SILVER SPRING, Md. -- An FDA advisory committee has voted against approval of liprotamase (Sollpura), a pancreatic enzyme product for cystic fibrosis and other diseases that cause pancreatic insufficiency, saying there is not enough evidence that the drug works better than agents already on the market.
The FDA's Gastrointestinal Drugs Advisory Committee voted 7-4, with one panelist abstaining, that liprotamase should not be approved for use in patients with cystic fibrosis, chronic pancreatitis, and pancreatic cancer -- diseases which compromise pancreatic function, resulting in severely impaired secretion of the digestive enzymes. Patients with exocrine pancreatic insufficiency cannot properly absorb lipids, resulting in weight loss and severe malnutrition.
Liprotamase, which is made by Cambridge, Mass.-based Alnara Pharmaceuticals, works by combining three enzymes that aid in helping the body digest proteins, complex carbohydrates, and triglycerides.
Most panelists agreed that the drug has exciting potential, but would like to see larger, longer-term studies comparing the drug with other pancreatic enzyme products (PEPs).
Liprotamase is a new type of PEP that, unlike other products on the market, is not made from pig pancreas, which its supporters see as a big draw, in case the nation's swine population was tainted in some way.
However, in Alnara's clinical trial, liprotamase was less effective than currently available products (Creon, Zenpep, and Pancreaze) although there are no head-to-head trials comparing liprotamase with porcine-derived PEPs.
The company's multicenter, double-blind trial randomized 138 patients with cystic fibrosis and exocrine pancreatic insufficiency to receive either liprotamase or placebo. The primary efficacy endpoint was the change in coefficient of fat absorption (CFA), which measures the percentage of fat absorption relative to dietary fat intake.
Patients on liprotamase experienced an average 11% improvement in CFA (P0.001). However, in earlier trials that supported approval for pancreatic enzyme products, that percent change was much larger, ranging from 25% to 40%.
"I just don't see substantial evidence of efficacy here," said panelist Weichung Shih, PhD a biostatistician at the University of Medicine and Dentistry of New Jersey.
Each of the PEPs contains enzymes in two major classes, the lipase class and protease class. Writing in briefing documents released in advance of Wednesday's hearing, FDA reviewers said the lower efficacy may have to do with the fact that porcine-derived PEPs have multiple enzymes in each major class, but the synthetic liprotamase has just one enzyme in each class.
"As such, multiple enzymes in each major class (i.e., phospholipases for the lipase class and chymotrypsin, trypsin, and carboxypeptidases for the protease class) function in digesting the components present in food," FDA reviewers wrote. "Therefore, it is biologically plausible that porcine-derived PEPs might allow for a more efficient digestion of food in the intestine."
Wednesday's panel was also not convinced that CFA is an accurate measure of whether PEPs work. A more accurate marker would be increases in patients' weight, height (for pediatric patients), and body mass index.
Early in the day, the panelists heard testimony from several cystic fibrosis patients and parents of kids with cystic fibrosis who urged the panel and the FDA to approve liprotamase, which requires patients to take drastically fewer pills than with porcine-derived PEPs.
People with cystic fibrosis must take handfuls of PEPs with every snack and meal to help them absorb fat and nutrients from the food they eat. However, liprotamase requires just a single pill each time the person eats.
The father of a little girl with cystic fibrosis told the panel that if his daughter took liprotamase instead of a porcine-derived PEP, she would cut her monthly pill intake by 335 each month.
A mother said her two teenagers with cystic fibrosis take upwards of 1,000 enzyme pills between them each month.
"It would make a huge difference in their [lives] to have another product," said Francine Healy.
Healy also said she wasn't aware until recently that the enzyme pills her children take are derived from pigs.
"I just learned in the past few weeks that it's made of ground-up pig pancreas and covered in plastic," she said. "If I think about the amount of pig products and plastic I've shoveled into my kids, I could weep. We need another option."
The panelists were split on whether the efficacy data to support the approval of liprotamase, and voted 5-5, with two members abstaining, that there are safety concerns with the drug, including distal intestinal obstruction syndrome (blockage of the intestines by thickened stool) and the rare chance of fibrosing colonopathy.
The FDA is not required to follow the advice of its advisory panels, although it often does.