GlaxoSmithKline plc Announces NEJM Publication of Phase 3b/4 Study of Ambrisentan and Tadalafil
Aug 26 15
GlaxoSmithKline plc announced publication of the AMBITION study, the first outcomes study to compare the safety and efficacy of investigational first-line combination therapy of Volibris (ambrisentan) and Adcirca (tadalafil) to first-line monotherapy of either treatment alone in treatment-nadve patients with pulmonary arterial hypertension (PAH). The AMBITION study was a randomised, double-blind Phase 3b/4 study designed to compare the efficacy and safety of ambrisentan in combination with tadalafil to monotherapy in treatment-nadve patients with WHO/NYHA functional class II and III PAH. In the study, 500 patients were randomised (2:1:1) to receive ambrisentan and tadalafil combination (n=253) or monotherapy with ambrisentan (n=126) or tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for ambrisentan and tadalafil, respectively). The AMBITION study was co-sponsored by GSK and Gilead. Eli Lilly and Company also provided funding and tadalafil drug supply for the study. The primary endpoint was time to first clinical failure event, defined as time from randomisation to the first occurrence of death (all-cause), hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response. Ambrisentan, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE-5 inhibitor, are each approved in the EU and other countries as once-daily treatments for PAH, (WHO Group 1) in patients with WHO/NYHA functional class II and III symptoms. GSK commercialises ambrisentan under the tradename Volibris(TM) in territories outside of the United States and Gilead commercialises ambrisentan under the tradename Letairis(TM) in the U.S. Ambrisentan has been granted orphan drug status for the treatment of PAH in Australia, Europe, Japan, Korea and United States. GSK also has an exclusive license from Eli Lilly and Company to promote tadalafil for PAH under the tradename Adcirca(TM) in Europe. PAH is a debilitating disease characterised by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide. Ambrisentan is contraindicated in pregnancy. Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans. Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs. It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals. Therefore breast-feeding is contraindicated in patients taking ambrisentan. In males, the development of testicular tubular atrophy in male animals has been linked to the chronic administration of endothelin receptor antagonists (ERAs), including ambrisentan. Ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH. Liver function abnormalities have been associated with PAH. Cases consistent with autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and hepatic enzyme elevations potentially related to therapy hav e been observed with ambrisentan. Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of ALT and/or AST3xULN. Tadalafil is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. Tadalafil is contraindicated in patients that have experienced acute myocardial infarction within the last 90 days and in patients that have severe hypotension (90/50 mm Hg). In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior
ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. Visual defects and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to consult a physician immediately. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical studies, and use in these patients is not recommended. The following groups of patients with cardiovascular disease were not included in PAH clinical studies: Patients with clinically significant aortic and mitral valve disease, patients with pericardial constriction, patients with restrictive or congestive cardiomyopathy, patients with significant left ventricular dysfunction, patients with life-threatening arrhythmias, patients with symptomatic coronary artery disease and patients with uncontrolled hypertension. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended. For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended. For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended. The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take tadalafil with these medicinal products.
Five Prime Therapeutics and Partner GlaxoSmithKline Reports Initial Data from Phase 1b Trial of Lung Cancer Treatment
Aug 24 15
Five Prime Therapeutics and partner GlaxoSmithKline reported results from the ongoing Phase 1b trial of FP-1039/GSK3052230 in patients with squamous non small cell lung cancer and mesothelioma. The Phase 1B trial being conducted by GlaxoSmithKline is evaluating the safety and efficacy of FP-1039/GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 gene amplified metastatic squamous NSCLC (Arm A). It is also evaluating it in combination with docetaxel in FGFR1 gene amplified metastatic squamous NSCLC that has progressed after at least 1 line of chemotherapy (Arm B) and finally in combination with pemetrexed + cisplatin in patients with untreated and unresectable malignant pleural mesothelioma (Arm C). GlaxoSmithKline continues to enroll patients in the study. Arm A and Arm C have advanced into the expansion phase and dose escalation is ongoing for Arm B. Five Prime licensed development and commercialization rights for FP-1039/GSK3052230 in the U.S., Europe and Canada to GSK, which funds clinical development. Five Prime retains rights outside of these regions as well as an option to co-promote FP-1039/GSK3052230 in the U.S.
GlaxoSmithKline plc and Novartis AG Enter into A Agreement on Cancer Drug
Aug 22 15
GlaxoSmithKline plc and Novartis AG announced that they had struck a deal for Novartis to pay GSK at least $300 million, and perhaps more than $1 billion, for the remaining rights to the drug ofatumumab. The drug already is approved for use in treating some cancers and is sold by Novartis under the name Arzerra. Novartis now will have the rights for any use of ofatumumab approved by regulators, most importantly multiple sclerosis. GSK gets $300 million when the deal is closed, $200 million if Novartis starts a phase III clinical study of ofatumumab in relapsing remitting multiple sclerosis, and contingent payments of up to $534 million if other development milestones are achieved. GSK would get royalties of 12% on any future net sales of ofatumumab in autoimmune indications. GSK had sold the cancer indication as part of a multibillion-dollar deal with Novartis in 2014. GSK kept oncology programs in its pipeline, but sold existing oncology drugs in exchange for the Novartis vaccine portfolio and a majority position in a new joint venture to sell over-the-counter consumer products. Novartis competes with Roche Holding AG and Teva Pharmaceutical Industries Ltd. in multiple sclerosis drugs. A key Novartis MS drug will lose patent protection in the next few years. Novartis' Sandoz generic division sells the first generic version of Teva's 20mg Copaxone medication.