Sigma Tau Aims For First FDA Approval Of Live Biotherapeutic

Subsidiary of Italian specialty firm is seeking to develop a biologic containing live microorganisms to prevent necrotizing enterocolitis, the most common GI complication in very low birth weight premature infants. Sigma-Tau had to write an IND without any existing FDA guidance and faces numerous complications both due to the pioneering nature of its work and the high-risk status of its trial subjects.

Sigma-Tau Pharmaceuticals Inc. has initiated a Phase I/II trial of STP206, a probiotic in development to prevent necrotizing enterocolitis in very-low birth weight premature infants, and if successful could obtain the first FDA approval of a prescription live biotherapeutic. But without any precedents, the clinical, regulatory and manufacturing risks run high.

Based in Gaithersburg, MD, Sigma-Tau, a U.S. affiliate of Italy’s Sigma-Tau Finanziaria SPA, faced the challenge of developing an IND protocol for FDA oversight of a brand new type of prescription drug, in this case a biological that contains live microorganisms such as bacteria or yeast intended to colonize the patient’s gastrointestinal tract and potentially provide a therapeutic benefit.

The risks are somewhat offset by the fact that there is no prophylactic or therapeutic treatment available for the disease Sigma-Tau is targeting. Necrotizing enterocolitis (NEC) has a high fatality rate and usually is addressed with surgery to partially remove the patient’s bowel, which can lead to other health issues, including short bowel syndrome, need for prolonged intravenous feeding and greater predisposition for serious infections.

The company, which conducted a Phase I study in adult volunteers in 2010, is now undertaking a 96-patient, placebo-controlled trial to investigate whether STP206 can prevent NEC in premature birth infants weighing 1.5 kg (about 3 pounds) or less.

In an interview, Sigma-Tau CEO Dave Lemus said the trial, which will include eight cohorts of 12 patients and dosed its first patient in February, might yield Phase Ib dose-escalation data around mid-2016 and final safety data from a Phase IIa portion in mid to late 2017.

Lemus said Sigma-Tau currently is the only company undertaking a clinical trial of a live biotherapeutic for any indication, as far as he is aware.

GianFranco Fornasini, Sigma Tau’s senior VP of scientific affairs, noted that FDA had not yet issued guidance on development of live biotherapeutics at the time the company filed the IND. The agency approved the IND but with a mandate to move very slowly in such a high-risk population.

“A couple of years ago, FDA issued guidance regarding the clinical development of live biotherapeutics,” Fornasini said, which seems informed by the agency’s experience with Sigma-Tau. “Probably some parts of the guidance related to the [chemistry, manufacturing and controls] of live biotherapeutics were created using a portion of the discussions we had with FDA to obtain the green light for our IND. I cannot say for certain that FDA used 100% of our expertise, but surely the submission of our IND and the subsequent discussions that we had with the agency were very important to preparing the guidance.”

Choosing The Right Bacteria

But while the company has improved its odds by going for a significant unmet medical need, the nature of the patient population presents its own set of risks for drug development even before Sigma-Tau addresses the challenges of pioneering a new type of therapeutic. Premature babies do not yet have fully developed immune systems, Fornasini said, and the company must choose live strains of bacteria to use while omitting any that might be pathogenic.

“The investigational drug, constituted by specific live bacteria, is [administered] via an inter-gastric tube,” he explained. “Safety is a major concern when these live bacteria are administered to premature babies. Great efforts were made to assure that the investigational drug is manufactured under good manufacturing practices (GMP), while maintaining the viability of the good bacteria and avoiding contamination with any potential pathogens.”

Other challenges incumbent in running a trial with such high-risk patients include that no more than 1 mL of experimental product can be administered in a dosing period and it is difficult to run clinical assays, drawing blood and other fluids, because the patients are small and fragile, the two executives noted.

The primary endpoints for the trial will be safety and tolerability, with a secondary endpoint of measuring ability to prevent NEC, Fornasini said. The trial is being conducted at various sites around the U.S. with the input of key opinion leaders.

“This is not a treatment trial; the drug product will be used for the prevention of NEC,” Fornasini said. “When NEC occurs, [doctors] have 72 hours to intervene and, in most cases, the babies have to undergo to surgery. The mortality rate, especially in very-low birth weight babies, is very high. The only way to change this prognosis and its mortality is to prevent its occurrence. That’s why we are targeting the most fragile population where the rate of NEC is very high, premature babies [weighing] 1.5 kg or below.”

NEC is the most common gastrointestinal disease in very-low birth weight infants, Lemus noted, and has a fatality rate of between 20% and 30%. Estimates are that 4,500 cases of NEC present each year in Europe, with about 1,000 deaths resulting, he added. In the U.S., there are roughly 60,000 very-low birth weight infants born each year.

Should Sigma-Tau advance to and through Phase III with ‘206 and the filing of a BLA, Lemus said that based on discussions with KOLs, the company will advocate that the drug be introduced at neonatal intensive care units nationwide and be given as a preventive agent to all very-low birth weight babies.

A pair of academic research papers published in the past decade seem to offer backing for that viewpoint. In 2008, scientists from the Cochrane Collaboration issued a review of data on using probiotics to prevent NEC in preterm infants. “Our review of studies found that the use of probiotics reduces the occurrence of NEC and death in premature infants born less than 1,500 grams,” the paper states, adding there are insufficient data to evaluate the potential benefits and risks of such a therapeutic approach in infants weighing less than 1,000 grams at birth.

In addition, four researchers writing in the April 19, 2010, edition of the journal Pediatrics stated that “we believe that probiotics should now be offered as a routine therapy for preterm neonates and that additional placebo-controlled trials are not warranted; however, selection of a safe and suitable product with documented probiotic properties and close monitoring of the target population is a must before offering this therapy as a routine in this high-risk but most deserving population.”

Parent company Sigma-Tau SPA, headquartered in Rome, expanded its portfolio in 2009 with the $300 million purchase of Enzon Pharmaceuticals Inc.’s specialty pharma business [See Deal]. The deal brought over an Indianapolis manufacturing site to be run by the U.S. affiliate, as well as leukemia drug Oncaspar (pegaspargase), enzyme replacement therapy Adagen (pegademase), lymphomatous meningitis drug DepoCyt (cytabarine) and anti-fungal Abelcet (amphotericin B), all of which are marketed in the U.S. by Sigma-Tau Pharmaceuticals.