More problems for Ono's astrocyte modulator stroke programme
This article was originally published in Scrip
Executive Summary
The continued development of Ono's astrocyte modulator Arocyte (ONO-2506) has been thrown into doubt by disappointing efficacy results from a Japanese Phase II/III study in acute ischaemic stroke.
The continued development of Ono's astrocyte modulator Arocyte (ONO-2506) has been thrown into doubt by disappointing efficacy results from a Japanese Phase II/III study in acute ischaemic stroke.
The company said that data from the trial had just been unlocked and that efficacy was "not as expected", although it gave no additional details. It will analyse the results further before deciding whether to continue with the development of the intravenously administered therapy.
The findings are the latest setback for the mid-sized Japanese company's troubled astrocyte modulator programme, which has been dogged by efficacy questions. Ono halted an in-house North American Phase II trial with ONO-2506 (then named Proglia) in 2005 because of uncertain benefits over placebo. A Phase II Japanese trial in Parkinson's disease with an oral formulation, Cereact (ONO-2506PO), was discontinued for efficacy reasons in 2006, and the product is also no longer listed in US development for Alzheimer's disease.
Ono holds global rights to the oral formulation, which remains in Phase II development in Europe for amyotrophic lateral sclerosis. However, mixed efficacy results from an initial Phase II European trial were also reported in this setting in 2005. The compound showed no overall significant benefit over placebo in terms of change in slow vital capacity, a standard measure of disease progression.
Ono has been pursuing a neuroprotective approach to the various target indications because disruption of the function of astrocytes, a type of glial cell, is thought to play a role in their progression. In acute ischaemic stroke, modulating the function of such cells was expected to help inhibit the expansion of the cerebral infarction area. The therapeutic approach also allows a longer window for administration after infarction onset compared with the three-hour limit for TPA therapy, as well as a reduced risk of cerebral haemorrhage.
Under a 2004 cross-licensing deal, Merck & Coacquired rights to ONO-2506 (the intravenous formulation) outside certain Asian territories, and is conducting a placebo-controlled, North American Phase II trial (as MK-0724) for the improvement of neurological damage and recovery from middle cerebral artery ischaemic stroke. This has a different design to Ono's previous North American study, and according to www.clinicaltrials.gov is assessing 8mg/kg/hr infusions for one hour daily over seven days.
While the study was actively recruiting as of September, it could be affected by the Japanese results and any Ono decision to halt development. The US firm holds rights to a backup compound under the 2004 agreement, which in return gave Ono Japanese rights to Merck's neurokinin-1 antagonist for chemotherapy-induced nausea and vomiting Emend (aprepitant, awaiting approval). Ono will also co-market Merck's DPP-4 inhibitor sitagliptin (Januvia) in Japan, as Glactiv; this was filed for approval in December.
The new clinical results come after Ono hauled back its financial guidance for the current fiscal year in August, following a difficult first quarter marked by generic and other competition. The firm disclosed at the same time that it had dropped the novel corticotropin-releasing factor receptor antagonist ONO-2333Ms, following disappointing efficacy results in a US Phase II trial for depression (Scrip Online, August 6th, 2008).