By Randall Osborne
Rheumatism. Just to define the word - "the study of arthritis and other diseases of the joints, muscles and bones" - can make a spry investor ache and feel old.
Part of the tired feeling comes from the rainy-day, can't-move-from-the-chair sound of the words, of course, but just as much may derive from the weakening effect of increasingly complicated investor choices in the field of rheumatology.
Immunex Corp.'s Enbrel (etanercept), first approved two years ago, remains a clear leader in the rheumatoid arthritis (RA) market. Centocor Inc.'s Remicade (infliximab), approved almost exactly one year after Enbrel's first FDA go-ahead, is also strong. Both are antitumor necrosis factor (TNF) drugs.
Enbrel took a giant leap forward in June, tripling its potential market size for Immunex and partner Wyeth-Ayerst Laboratories, when the FDA allowed the drug for delaying structural damage in patients with moderate to severe RA, to reduce signs and symptoms. It had been approved first to treat moderately to severely active RA in patients who have an inadequate response to one or more disease-modifying anti-rheumatic drugs.
Most recently, Immunex showed results from a long-term, open-label study indicating Enbrel kept working to reduce joint pain and swelling in moderate to severe RA patients - some for as long as four years.
Remicade, the Centocor drug, first was approved for use with methotrexate to treat RA in patients who do not respond to methotrexate alone. In July, an advisory panel recommended an expanded indication: reducing structural damage, as caused by RA and measured by radiograph. But the board refused to go along with Remicade's preventing such damage, and said the label ought to say only that the drug slows it down.
The broader label is important for Centocor, given Enbrel's added indication, which also has been won by Aventis Pharmaceuticals Inc.'s Arava, also a TNF inhibitor, approved in 1998.
Like no other field in biotech, rheumatology, because of its multiple levels, and especially because of the degrees of rheumatoid arthritis, offers varied opportunities for investors, said Franklin Berger, analyst with J.P. Morgan Securities in New York.
The more, the merrier.
"The size of the markets are so large and so different, there's ample opportunity," Berger said. "The lesson is that having two to five competitors tends to increase the size of the market. It tends to increase the awareness that treatment is possible and efficacious. The disease doesn't get better and it doesn't kill you, either. So, the concept that more competition is bad is counter-intuitively wrong."
In a decade, the discipline has matured, Berger said.
"Over the last 10 or 12 years, rheumatology's gone from being made up of science nerds and practicing rheumatologists - who were the sweetest guys in town, because they had no drugs to use; it was tea and sympathy - to the best science around," he told BioWorld Financial Watch.
Is the whole story Enbrel vs. Remicade? Maybe now, but the picture won't be as simple for long. At the annual meeting of the American College of Rheumatology, which concluded in Philadelphia last week, a roster of contenders lined up for evaluation.
There was the usual raft of longer-term supporting data, such as the four-year statistics on Enbrel, and Aventis' extension of successful 12-month trials into three two-year studies demonstrating relief for patients and improvements of physical function. Remicade, in two-year data from a Phase III pivotal study with methotrexate for structural damage, sustained benefit beyond one year.
"[Remicade] is still sub-blockbuster, but coming along well," Berger said. "It's perceived as being slightly more potent, but somewhat more troublesome."
But there was more.
Maybe most notable: Biotech heavyweight Amgen Inc. weighed in with studies on anakinra, its interleukin-1 receptor antagonist (IL-1RA), demonstrating the drug may slow joint destruction and boost quality of life for RA patients. Based on data from its Phase II study program, Amgen has filed for regulatory approval of anakinra in the U. S., Canada, Europe and Australia.
"Anti-TNF changed the industry," Berger said, and the research came about when scientists "had run out of row, so to speak," against RA.
"[The agents] seem to give you benefits in about 70 percent of the patients," Berger said. "The issue is, what can you do with the other 30 percent? That's the way Amgen's going to have to go."
Other firms had earlier-stage developments at the meeting, and had later-stage developments in other indications.
Genelabs Technologies Inc. provided favorable data from three Phase III studies with GL701 for lupus. The company submitted a marketing application to the FDA in September. GL701 is also called Aslera, or prasterone, which is the generic designation for dehydroepiandrosterone, a naturally adrenal hormone lacking in lupus patients.
"It was a very gutsy trial," Berger said.
Protein Design Labs Inc. presented Phase I clinical results on its investigational drug, Smart Anti-Gamma Interferon Antibody, showing the drug is safe. PDL said it plans to initiate a Phase I/II clinical trial of the antibody in Crohn's disease by year's end.
"That's a key initiator," Berger said of the antibody. "It's at one of the tops of the [immune system] cascade, so a lot of things come off it."
Targeted Genetics Corp. offered data from ongoing studies of delivery of the gene that encodes soluble tumor necrosis factor receptor-immunoglobulin Fc fusion protein in a rat model of experimental arthritis. Cloned by Targeted Genetics in 1998, the gene was delivered using the company's adeno-associated virus vectors to suppress joint inflammation, pannus formation and cartilage and bone destruction in the ankle as well as the contralateral joint.
Scios Inc.'s preclinical data on SCIO-469 showed it inhibits p38, a modulator of pro-inflammatory factors including TNF-alpha, IL-1 and cyclooxygenase-2, known to contribute to symptoms and the advance of the disease. The company said it expects to have data from a Phase I study during the first quarter of next year.
Berger also found promise in Alexion Pharmaceuticals Inc.'s work with complement inhibitors against RA.
Alexion has two C5 complement inhibitors, 5G1.1-SC and 5G1.1, in eight clinical development programs. Both products are aimed at interrupting the complement cascade at the C5 spot, so that the normal upstream disease-preventing functions of complement remain intact, while production of the abnormal downstream disease-causing actions of complement are blocked.
5G1.1-SC is in bypass efficacy and myocardial infarction trials. The second product, 5G1.1, is in a Phase II efficacy trial for the treatment of chronic rheumatoid arthritis, among others.
"That's a smoking gun," Berger said. "They're in Phase II now."
For investors looking to stay ahead of the curve, the Amgen news may hold possibilities. The picture hasn't changed greatly from one year ago at the same scientific meeting - but, in biotech, the lack of change is noteworthy. In the case of Amgen's drug, which has made considerable progress since last year, the steadiness may foretell an edge against Remicade and Enbrel, especially in early RA patients.
The Amgen product apparently is more effective than TNF inhibitors in reducing bone erosion and cartilage destruction, and thus might find a role in early RA patients with erosive disease, Berger wrote in a research note. Or it might find a place in very advanced RA cases, where the TNF inhibitors no longer work.
What's more, a poster by the FDA at the meeting pointed out that blocking TNF, like Remicade and Enbrel, can raise the risk of infections. The numbers turned out to be tiny: only three of 820,000 Enbrel patients and 17 of 150,000 using Remicade. For them, however, the news was bad. They got tuberculosis. And the FDA said the reportage of treatment-associated infection may be low.
Also, two patients in the Remicade group and 82 in the Enbrel group got herpes zoster. Separately, the FDA said nine of 77,152 Enbrel patients had a demyelination event, serious enough in some cases to require treatment for multiple sclerosis.
Because Amgen's product boasts a strong safety profile, even with its more modest efficacy, the drug seems likely to corner at least a niche. The studies detailed in the meeting were a part of the biologics license application filed last December, and Amgen has said two more studies on safety and efficacy will be added as a supplementary filing early next year, which has delayed the approval schedule for the drug - now expected to launch late, rather than early, next year, Berger said.
"Amgen has its place, but it's not going to supplant Enbrel and [Remicade]," he said. "Amgen's working on its own anti-TNF agent, but the amount of drug you need every year is copious, almost a gram a week," he added.
Rheumatology requires more of investors, in terms of study and care, but the rewards are more abundant, too, Berger said - thanks to a wiser industry.
"One never likes to gamble, and there are multiple approaches," he said. "The pathways are finally elucidated, and there's clearly success in the clinic. We're on the right path."