Project: 2-Iminobiotin for the treatment of perinatal asphyxia

2-Iminobiotin for the treatment of perinatal asphyxia

This is a summary of the request.

Perinatal asphyxia occurs when gas exchange between the foetus and mother is disrupted, resulting in hypoxia (shortage of oxygen), hypercarbia (excess of carbon dioxide) and combined metabolic and respiratory acidosis, eventually leading to global cerebral ischaemia. This result in primary cell injury After a period, ranging from 6-178h following resuscitation, a secondary energy failure begins, resulting in delayed cell death. This intervening period between the primary and secondary phases of injury offers a window for therapeutic intervention.

The incidence of perinatal asphyxia in Europe is approximately 6.8 per 1000 newborns and 0.7 per 10,000 population. Despite major improvements in obstetric and perinatal care, perinatal asphyxia remains one of the major causes of neonatal morbidity and mortality. Depending on the literature cited, 4% to 20% of those affected die and 25% are severely handicapped due to long-term complications such as cerebral palsy, mental retardation with learning difficulties, cerebral visual impairments and/or epilepsy.

Disease management after hypoxic-ischaemia always begins with supportive care: establish adequate oxygenation and restore circulation by appropriate, rapid and effective resuscitation. It is vital to maintain adequate ventilation, systemic blood pressure, tissue perfusion, and normoglycaemia, in order to control seizures and to correct electrolyte and acid-base disorders.

Currently there are no approved specific pharmaceutical treatments for perinatal asphyxia. Standard treatment mainly consists of medication to reduce symptoms, such as sedatives, anaesthetics, anti-epileptics and antibiotics (also to prevent ventilator-associated pulmonary infections). In the past few years hypothermia (whole body hypothermia or selective head cooling) has been introduced to reduce morbidity and mortality following perinatal asphyxia in term born neonates.

2-Iminobiotin (2-IB) is being developed as the first pharmaceutical treatment of perinatal asphyxia. 2-IB is a selective inhibitor of the neuronal (nNOS) and inducible (iNOS) iso-enzymes both of which play a role in the secondary damage resulting from perinatal asphyxia.

In vivo, the efficacy of 2-IB has been demonstrated in piglet and rat models of perinatal asphyxia.

In rats, the effects of 2-IB in asphyxiated newborn rats was investigated in rats at 3, 7 and 12 days of age resembling the stage of brain development of premature, near term and term human babies. 2-IB was found to be effective in both improving early parameters and behavioural tests after 6 weeks. Most of the effects were only significant in female rats.

Piglets were chosen since the brains of newborn piglets are most representative for the human brain in newborns. Several studies were performed each showing that 2-IB in a 0.2 mg/kg/dose i.v. every four hours for 6 doses has positive effects on relevant early parameters including neuronal death, aEEG and caspase 3 –activity.

In a dose finding study in another piglet model, doses of 0.1, 0.2 and 1.0 mg/kg/dose i.v. every 4h for 6 doses in total demonstrated efficacy on primary outcome parameters, including survival with a normal aEEG at 48h post hypoxia-ischaemic insult; and decreased caspase-3 activity in the thalamus. The 0.2 mg/kg dose appeared to be most promising.

In the piglet studies no difference between the genders was seen.

Safety has been tested in several animal models including juvenile rats and minipiglets. Also a phase I clinical study has been performed in healthy, male adults. These studies have shown that there is a substantial safety margin for the doses to be given in clinical care.

Pharmacokinetic studies have shown that 2-IB is almost completely cleared by the kidneys. Clearance appeared to increase linearly with body weight across different species. Based on this observation it can be concluded that across species, including piglets and humans, the dose/kg can remain constant to achieve similar exposure.

The next step is a phase II study in affected human newborns. The phase II studies are currently being planned: first a phase II in neonates not being treated with hypothermia and secondly a study in neonates receiving hypothermia. Phase II studies will be followed by larger phase III studies. If all goes according to plan, marketing registration is expected to be completed in 2017.