Closely held rEVO Biologics is enrolling patients in a Phase 3 clinical trial of its ATryn recombinant human antithrombin for the treatment of early-onset preeclampsia, with top-line data expected in the second quarter of 2016.
“This is a potentially life threatening disorder of pregnancy and a devastating unmet medical need,” Yann Echelard, president and CEO, says in an interview with BioTuesdays.com.
“There is no approved therapeutic to treat preeclampsia and the only way to stop it is to deliver a severely premature baby,” he adds.
The French biopharmaceutical group, LFB, wholly owns rEVO, which was formerly GTC Therapeutics. LFB is the world’s sixth-largest manufacturer of plasma-derived medicinal products and the only company authorized to fractionate plasma in France.
rEVO’s ATryn is the first and only approved recombinant human antithrombin in the U.S. and Europe for the treatment of pregnant women with Hereditary Antithrombin Deficiency (HD AT). It is an orphan disease, with a U.S. incidence of one in every 3,000 to 5,000.
Mr. Echelard says that more than 2,000 patients have already been treated with ATryn in the U.S. ATryn has a compelling safety profile, as well as a five-year post-marketing study that showed no signs of immunogenicity, he adds.
“We think ATryn can be a great product for preeclampsia because it avoids the pathogen risk of plasma-derived products and [because] recombinant manufacturing is scalable, which reduces the risk of shortages,” Mr. Echelard contends.
He points out that ATryn’s mechanism of action lends itself to a broad range of critical care conditions by regulating the activity of blood clotting proteins to inhibit thrombin, reducing blood pressure by stimulating prostacyclin secretion in blood vessels and inhibiting inflammatory activity of neutrophils.
Mr. Echelard suggests that antithrombin treatment has the potential to mitigate progression of preeclampsia through anticoagulant and anti-inflammatory properties.
Risk factors for preeclampsia include hypertension, diabetes, obesity and age of the mother. Early in pregnancy, new blood vessels develop and evolve to send blood to the placenta. In women with preeclampsia, inadequate placental development leads to abnormally small spiral arteries, which limits the amount of blood that can flow through them.
Approximately 5% of all pregnancies in the U.S. result in preeclampsia and the incidence is rising, Mr. Echelard says, noting that up to 1.5% of pregnancies result in severe preeclampsia.
According to the Preeclampsia Foundation, the annual cost of treating the disorder is some $7-billion in the U.S., excluding the cost of treating various chronic conditions associated with premature births caused by preeclampsia.
About 5,000 pregnancies a year result in preeclampsia in weeks 24 to 28, with about 11,000 annual pregnancies in weeks 29 to 33. “These are the two populations we’re focusing on,” Mr. Echelard says.
Standard of care prior to week 34 of pregnancy involves hospitalizing the mother, 24-hour monitoring, and treatments with corticosteroids, anti-hypertensives and magnesium sulfate, among other things.
“Our approach is to treat women with standard of care and ATryn in weeks 24 to 28 in order to safely extend pregnancy as long as possible, which is critically important,” Mr. Echelard says.
He explains that if a baby is delivered at week 24, it has a 50% chance of dying, but at week 28, the mortality rate drops to 5%. Likewise, if a premature baby born at week 24 is discharged from hospital, it has a greater than 90% chance of developing a disability, but at week 28, the chance of disability drops to 40%.
In rEVO’s PRESERVE-1 Phase 3 trial, 120 women with preeclampsia in weeks 24 to 28 are being randomized 1:1 for treatment with ATryn plus standard of care or placebo plus standard of care. Patients will receive continuous dosing until delivery or week 34.
The primary endpoint in the study is prolongation of pregnancy, while secondary endpoints include improvements in adverse neonatal outcomes.
With standard of care, women with preeclampsia can remain pregnant for around seven days, Mr. Echelard says. “With ATryn, our hope is to extend pregnancy for two weeks, which would have a significant effect on baby survival and long-term disabilities.”
If the PRESERVE-1 trial is successful, he says the company plans to begin PRESERVE-2 to enroll women with preeclampsia in weeks 29 to 33, using many of the same three dozen or so hospitals in the U.S. and Canada that will be involved in the current trial.
Assuming PRESERVE-1 data is sufficiently robust in the second quarter of 2016, rEVO plans to file a supplemental biologic license application with the FDA in the third quarter of 2016, which could lead to regulatory approval in 2017.
“We believe the market opportunity of ATryn in preeclampsia can be $500 million to $2-billion,” Mr. Echelard suggests.
He says the company plans to leverage its existing small sales force that promotes its antithrombin products to launch ATryn for preeclampsia, if approved. He figures an addressable field force of 40-to-60 sales reps could cover about 125 hospitals in the U.S., with tertiary neonatal intensive care units, and some 4,000 Ob/Gyns with high-patient volumes.
The FDA previously granted orphan drug designation to ATryn for the HD AT indication and rEVO plans to seek a similar designation for preeclampsia in weeks 24 to 28.
The company has four U.S. patents and two pending covering recombinant antithrombin and methods for its use and production. Patents also are pending for the use of ATryn in preeclampsia that would extend intellectual property protection until 2033.
Referring to its pipeline, Mr. Echelard says the company plans to seek regulatory approval in the U.S. for two products now sold by parent LFB in Europe: Wilfactin for the prophylactic treatment of von Willebrand Disease, a bleeding condition in pregnancy; and Clottafact for fibrinogen deficiency and eventually post-partum hemorrhage. Wilfactin could reach market around the same time as ATryn for preeclampsia, he adds.
rEVO’s preclinical drug candidate is recombinant human alpha-1 antitrypsin. People with alpha-1 antitrypsin deficiency are particularly susceptible to developing emphysema. Mr. Echelard says development of a recombinant pulmonary-delivered recombinant formulation will accelerate after approval for preeclampsia.
In September, due to market conditions, rEVO called off plans for an IPO that would have raised $50-million to $60-million.
“We are still interested in opening the capital markets to rEVO and we are considering our options,” he adds. “But rEVO is fully financed by our parent company, so we don’t have to raise money.”