West Coast Editor

NEW YORK - Monoclonal antibodies, once trumpeted as the wave of the future, then dismissed by some experts (while still touted by the faithful), are coming into their own at last - and it's been a long, strange trip, noted analyst Matthew Geller at the BIO CEO & Investor Conference here.

Geller, managing director of CIBC World Markets in New York, offered a lively overview of the antibody field during his introduction to a panel discussion that packed the meeting room in the Waldorf-Astoria Hotel. He recalled his first talk as a biotech analyst 11 years ago at a BIO meeting in Toronto.

"I got up there and I said about half the products approved in five to 10 years would be antibodies," he said. "One of the other individuals there, who was a thought leader in the field said, You're out of your mind, antibodies are dead, they're a complete failure, this is never going to happen.' We bet a dollar."

Geller won, and the man never paid out, "but his successor at that particular fund felt very guilty about it and I hit him up. He paid me two dollars back - which I could have made very easily by investing in some of the more successful companies that have dealt with antibodies."

Specificity and the lack of longer-term immune response are the keys to that success, Geller said. "Sometimes you can get really lucky and a mouse antibody or a chimeric antibody can work extremely well, like Rituxan," he said. "Sometimes you can even get a fully human antibody that has immunogenicity problems. It's really a matter of engineering and this whole thing has become an art form."

Rituxan (rituximab), from South San Francisco-based Genentech Inc., was approved in 1997 for relapsed or refractory, low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma. Geller also named as a success Remicade (infliximab), from Centocor Inc., of Malvern, Pa., the only biologic to win approval for rheumatoid arthritis and Crohn's disease.

"We've just started to see some of the fully human antibodies enter the market, some really interesting and exciting ones like Amgen's [AMG-162] for osteoporosis," Geller said.

Thousand Oaks, Calif.-based Amgen Inc. reported at the American Society of Bone and Mineral Research in September that twice-yearly injections of AMG 162 significantly increased bone mineral density compared with placebo after 12 months. The product is in Phase III trials. Geller also pointed to Humira (adalibumab), the tumor necrosis factor blocker from Abbott Laboratories, of Abbott Park, Ill., approved in the U.S. and Europe for moderately to severely active rheumatoid arthritis.

The big hit lately, of course, is Tysabri (natalizumab, formerly Antegren), the alpha-4 antagonist from Cambridge, Mass.-based Biogen Idec Inc., which has turned out to be "so amazingly superior" to other antibodies for multiple sclerosis.

"Initially, a lot of the pharma companies shied away from antibodies because they thought you have to have a pill, people are never going to go for an injection, and now we're seeing even infusions like Tysabri are very popular," Geller said. "An infusion may even be more convenient if you only have to go once or twice a month for it, as opposed to popping pills once or several times a day."

Humanization "really was the first technology to create these non-immunogenic antibodies, and Protein Design Labs has about seven or eight licensed products on the market right now," he said.

Conjugates and immunotherapies as "smart bombs" have become the next steps in antibody work, Geller noted. Meanwhile, pharmaceutical companies such as F. Hoffmann-La Roche Inc., of Nutley, N.J. - which "rejected this whole idea because they just wanted pills" - have found themselves in ironic situations.

PDL developed the asthma drug Zenapax (daclizumab), licensed it to Roche, then licensed part of it back. Last fall, about a year after regaining rights in all indications except transplant rejection, PDL signed a potential $205 million co-development and marketing deal with Roche. (See BioWorld Today, Sept. 17, 2004.)

"We've seen a real evolution where major pharma companies like the Roches of the world have realized how valuable these are, how you can get multibillion dollar products out of antibodies, and [they] have come back into the field - unfortunately maybe a little bit late for companies like Merck and Pfizer."

The "inflection point" for antibodies was 2004, when the "whole investment world went crazy about Avastin, probably a little bit too crazy," Geller said. Some estimated the colorectal cancer compound bevacizumab from Genentech Inc., which Geller allowed was "spectacular" in its efficacy, could be a $5 billion to $10 billion drug. Avastin targets vascular endothelial growth factor.

"Things got a little bit out of control," he said. "They forgot the good news is also the bad news, which is that there's also going to be competition. If someone gets a good idea, someone else is going to try to copy it."

The two-day BIO conference ended Thursday.