Mind The Gap: Another Pipeline Setback for AstraZeneca As NXY-059 Fails Efficacy Test for Stroke Treatment

In an unsettling prelude to its third-quarter results, AstraZeneca announced the most recent failure in its late-stage-development pipeline, as NXY-059, an investigational drug for the treatment of acute ischaemic stroke, which failed to show any meaningful efficacy in the SAINT (Stroke Acute Ischaemic NXY-059 Treatment) II trial. The company is ceasing any further development of the compound, which was licensed from U.S. biotechnology company Renovis, although it will analyse the pooled data from SAINT II and the previous SAINT I trial with NXY-059 "to ensure [data] for further stroke research are identified and communicated."

AstraZeneca acknowledged that the results were "disappointing for patients looking for new treatments for stroke, and for AstraZeneca as we seek to build our research and development pipeline", while pointing out that the outcome was "not without precedent, given the challenging nature of the science." In fact, there had already been strong hints that NXY-059 would not make the distance. AstraZeneca had postponed filing for marketing approval of the drug from the second half of 2006 to the first half of 2007, following mixed results from the SAINT I trial. These had indicated a statistically significant reduction of primary-outcome disability after acute stroke in patients taking NXY-059. However, there was no significant improvement against placebo if neurological impairment was measured on the U.S. National Institutes of Health Stroke Scale (NIHSS, see United Kingdom: 4 May 2005: AstraZeneca's Cerovive Produces Mixed Results in Phase III Study).

As no safety issues had emerged, AstraZeneca decided to press on with development of NXY-059. However, the latest data the follow-up SAINT II trial left no doubt that the compound was a lost cause for the treatment of ischaemic stroke. NXY-059 missed its primary-outcome goal of a statistically significant reduction in stroke-related disability, as measured by the modified Rankin Scale, compared with placebo. Nor, again, did it produce any statistically significant improvement in neurological status versus placebo on the NIHSS. Subgroup analyses, including time to treatment, did not show any treatment benefit, while mortality and the incidence and profile of adverse effects in patients receiving NXY-059 were similar to placebo. Nor was there any evidence of NXY-059 reducing the incidence of symptomatic intracranial haemorrhage—another potential application—when administered in combination with a thrombolytic (recombinant tissue plasminogen activator, rt-PA).

For AstraZeneca, the disappointing outcomes with NXY-059 sound the death knell for neuroprotectant compounds as a means of protecting against permanent damage after a stroke. According to Reuters, the company's head of development, John Patterson, said the company would not be looking for any further stroke projects in this field, as the company believed it had "done the definitive study here."

The end of NXY-059 is another setback in the notoriously volatile arena of research and development (R&D) for treatment of stroke. Ischaemic stroke is the most common form, accounting for an estimated 85% of cases, yet there is still only one currently approved product for this indication in the United States and Europe: Genentech's (U.S.) rt-PA Activase. Last year Japan's Ono Pharmaeutical said it was stopping North American trials of Proglia (ONO-2506) for the treatment of acute stroke, after the independent Data Safety Monitoring Board decided it was unlikely the compound would show any statistically significant efficacy against placebo in the current study design (see World: 26 May 2005: Healthcare and Pharma: World: Ono and Merck Halt North American Trials of Acute Stroke Drug Proglia).

Closer to home, scrapping NXY-059 deprives AstraZeneca of one of two late-stage drug candidates—the other is atherosclerosis treatment AGI-1067—which the company was hoping to launch by the first half of 2008. Analysts had tagged NXY-059 as a potential blockbuster in a stroke market estimated to be worth around US$3 billion. Other than new indications for the schizophrenia drug Seroquel, AstraZeneca's neuroscience pipeline now looks distinctly empty, with only one compound—AZD3480, a neuronal nicotinic receptor agonist for cognitive disorders/Alzheimer's disease—up to Phase II and the rest of the candidates either in Phase I trials or still at the preclinical stage.

Outlook and Implications

NXY-059 was always going to be a high-risk project, characteristically for the stroke category. But its failure will inevitably lead to further concerns about AstraZeneca's ability to steer new compounds through late-stage clinical development. Previous disappointments with promising candidates, such as cancer treatment Iressa, diabetes drug Galida and anticoagulant Exanta have left AstraZeneca overly dependent on new indications for stalwarts such as Seroquel and ulcer drug Nexium, while it hunts for new opportunities both internally and externally. John Patterson recently warned, however, that in-licensing was becoming increasingly competitive, with some small biotechs making unrealistic demands when negotiating agreements (see United Kingdom: 20 September 2006: AstraZeneca Continues Search to Fill Pipeline). In AstraZeneca's third-quarterresults presentation, investors will certainly be looking for assurances that the company has with which to fill this new gap.