Preterm Birth Problem

Preterm birth is the first cause of newborn death and morbidity worldwide, with over 1.1 million deaths per year.
Every year, an estimated 15 million babies are born preterm (before 37 completed weeks of gestation), which represents more than 1 in 10 babies.

Researches have demonstrated that in 70% of the cases, preterm birth is due to uteroplacental inflammation.

Common causes of uteroplacental inflammation leading to preterm birth include infections (often occult), multiple pregnancies, stress and chronic conditions such as diabetes; in cases where no cause is identified, sub-clinical inflammation is often observed.

The most common initial manifestation of impending preterm birth is preterm labor; other manifestations are premature rupture of the membranes, cervical dilatation or effacement.

A number of biological markers to predict risk of preterm birth are currently in development (David Olson Lab, Maternica Inc, University of Alberta; Sera Prognostic in Salt Lake City; Carmentix in Singapore and several universities).

Preterm birth cascade

Preterm birth also has significant economic impacts. Costs in the USA were reported by the US Institute of Medicine in 2007 to be $26 billion a year:

  • Normal delivery cost: ~$4,500
  • Preterm birth delivery: ~$50,000
  • After the neonatal period, life time medical cares reach: $500,000 per premature handicapped child

Product Description

 

Rytvela (a linear 7 amino acid peptide) is the first small drug candidate selective for the major pro-inflammatory interleukin-1 receptor. Pre-clinical efficacy has been corroborated by two independent blinded in vivo studies involving three independent academic laboratories (U of Montreal CHU Sainte-Justine and U of Alberta in Canada, and U of Adelaide in Australia). These in vivo studies reveal that Rytvela reduces uteroplacental inflammation, significantly reduces/suppresses preterm birth, improves neonatal survival and prevents major organ disruption including of brain, yielding normal growth/developmental trajectory.

Rytvela reduces gestational inflammation in vivo in the model of inflammation-induced by IL-1β

Vehicule IL-1β + Vehicle IL-1β + Rytvela
normal-rodent-uterus inflamed-rodent-uterus normal-looking-uterus

Why Rytvela?

There is currently no treatment to significantly prolong gestation and prevent adverse inflammation-triggered neurodevelopmental consequences and other organ deficiencies; there are over 1.1 million deaths per year worldwide and approximately the same number of infants born with handicap. It is paramount to address uteroplacental/fetal inflammation, the major cause of preterm birth. Rytvela is the first (and only) drug that tackles uteroplacental inflammation. Rytvela will be a paradigm-shift in treatment of women at risk of preterm birth, and will result in saving many lives and importantly reduce neurologic, respiratory, digestive (and cardiovascular) disability – with important socioeconomic impact.

PTB treatment currently available in some countries: Tocolytics

Drug/class Rational Effectiveness Side effect Comments
ß-mimetics
(Salbutamol, Terbutaline..)
Inhibit the uterus contraction. Delay the birth by some days.
No effect on outcome.
Palpitations, chest pain, headache, difficulty breathing, nausea and/or vomiting. Not approved, used off label in USA and Asia.
Indomethacin Prostaglandin Inhibitor. Stop the labor for some days. Most important side effect : Closure of the Ductus arteriosus limit the administration to some days. Not approved in North America, Australia and in Europe: Usage through out off label use.
Oxytocin receptor antagonists
(Atosiban, ObsEva OBE001,
Retosiban GSK)
Oxytocin causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Stop the labor for some days. No effect on outcome. Activity pro inflammatory. GSK is currently in clinical Phase 3.
 Calcium channel blockers
(15/20 products marketed all …dipine like nifedipine, amlodipine, nicardipine etc)
Inhibit contractility in smooth muscle cells. Stop the labor for some days to a week. Little effect on outcome. Decrease the respiratory distress syndrome. Good tolerability for the mother and the fetus. Some time co-administer with ß-mimetics.
17OH-progesterone IM
(Makena AMAG pharma, and Lucite pharma with an Oral from )
Progesterone is a major hormone to sustain pregnancy especially during the first Q. Prolonged pregnancy up to a week. But no or little activity on outcome Well tolerated but local tolerance can be an issue. Mostly used in prevention in women at risk.
17OH-progesterone Intravaginal Same Do not prolong pregnancy and no effect on outcome . (The optimum study) Well tolerated. Mostly used in prevention in women at risk.

None of these treatments address the uteroplacental inflammation

Rytvela, in brief:

  • Selective antagonist of IL1R
  • Prevents (and treats) uteroplacental inflammation
  • Prevents or significantly reduces preterm birth
  • Prevents or significantly reduces death at birth with normal growth of the newborn
  • Prevents organ disruption: newborn exhibit normal organ histology and function
  • Ready to start IND enabling program
  • ~4 years and from proof of concept (ph2a) in patients
  • Indication well protected until 2036 (PCT application filed 1st Q 2016)
  • Huge market

Rytvela Market Assessment – Annual Basis

United States

US Market Women known at risk
History of PTB, multiple fetuses…
Women “not at risk”
Clinical or biological diagnostic
 Number of preterm birth  150,000  350,000
 Market penetration  50% = 75,000  30% = 105,000
 Treatment selling price  $ 13,000
(~ 70 days treatment)
 $ 6,500
(~35 days treatment)
Potential revenue  ~$ 1 billion  ~$ 650 million

Global Market

  • US market estimated at ~ $ 1.65 billion
  • European market estimated at 70% of USA at ~ $ 1.1 billion
  • Japan market estimated at 10 % of USA + EU at $ ~270 million
  • ROW estimated at $ ~270 million

Global annual market expected to be > $ 3 billion


The Project

Independent in vivo studies

Two independent blinded in vivo pre-clinical studies have shown that Rytvela prevents uteroplacental inflammation and ensued adverse newborn consequences.

  1. First study conducted in the research laboratories of the CHU Sainte-Justine in Montreal, Canada by:
    Dr. Sylvain Chemtob, Christiane Quiniou and William Lubell
    This study was performed thanks to a grant from the Bill & Melinda Gates foundation (Nadeau-Vallée M, et al. J Immunol. 195:3402-3415,2015).
  2. Second study conducted independently at the Robertson Research Institute, University of Adelaide, Australia by:
    Peck Y. Chin (Loretta), Lachlan M. Moldenhauer, William D. Lubell, David M. Olson, Dr Sylvain Chemtob and Professor Sarah A. Robertson

 

 

Hopital-Sainte-Justine - three-models-ofThese 2 studies demonstrate that Rytvela:

  • reduces uteroplacental inflammation
  • significantly reduces/suppresses preterm birth, newborn death
  • prevents organ disruption, yielding normal growth trajectory

 

 

Rytvela prevents prematurity in models of inflammationRytvela suppresses LPS-induced preterm birth

Effect of Rytvela on cytokine gene

Effect of gestational inflammation on exposed fetal lung


Rytvela Development Timelines

Rytvela Development Timelines

 


Research Partners

Research and development financing foundations for Rytvela

  • Bill and Melinda Gates foundation / gapps
  • Canadian Institutes of Health Research
  • Consortium québécois sur la découverte du médicament
  • Le Fonds de Recherche du Québec – Santé
  • March of Dimes
  • Natural Sciences and Engineering Research Council of Canada
  • National Natural Science Foundation of China

Other foundations

  • Burroughs Wellcome fund
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • PremUP
  • The Fetal Medicine Foundation
  • Tommy’s