ESA safety concerns cited as Neose pulls plug on NE-180

The Horsham, Pennsylvania-based company is also laying off around 35 per cent of its staff, including senior vice president and general counsel Debra Poul, as a result of its decision not to proceed any further with NE-180. This leaves around 30 employees and enough cash, Neose believes, to last it until at least until the third quarter of 2008. The company, which is developing modified versions of therapeutic proteins using its proprietary enzymatic pegylation technology, GlycoPEGylation, was at pains to stress that pulling the plug on NE-180 had nothing to do with any specific safety or efficacy concerns about the drug. The long-acting EPO had started a Phase II clinical trial in renal patients last September, while a Phase II study in patients with chemotherapy-induced anaemia had already begun earlier in the year. NE-180 was being developed for the treatment of anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy, and for the treatment of anaemia associated with chronic kidney disease, including patients both on and not on dialysis. By extending the half-life of EPO through PEGylation, which involves joining the protein to a polymer (polyethylene glycol) that protects it from being broken down in the body, NE-180 promised a favourable dosing profile of once every three weeks for the chemotherapy and once every four weeks for the renal indication respectively. According to Neose, preclinical data had shown comparability to Amgen's anaemia blockbuster Aranesp (darbepoietin alfa), while single doses in a Phase I clinical trial had been generally well tolerated, with no serious adverse events, and had generated potent, dose-dependent erythropoietin activity. There were already some warning signs last year, though. In August Neose said that, due to sluggish patient enrolment, it did not expect to complete its Phase II trial with NE-180 in chemotherapy-induced anaemia by year-end as planned. The company addressed that problem by amending the protocol from a single-country, multi-site trial to one taking in six countries with multiple investigator sites in each. Neose had already weathered a substantial delay in the US development programme for the drug. NE-180 was on clinical hold from July 2005 to March 2007, after the US Food and Drug Administration (FDA) asked for additional manufacturing and preclinical information to complete its review of Neose's investigational new drug application. As Neose president and chief executive officer Dr George Vergis noted in a conference call, the whole ESA category was subject to closer regulatory scrutiny throughout 2007, based on clinical data that suggested an increased risk of tumour growth and serious cardiovascular adverse events in certain settings. In the wake of "numerous​" regulatory actions taken by the FDA and the European Medicines Agency (EMEA) over ESAs, and their subsequent impact on product labelling and reimbursement policies for the category, sales of products such as Aranesp, Epogen (epoetin alfa) and Procrit (epoetin alfa) had declined "significantly", Dr Vergis pointed out. The FDA's actions alone last year included two sets of labelling revisions (boxed warnings and other safety-related information), introduced in March and then in response to advisory committee meetings on the safety and efficacy of ESAs in cancer and chronic kidney failure patients respectively in May and September 2007. These labelling changes led to restrictions in the Centers for Medicare and Medicaid Services' coverage plan for ESAs in the oncology setting. A knock-on effect of these setbacks, Dr Vergis added, had been a substantial hit to the market capitalisation of Neose and other companies with development-stage ESAs. Unsurprisingly, they also deterred potential development partners. With incremental spending on the NE-180 programme expected to reach $60-$80 million over the next two years, it was essential that Neose fulfilled its goal of finding a partner for the compound during Phase II trials. However, a formal evaluation process showed a "lack of partnering interest in the near term​", nor could the company "hazard a guess as to whether a viable partner could be obtained in the long term​", Dr Vergis told the conference call. Neose will now focus its energies on the rest of its pipeline, namely four product candidates targeting an estimated combined marketing opportunity of $8 billion. Unlike NE-180, all of these compounds are already partnered and their development fully funded. Dr Vergis believes they offer "clear differentiation in their respective categories​" and the potential to create "significant shareholder value​". The most advanced of these programmes is GlycoPEG-GCSF for neutropenia associated with immunosuppressive chemotherapy, which Neose is co-developing with Germany's BiogeneriX (ratiopharm). Last November the development partners announced encouraging data from two Phase I studies with GlycoPEG-CSF, including around a 30 per cent improvement in neurophil count response and a 60 per cent increase in bioavailability compared with Amgen's Neulasta (pegfilgrastim). BiogeneriX is expected to start a multi-country, multi-site Phase II trial in the second half of this year comparing several doses of GlycoPEG-CSF with the standard dose of Neulasta in up to 200 breast cancer patients receiving chemotherapy. Neose also says it is "proceeding well​" in its collaboration with Denmark's Novo Nordisk to develop long-acting pegylated versions of the haemostasis compounds Factor VIIa, Factor VIII and Factor IX. The Factor VIIa product, targeting bleeding episodes in patients with inhibitors to Factors VIII or IX, is in Phase I development. Neose's GlycoPEGylation platform uses a slightly different approach from other PEGylation techniques, by linking the polyethylene glycol to glycan groups on the protein that are distant from its active site, hence retaining the compound's biological activity. Since PEGylation requires chemical modification of the protein, in some cases this can impair the drug's activity if the active site of the molecule is impeded.