By Karen Pihl-Carey

In a pivotal Phase III study, Schering-Plough Corp. and Enzon Inc. demonstrated that PEG-Intron is twice as active as Intron-A in achieving sustained loss of detectable hepatitis C virus (HCV) in adult patients.

The results, reported for the first time at the 35th Annual Meeting of the European Association for the Study of the Liver in Rotterdam, the Netherlands, are the basis for a biologics license application (BLA) submitted to the FDA in December.

"We're just extremely excited that PEG was able to double the efficacy of Intron-A, Schering's second-largest selling product," said Kenneth Zuerblis, vice president of finance and chief financial officer at Piscataway, N.J.-based Enzon.

The trial showed that a once-weekly dose of PEG-Intron (peginterferon alfa-2b) injection was twice as active as Intron-A (interferon alfa-2b, recombinant) injection given three times weekly.

Analysts have said PEG-Intron likely will cannibalize Intron-A. They also have said PEG-Intron has a sales potential of more than $500 million. Enzon will receive between 7 percent and 7.5 percent in royalties on all worldwide sales.

"Our expectations," Zuerblis told BioWorld Today, "are based on the fact that this is a once-a-week product, as opposed to three times a week, with double the efficacy and similar side effects."

PEG-Intron combines Enzon's polyethylene glycol (PEG) technologies and Schering-Plough's Intron-A. PEG is used to improve the delivery, safety and efficacy of proteins and small molecules with known therapeutic efficacy. Schering-Plough holds an exclusive worldwide license to PEG-Intron.

In the Phase III trial, PEG-Intron showed higher rates than Intron-A of sustained response and was just as well tolerated at all three doses studied - 0.5, 1 and 1.5 mcg/kg. A total of 1,219 patients who were positive for serum HCV-RNA and who had elevated liver enzymes were treated with one of the three doses once weekly or with Intron-A administered three times weekly for 48 weeks. The primary endpoint was sustained loss of detectable HCV-RNA at 24 weeks from the end of the 48 weeks of treatment.

The rates of sustained virologic response were influenced by genotype, ranging from 11 percent for patients with genotype 1, the predominant genotype worldwide and the most difficult to treat, to 49 percent for patients with genotype 2 or 3. This compared to response rates ranging from 6 percent to 28 percent for patients treated with Intron-A.

Adverse events for all doses of PEG-Intron were similar to those for Intron-A, with most being mild to moderate, as well as manageable with a dose adjustment. The most common side effects with PEG-Intron were flu-like symptoms, such as headache, fatigue, myalgia and fever, which appeared to decrease in severity as the treatment continued.

Schering-Plough and Enzon also reported results from a Phase II dose-ranging study of PEG-Intron in combination with Rebetol (ribavirin, USP) capsules. The results indicate that Rebetol enhances the antiviral activity of PEG-Intron and that sustained virologic response with the combination therapy is dose-dependent. A total of 72 patients with chronic HCV and compensated liver disease were part of the Phase II, open-label, randomized, controlled study.

"While it's a very small trial, we were able to show 60 percent of viral load reduction," Zuerblis said.

The combination therapy now is in Phase III trials. PEG-Intron also is being tested in Phase III trials for malignant melanoma and chronic myelogenous leukemia, and is in early-stage trials for other solid tumors and forms of leukemia.

Schering-Plough submitted a BLA for PEG-Intron to treat chronic hepatitis C in December, and the companies expect a decision sometime this year. (See BioWorld Today, Jan. 6, 2000, p. 1.)

In February, the Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products recommended approval of PEG-Intron as a treatment for hepatitis C.

"Once you get CPMP approval, it takes about three months to get the final approval," Zuerblis said.

Enzon's stock (NASDAQ:ENZN) closed Monday at $39.25, up $2.