FDA Approval Summary: Osimertinib for Adjuvant Treatment of Surgically Resected Non-Small Cell Lung Cancer, a Collaborative Project Orbis Review.

On December 18, 2020, the FDA approved osimertinib as adjuvant therapy in patients with non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations, as detected by an FDA-approved test. The approval was based on the ADAURA study, in which 682 patients with NSCLC were randomized to receive osimertinib (n = 339) or placebo (n = 343). Disease-free survival (DFS) in the overall population (stage IB-IIIA) was improved for patients who received osimertinib, with an HR of 0.20; 95% confidence interval (CI), 0.15-0.27; P < 0.0001. Median DFS was not reached for the osimertinib arm compared with 27.5 months (95% CI, 22.0-35.0) for patients receiving placebo. Overall survival data were not mature at the time of the approval. This application was reviewed under FDA's Project Orbis, in collaboration with Australia Therapeutic Goods Administration, Brazil ANVISA, Health Canada, Singapore Health Sciences Authority, Switzerland Swissmedic, and the United Kingdom Medicines and Healthcare products Regulatory Agency. This is the first targeted therapy adjuvant approval for NSCLC and has practice-changing implications.

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review.

On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.

Nanomedicines - Tiny particles and big challenges.

After decades of research, nanotechnology has been used in a broad array of biomedical products including medical devices, drug products, drug substances, and pharmaceutical-grade excipients. But like many great achievements in science, there is a fine balance between the risks and opportunities of this new technology. Some materials and surface structures in the nanosize range can exert unexpected toxicities and merit a more detailed safety assessment. Regulatory agencies such as the United States Food and Drug Administration or the European Medicines Agency have started dealing with the potential risks posed by nanomaterials. Considering that a thorough characterization is one of the key aspects of controlling such risks this review presents the regulatory background of nanosafety assessment and provides some practical advice on how to characterize nanomaterials and drug formulations. Further, the challenges of how to maintain and monitor pharmaceutical quality through a highly complex production processes will be discussed.

The histone deacetylase inhibitors MS-275 and SAHA suppress the p38 mitogen-activated protein kinase signaling pathway and chemotaxis in rheumatoid arthritic synovial fibroblastic E11 cells.

MS-275 (entinostat) and SAHA (vorinostat), two histone deacetylase (HDAC) inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA). To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK) signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α  MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1), an endogenous suppressor of p38α  in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation) of p38α  was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and macrophage migration inhibitory factor (MIF) in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.

Quantification of oxyresveratrol analog trans-2,4,3',5'-tetramethoxystilbene in rat plasma by a rapid HPLC method: application in a pre-clinical pharmacokinetic study.

A rapid HPLC method was developed and validated for the quantification of oxyresveratrol analog trans-2,4,3',5'-tetramethoxystilbene (oxyresveratrol tetramethyl ether, OTE) in rat plasma. Chromatographic separation was achieved on an RP-HPLC column, which was protected by a guard column through a 12 min gradient delivery of a mixture of acetonitrile-water at 50°C. The UV absorbance at 325 nm was recorded. The retention time of OTE and trans-stilbene (internal standard) was about 7.7 and 8.4 min, respectively. The calibration curves were linear (R(2) ≥ 0.9986) with a lower limit of quantification of 15 ng/mL. The intra- and inter-day variations, in terms of RSD, were all lower than 9.8% while the intra-day and inter-day bias ranged from -8.3 to +9.2%. The pharmacokinetics of OTE was assessed in rats using 2-hydroxypropyl-ß-cyclodextrin as a dosing vehicle. After intravenous administration, OTE possessed a long terminal elimination half-life (t(1/2) (λz) = 481 ± 137 min) and slow clearance (Cl = 29.1 ± 3.7 mL/min/kg). Upon oral administration, OTE was rapidly absorbed. However, it only displayed minimal plasma exposure and its absolute oral bioavailability (F) was as low as 4.5 ± 3.2%. Fortunately, the levels of OTE after single oral administration were sufficient to inhibit human cytochrome P450 1B1.

Determination of Z-3,5,4'-trimethoxystilbene in rat plasma by a simple HPLC method: application in a pre-clinical pharmacokinetic study.

A simple HPLC method had been developed and validated to quantify Z-3,5,4'-trimethoxystilbene (Z-TMS), a phyto-stilbene with potent anti-cancer activities in rat plasma. Chromatographic separation was achieved on a reversed phase-HPLC column, which was protected by a guard column through a 13.5-min gradient delivery of a mixture of acetonitrile and water at a flow rate of 1.5 ml/min at 50 degrees C. The UV absorbance at 300 nm was recorded. Z-TMS and E-stilbene (internal standard) eluted at 8.8 and 9.3 min, respectively. The calibration curve was linear within the range of 33-2500 ng/ml (R(2)>0.9995) and 10 ng/ml was the lower limit of detection. The intra- and inter-day precisions were good and the relative standard deviation was all lower than 10%. The analytical recovery of Z-TMS in plasma ranged from 94.6+/-9.1% to 97.0+/-2.1%. This HPLC method was successfully applied to assess the pharmacokinetic profile of Z-TMS in Sprague-Dawley rats using hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) as a dosing vehicle. Although Z-TMS displayed negligible oral bioavailability, it had a fairly long terminal elimination half-life, abundant plasma drug exposure and limited clearance following intravenous administration. As Z-TMS had favorable intravenous pharmacokinetic profile, further investigation on its potential as a cancer chemotherapeutic agent is warranted.

Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-kappaB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells.

OBJECTIVES: MS-275 and suberoylanilide hydroxamic acid (SAHA) are histone deacetylase (HDAC) inhibitors currently tested in oncology trials. They have also been found to display potent anti-rheumatic activities in rodent models for RA. However, the anti-rheumatic mechanisms of action remain unknown. The study was carried out with the intent of determining the anti-inflammatory and anti-rheumatic mechanisms of the HDAC inhibitors. METHODS: In this study, the anti-rheumatic mechanisms of MS-275 and SAHA were investigated in several cell culture models. RESULTS: MS-275 and SAHA inhibited human RA synovial fibroblastic E11 cell proliferation in a non-cytotoxic manner. The anti-proliferative activities were associated with G(0)/G(1) phase arrest and induction of cyclin-dependent kinase inhibitor p21. In addition, MS-275 and SAHA suppressed lipopolysaccharide (LPS)-induced NF-kappaB p65 nuclear accumulation, IL-6, IL-18 and nitric oxide (NO) secretion as well as down-regulated pro-angiogenic VEGF and MMP-2 and MMP-9 production in E11 cells at sub-micromolar levels. At similar concentrations, MS-275 and SAHA suppressed LPS-induced NF-kappaB p65 nuclear accumulation and IL-1beta, IL-6, IL-18 and TNF-alpha secretion in THP-1 monocytic cells. Moreover, NO secretion in RAW264.7 macrophage cells was also inhibited. CONCLUSIONS: In summary, MS-275 and SAHA exhibited their anti-rheumatic activities by growth arrest in RA synovial fibroblasts, inhibition of pro-inflammatory cytokines and NO, as well as down-regulation in angiogenesis and MMPs. Their anti-rheumatic activities may be mediated through induction of p21 and suppression of NF-kappaB nuclear accumulation.