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Purpose Fruquintinib (HMPL-013) is a novel oral small molecule compound that selectively inhibits vascular endothelial growth factor receptors-1, -2, and -3 with potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose and dose-limiting toxicities, safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of fruquintinib. Methods Patients 18–70 years old with advanced solid tumors refractory to standard therapies were recruited. Fruquintinib was administered orally in 4-week repeating cycles in two regimens, either once daily continuously or once daily for 3-week on/1-week off, until discontinuation due to toxicity or tumor progression. Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.3. Pharmacokinetic parameters were measured after a single dose and in multiple dosing. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.0. Results Forty patients were enrolled into 5 cohorts in continuous regimen and 2 cohorts in 3-week-on/1-week-off regimen. The most common grade 3/4 adverse events were hand–foot skin reaction, hypertension, and thrombocytopenia. PK analysis showed good and rapid absorption followed by slow terminal elimination with a mean half-life of approximately 42 h which was consistent across all dose groups. Thirty-four patients were evaluable for tumor response, including 14 with partial response and 14 with stable disease. Conclusions Fruquintinib showed an acceptable safety profile and preliminary evidence of anti-tumor activity in patients with advanced solid tumors. The recommended dose was determined to be either 4 mg QD on a continuous regimen or 5 mg QD on a 3-week-on/1-week-off regimen.

Background/aimsTo compare fluctuations of central subfield retinal thickness (CSRT) in patients with neovascular age-related macular degeneration undergoing ranibizumab pro re nata versus aflibercept bimonthly treatment in a prospective 12 month, phase IV, randomised, multicentre study.MethodsRanibizumab was administered according to best-corrected visual acuity (BCVA) and/or disease activity detected on spectral domain optical coherence tomography. Aflibercept was administered at three initial monthly visits followed by bimonthly treatment. CSRT stability was evaluated between months 3 and 6. CSRT stability was compared between groups and correlated with functional outcomes at month 12.ResultsFluctuations of CSRT showed a least-squares (LS) mean (95% CI) difference of −4.12 (−10.22 to 1.98) µm between ranibizumab (25.16 (20.09 to 30.24) µm) and aflibercept groups (29.28 (24.14 to 34.43) µm) (p=0.1850). A predefined analysis of retinal stability, adjusted for baseline CSRT, showed a LS mean (95% CI) difference of −6.53 (−12.47 to −0.58 µm) in favour of ranibizumab (23.53 (18.58 to 28.49) µm) versus aflibercept (30.06 (25.04 to 35.07) µm) (p=0.0315). Pearson’s correlation coefficient demonstrated no correlation between the mean amplitude of CSRT fluctuation between months 3 and 6, and BCVA at month 12 (r = −0.0888). Adverse event rates were low.ConclusionsNumerical differences in retinal thickness fluctuations between months 3 and 6 were detected between treatment regimens. While the presence of fluctuations has previously been shown to have a negative impact on functional outcomes, our data showed no correlation between the mean amplitude of fluctuations and functional outcomes at month 12.

Purpose To predict potential treatment need during treat-and-extend (T&E) anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (nAMD) using an artificial intelligence (AI) model trained using transfer learning. Methods ARIES and ALTAIR were randomized controlled Phase 3b/4 trials assessing intravitreal aflibercept (IVT-AFL) in patients with nAMD. Following treatment initiation with three monthly injections of IVT-AFL, treatment intervals were re-assessed continuously during the study based on prespecified criteria. In this post- hoc analysis, spectral domain optical coherence tomography (SD-OCT) scans from Week (Wk) 8 and Wk 16 visits from patients treated with T&E regimens of 2 mg IVT-AFL over 2 years were utilized to predict individual treatment intervals and frequency. Automated image segmentation of the SD-OCT scans was performed, predictive models of treatment intervals and frequency were developed using machine learning or logistic regression methods, and their performance was evaluated using a fivefold cross-validation. A transfer learning technique was used to adapt existing AI models previously trained on a pro-re-nata therapy regimen to the T&E dataset. Results In total, 205 ARIES and 112 ALTAIR patient datasets were used for training and evaluation. The following results were achieved with an AI model trained using transfer learning (for ARIES) and logistic regression (for ALTAIR). For prediction of the first treatment interval (short [< 12 weeks] or long [≥ 12 weeks]) following treatment initiation, at Visit 4 (Wk 16), the AI model achieved an area under the receiver operating characteristic curve (AUC) of 0.87 and 0.78 for ARIES and ALTAIR, respectively. For assessment of the individual frequency of IVT-AFL in the first and second study years, the model achieved an AUC of 0.84 and 0.79, respectively, for ARIES, and 0.79 and 0.78, respectively, for ALTAIR. For prediction of the last intended individual treatment interval at the end of Year 2, the AI model achieved an AUC of 0.74 and 0.77 for ARIES and ALTAIR, respectively. Conclusion AI trained using transfer learning can be used to predict potential treatment needs for anti-VEGF treatment in nAMD based on SD-OCT scans at Wk 8 and Wk 16, supporting medical decisions on interval adjustments and optimizing individualized IVT-AFL treatment regimens. Key messages What is known Due to the high treatment burden associated with frequent clinic visits and anti-vascular endothelial growth factor injections required for the treatment of patients with neovascular age-related macular degeneration (nAMD), it would be beneficial to be able to predict potential future treatment need, at initial stages of treatment. What is new An artificial intelligence (AI) model, previously trained with a real-world pro re nata -treated cohort, can be re-trained and applied to datasets from patients treated with treat-and extend regimens in the clinical study setting to predict potential treatment need. AI may be used to predict potential treatment needs for intravitreal aflibercept treatment in nAMD based on optical coherence tomography scans at Weeks 8 and 16, supporting medical decisions on interval adjustments and optimizing individualized treatment regimens.

Purpose To evaluate 2-year efficacy, durability, and safety of faricimab in the TENAYA Japan subgroup and pooled global TENAYA/LUCERNE cohort of patients with neovascular age-related macular degeneration (nAMD). Methods Subgroup analysis of TENAYA/LUCERNE (NCT03823287/NCT03823300): phase III, multicentre, randomised, active comparator–controlled, double-masked, non-inferiority trials. Treatment-naïve patients aged ≥ 50 years with nAMD were randomised (1:1) to intravitreal faricimab (6.0 mg up to every 16 weeks [Q16W] after 4 initial Q4W doses) or aflibercept (2.0 mg Q8W after 3 initial Q4W doses). Outcomes were assessed through year 2 for the TENAYA Japan subgroup ( N  = 133) and global pooled TENAYA/LUCERNE cohort ( N  = 1329). Results Vision and anatomic improvements achieved with faricimab at year 1 were maintained over 2 years and were generally comparable between the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Adjusted mean best-corrected visual acuity (BCVA) change from baseline at year 2 for the TENAYA Japan subgroup and global pooled TENAYA/LUCERNE cohort was +7.1 (3.7–10.5) and +4.4 (3.2–5.5) letters in the faricimab arm, respectively, and +5.2 (1.9–8.6) and +4.3 (3.1–5.4) letters in the aflibercept arm, respectively. At week 112, the proportion of faricimab-treated patients on Q16W dosing was 61.0% and 63.1% in the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Faricimab was well tolerated through year 2. Conclusion Year 2 TENAYA Japan subgroup findings for faricimab were generally consistent with the pooled global TENAYA/LUCERNE results in patients with nAMD. Vision and anatomical benefits with faricimab were similar to those with aflibercept but with fewer injections.

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF), a key regulator of angiogenesis. It binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, and, thus, prevents them from binding to and activating their cognate receptors. In the USA and EU, intravenously administered aflibercept in combination with an infusion of leucovorin, fluorouracil and irinotecan (FOLFIRI) is approved for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after treatment with an oxaliplatin-containing regimen. The efficacy of aflibercept in this indication was assessed in a multinational, pivotal phase 3 trial (VELOUR), in which the approved regimen of aflibercept 4 mg/kg every 2 weeks plus FOLFIRI significantly prolonged median overall survival by 1.44 months compared with FOLFIRI alone (primary endpoint). The addition of aflibercept also significantly prolonged progression-free survival and significantly increased the objective response rate compared with FOLFIRI alone. Addition of aflibercept to FOLFIRI was associated with anti-VEGF-related adverse events and an increased incidence of FOLFIRI-related adverse events, but the tolerability of the combination was generally acceptable in this pre-treated population. The most common grade 3 or 4 adverse events with aflibercept plus FOLFIRI included neutropenia, diarrhoea and hypertension. In conclusion, aflibercept plus FOLFIRI is a useful treatment option for patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen, with or without bevacizumab.

Cervical cancer stands as a prevalent gynaecologic malignancy affecting women globally, often linked to persistent human papillomavirus infection. Biomarkers associated with cervical cancer, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E, show upregulation and are linked to angiogenesis and lymphangiogenesis. This research aims to employ in-silico methods to target tyrosine kinase receptor proteins—VEGFR-1, VEGFR-2, and VEGFR-3, and identify novel inhibitors for Vascular Endothelial Growth Factors receptors (VEGFRs). A comprehensive literary study was conducted which identified 26 established inhibitors for VEGFR-1, VEGFR-2, and VEGFR-3 receptor proteins. Compounds with high-affinity scores, including PubChem ID—25102847, 369976, and 208908 were chosen from pre-existing compounds for creating Deep Learning-based models. RD-Kit, a Deep learning algorithm, was used to generate 43 million compounds for VEGFR-1, VEGFR-2, and VEGFR-3 targets. Molecular docking studies were conducted on the top 10 molecules for each target to validate the receptor-ligand binding affinity. The results of Molecular Docking indicated that PubChem IDs—71465,645 and 11152946 exhibited strong affinity, designating them as the most efficient molecules. To further investigate their potential, a Molecular Dynamics Simulation was performed to assess conformational stability, and a pharmacophore analysis was also conducted for indoctrinating interactions.

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150-200 microg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD). TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300). Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [−1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [–1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]). Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD. F Hoffmann-La Roche.

The phase III CONFIRM clinical trials demonstrated that metastatic colorectal cancer patients with elevated serum lactate dehydrogenase (LDH) had improved outcome when the vascular endothelial growth factor receptor (VEGFR) inhibitor PTK/ZK (Vatalanib) was added to FOLFOX4 chemotherapy. We investigated the hypothesis that high intratumoral expression of genes regulated by hypoxia-inducible factor-1 alpha (HIF1α), namely LDHA, glucose transporter-1 (GLUT-1), VEGFA, VEGFR1, and VEGFR2, were predictive of outcome in CONFIRM-1. Tumor tissue was isolated by laser-capture microdissection from 85 CONFIRM-1 tumor specimens; FOLFOX4/placebo n =42, FOLFOX4/PTK/ZK n =43. Gene expression was analyzed using quantitative RT-PCR. In univariate analyses, elevated mRNA expression of LDHA, GLUT-1, and VEGFR1 were associated with response to FOLFOX4/PTK/ZK. In univariate and multivariate analyses, elevated LDHA and VEGFR1 mRNA levels were associated with improved progression-free survival in FOLFOX4/PTK/ZK patients. Furthermore, increased HIF1α and VEGFR2 mRNA levels were associated with decreased survival in FOLFOX/placebo patients but not in patients who received FOLFOX4/PTK/ZK. These are the first data suggesting intratumoral mRNA expression of genes involved in angiogenesis/HIF pathway may predict outcome to VEGFR-inhibitors. Biomarkers that assist in directing VEGFR-inhibitors toward patients with an increased likelihood of benefit will improve the cost-effectiveness of these promising agents.