Figure S3. Mouse plasma PK profiles for exarafenib and plixorafenib.

Figure S1. Preclinical characterization of PF-07799933 and comparison to other RAF inhibitors.

PURPOSE:To investigate the potential association of semaglutide use and neovascular age-related macular degeneration (NVAMD). DESIGN:Retrospective study across 12 databases in the Observational Health Data Sciences and Informatics network from December 1, 2017, through December 31, 2024. PARTICIPANTS:Adults with type 2 diabetes (T2D) taking semaglutide, other glucagon-like peptide-1 receptor agonists (GLP-1RAs; e.g., dulaglutide or exenatide), or non-GLP-1RAs (e.g., empagliflozin, sitagliptin, or glipizide). METHODS:The association between semaglutide use and NVAMD was assessed using 2 approaches: an active-comparator cohort design and a self-controlled case series analysis. The former used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The latter used conditional Poisson regression models to estimate incidence rate ratios (IRRs). A random-effects meta-analysis was used to generate network-wide HR and IRR estimates. MAIN OUTCOME MEASURES:Two definitions of NVAMD, one based on condition codes alone (NVAMD-C) and one based on condition codes and procedures (NVAMD-CP). RESULTS:A total of 227 971 new users of semaglutide were included in the study. The risk of NVAMD among semaglutide users was similar to that of users of dulaglutide (NVAMD-C: HR, 0.57; 95% CI, 0.21-1.57; P = 0.28; NVAMD-CP: HR, 0.25; 95% CI, 0.05-1.27; P = 0.10), empagliflozin (NVAMD-C: HR, 0.98; 95% CI, 0.54-1.79; P = 0.94; NVAMD-CP: HR, 0.79; 95% CI, 0.38-1.64; P = 0.52), sitagliptin (NVAMD-C: HR, 2.08; 95% CI, 0.90-4.83; P = 0.09; NVAMD-CP: HR, 1.80; 95% CI, 0.55-5.86; P = 0.33), and glipizide (NVAMD-C: HR, 0.83; 95% CI, 0.35-2.02; P = 0.69; NVAMD-CP: HR, 0.50; 95% CI, 0.21-1.19; P = 0.12). No evidence was found of increased or decreased risk for NVAMD associated with semaglutide exposure (NVAMD-C: IRR, 0.92; 95% CI, 0.67-1.26; P = 0.60; NVAMD-CP: IRR, 1.02; 95% CI, 0.76-1.36; P = 0.92) nor with any of the other GLP-1RAs or non-GLP-1RAs. CONCLUSIONS:We detected no differences in the risk of NVAMD associated with semaglutide use among adults with T2D. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. The Article Publishing Charge (APC) for this article was paid by Johns Hopkins University.

Table S5. Preliminary mutation analysis

Table S2. X-ray crystallography data collection and refinement statistics

Figure S2. Crystal structures of BRAF kinase domain with PF-07799933 or encorafenib.

Table S6. Antibodies used for preclinical experiments

Table S1. Cell lines used for cell-based pERK assays in Figure 1A

Table S4. Treatment-Emergent Adverse Events (≥3 patients) with PF-07799933 monotherapy and combination therapy

Figure S5. Efficacy for BRAF non-V600/Class II and Class III-mutant cancer patients.

Figure S4. Patient PK profiles for PF-07799933.

Table S3. Demographic and clinical characteristics of the patients

Supplementary Table 6: Disposition of all patients enrolled to Dose Level 1

Supplementary Table 4: Pharmacokinetics of PF-07284892 in preclinical species

Importance:Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D). Objective:To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network. Design, Setting, and Participants:This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non-GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals' risks during exposure and nonexposure periods for each drug. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model. Exposures:GLP-1RA and non-GLP-1RAs. Main Outcomes and Measures:NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific. Results:The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum's deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non-GLP-1RAs using the sensitive NAION definition-empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001). Conclusions and Relevance:Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.

Supplementary Table 1: X-ray crystallography data collection and refinement statistics

Supplementary Figure 7: PF-07284892 sensitizes a patient with GOPC-ROS1 fusion-positive pancreatic cancer to lorlatinib

Supplementary Figure 2: Intermittent dosing of PF-07284892 preserves efficacy and improves tolerability preclinically