A second patient enrolled in a phase III trial of Zafgen’s obesity drug candidate beloranib has died, placing the future of the programme in doubt.
In the wake of the first fatality in October, Zafgen called a halt to the study – which involved patients with a genetic disorder called Prader-Willi syndrome (PWS) – in order to investigate whether the death was linked to the drug. PWS is characterised by insatiable appetite and excessive weight gain.
The cause of death was “driven by a thromboembolic event”, according to Zafgen, and when the FDA imposed a partial clinical hold on the study shortly afterwards it cited a risk of blood clots in prior studies.
As a result Zafgen decided to terminate the trial and analyse the data accrued to date, and said last month that six blood clot-related incidents had occurred in its trials to date, all but one of which were deemed by investigators to be unrelated to the study drug.
News of a second death earlier this week – this time attributed to blood clot in the lung – has heightened concerns and led to a 60% decline in Zafgen’s share price yesterday as investors bolted for the exits.
Thomas Hughes, Zafgen’s chief executive, said: “Our thoughts are with the patient and their family at this time.
“Patient safety remains our top priority and we are investigating the circumstances around this event,” he added, noting that the company is in discussions with the FDA “while we determine the next steps with the beloranib programme”.
Under the partial clinical hold, Zafgen is required to assess thrombotic risk and activity on a patient-by-patient basis before returning them to open-label treatment.
Beloranib is a first-in-class drug that acts as an inhibitor of methionine aminopeptidase type 2 (MetAP2), an enzyme thought to play a role in control of metabolism in cells, reducing the biosynthesis of lipids and increasing lipid oxidation.
Short-term phase II clinical trials in obese individuals have suggested that the drug can achieve an average weight loss of 11kg over 12 weeks at a dose of 2.4mg given twice a week by subcutaneous injection.
Zafgen is thought to have a lead in the development of drugs in the class although other firms – including AbbVie and Johnson & Johnson – have MetAp2-targeting development programmes.
The company licensed rights to beloranib from CKD Pharma of South Korea and has a phase IIb trial ongoing of the candidate in severe obesity complicated by type 2 diabetes, which is also subject to the clinical hold.
Analysts suggested that the toxicity concern could give beloranib a tough time getting through regulatory reviews, particularly in obesity, although some have suggested PWS could be easier.
“Patients with PWS are on average morbidly obese and suffer from a range of developmental issues and have a variety of health issues that leads to early death,” said Hughes recently. “The average life expectancy is estimated to be approximately 30 to 32 years.”