COVID-19. Treatment-emergent adverse events included nausea (12/309 patients [3.9%] with LY-CoV555 monotherapy; 3/112 [2.7%] with LY-CoV555 + LY-CoV016 vs 6/156 [3.8%] with placebo), dizziness (9 [2.9%]; 0 vs 3 [1.9%]) and pruritus (5 [1.6%]; 2 [1.8%] vs 1 [0.6%]). [Data from a Lilly presentation providing additional data on its SARS-CoV2 neutralizing antibody program] Company Communication

In clinical trials of the antibody LY-CoV555 (SARS-CoV-2 spike protein inhibitor), isolated cases of drug-related infusion reactions and hypersensitivity were reported, including 2 cases of serious infusion reactions. [Data from a Lilly communication providing a comprehensive update on its SARS-CoV-2 neutralizing antibody programs] Company Communication

First-in-human phase I study of oral dubermatinib (AXL inhibitor; 1.5-50 mg/m2) in patients with advanced solid tumors. The most common drug-related adverse events (DRAEs) were nausea, vomiting and diarrhea. Grade 4 dose-limiting thrombocytopenia was observed at 28 mg/m2. Other DRAEs are listed. Congress Alert

First-in-human phase I study of ONO-4578 (EP4 receptor antagonist), alone or combined with nivolumab (PD-1 inhibitor; 240 mg q2w), in patients with advanced or metastatic solid tumors. Treatment-emergent adverse events (TEAEs) reported with ONO-4578 monotherapy included duodenal ulcer (2 patients at 60 mg and 1 grade 3 event at 100 mg), increased ALT/AST, decreased white blood cell count and grade ≥3 anemia (2 patients at 100 mg each). Other TEAEs are listed. Congress Alert

Phase Ib clinical trial of BI 836880/BI 754091 combination in 50 patients with solid tumors. The most common adverse events (AEs) were asthenia (11 patients [22%]), hypertension (10 [20%]), nausea (9 [18%]), cough (7 [14%]), dyspnea, vomiting (6 each [12%]) and diarrhea (5 [10%]). 9 patients experienced immune-related AEs, including hypothyroidism (3), arthralgia, myalgia, increased ALT/AST, increased blood lactate dehydrogenase, interstitial lung disease, vomiting, pruritus and papular rash (1 each). Other AEs are listed. Congress Alert

Conclusions from a Periodic Safety Update Report on Lynparza (olaparib; PARP-1/2 inhibitor). Based on a review of cases reported, a causal relationship between olaparib and erythema nodosum and angioedema is considered reasonable. Section 4.8 (undesirable effects) should be updated to include erythema nodosum and angioedema with frequency "rare" and "uncommon", respectively. Regulatory Agency Communication

First-in-human study of M8891 (MetAP2 inhibitor) in 26 patients with advanced solid tumors. Common adverse events (AEs) were platelet count decrease (including thrombocytopenia; 13 patients [50%] any grade; 5 [19.2%] grade ≥3), decreased appetite, nausea (8 [30.8%] each), AST increase (8 [30.8%]; 1 [3.8%]) and anemia (7 [26.9%]; 4 [15.4%]). Other AEs are listed. Congress Alert

The PMDA has updated the package insert of Zosyn (piperacillin/tazobactam) to include the risk of hypokalemia in the “Clinically Significant Adverse Reactions” section. Regulatory Agency Communication

The PMDA has updated the package insert of vonoprazan-containing products (excluding aspirin/vonoprazan fumarate) to include the risk of anaphylactic shock and hepatic impairment in the “Clinically Significant Adverse Reactions” section. Regulatory Agency Communication

The FDA has updated the product information of Avastin (bevacizumab; VEGF inhibitor), adding arterial (including aortic) aneurysms, dissections and rupture as adverse reactions reported postmarketing. Regulatory Agency Communication

First-in-human phase I study of ISU104 (HER3 inhibitor; 20 mg/kg) alone or in combination with cetuximab (EGFR inhibitor; 250 mg/m2) in patients with head and neck squamous cell carcinoma. Treatment-emergent adverse events (TEAEs) reported in both treatment groups were stomatitis (3/6 patients with ISU104 monotherapy vs 4/12 with ISU104/cetuximab), diarrhea (2 vs 9) and acneiform dermatitis (2 vs 6). 1 patient in the ISU104 group experienced grade 3 dyspnea. Grade 3 TEAEs in ISU104/cetuximab group were increased alanine aminotransferase (2), rash, acneiform dermatitis and diarrhea (1 each). Other TEAEs are listed. Congress Alert

Phase I study of the monoclonal antibody MIL62 (CD20 inhibitor; 200-1,500 mg) in 27 Chinese patients with B-cell non-Hodgkin’s lymphoma. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (15 patients), leukopenia and neutropenia (14 each). Other TRAEs and adverse events of special interest are listed. Congress Alert

Phase II study evaluating the efficacy and safety of pamiparib (PARP-1/2 inhibitor; 60 mg bid) in Chinese adults with advanced ovarian cancer. Treatment-emergent adverse events (≥20%) were anemia (101 patients [89.4%] any grade; 47 [41.6%] grade ≥3), nausea (77 [68.1%]; 1 [0.9%]), decreased neutrophil count (69 [61.1%]; 38 [33.6%]), decreased white blood cell count (68 [60.2%]; 22 [19.5%]), vomiting (57 [50.4%]; 5 [4.4%]), decreased platelet count (35 [31.0%]; 5 [4.4%]), decreased appetite (34 [30.1%]), asthenia (32 [28.3%]; 1 [0.9%]), diarrhea (25 [22.1%]; 3 [2.7%]), increased AST (24 [21.2%]; 1 [0.9%]), decreased lymphocyte count (24 [21.2%]; 8 [7.1%]), increased ALT (23 [20.4%]; 1 [0.9%]) and leukopenia (23 [20.4%]; 12 [10.6%]). Congress Alert

Phase I clinical trial evaluating dostarlimab (PD-1 inhibitor; 500 mg q3w or 1,000 mg q6w) in 67 patients with non-small cell lung cancer. Immune-mediated adverse events considered related to treatment included hypothyroidism (7 patients [10.4%]), pneumonitis (5 [7.5%]), rash (3 [4.5%]), hyperthyroidism, increased amylase and diarrhea (2 [3%] each). Grade ≥3 immune-related adverse events were adrenal insufficiency, increased lipase, rash, pneumonitis and increased transaminases (1 [1.5%] each). Congress Alert

Phase II study of the antibody-drug conjugate tisotumab vedotin (coagulation factor III/tubulin polymerization inhibitor; 2 mg/kg q3w) in 101 patients with recurrent or metastatic cervical cancer. The most common treatment-related adverse events (TRAEs) were alopecia (38% patients), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (26%; 2% grade ≥3), dry eye (23%), myalgia (15%), anemia, asthenia (13%; 1% each), arthralgia (12%), decreased appetite, keratitis (11% each) and pruritus (11%; 1%). 1 patient died due to septic shock, which was considered treatment-related. Other TRAEs of interest are listed. Congress Alert

The FDA has updated the product information of Asacol (mesalamine; COX-1/COX-2/5-LOX inhibitor and PPARgamma agonist) to include warnings about malaise, pruritus, conjunctivitis, photosensitivity reactions (also reported with sulfasalazine), nephrolithiasis and kidney toxicity (observed in animal studies). Nephrolithiasis has also been added as an adverse reaction reported postmarketing. Regulatory Agency Communication

Phase III study assessing the efficacy and safety of Reyvow (lasmiditan; 5-HT1F receptor agonist; 100 or 200 mg) for acute treatment of migraine in 1,471 adult patients. The most frequent treatment-emergent adverse events with Reyvow (≥2% in either dose group) were dizziness, paresthesia, fatigue, nausea, vertigo (sensation of spinning or movement), somnolence (sleepiness), hypoesthesia (diminished sensation), muscle weakness, asthenia (abnormal physical weakness) and abnormal feeling. [Data from a Lilly communication announcing that Reyvow demonstrated superiority over placebo in all endpoints of a phase III study in patients with migraine] Company Communication

Clinical trial evaluating the efficacy and safety of garetosmab (inhibin beta A chain inhibitor; 10 mg/kg q4w) in 44 patients with fibrodysplasia ossificans progressiva. Garetosmab was associated with an increased incidence of epistaxis, headache, acne, madarosis and skin infections. Congress Alert

Phase I dose-escalation and dose cohort expansion studies of senaparib (IMP4297; PARP-1/2 inhibitor) in 53 Chinese patients with advanced solid tumors. Common treatment-related adverse events (TRAEs; ≥15%) were white blood cell decrease (23/53 patients [43.4%]), platelet count decrease (14 [26.4%]), hemoglobin decrease, anemia, decreased appetite and asthenia (13 [24.5%] each). Other TRAEs are listed. Congress Alert

Phase I trial of SL-801 (felezonexor; exportin-1 inhibitor) in 58 patients with advanced solid tumors. The most common treatment-emergent adverse events (TEAEs) were nausea (72%), vomiting (66%), fatigue (53%), decreased appetite (31%), diarrhea (29%) and dehydration (22%). Grade 3 TEAEs included nausea and anemia (9% each), fatigue (7%), diarrhea (4%), hypophosphatemia (5%), hypokalemia and hyponatremia (3% each). Congress Alert

First-in-human phase I/II study of ODM-207 (BET inhibitor) in 36 patients with advanced solid tumors. Common treatment-related adverse events (TRAEs) were thrombocytopenia (28 patients), nausea, decreased appetite (20 each), fatigue (17), diarrhea (14), vomiting, headache (10 each), dysgeusia (7), asthenia and weight loss (6 each). Grade ≥3 TRAEs were thrombocytopenia (6 [14.3%]), nausea (3 [8.6%]), fatigue (2 [5.7%]) and weight loss (1 [2.9%]).

Updated results from a phase III study comparing ripretinib (KIT/PDGFRalpha inhibitor; 150 mg qd) and placebo as ≥ 4th line therapy in patients with advanced gastrointestinal stromal tumors. The most common treatment-emergent adverse events (TEAEs) with at least one grade 3/4 event and significantly more frequent than with placebo were fatigue (40 [47%] patients; 3 [3.5%] grade 3/4), nausea (35 [41%]; 3 [3.5%]), abdominal pain (34 [40%]; 6 [7.1%]), constipation (31 [37%]; 1 [1.2%]) and myalgia (30 [35%]; 5 [12%]). Other TEAEs are listed. Congress Alert

Analysis from 3 phase I/II studies of entrectinib (ALK/Ros/TRK inhibitor) in patients with NTRK fusion-positive solid tumors with or without baseline central nervous system (CNS) metastases. The most frequent neurological adverse events (AEs) were dysgeusia (61/176 [34.7%] patients with baseline CNS metastases vs 152/328 [46.3%] patients without baseline CNS metastases), dizziness (64 [36.4%] vs 118 [36.9%]), paresthesia (28 [15.9%] vs 72 [22%]) and headache (37 [21%] vs 51 [15.5%]). Other neurological AEs are listed. Congress Alert

The FDA is evaluating the need for regulatory action regarding the potential association between Zolgensma (onasemnogene abeparvovec-xioi; SMN1 gene therapy/survival of motor neuron protein expression enhancer) and thrombotic microangiopathy. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between the CDK4/6 inhibitors Ibrance (palbociclib), Kisqali (ribociclib) and Kisqali Femara co-pack (ribociclib, letrozole) and Stevens-Johnson syndrome. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between proton pump inhibitors (rabeprazole, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, esomeprazole/naproxen, aspirin/omeprazole, omeprazole/sodium bicarbonate) and hypocalcemia and parathyroid hormone disorders. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between GLP-1 receptor agonists (lixisenatide, exenatide, semaglutide, liraglutide, albiglutide, dulaglutide, insulin glargine/lixisenatide, insulin degludec/liraglutide) and hypoglycemia. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between fibric acid derivatives (fenofibrate, fenofibric acid) and drug-induced liver injury. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between Erleada (apalutamide; androgen receptor antagonist) and toxic epidermal necrolysis. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between Darzalex (daratumumab; CD38 inhibitor) and Darzalex Faspro (daratumumab/hyaluronidase) and listeriosis. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between CGRP/CGRP receptor antagonists (fremanezumab, erenumab-aooe, galcanezumab, eptinezumab) and Stevens-Johnson syndrome. Regulatory Agency Communication

The FDA is evaluating the need for regulatory action regarding the potential association between Aubagio (teriflunomide; DHODH inhibitor) and drug reaction with eosinophilia and systemic symptoms. Regulatory Agency Communication

Results from the phase II expansion part of a clinical study of mobocertinib (EGFR/HER2 inhibitor; 160 mg qd) in 136 patients with non-small cell lung cancer. The most common treatment-related adverse events were diarrhea (83% patients; 21% grade ≥3), nausea (43%; 4%), rash (33%; 1%), vomiting (26%; 4%), decreased appetite (26%; 1%), fatigue (22%; 1%) and dry skin (21%). Similar adverse event rates were reported in the subset of patients with EGFR exon 20 insertions and patients treated at other doses. Congress Alert

First case report of Ewing's sarcoma in a teenage patient treated with ustekinumab (IL-12/IL-23 inhibitor) for refractory Crohn's Disease.

Phase I trial of monepantel (Zolvix; p70S6K inhibitor) in 8 patients with solid tumors. 41 adverse events (AEs) were reported as possibly, probably or definitely related to the study drug, including nausea (7 subjects), decreased appetite, dysgeusia, diarrhea (3 each), tachycardia and abdominal pain (1 each). 1 patient had grade 3 lethargy and fatigue and grade 4 insomnia (all possibly related to monepantel). Other treatment-related AEs are listed.

The special warnings and precautions for use section of the EMA EPAR for Jyseleca (filgotinib) indicates that it may cause immunosuppression when combined with other potent immunosuppressants, biologic DMARDs or other JAK inhibitors; infections (including serious infections); viral reactivation (including cases of herpes virus reactivation); increased risk of malignancies in patients with rheumatoid arthritis (including non-melanoma skin cancer); decreased fertility, which has been reported in preclinical studies; hematological abnormalities; increases in lipid parameters (including total cholesterol and HDL); and venous thromboembolism (including deep venous thrombosis and pulmonary embolism). Other warnings and precautions of filgotinib are listed, including those observed with other JAK inhibitor products. [Data from EMA European public assessment report for Jyseleca (filgotinib; JAK1 inhibitor)] Regulatory Agency Communication

Phase I/II study of the COVID-19 vaccine BNT162b1 (1 to 50 mcg) in 60 healthy adults. The most common solicited systemic events were dose-dependent reactogenicity, symptoms of which included fever, chills, headache, muscle pain, joint pain, injection-site pain and tenderness. Injection-site reactions were mainly pain and tenderness. Some manifestations of reactogenicity were severe (grade 3, including headache, chills, fatigue, muscle pain and fever. A dose-dependent increase in C-reactive protein and reduction in blood lymphocyte counts were also observed.

Phase III trial of niraparib (PARP-1/2 inhibitor) in 733 patients with advanced ovarian cancer. Treatment-emergent adverse events (TEAEs) were similar in patients aged <65 years and ≥65 years, the most common being thrombocytopenia (including platelet count decrease), anemia (includes anemia, hemoglobin decrease and anemia macrocytic), leukopenia (including neutropenia, neutrophil count decrease, white blood cell count decrease, neutropenic sepsis and febrile neutropenia) and hypertension (including blood pressure increase). Grade ≥3 TEAEs are listed. Congress Alert

Phase II clinical study of cemiplimab, alone or in combination with ipilimumab, in 28 patients with advanced non-small cell lung cancer. Common treatment-emergent adverse events (TEAEs) included decreased appetite, constipation, nausea, dyspnea and asthenia. 1 patient receiving combination therapy discontinued treatment due to treatment-related grade ≥3 infusion-related reaction, and another receiving cemiplimab died from a treatment-related cerebrovascular accident. Other TEAEs are listed. Congress Alert

Clinical trial of tarloxotinib (EGFR/HER2 inhibitor; 150 mg/m2 qw) in 23 patients with non-small lung cancer. The most common treatment-emergent adverse events were QT prolongation (14 [60.9%]; 8 [34.8%] grade ≥3), rash (10 [43.5%]; 1 [4.3%]), diarrhea (5 [21.7%]; 1 [4.3%]) and nausea (5 [21.7%]; 0). 1 patient developed grade 3 transaminitis and another had a drug-related infusion reaction. Congress Alert

The FDA has updated the product information of Yervoy (ipilimumab; CTLA-4 inhibitor) to include novel safety data from a clinical trial evaluating nivolumab/ipilimumab for the treatment of malignant pleural mesothelioma. Regulatory Agency Communication

The FDA has updated the product information of Opdivo (nivolumab; PD-1 inhibitor) to include novel safety data from a clinical trial evaluating nivolumab/ipilimumab for the treatment of malignant pleural mesothelioma. Regulatory Agency Communication

The EMA’s PRAC has started to review a safety signal to assess the potential association between Veklury (remdesivir; viral RNA polymerase inhibitor) and acute kidney injury in patients with COVID-19. Regulatory Agency Communication

AstraZeneca’s phase III study of its COVID-19 vaccine AZD1222 has been further delayed after the FDA requested a more exhaustive investigation including data from the same viral vector platform. In early September, the study was put on hold after a participant was hospitalized due to suspected transverse myelitis.

Phase II trial of futibatinib (FGFR inhibitor; 20 mg qd) in 67 patients with intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements. Treatment-related adverse events (TRAEs; reported in ≥15% patients) were hyperphosphatemia (54 patients [81%] any grade; 18 [27%] grade 3), diarrhea (25 [37%]), dry mouth (22 [33%]), alopecia (20 [30%]) and dry skin (18 [27%]). AEs of special interest include hyperphosphatemia and nail and eye toxicities. Other special AEs and TRAEs are listed. Congress Alert

First-in-human phase I study of vibostolimab (TIGIT inhibitor; 200 mg), alone or in combination with pembrolizumab (PD-1 inhibitor; 200 mg) in patients with non-small cell lung cancer. The most common treatment-related adverse events (AEs) were fatigue (9/41 patients [22%] with vibostolimab vs 8/38 [21%] with vibostolimab/pembrolizumab), rash (8 [20%] vs 8 [21%]), pruritus (5 [12%] vs 13 [34%]), arthralgia (5 [12%] vs 0), and decreased appetite (4 [10%] vs 4 [11%]). 1 patient receiving vibostolimab/pembrolizumab died from treatment-related pneumonitis. Other AEs are listed. Congress Alert

First-in-human phase I study of the bispecific antibody RO7122290 (4-1BB activator/fibroblast activation protein alpha ligand; 5-2,000 mg qwk), alone or combined with atezolizumab (1,200 mg q3w), in patients with advanced solid tumors. Immune-mediated adverse events (AEs) considered related to treatment included rash (13/62 patients [21%] with RO7122290; 13/53 [24.5%] with RO7122290 plus atezolizumab), pneumonitis (3 [4.8%]; 4 [7.5%]) and hypothyroidism (0; 4 [7.5%]). Dose-limiting toxicities were grade 3 febrile neutropenia and cytokine release syndrome with RO7122290, and grade 3 pneumonitis with RO7122290 plus atezolizumab. Other AEs are listed. Congress Alert

Phase I/II dose finding study of bexmarilimab (stabilin-1 antagonist; 0.1-10 mg/kg) in 30 patients with advanced cancer. The most common treatment-related adverse events were fatigue (5 patients [16.7%]), pyrexia (4 [13.3%]), increased ALT, AST and alkaline phosphatase levels, abdominal pain, flushing and vomiting (2 each [6.7%]). 1 patient experienced grade 3 infected seroma, which was considered related to treatment. Congress Alert

First-in-human study of JNJ-64619178 (PRMT5 inhibitor; 0.5-4 mg) in 66 patients with advanced cancers. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (32 patients [48.5%]), nausea (27 [40.9%]), anemia (25 [37.9%]), fatigue (21 [31.8%]) and dysgeusia (17 [25.8%]). Common grade 3 TRAEs included anemia (12 [18.2%]), thrombocytopenia (6 [9.1%]), neutropenia (3 [4.5%]) and diarrhea (2 [3%]). Grade 4 thrombocytopenia was reported in 7 patients. Other TRAEs are listed. Congress Alert

Phase I study of the bispecific antibody AK104 (PD-1/CTLA-4 inhibitor) in 18 patients with mesothelioma. Common immune-related adverse events (AEs) included rash (5 patients [27.8%]), arthralgia, arthritis and infusion-related reactions (2 [11.1%] each). Grade ≥3 treatment-related AEs were pyrexia, infusion-related reaction and type 1 diabetes mellitus (1 [5.6%] each). Other AEs are listed. Congress Alert

Phase I clinical trial of BEZ235 (PI3K/mTOR inhibitor; 300 or 400 mg bid) in 24 patients with relapsed/refractory acute leukemia. The most common treatment-emergent adverse events (TEAEs) were nausea/vomiting (19 patients [79%]), diarrhea (17 [71%]; 2 [8%] grade 3-4), oral mucositis (17 [71%]; 1 [4%]), increased liver function tests (11 [46%]; 2 [8%]), hyperglycemia (8 [33%]; 2 [8%]) and anorexia (8 [33%]). Other TEAEs are listed.

The FDA has updated the product information of Kadcyla (ado-trastuzumab emtansine; HER2/tubulin polymerization inhibitor) to include the risk of congestive heart failure in the “Warning and Precautions” and “Adverse Reactions” sections. Regulatory Agency Communication

The FDA has updated the product information of Linzess (linaclotide; guanylyl cyclase-C activator), adding anaphylaxis, angioedema, rash (including hives/urticaria) and nausea as adverse reactions reported postmarketing. Regulatory Agency Communication

The FDA has updated the product information of Latisse (bimatoprost; FP receptor agonist) to include hordeolum and trichiasis as adverse reactions reported postmarketing. Regulatory Agency Communication

Phase II study comparing rezafungin and caspofungin (1,3-beta-glucan synthase inhibitors) in 134 patients with candidemia and invasive candidiasis. The most common treatment-emergent adverse events (TEAEs) were hypokalemia (16.4% with rezafungin vs 13.2% with caspofungin), diarrhea (13.4% vs 14.7%), vomiting (10.4% vs 7.4%), pyrexia (9.7% vs 8.8%) and anemia (9.7% vs 5.9%). Serious TEAEs included septic shock (7.5% vs 2.9%), sepsis (2.2% vs 2.9%), respiratory failure (2.2% vs 1.5%) and gastrointestinal hemorrhage (2.2% vs 0%). Other TEAEs are listed.

Ongoing phase I/II study assessing the safety and efficacy of 177Lu-satoreotide tetraxetan (sst2 receptor antagonist) in 35 patients with somatostatin receptor-positive neuroendocrine tumors. Grade 3/4 treatment-related hematological adverse events were reported in 12 (34.3%) patients: lymphopenia or decreased lymphocyte count (6 [17.1%]), thrombocytopenia or decreased platelet count (5 [14.3%]), neutropenia (2 [5.7%]) and anemia (1 [2.9%]). Congress Alert

Clinical study of BCX9930 (complement factor D inhibitor; 400 mg bid) in 4 patients with paroxysmal nocturnal hemoglobinuria. The most common drug-related adverse event was headache. 2 patients developed mild rashes. [Data from a BioCryst Pharmaceuticals presentation summarizing results from a dose-ranging trial of BCX9930 for paroxysmal nocturnal hemoglobinuria] Company Communication

Phase III study evaluating the safety of switching from oral to intravenous Uptravi (selexipag; IP receptor agonist) in 20 patients with pulmonary arterial hypertension. Adverse events reported with both formulations included headache, diarrhea, nausea, vomiting, pain in jaw, myalgia, pain in extremity, flushing and arthralgia. Infusion-site reactions occurred with intravenous Uptravi. [Data from a Johnson & Johnson communication announcing the submission of a New Drug Application to the FDA for intravenous Uptravi] Company Communication

Health Canada communication on the voluntary withdrawal of Fibristal (ulipristal acetate; progesterone receptor modulator) due to severe cases of drug-induced liver injury. Rare cases of liver injury, including severe liver impairment requiring liver transplantation, have been reported internationally. Regulatory Agency Communication

Results from phase Ib part of a phase Ib/II clinical study of erdafitinib combined with cetrelimab in 22 patients with urothelial carcinoma. The most common treatment-emergent adverse events (TEAEs) were stomatitis (16 [73%]), diarrhea, dry mouth (12 [55%] each), hyperphosphatemia (10 [46%]) and dysgeusia (8 [36%]). Grade 3 TRAEs were stomatitis (3 [14%]), nail discoloration, nail dystrophy, onycholysis, hypothyroidism, serous retinal detachment, autoimmune hepatitis, pneumonia, increased GGT and hyperphosphatemia (1 [5%] each). Serious TRAEs were pneumonia and diarrhea (both in 1 patient), serous retinal detachment and herpetic keratitis (1 each). Congress Alert

Phase I clinical study of the antibody-drug conjugate patritumab deruxtecan (DNA topoisomerase I/HER3 inhibitor; 5.6 mg/kg q3w) in 57 patients with EGFR-mutated non-small cell lung cancer. The most common treatment-emergent adverse events (TEAEs) were fatigue (33 [58%]; 5 [9%] grade ≥3), nausea (31 [54%]; 2 [4%]), thrombocytopenia (30 [53%]; 16 [28%]), decreased appetite (20 [35%]; 1 [2%]) and neutropenia (19 [33%]; 11 [19%]). 3 patients experienced treatment-related interstitial lung disease. Other TEAEs are listed. Congress Alert

First-in-human, phase I clinical study of MGD019 (bispecific PD-1/CTLA-4 inhibitor; 0.03-10 mg/kg q3w for 24 weeks then q6w) in 43 patients with advanced solid tumors. The most common treatment-related adverse events (TRAEs) were pruritus (23.3%), arthralgia, fatigue, rash (18.6% each), nausea (16.3%), infusion-related reaction (16.2%), myalgia and diarrhea (11.7% each). Grade 3 immune-related adverse events reported in patients at 10 mg/kg included maculopapular rash (3 patients), myocarditis, enterocolitis, hepatitis and bullous dermatitis (1 each). Other TRAEs are listed. Congress Alert

Preclinical development of the CD276-targeted antibody-drug conjugate MGC018. A toxicology study in cynomolgus monkeys found clinical signs such as an increase in mean body weight in all dose groups and a decrease at 10 mg/kg, hyperpigmentation, dry skin, erythema (at ≥6 mg/kg) and sparse hair; changes in clinical pathology including decreased neutrophil counts at ≥6 mg/kg, decreased lymphocytes at 10 mg/kg, decreased reticulocytes, increased C-reactive protein and fibrinogen, increases in AST and/or ALT and decreases in ALP; and histopathological findings such as skin epidermal hyperplasia, lymphocytic infiltrate and single cell necrosis.

The special warnings and precautions for use section of the EMA EPAR for Ayvakyt indicates that it may cause severe and serious hemorrhages (including gastrointestinal, hepatic, tumor and intracranial hemorrhages); cognitive effects (including memory impairment, confusional state and encephalopathy); fluid retention (including severe cases of localized/generalized edema); QT interval prolongation (including ventricular arrhythmias); gastrointestinal disorders (including diarrhea and vomiting); anemia, neutropenia and thrombocytopenia; and photosensitivity reactions. Other warnings and precautions of avapritinib are listed. [Data from EMA European public assessment report for Ayvakyt (avapritinib; KIT/PDGFRalpha inhibitor)] Regulatory Agency Communication

First-in-human phase I study of CC-90010 (BET inhibitor; 15-55 mg) in patients with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma. Common treatment-related adverse events (TRAEs) included thrombocytopenia (35/69 patients [51%] in part A; 11/14 [79%] in part B), diarrhea (27 [39%]; 8 [57%]), nausea (27 [39%]; 4 [29%]), asthenia (22 [32%]; 3 [21%]), dysgeusia (18 [26%]; 0) and stomatitis (16 [23%]; 2 [14%]). Other TRAEs are listed. Congress Alert

Phase I clinical trial of PRS-343 (HER2 inhibitor and 4-1BB activator; 0.0005-18 mg/kg), alone or combined with atezolizumab, in patients with solid malignancies. Common treatment-related adverse events (TRAEs) observed in the monotherapy group included infusion-related reaction (27/145 patients [19%]), fatigue, nausea (11 [8%] each), vomiting and chills (8 [6%] each). TRAEs reported in patients receiving PRS-343 plus atezolizumab included infusion-related reaction, vomiting (38/148 [26%] each), fatigue (12 [8%]) and nausea (8 [5%]). Other TRAEs are listed. Congress Alert

The PRAC has requested supplementary information on a potential association between statins (listed) and bullous pemphigoid. Regulatory Agency Communication

The PRAC has requested supplementary information on a potential association between pembrolizumab (PD-1 inhibitor) and systemic scleroderma. Regulatory Agency Communication

The PRAC has requested supplementary information on a potential association between ceftriaxone (bacterial penicillin-binding protein inhibitor) and hepatitis. Regulatory Agency Communication

The PRAC has requested monitoring for the potential association between vedolizumab (integrin alpha4beta7 antagonist) and Evans’ syndrome, autoimmune hemolytic anemia and immune thrombocytopenic purpura in the next Periodic Safety Update Report. Regulatory Agency Communication

The PRAC has recommended updating the product information of systemic and inhalation formulations of fluoroquinolones (listed) to include a warning of heart valve regurgitation, cervical artery dissection and aortic aneurysm and dissection. Regulatory Agency Communication

The PRAC has recommended updating the product information of pomalidomide (cereblon/VEGF inhibitor) to include a warning of progressive multifocal leukoencephalopathy. Regulatory Agency Communication

The FDA has updated the product information of Reyataz (atazanavir sulfate; HIV protease inhibitor), adding a warning about autoimmune hepatitis. Regulatory Agency Communication

The FDA has updated the product information of Opdivo (nivolumab; PD-1 inhibitor) to include the risk of hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia in the “Warnings and Precautions” and “Adverse Reactions” sections. Regulatory Agency Communication

The FDA has updated the product information of Lemtrada (alemtuzumab; CD52 inhibitor), adding the risk of cerebrovascular emergencies, acquired hemophilia A and Epstein-Barr virus infection to the “Warnings and Precautions” section. Acquired hemophilia A and viral hepatitis have been included as adverse reactions reported postmarketing. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Lumark (lutetium [177Lu] chloride). Based on data from literature, studies and spontaneous reports, a causal relationship between lutetium [177Lu] chloride and pancytopenia and neutropenia has been established. The product information will be updated with regards to the risk of extravasation and radiation nephropathy. Regulatory Agency Communication

First case report of asymmetrical resting tremor of both legs induced by levosulpiride (D2 receptor antagonist; 75 mg qd) in a Korean woman treated for dyspepsia. Congress Alert

First case report of chronic Pisa syndrome following long-term use of low-dose amisulpride (D2/D3 receptor antagonist; 200 mg qd) in a 47-year-old man with obsessive-compulsive disorder. Congress Alert

Phase IIIb study of galcanezumab (CGRP antagonist) in 462 patients with migraine. Treatment-emergent adverse events (AEs) more frequent with galcanezumab than with placebo included influenza (5% vs 3%), bronchitis, gastroenteritis, oropharyngeal pain (2% vs 1% each), fatigue (2% vs 0.4%), injection-site pruritus, injection-site edema (1% vs 0 each), injection-site hypersensitivity and injection-site swelling (0.4% vs 0). 1 patient in the galcanezumab group discontinued due to generalized rash. Serious AEs of hemorrhoids and tonsillitis were reported in 2 (1%) patients in the galcanezumab group. 1 patient on galcanezumab experienced a likely hypersensitivity event of toxic skin eruption.

2 phase III studies of fevipiprant (DP2 receptor antagonist; 150 or 450 mg qd) for reducing asthma exacerbations in patients with severe asthma. Adverse events (AEs; ≥5% in any group) included nasopharyngitis (76/595 [13%] with fevipiprant 150 mg; 79/586 [14%] with fevipiprant 450 mg vs 75/585 [13%] with placebo), upper respiratory tract infection (53 [9%]; 51 [9%] vs 45 [8%]) and headache (47 [8%]; 43 [7%] vs 33 [6%]). 2 (<1%) patients in the fevipiprant 450-mg group died from AEs.

Phase I trial of SARS-CoV-2 mRNA-1273 vaccine in 40 older adults (age groups 56-70 years or ≥71 years). The most common adverse events (AEs) included headache, fatigue, myalgia, chills and injection-site pain. 2 grade 3 AEs occurred after the second dose of the vaccine: fever (age group 56-70 years; 25 mcg dose) and fatigue (age group ≥71 years; 100 mcg dose). Other AEs are listed.

Results from phase II part of a clinical study of sintilimab in combination with IBI305 in 24 patients with advanced hepatocellular carcinoma. Reported treatment-related adverse events were proteinuria (8 [33.3%]; 3 [12.5%] grade ≥3), increased ALT, increased AST, hypertension, decreased platelet count (6 [25%]; 0 each), increased blood bilirubin, increased GGT (4 [16.7%]; 0 each), abnormal hepatic function (3 [12.5%]; 2 [8.3%]), hyperthyroidism (3 [12.5%]; 1 [4.2%]) and immune-mediated hepatitis (1 [4.2%]; 1 [4.2%]). Congress Alert

Phase I/II clinical trial comparing combined atezolizumab/CPI-444 and docetaxel in patients with non-small cell lung cancer. The most common adverse events (AEs) related to atezolizumab/CPI-444 were increased amylase and anemia (20% each). The most common docetaxel-related AEs were alopecia (50%), anemia, fatigue (29% each), asthenia and myalgia (21% each). 2 patients developed anti-drug antibodies to atezolizumab. 1 docetaxel-treated patient experienced a grade 5 AE. Congress Alert

Initial results from a phase Ib study of rose bengal disodium (RBD) plus pembrolizumab in 24 patients with metastatic cutaneous melanoma refractory to immune checkpoint inhibitors. Common adverse events (AEs) related to RBD included injection-site pain (8 patients) and injection-site edema (5). The most common AE related to pembrolizumab was fatigue (6). Other treatment-related AEs are listed. Congress Alert

Phase I clinical study of MK-4830 (leukocyte immunoglobulin like receptor B2 inhibitor), alone or in combination with pembrolizumab, in patients with advanced solid tumors. The most common adverse events (AEs; >5%) were fatigue, diarrhea, arthralgia, increased AST, decreased appetite, nausea, pruritus and vomiting with monotherapy; and fatigue, hypothyroidism, maculopapular rash, arthralgia and nausea with the combination. Grade 3-4 AEs included fatigue in both groups and increased AST with monotherapy. Congress Alert

The warnings section of the PMDA package insert for Jyseleca indicates that it may cause new or worsening serious or fatal infections such as tuberculosis (including extrapulmonary tuberculosis, tuberculous meningitis), pneumonia, sepsis, opportunistic infections and viral infections; and it may be related to the development of malignant tumors. [Data from PMDA package insert for Jyseleca (filgotinib; JAK1 inhibitor)] Regulatory Agency Communication

The precautions for use section of the PMDA package insert of Ecclock gel indicates that, due to its anticholinergic effects, it may cause an increase in intraocular pressure in patients with angle-closure glaucoma; urinary retention in patients with dysuria due to benign prostatic hyperplasia; dysuria in patients with benign prostatic hyperplasia; and an increased frequency of side effects such as mydriasis or dry mouth in patients with wounds, eczema, dermatitis, etc. at the application site due. [Data from PMDA package insert for Ecclock gel (sofpironium bromide; muscarinic receptor antagonist)] Regulatory Agency Communication

Phase Ib study of resiniferatoxin (TRPV1 activator) for the treatment of moderate-to-severe pain due to osteoarthritis of the knee. Treatment-emergent adverse events were expected based on the mechanism of action of resiniferatoxin and included post-injection pain, tachycardia and hypertension. Post-procedural pain was reported in nearly all patients treated with resiniferatoxin and the saline control. [Data from a Sorrento communication announcing positive results from a phase Ib trial of resiniferatoxin for reducing osteoarthritis knee pain] Company Communication

Swissmedic, together with Sanofi, have issued a Direct Healthcare Professional Communication restricting the indication of Lemtrada (alemtuzumab; CD52 inhibitor) due to the risk of serious adverse drug effects. Myocardial ischemia, myocardial infarction, severe or fatal neutropenia, and thrombocytopenia have been reported during postmarketing use of Lemtrada. A causal association between Lemtrada and acquired hemophilia A has been identified, whereas the link with autoimmune hepatitis and hemophagocytic lymphohistiocytosis is suspected. The product information of Lemtrada has been updated to include these and other adverse events (listed). Regulatory Agency Communication

New Zealand’s Medsafe has issued a safety communication warning about a potential association between bupropion (DAT/NET inhibitor) and risk of psoriasis exacerbation. This follows a case report of a 56-year-old patient whose psoriasis was exacerbated 15 days after starting bupropion. Regulatory Agency Communication

Phase Ib/II study of the sequential administration of APR-246 and azacytidine in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia. APR-246-related side effects were nausea, vomiting, dizziness and transient neuropathy. Congress Alert

Study assessing the adverse events profile of levothyroxine and liothyronine using the FAERS database. Adverse events reported with both drugs included fatigue (24.3% with levothyroxine vs. 8.6% with liothyronine), headache (13.9% vs. 6.9%), insomnia (11.1% vs. 2.8%), alopecia (9.4% vs. 6.2%), increased weight (9.1% vs. 6.2%), increased blood thyroid stimulating hormone (8.4% vs. 0.7%) and muscle spasms (8.1% vs. 2.1%). Congress Alert

Case series of 3 patients receiving ziconotide (Cav2.2 blocker) for chronic pain management. All patients developed orolingual dyskinesia. 1 patient exhibited movements of his head and wrists. 1 patient experienced twitching of the lower face and tongue. 1 patient developed mental status changes and hallucinations. Congress Alert

First-in-human phase I study evaluating the safety, pharmacokinetics and pharmacodynamics of LB-102 (5-HT7/D2/D3 receptor antagonist; 10-200 mg) in healthy volunteers. Adverse events included transient prolactin increase and QT interval prolongation at 200 mg. 1 subject experienced extrapyramidal symptoms including acute dystonia at 200 mg. Congress Alert

Interim analysis of a phase I/II clinical study of Ad26.COV2.S (SARS-CoV-2 proteins-directed immunity inducer; 5E10 or 1E11 vp) in healthy volunteers. The most common adverse events (AEs) were injection site pain, fatigue, headache, myalgia and fever. Other AEs are listed.

Phase I study of the antibody-drug conjugate XMT-1536 (sodium phosphate 2/tubulin polymerization inhibitor; 43 mg/m2) in 47 patients with ovarian cancer. The most common (>10%) treatment-related adverse events (TRAEs) were fatigue, nausea, decreased appetite, vomiting and increased AST. Grade ≥3 TRAEs included diarrhea, thrombocytopenia, constipation, increased AST, vomiting, myalgia, fatigue and anemia. Other TRAEs are listed. Congress Alert

Phase I study of cosibelimab (PD-L1 inhibitor) in 114 patients with cutaneous squamous cell carcinoma. The most common treatment-related adverse events (TRAEs) were fatigue (14.9%), rash (14%), hypothyroidism (8.8%), anemia, infusion-related reaction, nausea (7% each) and diarrhea (6.1%). Grade ≥3 TRAEs included fatigue and anemia (1.8% each). 2 patients experienced pneumonitis. Congress Alert

Phase I/II clinical trial of intratumoral tilsotolimod in combination with ipilimumab in 62 patients with advanced refractory melanoma. The most common treatment-emergent adverse events (TEAEs) were fatigue (32 [51.6%]; 4 [6.5%] grade 3/4), nausea (25 [40.3%]), anemia (24 [38.7%]), diarrhea (23 [37.1%]; 4 [6.5%] grade 3/4), pyrexia (22 [35.5%]), increased ALT (20 [32.3%]; 4 [6.5%] grade 3/4) and vomiting (19 [30.6%]). Other TEAEs are listed. Congress Alert

Swissmedic, together with MEDA pharmaceuticals, have issued a Direct Healthcare Professional Communication contraindicating the use of Ancotil (flucytosine; thymidylate synthase inhibitor) in patients with DPD deficiency due to a high risk of life-threatening toxicities (including stomatitis, mucosal inflammation, diarrhea, neutropenia and neurotoxicity). Regulatory Agency Communication

The FDA has updated the product information of Brilinta (ticagrelor; P2Y12 receptor antagonist) to include central sleep apnea and Cheyne-Stokes respiration as adverse reactions reported postmarketing. Regulatory Agency Communication

The warnings section of the PMDA package insert for Enaroy indicates that it may cause serious or fatal thromboembolic events such as cerebral infarction, myocardial infarction and pulmonary embolism. [Data from PMDA package insert for Enaroy (enarodustat; HIF-prolyl hydroxylase inhibitor)] Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Cosentyx (secukinumab; IL-17A inhibitor). Based on data from clinical trials and spontaneous reports, a causal relationship between secukinumab and fatigue, nausea and headache is considered at least reasonable. The product information will be updated accordingly. Regulatory Agency Communication

Phase III study of surufatinib (CSF-1R/FGFR1/VEGFR inhibitor; 300 mg qd) in 264 patients with pancreatic neuroendocrine tumors. The most common treatment-related adverse events (TRAEs) occurring more frequently than with placebo were proteinuria (55% vs. 46%), diarrhea (47% vs. 24%), increased blood thyroid-stimulating hormone (42% vs. 10%), increased blood bilirubin (35% vs. 19%) and hypertriglyceridemia (30% vs. 8%). Common grade ≥3 TRAEs included hypertension (37% grade 3; 1% grade 4), proteinuria (10%), hypertriglyceridemia (5%; 2%), vomiting and increased gamma-glutamyltransferase (3% each). Grade 5 TRAEs were decreased platelet count, gastrointestinal hemorrhage and cerebral hemorrhage (1% each). Other TRAEs are listed.