Shire has announced that its phase II study evaluating an investigational protein replacement, SHP607, did not meet its primary endpoint of reducing the severity of retinopathy of prematurity (ROP), a rare eye condition. The study, however, demonstrated clinically relevant effects in secondary endpoints related to the development of severe bronchopulmonary dysplasia (BPD), a chronic lung disease, and severe intraventricular hemorrhage (IVH), a type of brain injury, both of which have lifelong negative implications for normal development.
SHP607 is a recombinant human version of the naturally-occurring protein complex of insulin-like growth factor 1 (IGF-1) and its most abundant binding protein, IGF binding protein-3 (IGFBP-3).
The phase II study included 121 extremely premature infants (born between 23 weeks and 27 weeks +6 days) randomized at birth to either SHP607 or standard neonatal care, and treated continuously until an equivalent gestational age of 30 weeks. IGF-1 is a growth factor that plays a major role in the development of the growing fetus in the uterus. It is supplied by the mother until about 30 weeks of gestation when the fetus begins producing the growth factor on its own. Levels of IGF-1 dramatically decrease in infants born extremely premature (before 28 weeks of gestation), thereby increasing the risk for complications related to the lungs, brain, eyes and other organs.
The phase II top-line data showed a 53% reduction in the incidence of severe BPD, as defined by oxygen challenge testing, in all assessed patients that received SHP607, as compared to untreated infants; and an 89% reduction in those who achieved the prespecified target drug exposure, based on serum concentrations of IGF-1, as compared to untreated infants. The data also showed a 44% reduction in the incidence of severe IVH (Grade III and IV on centrally read ultrasounds) in all assessed patients that received SHP607, as compared to untreated infants; and a 64% reduction in those who achieved the prespecified target drug exposure based on serum concentrations of IGF-1, as compared to untreated infants. The secondary endpoint of time to discharge from neonatal intensive care was not met.
Approximately 28,000 infants in the U.S. are born extremely premature - before 28 weeks of gestation. The overall death rate (16%) in the phase II trial was consistent with mortality rates in this fragile population. There were more deaths in the treatment arm (20%) as compared to untreated babies (12%); however, no deaths were considered related to treatment. There were no serious adverse events related to the investigational medicinal product.
Research suggests that 60% of extremely premature infants experience one or more severe complications related to prematurity, which include: IVH (grade =3); BPD; or ROP. Severe complications can have life-long implications for the developing infant.
"This is the first controlled clinical trial to confirm the crucial role of IGF-1 in maturation of extremely preterm children," said Professor Neil Marlow of the University College London Hospitals, U.K., and one of the clinical trial investigators. "The reduction in BPD and IVH, as the two most important morbidities suffered by these children, are welcoming and a first in neonatal medicine. It will be important to confirm these findings in additional clinical studies."
Philip J. Vickers, Ph.D., head of R&D, Shire, said, "Although the study did not meet its primary endpoint, we are extremely encouraged by the topline secondary endpoints related to lung and brain. For severe complications related to the lung and brain, there are no approved treatment options, and these data support our commitment to further investigate the potential systemic benefits of SHP607 in this population where the unmet patient need is substantial."
Later this year, Shire expects to begin discussions with regulatory authorities about a phase III clinical program focusing on clinically relevant complications of prematurity.
The phase II study (ROPP-2008-01) was a multicenter, randomized, controlled study that compared SHP607 to standard neonatal care in 121 premature infants born at a gestational age of between 23 weeks and 27 weeks+6 days. Infants randomized to active treatment received a standardized dosage of 250µg/kg per day as a continuous 24-hour infusion from the day of birth (day 0) through postmenstrual age (defined as gestational age plus time elapsed from birth) of 29 weeks + 6 days, at which point the infant's body would begin producing enough IGF-1 to maintain sufficient levels in the blood. The target drug exposure was defined as at least 70% of measured IGF-1 levels within the normal intrauterine range and at least 70% of the intended duration of therapy based on gestational age. After the short-term treatment phase, all participants were followed to a postmenstrual age of 40 weeks ± 4 days.