PDC31 for the treatment of preterm labour

Scientific publications
Preterm labour is defined as regular contractions associated with cervical changes occurring before 37 weeks of gestation. Preterm birth has been declared a major public healthcare issue in the US, where preterm birth rates continue to rise. In 2006, nearly 500,000 infants (12.8%) were born preterm (Martin et al, 2007). Annual societal economic burden associated with preterm birth in the United States was estimated at $26.2 billion in 2005, or $51,600 per infant born preterm, about 10 times greater for preterm than for term infants (Behrman and Butler, 2007).

The need to delay preterm birth at early gestation (<32 weeks) is well recognized, since babies born before 32 weeks have the greatest risk of death and serious immediate morbidities such as respiratory distress syndrome. In addition, the need for intervention at later gestation (>33 weeks) is becoming increasingly clear. A recent study found that those infants born between 34 and 36 weeks of pregnancy were three times as likely to be diagnosed with cerebral palsy as full-term babies. In addition, late pre-term babies were 25% more likely than full-term babies to have learning, speech and other developmental delays or mental retardation (Petrini et al, 2008).

Investigators and caregivers are increasingly aware of the multi-factorial nature and complexity of preterm birth. Strategies for dealing with preterm birth can be classified into early and late interventions. Early intervention strategies include improved antenatal care and lifestyles, and more recently, prophylactic treatment of high-risk women with progesterone has been investigated. Late intervention strategies are primarily aimed at decreasing uterine contractions using tocolytics. There are currently no approved treatments for prevention of preterm birth in the United States and as a result preterm labour is not always treated. Current guidelines recommend administration of corticosteroids to the mother (to improve fetal lung maturation) as well as the use of tocolytics in order to stop contractions long enough to enable the administration of corticosteroids and to facilitate the transport of the mother to a tertiary center for further observation and treatment. In Europe, the beta-mimetics, salbutamol and terbutaline and the oxytocin/vasopressin antagonist atosiban (Tractocile™) are indicated for use between 24 until 33 completed weeks gestation. There is an urgent need for new safe and effective therapies to significantly prolong pregnancy and improve infant outcome at both early and later gestational ages.

PDC31 for the treatment of preterm labour

PDC31 is a synthetic octapeptide which is a potent, non-competitive, selective antagonist of the prostaglandin F2α (FP) receptor.

In non-clinical pharmacology studies, PDC31 has been shown to inhibit spontaneous and PGF2α -induced uterine contractions both in vitro and in vivo. In the two industry standard models used to predict efficacy in humans (mouse and sheep) PDC31 was shown to significantly prolong pregnancy.

In the recently completed phase I clinical trial for PDC31in healthy women with primary dysmenorrhea, PDC31 infusion was associated with a dose-dependent relief of pain, as well as a reduction in intrauterine pressure.

The rationale of blocking the action of PGF2α is based on the key role this molecule plays in the process of labour. Within the uterus, PGF2α is associated with stimulation of myometrial contraction, cervical ripening, placental separation and uterine involution. More recently, PGF2α has been shown to downregulate the progesterone receptor, leading to functional withdrawal of progesterone, which is thought to be the key trigger for the onset of labour (Goldman et al, 2005). Currently available tocolytics (including oxytocin antagonists) provide only short-term inhibition of uterine contractions and are used to enable administration of corticosteroids and/or gain time to transfer the mother to a facility equipped with neonatal intensive care. In contrast, PDC31 has the potential to revert the uterus back to a quiescent state and significantly prolong pregnancy. However, PDC31 would also be clinically useful to inhibit uterine contractility short-term, if proven to be a safer and more effective alternative to current tocolytics.

The strategy of selectively blocking PGF2α is attractive because the molecule has few maternal physiologic effects outside the uterus and equally few fetal physiologic effects. Moreover, because signalling through the FP receptor is a downstream event, blocking at this point has the potential to provide enhanced efficacy and safety, unlike inhibitors of prostaglandin synthesis (such as indomethacin) which affect both maternal and fetal prostaglandin synthesis.

PDC31 is an injectable formulation which will be administered as an intravenous (IV) infusion. This is ideal, since it is common to begin an IV infusion for hydration when a woman comes to the hospital with symptoms of preterm labour. PDC31 is designed to be administered through the infusion line in order to rapidly inhibit the progression of labour.

References:

  • Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Munson ML. Births: Final data for 2005. National vital statistics reports; vol 56 no 6. Hyattsville, MD: National Center for Health Statistics. 2007.
  • Behrman RE and Butler AS, ends (2007) Preterm birth: causes, consequences, and prevention / Committee on Understanding Premature Birth and Assuring Healthy Outcomes, Board on Health Sciences Policy (www.nap.edu)
  • Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr. 2009 Feb;154(2):169-76. Epub 2008 Dec 10.