Q&A: Advancing bronchopulmonary dysplasia prevention with vitamin A

Key takeaways:

• Although bronchopulmonary dysplasia is a rare disease, the rate of cases is going up.
• Researchers are developing a prevention therapy that utilizes aerosolized vitamin A with support from the NIH.

Despite the growing prevalence of bronchopulmonary dysplasia in preterm infants, there are no approved prevention drugs to reduce the risk for this condition.

However, with recent support from the NIH through a $3 million Small Business Innovation Research Phase IIB grant, the research and development of one prevention therapy is underway by Advent Therapeutics and Virender K. Rehan, MD, principal investigator at The Lundquist Institute, professor of pediatrics at the David Geffen School of Medicine at UCLA, chief of the division of neonatology and director of the Neonatal Care Unit, Harbor-UCLA Medical Center.

Rehan and Advent Therapeutics are working on an aerosolized vitamin A therapy, which recently received rare pediatric disease designation from the FDA. They hope to send vitamin A directly to an infant’s lungs to help prevent bronchopulmonary dysplasia (BPD) using a noninvasive delivery mode.

Healio spoke with Rehan to learn more about BPD, vitamin A and the impact this therapy would have on patient care if approved.

Healio: How prevalent is BPD in preterm infants and how does it affect their long-term prognosis?

Rehan: BPD is the most frequent serious complication of prematurity. Often chronic, it is extremely costly and tremendously challenging to these most-fragile premature babies and their families. Even with great advances in neonatal medicine, there are no approved therapies — BPD rates remain high and are increasing, and the rate of preterm births in the U.S. has just hit a 15-year high as reported by the March of Dimes.

BPD has a large at-risk patient population with more than 100,000 preterm infants born each year at risk in both the U.S. and E.U., and many more worldwide. There are approximately 15,000 new cases of BPD each year in the U.S. alone. BPD is expensive — with annual first year hospitalization costs in the U.S. averaging $442,000 with hospital stays averaging 103 days. Total annual U.S. health care costs of BPD approach $2.5 billion, and BPD often leads to lifelong disorders such as COPD, asthma, pulmonary hypertension, neurocognitive delays, growth failure and repeated hospitalizations.

Healio: What are current treatment options for bronchopulmonary dysplasia? Are they effective?

Rehan: Currently there are no approved therapies for prevention (and treatment) of BPD.

Intramuscular vitamin A has established its effectiveness in preventing BPD in at-risk preterm infants as shown in a large, seminal NIH/National Institute of Child Health and Human Development-supported clinical trial that was published in The New England Journal of Medicine, a comprehensive Cochrane Review that details 11 neonatal trials where vitamin A was used to prevent BPD. More recently, a Journal of Perinatology article supporting use of injectable vitamin A provides compelling health care economics for its use in hospital NICUs. Moreover, the NHLBI has stated in its guidelines that “vitamin A has been shown to convincingly and safely prevent BPD.”

Caffeine (citrate) given via IV is the only alternative drug therapy currently being used for “preventing” BPD and, despite years of use, BPD rates remain unacceptably high and thus it has not become a gold standard solution for BPD. Caffeine is often used to treat apnea of prematurity and decrease frequency and duration of this other common complication of preterm infants who have reduced respiratory drive. Other therapies such as steroids, including delivered via inhalation, and extended use of exogenous surfactant replacement therapies have also not proven to be effective.

Healio: You are developing an aerosolized vitamin A therapy to counteract this condition from occurring in preterm infants. Why does vitamin A have the possibility to prevent this condition? What was the reason behind the aerosolized delivery method of this therapy?

Rehan: Aerosolized therapy represents a gamechanger because it changes the neonatal treatment paradigm with noninvasive delivery directly to the targeted organ of interest — the lung — potentially allowing all BPD at-risk preterm infants to be treated, as well as the promise of serving more broadly as a universal supplementation.

Vitamin A is a potent morphogen with a multimodal mechanism of action that not only addresses vitamin A deficiency, but also importantly plays a key role in supporting normal lung development. In delivering the drug to the lung we have shown in a well-established preclinical model of BPD, as expected, a much more robust response than even intramuscular dosing. In this preclinical BPD model, we have shown that our optimized vitamin A (retinol palmitate) formulation when delivered noninvasively via inhalation results in development of normal, well-defined lung architecture as well as restoration of normal lung function including normal oxygen and CO₂ exchange.

I am fortunate to provide my neonatal and lung developmental research expertise to bridge the excellent scientific resources at The Lundquist Institute with Advent Therapeutics, which is a late-stage biotech built around a team of seasoned industry leaders. We are reinventing vitamin A for neonatal and pediatric unmet medical needs, and we are targeting neonatal orphan drug commercial opportunities. Our lead injectable product should be approvable within 16 to 18 months. Advent has plans to self-commercialize and medically support its vitamin A products in the U.S.

Healio: If approved, how will this therapy impact patient care? Would all preterm infants be candidates, or would they have to meet certain criteria?

Rehan: Because most preterm infants are vitamin A deficient, and oral bioavailability of vitamin A is significantly reduced in the first few weeks of life, both optimized intramuscular and aerosol formulations have a place not only in addressing vitamin A deficiency and associated complications that go beyond BPD such as retinopathy of prematurity (ROP), increased risk for neonatal sepsis, etc, but also other critical organ development.

Advent Therapeutics’ proprietary and specifically designed preparation is highly pure, water-miscible and is optimally tailored for administration to fragile preterm neonates. The drug does not contain chlorobutanol nor other preservatives that may be of concern with respect to sensitivity and/or potential toxicity. We have also removed citrate from our formulation, as injection-site pain is attributed to presence of citrate. For example, a citrate-free Humira (adalimumab) formulation was introduced in 2016 by AbbVie specifically to address this issue. So, a citrate-free vitamin A formulation should alleviate some of the tolerability concerns of the intramuscular injectable form and increase uptake by the NICU staff who have had concerns from the existing and only vitamin A product that is available and only for intramuscular injection.

But the real breakthrough is with our optimized aerosol vitamin A formulation which could be delivered to all preterm infants noninvasively via inhalation route for target lung delivery to address those at risk for BPD but also for ensuring adequate vitamin A supplementation. The lungs can serve as an excellent route for systemic drug-delivery given their large surface area for absorption of water miscible products. Indeed, our preclinical data show that we can achieve adequate systemic blood levels of vitamin A with the inhalation route, which are equivalent to those achieved via intramuscular delivery in newborn preclinical models.

Healio: What are the next steps in development/approval now that you have received the SBIR phase 2B grant?

Rehan: We have a full research and development, regulatory and product roadmap outlined with important regulatory and pre-commercialization/commercialization milestones defined. This includes leveraging our U.S. FDA (and E.U.) orphan drug designations, FDA rare disease drug designation and other regulatory pathways such as FDA fast track approval path to support addressing a clear unmet medical need. We expect our injectable vitamin A preparation to be approved next year, and our breakthrough aerosolized formulation to be approvable within 3 years.

References:

• Couroucli XI, et al. J of Perinatol. 2016;doi:10.1038/jp.2016.76.
• Darlow BA, et al. Cochrane Database Syst Rev. 2016;doi:10.1002/14651858.CD000501.pub4.
• Lundquist Institute investigator Dr. Virender Rehan and Advent Therapeutics awarded $3 Million NIH small business innovation research grant for life-saving premature infant research. https://lundquist.org/news/lundquist-institute-investigator-dr-virender-rehan-and-advent-therapeutics-awarded-3-million. Published July 25, 2023. Accessed July 25, 2023.
• Tyson JE, et al. N Engl J Med. 1999;doi:10.1056/NEJM199906243402505.