MEDMONITOR - Pearls from Recent Medical Journals and Conferences
JOURNAL OF RHEUMATOLOGY, November 2001; 28:2409-2415: Investigators led by
Dr. Terence Gibson from Guy's Hospital, London found that rheumatoid arthritis (RA) patients receiving treatment with disease-modifying
anti-rheumatic drugs (DMARDs) have a higher mortality rate than the general
population as well as deteriorating function despite continuous treatment
with DMARDs. This 10-year prospective study highlights the need for better
therapies than existing DMARDs, which include Immunex's (NASDAQ: IMNX, being
acquired by Amgen) methotrexate, generic methotrexate (from Baxter [NYSE:
BAX], Mylan [NYSE: MYL], Roxane, and Lederle), sulfasalazine (from Pharmacia
[NYSE: PFA] and Watson [NYSE: WPI]) and azathioprine (from Geneva and Mylan
as well as Prometheus's Imuran). The investigators studied 289 RA patients
continually using DMARDs. Of the 289, 71 patients died, yielding a standardized mortality rate of 1.302 (1.0 would be a mortality rate equal to
that of the general population). 92 patients were alive but not available
for follow-up. The remaining study subjects were studied at baseline, 5, and
10 years for the RA parameters: median joint tenderness, morning stiffness,
grip strength, hemoglobin, and erythrocyte sedimentation rate. DMARDs were
not able to achieve a statistically significant impact on any of these objective parameters. Moreover, Health Assessment Questionnaire scores and
radiographic scores significantly decreased, indicating that the agents had
a sub-optimal impact on subjective features of the disease and quality of
life. By the study's end, 19% of the study subjects had undergone joint surgery.
The authors cited that, as early as 1988, investigators had suggested that
short-term RA studies would often give rise to false expectations. These
researchers believed that radiologic and laboratory values (used as endpoints in phase II and III clinical trials) are over-emphasized at the
expense of long-term outcomes of functional status and death. This study
strengthens these hypotheses, and also highlights the importance of non-efficacy based issues of clinical effectiveness in determining the
limitations of marketed drugs.
Methotrexate, sulfasalazine, and azathioprine are no longer the drugs of
choice for most RA sufferers. Novel agents such as Pharmacia (NYSE: PFA) and
Pfizer's (NYSE: PFE) Celebrex, Merck's (NYSE: MRK) Vioxx, Immunex's
Enbrel, and Centocor's (a division of Johnson & Johnson, NYSE: JNJ) Remicade are now
preferred. Although widely used to treat RA, long term data similar to those
described for the DMARDs is scarce and of low statistical power. These agents remain clinically indistinct with sub-optimal usage patterns. New
agents for RA include Merck's Arcoxia (NDA submitted), Amgen's (NASDQ:
AMGN) Kineret (awaiting launch, especially promising in combination with
Enbrel), and Cambridge Antibody Technologies' (NASDAQ: CATG) D2E7 (phase III). The
DMARD study demonstrates that long-term trials looking at mortality and quality of life issues are needed for these agents.
--
NATURE MEDICINE, January 2002; 8:14-16,27-34: Studies using mutant mouse
models suggest that the integrins alphaVbeta3 and alphaVbeta5 are not involved in angiogenesis (growth of new blood vessels). Previous work had
suggested that alphaVbeta3 and alphaVbeta5 integrins are essential for tumor
angiogenesis. But mice that do not produce these integrins actually had enhanced tumor growth compared to normal mice. Both mice and people have
several integrin family members in addition to alphaVbeta3 and alphaVbeta5.
The new work demonstrates the complexity of molecular interactions between
integrins.
The mutant mice data call into question the value of therapeutics that target alphaVbeta3 and alphaVbeta5 integrins, such as MedImmune (NASDAQ:
MEDI) and Applied Molecular Evolution's (NASDAQ: AMEV) alphaVbeta3 antagonist,
Vitaxin. However, results using a mouse model where certain integrins are missing completely can only suggest, not predict, the
responses from inhibition of the analogous human proteins using a drug. Vitaxin is a humanized monoclonal antibody in phase I clinical trials in
cancer-related indications and rheumatoid arthritis with developmental plans
in place for restenosis.
--
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, December 18, 2001;
98:15113-15118: Researchers, led by Dr. Antonio Bedalov, at the Fred Hutchinson Cancer Research Center in Seattle identified a small molecule,
"splitomicin," that targets a protein responsible for inactivating
transcription, the silent information regulator (SIR) 2p protein. Investigators screened 6,000 compounds from the National Cancer Institute
repository in order to identify those compounds that disrupted transcription
inactivation ("silencing" of genes) in regions near the ends of chromosomes
(telomeres) in brewer's yeast (Saccharomyces cerevisiae). Cells grown in the
presence of splitomicin displayed disrupted silencing in not only telomeric
regions, but also other disease-associated loci. The investigation went on
to also demonstrate that SIR2p is required for maintaining a silent state,
even in non-dividing cells.
The work shows that:
1. "Silent" DNA is not static; genes in the silenced region can become active.
2. "Silent" DNA is in a dynamic equilibrium with SIR2p and other silencing
factors
3. SIR2p is an attractive drug target because it modulates p53 tumor suppressor activity, and may therefore decrease cancer risk.
4. Splitomicin may aid in assessing SIR2p and related proteins as drug targets for treatment of cancer, cataracts, sickle cell anemia, and other
diseases.
--
OBSTETRICS AND GYNECOLOGY, December 2001; 98:989-995: Both low molecular
weight heparin and external pneumatic compression are effective for the prophylaxis of venous thromboembolism (VTE) for women undergoing surgery for
gynecologic malignancy. Researchers led by Dr. Daniel L. Clarke-Pearson assessed 211 women over 40 years of age undergoing major surgery for
gynecologic malignancy. The study subjects were randomized to receive either
low molecular weight heparin or external pneumatic compression. Two low molecular weight heparin recipients and one external pneumatic compression
recipient developed venous thrombosis. The bleeding complication profile for
each was reassuring, and the number of perioperative transfusions and estimated intraoperative blood loss was similar in both groups. The authors
concluded that both modalities "are acceptable methods of thromboembolism
prophylaxis in patients undergoing major abdominal surgery for gynecologic
malignancy," and that "unlike unfractionated heparin, an increased frequency
of bleeding complications is not associated with.low molecular weight heparin."
This modestly powered investigation adds to the literature supporting the
continued use of low molecular weight heparin in the prevention of deep vein
thrombosis (DVT) that may lead to pulmonary embolism (PE) in patients undergoing abdominal and pelvic surgery. Its use is favored over pneumatic
compression in the majority of cases. As novel prophylactic agents enter the
clinic, such as the recently FDA-approved Arixtra from Sanofi-Synthélabo
(Paris: SASY) and Organon (a division of Akzo Nobel, NASDAQ: AKZOY) and the
late-stage developmental compound Exanta from Astra Zeneca (NYSE: AZN), low
molecular weight heparins must continue to demonstrate both experimental
efficacy and real world effectiveness. Marketed low molecular weight heparins are Aventis's (NYSE: AVE) Lovenox (a.k.a. Klexane and
Claxane), Pharmacia's (NYSE: PHA) Fragmin, and Bristol-Myers Squibb's (NYSE:
BMY) Innohep. A review of the competitive landscape of the anticoagulation
marketplace is available in Btech Investor Reports: Out of the ASHes - The
Resurrection of Anticoagulant Therapy (December 18, 2001).
BTECH NEWS
by Leon Henderson, M.D.
Bennett Weintraub, Ph.D.
Christopher Martin
www.btechnews.com
December 31, 2001
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