Washington Editor

Although top-line results of a Phase III efficacy trial showed that Altus Pharmaceuticals Inc.'s cystic fibrosis drug Trizytek (ALTU-135) hit its primary endpoint of improvement in fat absorption, the benefit was smaller than expected and results differed across various geographies.

As a result, said analyst Eric Schmidt, of Cowen & Co., "there is a lack of visibility on whether Trizytek will be able to garner FDA approval without additional data."

Investors reacted by pushing the Cambridge, Mass.-based firm's shares (NASDAQ:ALTU) down 49.4 percent Tuesday. The stock closed at $2.50, a drop of $2.44.

CEO Georges Gemayel said Altus will be completing a full dataset analysis over the next several weeks of the 163-patient, double-blind, placebo-controlled Phase III efficacy trial of Trizytek, a porcine-free enzyme replacement therapy designed to improve fat, protein and carbohydrate absorption in patients with exocrine pancreatic insufficiency.

The details of that analysis will be presented in Orlando in October at the North American Cystic Fibrosis Conference, Gemayel told BioWorld Today.

Cystic fibrosis is a life-threatening genetic disease that causes serious lung infections and digestive complications, including poor absorption and digestion of food.

Most patients with the condition, which affects about 30,000 children and adults in the U.S., experience exocrine pancreatic insufficiency, a deficiency of pancreatic enzymes that causes poor absorption of essential nutrients, which often leads to malnutrition, impaired growth and reduced survival.

Trizytek, an oral one-capsule-per-meal dosing regimen, is intended to replace the missing digestive enzymes.

The Phase III efficacy study results showed that patients treated with Trizytek had a statistically significant improvement in coefficient of fat absorption (CFA) compared with placebo, Burkhard Blank, Altus' chief medical officer, explained during a conference call to investors and analysts. Trizytek improved CFA levels by 15.1 points vs. placebo in the severely affected patient population and by 10.6 points compared with placebo in the overall population, he said.

However, the firm's statistical plan called for a 30-point improvement in CFA.

Gemayel said the results were affected by a "marked difference" between patients at study sites in and outside of the U.S.

Patients at three of the six non-U.S. study sites showed no real difference between Trizytek and placebo, he said.

Gemayel said his company is investigating possible factors that may have affected the results outside the U.S.

"Understanding these differences is very important," he said.

Analyst Eun Yang, of Jefferies & Co. Inc., noted that the geographic discrepancy may be blamed partly on a lack of protocol adherence.

But Gemayel called that hypothesis "speculation" and noted that results of the study at three of the non-U.S. sites mirrored those at centers in the U.S.

"No one knows," he said, noting that his firm had just days earlier received the data.

"At this stage, we have not been able to do a thorough investigation to understand what happened," Gemayel said, adding that he did "not believe that it will be discovered that it is a violation of the study protocol."

He contended that there could be several factors that played a role in the reason why the results varied widely at three of the non-U.S. sites, including the possibility that the drug was not stored correctly and lost its potency or there could be a yet-to-be discovered error in the data.

"There are a lot of things which we really need to look at. It is a complicated protocol," Gemayel said. He declined to identify the foreign countries where Trizytek was studied.

Blank noted that patients treated with Trizytek also had a statistically significant improvement in coefficient of nitrogen absorption, a measure of protein absorption, compared with placebo - a secondary endpoint.

However, there was not a statistically significant improvement in carbohydrate absorption compared with placebo on the starch challenge test, Blank said.

The results also showed there was a significant decrease in stool weight in Trizytek-treated patients compared with placebo, he said, calling those results important.

Jefferies' Yang called the decreased stool weight associated with Trizytek treatment "quite encouraging" and a "clear sign of improved absorption."

Yang noted that the FDA considers an average 10 percent increase in fat absorption, or 10 g extra fat, as clinically meaningful, equating to a weight gain of about 8-9 lbs. a year.

"If one-year long-term safety data show a weight gain or maintenance in this patient population, we believe that would be very clinically meaningful," Yang said in a research note.

Blank also noted that Trizytek was well tolerated and had a favorable safety profile in the trial, with no serious adverse events attributed to the drug.

Altus has requested a meeting with the FDA to discuss the study's results and obtain feedback from the agency, Gemayel said.

"We expect the meeting to happen in November," he said, adding that the firm expects to file a new drug application in the second half of 2009.

A favorable meeting with regulators, Cowen's Schmidt said, could support that time frame for the NDA filing.

Factors favoring FDA consideration include an orphan population, Trizytek's clean safety profile, the drug's superior characterization and consistency relative to porcine-derived products and its larger clinical database, Schmidt surmised.

But on the other hand, he said, the FDA appears inclined to view Trizytek as a new product and would therefore "hold it to a higher standard."

Enzyme replacement products currently in use for pancreatic insufficiency are all derived from swine, Gemayel noted.

"Due to the uncertainties with therapeutics that contain animal-derived ingredients, we believe there is a need for new products that are derived from recombinant technology," he argued.

Most of the pancreatic enzyme replacement products sold in the U.S. - an $850 million market - are considered unapproved drugs by the FDA. The agency has given manufacturers of those products until April 2010 to come into compliance.

Trizytek, a drug manufactured using Altus' recombinant technology by blending lipase, protease and amylase enzymes, has the potential to be the first porcine-free enzyme replacement therapy for patients with pancreatic insufficiency, Gemayel said.

While Wall Street may have viewed the yet-to-be answered questions about the Phase III top-line results of Trizytek as a potential threat to Altus' future financing strategies, the cystic fibrosis community recognized the strength of the data, he said.

Trizytek's one capsule per-meal dosing, said Robert Beall, CEO of the Cystic Fibrosis Foundation, will help drive better compliance and enhance long-term patient health outcomes. "Currently, the dosing regimens for enzymes can be a challenge for patients," he said in a statement. "We are very encouraged by the Trizytek efficacy data because this treatment will offer important new benefits to CF patients who need enzyme replacement therapy."