Thursday, June 16, 2016

Osimertinib | Mutant Selective EGFR Inhibitor | Kinase Inhibitor | Orphan Drug | Treatment for NSCLC

Osimertinib [N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide] is an oral, small molecule, irreversible and mutant-selective inhibitor of epidermal growth factor receptor (EGFR) kinase activity. Chemically, Osimertinib is a mono-anilino-pyrimidine compound that is structurally and pharmacologically distinct from all other third-generation tyrosine kinase inhibitors (TKIs) including CO-1686 and WZ4002 [1, 2].

Osimertinib: 2D and 3D Structure

Osimertinib is designed in such a manner that it irreversibly and selectively targets both sensitizing and resistant-T790M mutant EGFR whilst harboring less activity towards wild-type EGFR. Osimertinib has been developed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. 

Osimertinib was granted US FDA breakthrough therapy designation, orphan drug status and fast track status for non-small cell lung cancer (NSCLC) in 2014, and was granted US FDA priority review designation by early September 2015. In May 2015, Osimertinib was granted accelerated assessment status in the same indication in the EU, and received priority review status in Japan in the third quarter of 2015. 

Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy [1].

Dosages and Approvals:
In Nov 2015, Osimertinib (Tradename: Tagrisso) a third-generation EGFR TKI that targets tumours with certain EGFR mutations, including T790M,got an  accelerated approval from the US FDA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as detected by an FDA-approved test) who have progressed on or after EGFR TKI therapy.
The recommended dosage of Osimertinib is 80 mg once daily until unacceptable toxicity or disease progression (PD). Osimertinib tablets (available as 40 and 80 mg) can be taken with or without food, or in patients who have difficulty swallowing solids, dispersed in about 50 mL of noncarbonated water and immediately consumed or administered via nasogastric tube. 
A joint effort of AstraZeneca and University of Cambridge since 2014 is credited with discovery of Osimertinib, where the university’s researchers gain access to key compounds from AstraZeneca’s investigation pipeline, including Osimertinib. In October 2015, AstraZeneca entered into a collaborative agreement with Eli Lilly to investigate the use of Osimertinib as combination therapy (with Ramucirumab or Necitumumab) in patients with solid tumours.

Osimertinib Synthesis

J Med Chem 2014, 57(20), 8249-8267: It is one of the earliest reported synthetic route for Osimertinib. The article details the design, discovery and activity of Osimertinib and its various analogues.

Starting Material (Route 1):

Route 2: Shorter with better yields too !!!

Final Synthesis:


1H NMR (Estimated) for Osimertinib

Experimental: 1H NMR (400 MHz, DMSO, 22 °C) δ 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.2-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s).
13C-NMR (Estimated) for Osimertinib

Experimental: 13C NMR (176 MHz, DMSO, 22 °C) δ 32.8, 42.6, 45.1, 55.7, 56.0, 56.8, 105.3, 107.1, 110.4, 112.4, 113.3, 120.8, 121.2, 121.9, 125.3, 125.5, 125.9, 127.7, 132.4, 133.8, 137.3, 137.7, 145.8, 157.6, 158.9, 159.8, 161.5, 162.3.

Sideeffects: The most common adverse events (AEs) of any grade with Osimertinib (occurring with greater than 20 % incidence) were diarrhea (47 %), rashes and acne (group term; 40 %), nausea (22 %), decreased appetite (21 %) and dry skin (20 %). The incidences of some adverse events, including diarrhoea and rash, increased in a dose-dependent fashion.
Based on clinical trial data, the US prescribing information for Osimertinib carries warnings and precautions regarding the increased risk of ILD/pneumonitis, QTc interval prolongation and cardiomyopathy during treatment.

Results from clinical trials reveal that pneumonitis-like events were reported in six patients (2.4 %), all of whom stopped treatment and had resolved or were resolving at the time of analysis. Eleven patients (4.3 %) experienced prolongation of QTc interval and six patients (2.4 %) reported hyperglycaemia during Osimertinib treatment; none of these patients required dosage reduction or drug discontinuation. Of the seven fatal adverse events with Osimertinib, one case of pneumonia was considered to be possibly treatment-related.

1. Greig, S. L. Osimertinib: First Global Approval. Drugs 2016, 76(2), 263-73. (FMO only)
2. Finlay, M. R.; et. al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014, 57(20), 8249-67. (FMO only)