New Hope for Newborns: How a TSRI Scientist Brought a Life-Saving Drug from the Lab to the Clinic

By Madeline McCurry-Schmidt

The call was about a baby—a 1.5-lb. baby who couldn’t breathe. The newborn needed help to prevent his underdeveloped lungs from collapsing.

When Charles G. Cochrane, MD, professor emeritus at The Scripps Research Institute (TSRI), picked up the phone, the infant was en route to San Diego’s Sharp Hospital. Cochrane rushed to the hospital in time to see the premature baby receive a dose of Surfaxin^® (lucinactant), a drug he had spent two decades developing.

“Three hours later, the baby was taken off the ventilator and was breathing perfectly normally,” said Cochrane. “Seeing things like that warms your heart.”

Surfaxin^® was approved in March 2012 to treat Respiratory Distress Syndrome (RDS), a condition that strikes preterm infants whose lungs lack surfactant, a coating of rigid proteins that keeps the spherical air sacks in the lungs from collapsing. The drug has already helped thousands of premature infants.

According to the World Health Organization, RDS is the most common complication and a leading cause of death in preterm infants. A famous case of RDS was the death of Patrick Kennedy, son of President John F. Kennedy and Jacqueline Bouvier Kennedy, who died two days after his birth by emergency C-section, five and a half weeks before his due date. 

A Unique Protein

Surfaxin^®’s journey from laboratory to clinic started in the late 1980s when a doctor named Allen Merritt brought Cochrane a sample of human surfactant isolated from amniotic fluid. Surfactant lowers the surface tension forces in the tiny air sacks—the alveoli—of the developing lung. With a lining of surfactant, the lungs are stable and will not collapse when a baby breathes out. An absence or reduction of surfactant leads to the respiratory distress experienced by premature infants.

Merritt, a neonatologist working at that time in the Department of Pediatrics at the University of California, San Diego, was hoping to identify the proteins in the sample.

Cochrane had done a lot of work isolating proteins, and his curiosity was peaked. He set up a test using a separatory column, which isolates proteins according to their charges and sizes. That’s when things got strange.

Typically, proteins drift down and separate as they interact with the aqueous solution in the column. The proteins in Merritt’s sample, however, stayed at the top of the column, forming an opaque white layer.

“These were the first proteins in all of biology not to be aqueous-soluble,” said Cochrane. “This was something really crazy.”

Though surfactant can consist of several proteins, Cochrane and Merritt believed that Surfactant Protein B (SP-B) could be the key to keeping the lungs open. They tested SP-B in animal models and saw that breathing improved after they administered the protein. 

Merritt, who was new to the research world, remembers being inspired by Cochrane’s commitment to learn more. “It was Charley’s genius, really. He said, ‘Let’s take this protein apart and find out the peptides in it,’ ” said Merritt.

Discovering the Peptide Pattern 

Cochrane’s research into surfactant started as a search for knowledge, but as he learned more about the structure of SP-B, he believed he could create a synthesized version of the protein for use as a drug.

To picture the structure of SP-B, imagine a backyard fence. Long phospholipids line up in a row, like vertical boards on the fence. But the vertical boards tend to tilt forward and backward. The SP-B, or the synthetic peptides that mimic SP-B, are positioned like horizontal crossbeams to interact with the phospholipids and produce lateral stability. 

When Cochrane looked at this structure of SP-B, he spotted a crucial pattern: Though most amino acid residues in the sequence were hydrophobic (repelling water), about every fifth amino acid residue was hydrophilic (attracting water). This combination kept the surfactant in a horizontal pattern and the surfactant dispersed, coating the surface of the alveoli.

Cochrane realized that it was the pattern of hydrophobic and hydrophilic amino acid residues that was important, rather than the sequence of the amino acids themselves. “Again, that is unique in biology,” he said.

By focusing on the pattern and not the specific amino acid residues, Cochrane was able to create a simpler version of the protein in his lab. Cochrane chose leucine, a hydrophobic amino acid, to stand in for all the hydrophobic amino acid residues in the natural version of SP-B. For the hydrophilic amino acids, Cochrane used arginines or lysines, which had the right charge to bond with the hydrophilic polar head groups at the base of the phospholipid rows. 

Cochrane, Merritt and University of California, San Diego Professor of Pediatrics Greg Heldt tested the synthesized SP-B and several peptide surfactants in animal models, and their success led to approval for a large-scale clinical trial in human infants. They needed to prove to the Food and Drug Administration (FDA) that it was safe and effective—after all, a synthesized protein would represent an entirely new class of drugs.

A Safer Drug

At the same time, several animal-derived surfactants came on the market. These versions had been approved more quickly by the FDA, which was more familiar with the process of creating animal-derived drugs. The animal-derived surfactants mostly came from swine and cattle, and though they were effective, they came with some risks. 

When surfactant is extracted from animals, partially broken-down phospholipids are also extracted. These phospholipids can cause inflammation and lead to a chronic lung disease called broncopulmonary dysplasia. Infants who develop broncopulmonary dysplasia tend to spend more time on a ventilator, which can further damage the lungs.

Also, because animal-derived surfactants are foreign to the human body, a baby’s immune system will build antibodies against the proteins in the surfactant. If that baby receives another dose of the surfactant later in life, the body can produce an inflammatory reaction.

But Cochrane’s synthetic version of surfactant, called Surfaxin®, contained no broken-down phospholipids, and multiple studies showed that it prompted no immune response. In a clinical trial of 1,294 infants, published in the journal Pediatrics in 2005, Surfaxin® showed a significant improvement over a bovine-derived surfactant. The data showed improvements in RDS at 24 hours after birth and lower RDS-related mortality in the two weeks after birth. A second trial showed Surfaxin® to be better than the porcine surfactant. 

“It worked beautifully,” said Cochrane. The Phase 3 clinical trials, run by Discovery Laboratories, which was formed in 1996, yielded positive results and the drug was approved.

Cochrane said animal-derived surfactants are being phased out as hospitals see the advantages of Surfaxin®. Because infants on Surfaxin® have lower mortality and spend less time on a ventilator, hospitals that use Surfaxin® can also reduce the cost of patient care. 

“It was Charley’s open-mindedness, his curiosity and his willingness to analyze the problem that is the reason Surfaxin® exists,” said Merritt. “It’s something that clearly saves lives,”

Plans for the Future

Cochrane and Merritt see many additional possibilities for Surfaxin®. For example, it may reduce inflammation in the bronchial tubes for patients with asthma or chronic obstructive pulmonary disease (COPD). Surfaxin® also has antimicrobial properties and promotes activity in the cilia, the tiny protuberances that push dirt and mucus out of the lungs. Because of these properties, Cochrane believes Surfaxin® could help people with cystic fibrosis get rid of dangerous plaques that build up in the lungs and benefit the millions of people with chronic rhinosinusitis.

“It’s one agent for many diseases,” said Cochrane. 

Cochrane and Merritt, with Discovery Labs, are currently focused on bringing an aerosol version of Surfaxin^®, called Aerosurf^®, to market. They believe Aerosurf^® could solve a second major issue in treating RDS: the need for a ventilator.

Though Cochrane’s synthetic version of surfactant keeps the lungs open, it does require that an infant be placed on a ventilator for a short period of time to help the lungs deal with the introduction of the liquid drug. But with the aerosol version, a baby could breathe without struggling against any liquid in the lungs. Bypassing the ventilator would also help babies in areas of the world where ventilators are scarce or nonexistent.

New Hope for Patients and Parents

Aerosurf^® is being tested in a clinical trial in the San Diego area, which means Cochrane has had a chance to see it in action. He recently got a call about another baby in distress. Doctors were getting ready to administer Aerosurf^®—would Cochrane like to be there?

He arrived to watch the doctors begin administration of the aerosol drug. The staff of the Intensive Care Unit gathered around and watched as the tiny baby held her father’s finger. The baby labored to breathe, her chest heaving up and down. 

Then, just minutes after starting to breathe the drug, the baby began respiring easily and did not have to go onto a ventilator. 

“Seeing that little baby breathe smoothly—I was about in tears the whole time,” Cochrane said.

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