By Randall Osborne
West Coast Editor
SAN FRANCISCO ¿ On a rainy Monday morning, with just the sort of weather that many say makes their aching joints act up, the 65th annual meeting of the American College of Rheumatology went into full swing here, with Amgen Inc. offering multiple posters updating the progress of its arthritis drug Kineret (anakinra), recommended for approval by an advisory panel in August.
Among the posters is what Rebecca Hamm, the company¿s manager of corporate communications, called the ¿newest of the new¿ ¿ complete data from the largest safety trial ever conducted with a biologic.
¿Preliminary results [from the same trial] were reported at the advisory panel meeting, but this is the first time we¿ve had everything together, ready to go,¿ Hamm told BioWorld Today.
The Phase II results with 1,414 patients (randomized 4:1 for anakinra:placebo) in a double-blind, placebo-controlled study showed that, at the end of six months, the most frequent adverse event was a mild to moderate reaction at the injection site, in 74 percent of patients. Those who didn¿t have the reaction in the first month were unlikely to have it at all, the company found.
For infectious episodes, the incidence was similar in the Kineret group and the placebo group, 41 percent and 44 percent, respectively, although serious infections showed up a bit more often in Kineret patients than in placebo patients ¿ 2 percent and 0.4 percent, respectively.
¿We¿re not seeing any cases of sepsis, or opportunistic infections, tuberculosis, any of those things that have been a concern, frankly, with some of the other agents out there,¿ Hamm said.
When the FDA¿s Arthritis Advisory Committee gave Thousand Oaks, Calif.-based Amgen the blessing for Kineret by a 6-2 vote, the panel did so despite members noting the drug, a recombinant human protein that antagonizes the receptor associated with interleukin-1, showed only modest efficacy.
Bob Baltera, senior director of development for Amgen, oversees the Kineret program, and said efficacy questions will be further addressed Thursday at the ACR meeting, when a poster session will offer complete data from the efficacy trial cited at the August meeting.
¿You¿re not going to see anything different from the scene that was presented at the advisory panel,¿ Baltera told BioWorld Today. ¿Nothing¿s changed, and there¿s no new analysis of the data.¿ But the picture is more complete, he said, and is expected to allow for more discussion than the regulatory environment called for.
Meanwhile, Amgen also offered data from several other Phase II/III studies showing Kineret improved quality of life for patients.
The studies are ¿really focused on how the patient feels,¿ Baltera said. ¿This is more in tune with what rheumatologists see when a patient comes into their offices. [The commonly used ACR-20 responder index] is similar to the Dow Jones Industrial Average. It¿s a basket of items that tells you how the market¿s doing,¿ but doesn¿t tell much specifically, he said.
¿Patients feel very good [on Kineret],¿ Baltera said. ¿Beyond a shadow of a doubt, they do better.¿
The studies measured pain, productivity and physical disability using such gauges as the Health Assessment Questionnaire.
Said Hamm: ¿Kineret is affecting this score very well. We know for sure the disability is getting better from baseline.¿
She added that such tests have ¿never been done in rheumatology,¿ although they are fairly common in evaluating cardiac patients.
One placebo-controlled study, in 473 patients, found that ¿over the course of six months, patients are gaining back 13.7 days¿ ¿ not bad, considering that, ¿on average, an RA patient is losing about six days of work per month,¿ Hamm said.
Another of the studies, a ¿meta-analysis¿ of three clinical trials that added up to 1,003 patients, showed that Kineret with or without methotrexate had a consistently greater impact on patient-reported measures than physician-reported measures.
It makes sense, Hamm noted.
¿Doctors aren¿t as good necessarily at assessing a swollen or tender joint as patients are at assessing how they¿re feeling overall,¿ she said.
Still more posters dealt with other potential products in the Amgen pipeline, including a Phase II double-blind, randomized extension study in 502 patients with PEGylated Soluble Tumor Necrosis Factor Type I in RA.
Patients who completed previous Phase II studies were eligible, and were treated for an average of seven months, mostly continuing with their single or combination background disease-modifying treatments.
Ten percent had mild to moderate reactions at the injection site and 5 percent were determined to be related to treatment, but no patients withdrew because of them. No neutralizing antibodies showed up, nor did treatment-related effects on laboratory variables or vital signs. Twelve serious infectious episodes were recorded, three of them determined to be related to the study treatment.
¿It¿s probably too early to make conclusions about this, but directionally it¿s looking good, and exposure is up to about 300 days,¿ Hamm said.
In another Phase I study, she said, ¿we¿re trying to elucidate the difference between our anti-TNF and, in particular, etanercept. We know the composition of the molecules are different, but what does that actually mean inside the body? This is a pharmacogenomic study we¿ve done in house, looking at the binding affinities between the two molecules.¿
Etanercept is marketed as Enbrel by Immunex Corp., of Seattle.
Hamm called the study ¿more of a novelty, kind of interesting. The take-away is that there appear to be different binding affinities. We don¿t know what that means in the clinic yet, but [our drug] appears to be able to bind better to TNF.¿
Yet another study is with osteoprotegerin, or OPG, which tested its ability to help animals with arthritis keep their bone density, with encouraging results. The drug is the subject of experiments with NASA, which will have mice aboard the space shuttle to be launched next week, Hamm said.
OPG is the recombinant version of a naturally occurring protein that may be a critical regulator of bone mass.
¿We¿re sending up mice that have been treated with OPG and some that have not, to see what happens to their bone mineral density,¿ she said. ¿When you¿re in zero gravity, it¿s like having serious osteoporosis.¿
OPG is ¿a whole class, so we¿re looking at a number of different targets¿ in Phase I studies, she added.
Amgen, Hamm said, has been ¿a company focused on nephrology, or anemia-related diseases, and oncology. This is the first time we¿ve entered an entirely new therapeutic area. Our CEO says it¿s like putting a third leg on the stool, and we have an entire business unit built up to support not just Kineret, but all the products we¿re looking at in inflammation and bone disease.¿
As for the pipeline leader Kineret ¿ which was a prospective sepsis treatment that Amgen acquired when it bought Boulder, Colo.-based Synergen Inc. in late 1994 ¿ its progress with the FDA has been satisfying, Baltera said.
¿We¿re hoping to get a response by the end of this year,¿ he said. ¿There¿s a general buzz going around the meeting, among rheumatologists. Hopefully, very soon there will be another therapy for them to use.¿
Amgen¿s stock (NASDAQ:AMGN) closed Monday at $56.27, down 62 cents. The ACR meeting continues through Thursday.
In other news from the meeting:
¿ Abbott Laboratories Inc., of Abbott Park, Ill., said results from its Phase II trial called Armada, or Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with Rheumatoid Arthritis, suggest that it reduces the signs and symptoms of moderate to severe rheumatoid arthritis. D2E7, a fully human monoclonal antibody, is designed to block the activity of TNF-alpha. The study included 271 patients in a 24-week, double-blind, placebo-controlled study.
¿ Genmab A/B, of Copenhagen, Denmark, said HuMax-CD4 showed a statistically significant dose response in doses up to 160 mg in initial results of a psoriasis Phase II study. In addition, mean Psoriasis Area Severity Index scores were reduced in all treatment groups with a 30 percent difference between the placebo and 160-mg dose groups. HuMax-CD4 also was safe and well tolerated. These initial results are based on data at seven weeks from 79 of 85 patients in the study.
¿ Immunex Corp., of Seattle, presented Phase III results of Enbrel in psoriatic arthritis, a product it co-markets in North America with Wyeth-Ayerst Laboratories, a division of Madison, N.J.-based American Home Products Corp., data already under review by the FDA following an NDA filing in July. The 24-week, multicenter, randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of Enbrel at 25 mg subcutaneously injected twice weekly vs. placebo in 205 patients with psoriatic arthritis. Of those, 59 percent of 101 patients receiving Enbrel achieved an ACR20 response compared to 15 percent of 104 patients receiving placebo after 12 weeks. Among other findings, 72 percent of patients achieved a treatment response receiving Enbrel, compared to 31 percent of patients receiving placebo after 12 weeks of treatment, using the PsARC measurement. (See BioWorld Today, July 18, 2001.)
¿ Pharmacia Corp., of Peapack, N.J., and Celltech Group plc, of Slough, UK, said results of the a Phase II trial of CDP870 ¿ a humanized, pegylated TNF-alpha inhibitor ¿ for rheumatoid arthritis showed higher doses appeared to lead to better results. The double-blind, placebo-controlled, multicenter, dose-ranging, parallel-group study included 203 patients who were intolerant of, or had an inadequate response to, at least one disease-modifying anti-rheumatic drug. The percentage of patients achieving an ACR 20/50/70 response at week 12 was 15/0/0 for placebo and 21/8/5, 20/5/3, 34/17/7 and 60/40/29 for CDP870 in doses of 50, 100, 200 and 400 mg, respectively.