Faustman D, Davis M.
Nat Rev Drug Discov. 2010 Jun;9(6):482-93. doi: 10.1038/nrd3030. Epub 2010 May 21. Review.
- PMID:
- 20489699
- [PubMed - indexed for MEDLINE]
4.
Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL.
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13644-9. doi: 10.1073/pnas.0803429105. Epub 2008 Aug 28.
- PMID:
- 18755894
- [PubMed - indexed for MEDLINE]
sadly Obama is only interested in the science of the measles and little else.
Result Filters
Cell Mol Life Sci. 2005 Aug;62(16):1850-62.
The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis.
Abstract
Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha
antagonists have provided clinical benefit to many patients, but their
use also is accompanied by new or aggravated forms of autoimmunity. Here
we propose a mechanistically based hypothesis for the adverse events
observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha
activity as a treatment for some forms of autoimmunity. Activation
defects in the transcription factor nuclear factor kappaB leave
autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha,
by destroying autoreactive T cells, appears to be a highly targeted
strategy to interrupt the pathogenesis of type 1 diabetes, lupus and
certain forms of autoimmunity.
Result Filters
PLoS One. 2012;7(8):e41756. doi: 10.1371/journal.pone.0041756. Epub 2012 Aug 8.
Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes.
Faustman DL1, Wang L, Okubo Y, Burger D, Ban L, Man G, Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan DM.
Abstract
BACKGROUND:
No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.METHODOLOGY/PRINCIPAL FINDINGS:
Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs.1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95(th) percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.CONCLUSIONS/SIGNIFICANCE:
We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.TRIAL REGISTRATION:
ClinicalTrials.gov NCT00607230.Comment in
- Targeting innate immunity to treat long-term type 1 diabetes. [Regen Med. 2012]
The Wall Street Journal
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Earnings
Merck Sales Fall on Stronger Dollar, Patent Expirations
New Concerns Over Prospects for Experimental Hepatitis C Treatment Weigh on Shares
Merck’s fourth-quarter sales declined, weighed down by a stronger U.S. dollar and patent expirations. The Merck logo is seen on a stained glass panel at a Merck company building last year in Kenilworth, N.J. ENLARGE
Merck’s fourth-quarter sales declined, weighed down by a stronger U.S. dollar and patent expirations. The Merck logo is seen on a stained glass panel at a Merck company building last year in Kenilworth, N.J. Photo: Associated Press
By
Peter Loftus
Updated Feb. 4, 2015 2:21 p.m. ET
0 COMMENTS
Merck and Co.’s fourth-quarter sales declined on a stronger U.S. dollar and patent expirations for top drugs, while a weaker-than-expected 2015 outlook and new concerns over prospects for an experimental hepatitis C treatment weighed on Merck shares.
The Kenilworth, N.J., company has accelerated its development of a two-drug combination that it hopes will tap into a multibillion-dollar market for treatments of the liver disease hepatitis C. But two new developments raised questions about how successful Merck’s product can be, and when it might reach the market.
Gilead Sciences Inc. said Tuesday it expects to give deeper discounts on its market-leading hepatitis C drugs Sovaldi and Harvoni this year, as Gilead competes with discounts that rival AbbVie Inc. is offering for its new treatment, Viekira Pak. The deep discounts from rivals could pressure Merck’s ability to command a high price for its own regimen, a combination of the drugs grazoprevir and elbasvir, if regulators clear the treatment for sale.
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Adam Schechter, head of Merck’s drug-and-vaccine-marketing division, said in an interview that the discounts for hepatitis C drugs had reached a magnitude “faster than that which you would typically see in other markets.” But he said Merck is still bullish about its hepatitis C market opportunity. The companies are giving discounts off high list prices for the drugs, which cost $83,300 to $94,500 per patient for 12 weeks of treatment. Public health officials, insurers and members of Congress have criticized the high prices.
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Merck also said Wednesday that the Food and Drug Administration plans to rescind the “breakthrough therapy” designation it granted Merck’s hepatitis C regimen in 2013, citing the recent introduction of other treatments for hepatitis C. The FDA designates certain experimental medicines as breakthroughs if early tests indicate they would be a substantial improvement over existing options for serious diseases. The FDA tries to speed the development and review of breakthrough drugs by working closely with the manufacturer and has approved several ahead of schedule.
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An FDA withdrawal of breakthrough status for Merck’s hepatitis C regimen could extend the agency’s review period of Merck’s application by about four months, said Leerink Partners. The FDA allows companies an opportunity to justify its product’s continued designation as a breakthrough, and Merck officials said they would meet with the FDA to discuss the matter. Merck said it still plans to file for regulatory approval by midyear.
“We believe that it does have breakthrough attributes,” Roger Perlmutter, chief of Merck’s research-and-development unit, said in an interview.
An FDA spokeswoman declined to comment.
Shares of Merck tumbled 3.5% to $58.88 in recent trading Wednesday. The losses were greater for Gilead and AbbVie, down 7.4% and 7% respectively.
For the fourth quarter, Merck reported earnings of $7.32 billion, or $2.54 a share, up from $781 million, or 26 cents a share, a year earlier. The results included a gain of $11.2 billion related to the company’s sale of its over-the-counter unit last year to Bayer AG.
Excluding the gain and other items, per-share earnings fell to 87 cents from 88 cents but topped Wall Street expectations.
Sales in the quarter fell 7.4% to $10.48 billion from the year-earlier quarter, short of analysts’ estimates, with foreign-exchange accounting for three percentage points of the drop. Sales of the anti-inflammatory drug Remicade, which Merck markets in certain countries outside the U.S., declined 10% due to competition from copycat versions in Europe. Sales of Merck’s new cancer immunotherapy Keytruda were $50 million.
Merck said it expected to post $3.32 to $3.47 a share in earnings this year, with $38.3 billion to $39.8 billion in sales, weighed down by currency trends. Analysts polled by Thomson Reuters had recently projected $3.49 a share in profit and $40.5 billion in revenue.
— Michael Calia contributed to this article.
Write to Peter Loftus at peter.loftus@wsj.com
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