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NIH doctors slam Lilly's marketing tactics
Three doctors affiliated with the National Institutes of Health have taken a public stand against tactics employed by pharmaco Eli Lilly to market its anti-sepsis drug Xigris. The doctors say Lilly has engaged in a no-holds-barred battle to win market share for Xigris, which with revenues of $200 million a year has fallen far short of sales projections. In an article for the New England Journal of Medicine, the physicians say that Lilly inappropriately used PR tactics to spread rumors that the drug, monumentally expensive at $8,000 for a four-day course of treatment, was in short supply due to rationing. It appears that they were hoping doctors would pressure health plans, who were doubtless also in Lilly's sights. The article's authors also criticize the drug company's decision to fund the "Surviving Sepsis" campaign, led by physicians with financial ties to Lilly.
While the campaign developed treatment guidelines which--surprise, surprise!--encouraged the use of Xigris, the journal article's authors say that older, dramatically cheaper antibiotics work equally well. In fact, they suggest that it may be unethical not to use antibiotics, given that they are known to be effective while Xigris is still comparatively untested. The NIH doctors authoring the journal article are not the first to criticize Xigris, which has been on the market since 2001. An advisory panel reviewing the drug prior to approval by the FDA had significant doubts as to its efficacy, The New York Times reports.
To get more background on the Xigris furor:
- read this article in The New York Times
- read this NPR piece
the password for the webinar is either dor or dorb
Jelly
You are getting to excited over the dndn business.
I was more agitated about geoff Alan's self imposed injunction, and I didn't even own Insmed at the time. I just felt bad for the kids and the people with MMD
Alan is a POS in capital letters.
Have you ever looked at dorb Dor Biopharma. Go to dor board I would like your input
way o/t: Could MCU have saved him? I couldn't resist
You probably know mcu isn't in trials for heart failure, just reduction of MI or death after cabg surgery, for now
feuerstein
Last word: Many of you know that I worked on Wall Street for two years. It was a great experience.
It wasn't that good an experience or he wouldn't have gone back to writing
dor webcast
If you liked the broadcast you played here is a webinar which is more scientifically focused
http://www.videonewswire.com/event.asp?id=37602
medicure
that came from montgomery
Merck is conducting a 3 thousand patient study in Europe to show that aggrastat is as good or better than Integrelin and
reopro
* Yesterday Medicure Inc. reported 3Q07 EPS of ($0.08) and
indicated
that its pivotal Phase III for MC-1 is on track to complete
enrollment in November. We expect Phase III results from MC-1 in
1Q08. Medicure reported 3Q07 Aggrastat revenues of $2.52M. We
find
it encouraging that Aggrastat sales are up nicely
quarter-over-quarter. Our long-term estimates, primarily driven
by
MC-1, remain unchanged. We have made minor changes to our
near-term estimates based on a better understanding of near-term
cost drivers.
* Approximately 90% of Medicure's R&D expenses are attributable to
MC1. There were significant up-front costs in starting the MC-1
trial, which resulted in higher than normal R&D in Q3. R&D is
likely to be high over the next few quarters as Medicure
continues
to enroll patients, after which we believe it is likely to
decline
from current levels.
* Due to its poor brand image in the US, we give very little credit
to Aggrastat. However, we believe its brand image could be
improved with additional data from head-to-head studies against
competitors such as ReoPro and Integrillin. We were pleasantly
surprised to hear on the conference call that Merck is running
several large trials to prove equivalence of Aggrastat. Positive
results from these trials could lower the risk for Medicure in
running similar trials in the US, which could eventually lead to
substantial sales growth for Aggrastat, in our view. We believe
that results from these trials could become available as soon as
at ACC next year. We are not altering our current Aggrastat
forecast of no change in sales from 2007 to 2012.
* Management clarified that the p-value needed for success in the
Phase III trial was close to 0.05 but lower than that, and at the
same time much higher than 0.01. We believe this is a good
revelation because there have been rumors that the statistical
barrier for the Phase III trial is very high owing to the
substantially low p-value that is required to be met.
http://www.monty.com/please-see/disclaimer3.htm
* Yesterday Medicure Inc. reported 3Q07 EPS of ($0.08) and
indicated
that its pivotal Phase III for MC-1 is on track to complete
enrollment in November. We expect Phase III results from MC-1 in
1Q08. Medicure reported 3Q07 Aggrastat revenues of $2.52M. We
find
it encouraging that Aggrastat sales are up nicely
quarter-over-quarter. Our long-term estimates, primarily driven
by
MC-1, remain unchanged. We have made minor changes to our
near-term estimates based on a better understanding of near-term
cost drivers.
* Approximately 90% of Medicure's R&D expenses are attributable to
MC1. There were significant up-front costs in starting the MC-1
trial, which resulted in higher than normal R&D in Q3. R&D is
likely to be high over the next few quarters as Medicure
continues
to enroll patients, after which we believe it is likely to
decline
from current levels.
* Due to its poor brand image in the US, we give very little credit
to Aggrastat. However, we believe its brand image could be
improved with additional data from head-to-head studies against
competitors such as ReoPro and Integrillin. We were pleasantly
surprised to hear on the conference call that Merck is running
several large trials to prove equivalence of Aggrastat. Positive
results from these trials could lower the risk for Medicure in
running similar trials in the US, which could eventually lead to
substantial sales growth for Aggrastat, in our view. We believe
that results from these trials could become available as soon as
at ACC next year. We are not altering our current Aggrastat
forecast of no change in sales from 2007 to 2012.
* Management clarified that the p-value needed for success in the
Phase III trial was close to 0.05 but lower than that, and at the
same time much higher than 0.01. We believe this is a good
revelation because there have been rumors that the statistical
barrier for the Phase III trial is very high owing to the
substantially low p-value that is required to be met.
http://www.monty.com/please-see/disclaimer3.htm
dorb makes forbes and street.com
DOR Rejects Cell Therapeutics Offer
Associated Press 04.12.07, 11:17 AM ET
http://www.forbes.com/feeds/ap/2007/04/12/ap3606119.html
Biopharmaceutical company DOR BioPharma Inc. said Thursday it rejected an unsolicited, nonbinding offer by cancer drug developer Cell Therapeutics to buy the company.
The disclosure, in a filing with the Securities and Exchange Commission, did not include details of Cell Therapeutics' offer, but DOR BioPharma said its board concluded the offer was "inadequate."
Seattle-based Cell Therapeutics focuses on cancer treatments. Officials weren't immediately available to comment on the rejected offer Thursday morning.
Shares of Cell Therapeutics fell 22 cents, or 12 percent, to $1.61 on the Nasdaq Stock Market (nasdaq: NDAQ - news - people ) in morning trading. The stock has traded between $1.12 and $2.53 over the last 52 weeks. DOR shares were unchanged at 62 cents on the over-the-counter Bulletin Board.
Thursday's Health Winners & Losers
By Robert Holmes
TheStreet.com Staff Reporter
4/12/2007 5:57 PM EDT
Click here for more stories by Robert Holmes
http://www.thestreet.com/_yahoo/newsanalysis/winnershealth/10349929.html?cm_ven=YAHOO&cm_cat...
Health care and biotech stocks followed the broader market's upward trend Thursday, thanks to merger and acquisition talk coming out of MedImmune (MEDI - Cramer's Take - Stockpickr - Rating).
Shares of the company jumped 15.3% after it indicated the possibility of a sale of the company. MedImmune's board has already authorized management to field potential offers. The stock added $5.79 to $43.63.
The Amex Biotechnology Index, of which MedImmune is a component, climbed 2.5%. Fellow components Imclone Systems (IMCL - Cramer's Take - Stockpickr - Rating) and Gilead Sciences (GILD - Cramer's Take - Stockpickr - Rating) rose 2.9% and 3%, respectively.
Elsewhere, the Amex Pharmaceutical Index was 1.1% higher, thanks to gains of 1.6% in Pfizer (PFE - Cramer's Take - Stockpickr - Rating), 2.3% in Amgen (AMGN - Cramer's Take - Stockpickr - Rating) and 0.9% in Schering-Plough (SGP - Cramer's Take - Stockpickr - Rating).
On the losing side, Genentech (DNA - Cramer's Take - Stockpickr - Rating) fell 1.3%, even after the company reported a 43% rise in first-quarter results compared to the year-ago period. Adjusted earnings of 74 cents a share topped the Thomson First Call consensus. Still, shares were off $1.06 at $81.63.
Cell Therapeutics (CTIC - Cramer's Take - Stockpickr - Rating), which jumped 13% Wednesday after its Xyotax drugs received "fast track" designation from the Food and Drug Administration, completely erased the previous session's gain.
DOR BioPharma (DORB - Cramer's Take - Stockpickr - Rating) rejected a bid from Cell Therapeutics, claiming that the price offered in January was inadequate. Cell Therapeutics shares lost 35 cents, or 19.1%, to $1.48.
Among other decliners, MedcoHealth (MHS - Cramer's Take - Stockpickr - Rating) slid 39 cents to $71.32. Adolor (ADLR - Cramer's Take - Stockpickr - Rating) was off 5 cents, or 1.4%, at $3.64.
dorb
I had actually wanted that buyout to remain as a support for the stock. I think it is a very good sign that the stock actually went up when Dor told ctic to buzz off
Critical Therapeutics (CRTX) Outperform (1)
CRTX Shares May Move Ahead Of Zileuton CR Review Deadline
Conclusion: Critical Therapeutics' recent co-promotion agreement with Dey Labs improves visibility on the Zileuton CR sales ramp, given the established presence of Dey's 200-rep respiratory specialist sales force. The FDA's 10-month review deadline for Zileuton CR is May 31st: we project an approvable letter followed by final approval and launch later this year. We project Zileuton franchise sales of $125MM in 2011, based on 2-3% share of the U.S. moderate/severe asthma market. Critical Therapeutics also gains co-promotion rights to a Dey COPD product which is currently pending approval. And we believe the HMGB1 antibody program (with MedImmune) has intriguing potential as a broad inflammatory mediator. With approximately $1.20 in net cash per share, we believe CRTX shares are attractively valued.
Zileuton CR Could Hit The Market In H2. Zileuton CR is a twice-daily tablet formulation of zileuton (Zyflo is 4 times daily), and could resolve a key compliance issue with Zyflo. We project an approvable on May 31st, but may have a better idea of the issues following a labeling meeting on May 3rd. There is risk to the approval timing: the single-dose trial did not meet bioequivalence specs, although the mutiple-dose trial is more important.
Dey Co-Promotion Agreement Adds Marketing Muscle. The co-promotion deal signed with Dey Labs on March 14th adds 200 respiratory specialty reps to promote zileuton CR, $12MM of milestone payments in 2007 (assuming zileuton CR approval and launch this year), and a second product to the CRTX reps' bag. We have raised our out-year zileuton franchise sales estimates following the deal. And CRTX retains 65-70% of the zileuton CR sales dollars.
CRTX Shares Still Look Undervalued. Based on our sum-of-the-parts valuation analysis we still view CRTX shares as undervalued. Approval of zileuton CR is the key near-term catalyst.
Ian Sanderson
(617) 946-3922
ian.sanderson@cowen.com
Ken Cacciatore
(646) 562-1305
ken.cacciatore@cowen.com
I and most other people that look at the orbec data see that it the result of the trial makes it more than a marginal drug.
I think that the odac committee will see it too. We will see, there is no reason to have patients die to prove a point.
Prosecutors send messages - and admit they are doing so. Government customers do so with their defense contractors - and admit doing so. Contractors do with their subcontractors - and admit doing so. I myself have done so - and acknowledged it
Why would people at the FDA be different? They are less versed in how to manage an unruly set of potential applicants?
Prosecutors send messages to make things harder on people who break the law.
That is a lot different than making cancer patients pay with their lives because a company got a positive opinion from a panel.
If they want to stop a rush of NDA's that shouldn't be submitted because of the leniant panel they don't have to accept the NDA for filing. Game over
correction to orbec data
On intention-to-treat analysis, oral BDP was associated with 37% and 45% reductions in the risk of GVHD-treatment failure at study day 50 and at 30 days follow-up, respectively. The corresponding risk reductions among patients eligible for the prednisone taper at day 10 were 61% and 62%.
By day 200 after transplantation, 5 BDP-treated patients had died compared with 16 control patients, a risk reduction of 67% (p = 0.03). The reduction in mortality risk with BDP was even more pronounced among subjects who had received unrelated and HLA-mismatched stem cells -- 91% (p = 0.02). The survival benefit was still apparent 1 year after randomization.
The P value at 200 day survival is .013, not .03
As I said the data is not supericially similar, Provenge data doesn't come close
From David Miller's article
On May 9 and 10, ODAC meets in DC. On May 9, a superficially similar NDA for a drug from pink sheet company DOR BioPharma (DORB) called orBec will be in front of the committee. Despite potentially compelling efficacy data, I believe Dr. Pazdur will take out his “Provenge frustration” on orBec.
David used certain terms to make Dorb chances worse than they are and denegrate the company.
a pink sheet company is even lower than the bulletin board but that is how he termed it
Using the term superficially similar also denegrates orbec data. there is nothing similar about the data. Orbec's data is much stronger. It isn't even close
data comparison
The patients on provenge lived for a bit over 24 months and the patients on placebo lived for a bit over 20. The best thing you can say about Provenge is that it is safe and doesn't cause side effects. You could say the same about water as long at you don't drown yourself in it.
On intention-to-treat analysis, oral BDP was associated with 37% and 45% reductions in the risk of GVHD-treatment failure at study day 50 and at 30 days follow-up, respectively. The corresponding risk reductions among patients eligible for the prednisone taper at day 10 were 61% and 62%.
By day 200 after transplantation, 5 BDP-treated patients had died compared with 16 control patients, a risk reduction of 67% (p = 0.03). The reduction in mortality risk with BDP was even more pronounced among subjects who had received unrelated and HLA-mismatched stem cells -- 91% (p = 0.02). The survival benefit was still apparent 1 year after randomization.
Another important factor is the numbers above are very much the same as the results observed in Orbec's phase 2 trial. This means it would be hard to prove that the great data seen in the orbec trial was a statistical anomaly. Dendreon's Provenge has no such data. they have changed their endpoints around so much it can make you dizzy.
So as far as I see, to say the data is superficially similar shows that he is not giving orbec the credit it is due and the fact that he was right about the panel meeting is more a fact that he was lucky to have people on the panel that were looking more at the the risk than the benefit part of the risk benefit profile
Another thing is not only does orbec have great efficacy but it actually reduces side effects. As you know prednisone is very toxic, so removing it from the regiman improves quality of life
to be very honest I am very upset that he mentions Dor in the way he did.
One more thing is many oncologists are trying to make a slurry of Orbec themselves and giving it to their patients because they know the benefit. the problem is this gives the immediate release part of the treatment but not the extended release part. These doctors will probably testify at the meeting. The fda usually likes to control that sort of thing.
Beclomethasone is an already approved drug and new formulations of already approved drugs have a higher success rate on approvals than new molecular entities
David, stick it
But the timing of Gold's sale sends a bad signal to investors. It doesn't fill me with warm, fuzzy -- or confident -- feelings. If I were in Gold's shoes (and I'm most decidedly not), I would have waited for the FDA decision before selling shares.
That's just me -- I'm not here to tell Gold that he screwed up or that he did the right thing. I still like Dendreon. I still like Provenge, and I think it gets approved on May 15.
I don't have a position in Dendreon but Fuerstein sounds very amateurish when he says the above. If Gold was selling before the meeting that would have sent a bad signal. He is selling after the meeting when the data is out in the open. Everyone is on an even playing field and Gold is taking profits. The sale should not effect his analysis of that data he sees and the sale shouldn't make him more nervous.
And unless he is in the position of selling 2 million dollars worth of stock in one day he shouldn't say that he would have held the stock, because he really doesn't know that. As a professional he should know that trading opportunities sometimes have you do things that you didn't intend to do.
Does anyone follow MCU - Medicure? Your opinion please?
Based on my last meeting with Burt Friesen I do not believe that a partnership will be signed in the immediate future. Many investors want to see a partner to validate the technology. That way they can trade out of the stock on the news. The fact that I don’t think there will be a partner removes one of the catalysts that I was looking for. It appears that I will have to be content with what I believe will be growing sales of the already approved product, Aggrastat, and the completion of the trial of MC-1 in CABG surgery. In the phase 2 trial of MC-1 the drug had a reduction of myocardial infarction, stroke and death of 37 percent with a p-value of .028. That is very statistically and clinically significant. If you remove stroke, endpoint results improve dramatically. Non-fatal myocardial infarctions and death were reduced by 43 percent with a p-value of .009. The FDA has agreed to remove stroke, as an endpoint. Stroke will only be followed as an adverse event where it belongs. The company included stroke as one of the endpoints in the phase 2 trial because the mechanism of action of the drug should actually reduce the severity of a stroke. The drug would not prevent stroke, so they miscalculated by including it in the endpoint. That is what phase 2 trials are for. The amazing thing in the case of Medicure is that most phase 2’s are used to determine what you need to do to get a positive phase 3 result. In Medicure’s case, the FDA has accepted the phase 2 trial as a pivotal study. Medicure only needs to complete one phase 3-trial. This is very unusual indeed.
Of course there are others on the board that think the drug doesn't work. I have been doing this long enough. I make my own decisions
No, because if it is approved the "example" will be narrow. If you fail a primary surrogate and hit a survival endpoint in an ITT population where every valid imbalance test you throw at it allows the data to retain the clinically-relevant survival benefit, you should be approved and DNDN would be a fine example of that.
Those who suggest it is a bad precedent typically still can't get their heads around the fact this was NOT a crappy BLA. They still tend to think the difference can be explained by imbalances. They still tend to think the differences can be explained by chemo. None of that is true, regardless of what they believe. Even the FDA agrees.
The only problem with the Provenge BLA was biostatistical (what does it really mean in terms of patients when you choose one endpoint instead of another to be the "primary") and the issue of whether 9902a was "supportive." Since CBER has a tradition of being more flexible in approving single-study BLAs, approval of the Provenge BLA is not that far afield.
In any case, the FDA will allow Pazdur to backstop them at the May 9/10 meeting. He's expert at "sending messages" to the detriment of patients.
this is what everyone tells you about dor biopharma and you pooh pooh it
ChemGenex Announces Initiation of Second Phase 2/3 Clinical Trial for Ceflatonin(R) in CML
Tuesday April 3, 2:02 pm ET
MELBOURNE, Australia & MENLO PARK, Calif.--(BUSINESS WIRE)--ChemGenex Pharmaceuticals (ASX: CXS, NASDAQ: CXSP) announced today that it has treated the first patient in a new phase 2/3 clinical study (CML-203) designed to evaluate the efficacy of Ceflatonin® (homoharringtonine or HHT) in patients with chronic myeloid leukemia (CML) who have failed or were intolerant to treatment with two or more prior tyrosine kinase inhibitors (TKIs). The new study is designed to complement the ongoing registration-directed clinical trial in CML patients with the T315I point mutation and will recruit CML patients from chronic, accelerated and blast-phase disease states.
ADVERTISEMENT
CML patients routinely receive treatment with imatinib mesylate (Gleevec®) and dasatinib (Sprycel®), TKIs that are approved in both the United States and Europe. In addition, other TKIs are available as experimental therapies. Patients who are resistant or intolerant to the approved TKIs have limited treatment options. The CML-203 study is designed to evaluate whether Ceflatonin can provide clinical benefit to such patients.
The first patient was enrolled into CML-203 at the MD Anderson Cancer Center in Houston, Texas, and ChemGenex is expanding the study to an estimated 15 centers through the United States and Europe. It is anticipated that 50-75 patients will be enrolled into CML-203, and that initial data from the study will become available in the first half of calendar year 2008. The primary endpoint for the study will be hematologic response rate, and the cytogenetic response rate will be one of the secondary endpoints assessed.
"Initiation of the CML-203 study represents the achievement of another important milestone for ChemGenex," said Greg Collier, Ph.D., ChemGenex's Managing Director and Chief Executive Officer. "This is a companion study to our ongoing CML-202 study, which will form the basis of our initial new drug application (NDA). CML-203 should provide the basis for filing a supplementary NDA, thereby expanding the potential market for the drug."
Clinical Trial Details
CML-203 is a multi-national open-label study which has opened initially at the MD Anderson Cancer Center in Houston, Texas. The trial will expand to approximately 14 additional centers in both the United States and Europe.
In the remission induction phase of treatment, patients will receive 1.25 mg/m2 HHT by subcutaneous injection two times a day for 14 consecutive days, with cycles repeated every 28 days. In the remission maintenance phase, patients will receive 1.25 mg/m2 HHT by subcutaneous injection two times a day for 7 consecutive days, with cycles repeated every 28 days. Patients will be stratified according to stage of disease, i.e. chronic phase (CP), accelerated phase (AP), or blast phase (BP) CML. The study will be conducted in two stages, using a Simon two-stage study design for each patient subpopulation. During the first stage, 13 evaluable patients from each patient subpopulation (CP, AP, BP CML) will be enrolled. If one or more responses are seen during the first stage of a subpopulation, another 12 evaluable patients from that subpopulation will be enrolled in the second stage. It is anticipated that a maximum of 75 patients will be enrolled into the study, if all three subpopulations proceed to the second stage. The primary and secondary endpoints are hematologic and cytogenetic response rates, respectively.
About Ceflatonin
Ceflatonin (HHT) is a potent inducer of apoptosis (programmed cell death) in myeloid cells and inhibits angiogenesis (blood vessel formation). In phase 2 studies, Ceflatonin has demonstrated clinical activity in patients with CML, both as a single agent and in combination with other chemotherapeutic drugs. ChemGenex is developing Ceflatonin for the treatment of CML, and pilot studies are underway in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML).
Ceflatonin has a different mechanism of action than tyrosine kinase inhibitors (TKIs), and ongoing clinical studies seek to determine:
1. Efficacy in treatment of CML patients who have developed
resistance to TKI therapy due to development of the T315I bcr-abl
kinase domain point mutation. The T315I bcr-abl mutation, which
develops in some CML patients treated with TKIs, is associated with
resistance to Gleevec and Sprycel;
2. Efficacy in CML patients who have failed therapy with or are
intolerant to two TKIs, e.g., Gleevec and Sprycel and;
3. Efficacy as combination therapy with Gleevec, for the treatment of
residual disease and to prolong Gleevec sensitivity in CML patients
who have developed resistance to Gleevec.
Ceflatonin is not approved by the FDA as a treatment in any indication and is currently being evaluated in clinical trials for efficacy and safety for future regulatory applications.
About Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is a cancer of the blood cells caused in the majority of cases by an acquired genetic defect called the bcr-abl mutation. This defect occurs when genetic material from two chromosomes (9 and 22) swaps places, creating the so-called Philadelphia chromosome. The bcr-abl mutation interferes with normal cell replication processes, leading to an abnormal proliferation of white blood cells.
CML usually occurs in adults and typically progresses through three phases. Patients generally are diagnosed in 'chronic phase', progress through 'accelerated phase' and then may die if the disease progresses to 'blast phase'. CML incidence is relatively consistent, occurring at about 1 to 2 per 100,000 people, and the global CML market for therapeutics is significant.
Ceflatonin® is a registered trademark of ChemGenex Pharmaceuticals Limited.
Gleevec®/Glivec® is a registered trademark of Novartis AG.
Sprycel® is a registered trademark of the Bristol-Myers Squibb Company.
About ChemGenex Pharmaceuticals Limited (www.chemgenex.com)
ChemGenex Pharmaceuticals is a pharmaceutical development company dedicated to improving the lives of patients by developing therapeutics in the areas of oncology, diabetes and obesity. ChemGenex harnesses the power of genomics for target discovery and validation, and in clinical trials to develop more individualized therapeutic outcomes. ChemGenex's lead compound, Ceflatonin®, is currently in phase 2/3 clinical trials for chronic myeloid leukemia (CML) and Quinamed® is in phase 2 clinical development for prostate, breast and ovarian cancers. The company has a significant portfolio of anti-cancer, diabetes and obesity programs, several of which have been partnered with international pharmaceutical companies. ChemGenex currently trades on the Australian Stock Exchange under the symbol "CXS" and on NASDAQ under the symbol "CXSP".
Safe Harbor Statement
Certain statements made herein that use the words "estimate", "project", "intend", "expect", "believe", and similar expressions are intended to identify forward-looking statements within the meaning of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements involve known and unknown risks and uncertainties which could cause the actual results, performance or achievements of the company to be materially different from those which may be expressed or implied by such statements, including, among others, risks or uncertainties associated with the development of the company's technology, the ability to successfully market products in the clinical pipeline, the ability to advance promising therapeutics through clinical trials, the ability to establish our fully integrated technologies, the ability to enter into additional collaborations and strategic alliances and expand current collaborations and obtain milestone payments, the suitability of internally discovered genes for drug development, the ability of the company to meet its financial requirements, the ability of the company to protect its proprietary technology, potential limitations on the company's technology, the market for the company's products, government regulation in Australia and the United States, changes in tax and other laws, changes in competition and the loss of key personnel. These statements are based on our management's current expectations and are subject to a number of uncertainties that could change the results described in the forward-looking statements. Investors should be aware that there are no assurances that results will not differ from those projected.
Contact:
ChemGenex Pharmaceuticals
Dr. Greg Collier, CEO and Managing Director
Australia: +61 3 5227 2752
USA: +1 650-474-9800 ext 103
or
Dr. Dennis Brown, President and Director
USA: +1 650-474-9800 ext 108
Australia: +61 3 5227 2703
--------------------------------------------------------------------------------
Source: ChemGenex Pharmaceuticals
Medicure article
I believe the goal of the company would be to have a late breaker at ACC next year
Winning over hearts
Erin Pooley
From the March 26, 2007 issue of Canadian Business magazine
In the global cardiovascular drug industry, Medicure Inc. is a David among the Goliaths. With just 90 employees and a market capitalization of less than $140 million, the Winnipeg-based drug-discovery company is a small player compared to the pharmaceutical giants that compete in the US$70-billion heart-disease space. But despite its size, Medicure is working on a drug with the capacity to reduce the risk of heart damage due to cardiovascular disease — the No. 1 killer in both Canada and the United States. Recent safety concerns regarding drug-coated stents — an alternative treatment to coronary artery bypass surgery — could also pump some new life into this biotech's sagging share price (TSX: MPH).
Currently in pivotal Phase 3 trials, Medicure's MC-1 drug is a cardio-protectant, designed to reduce the damage to the heart when arteries are blocked and when they are subsequently reopened after bypass surgery. In a previous trial involving 900 bypass patients, the drug reduced the heart attack rate by nearly 50% in the first 30 days. If Phase 3 trials are successful — results are expected in March 2008 — MC-1 could be on the market in the U.S. as early as the beginning of 2009, following shortly after in Canada. (Medicure has already received fast-track approval from the U.S. Food and Drug Administration for MC-1.)
"I call it the second Aspirin," says Claude Camiré, a biotechnology analyst at Toronto-based Paradigm Capital Inc. "A lot of people use Aspirin or blood thinners [after surgery], but those only help your blood flow — they don't really protect your heart like MC-1. I think Medicure has a good chance of succeeding." Camiré rates MPH a Buy, with a 12-month price target of $3.
Shares in Medicure reached as high as $2.24 a year ago but now trade at around $1.20, despite speculation late last year they might pop, pending the announcement of a marketing partnership with a U.S. firm. Although nothing materialized, that option is still on the table, says co-founder, president and chief executive Bert Friesen (left). "We have stated that we are certainly open and interested, but only if it maximizes the value to the shareholders," he says. "If a partnership deal of significant value is presented to us before the data, we could still entertain it, but we're keeping the options open."
Camiré says Medicure could also be considered a target for acquisition, with Connecticut-based biotech firm Alexion Pharmaceuticals Inc. a possible buyer. "The recent failure of Alexion's similar type of drug in Phase 3 for the same indication as MC-1 could give an extra edge for Medicure," he says. "It may be looking to buy."
In the meantime, Medicure will continue to capitalize on safety concerns regarding drug-eluting stents — tiny, drug-coated tubes made of metal mesh that are implanted in the coronary artery after angioplasty to keep arteries open longer. Considered less invasive than bypass surgery — which involves grafting part of a healthy blood vessel onto a blocked coronary artery — drug-coated stents soared in popularity when they were approved by Health Canada in late 2002 and by the U.S. FDA in 2003. Vancouver-based device maker Angiotech Pharmaceuticals Inc. (TSX: ANP; Nasdaq: ANPI) — which was in partnership with Massachusetts-based Boston Scientific Corp. — saw its shares climb as high as $38 three years ago with the introduction of its drug-coated Taxus stent to North America. Recent news of the increased risk of blood clots in stent patients, however, has put Angiotech's stock on life support — it now flutters around $7 on the Toronto market. "Angiotech has seen a dramatic reduction in royalty revenue, which has caused a significant ripple effect through the company's financial situation," writes UBS analyst Jeff Elliott in a recent research report.
While Friesen is careful to point out that drug-eluting stents are not going away — and that the risk of blood clots is still relatively low — he remains hopeful the news will mean an uptick in the number of bypass surgeries performed each year in North America and, consequently, the amount of MC-1 prescribed as a post-surgery treatment. His five-year vision for Medicure is to become an integrated Canadian pharmaceutical company with "up to three products on the market [and] other ones in the pipeline — all focused in the cardiovascular space."
Medicure currently has the exclusive U.S. licensing rights to Aggrastat — a blood thinner — and has concluded Phase 2 trials on MC-4232, a combination drug intended to reduce high blood pressure in diabetic patients. With $45 million of cash on hand and a reported $1.4 million in second-quarter sales for the period ending Nov. 30 — compared to no revenue a year earlier — the company's goal is to ramp up Aggrastat sales, which could reach as high as $70 million by 2010, according to Camiré. Like all biotechs, Medicure does not come without risks, although analysts say the company is in a good position to finance MC-1's third — and final — trial, and there appear to be no competing drug candidates.
In the meantime, the company will have to work hard to muscle its way into the highly competitive — and fast-growing — field of cardiovascular drug development, where billion-dollar pharmaceutical companies easily outnumber the Medicures of this world. A battle of biblical proportions, indeed.
Canada US
Chill out...
I meant 3/31/07, and will correct that next post however....
for your information full enrollment is slated to take place over a one year period from Novemeber '06 until November '07.
Of course it may be completed sooner but if it takes the full time frame then my timeline is accurate. There could already be several hundred patients completed the trial but if the last person isn't enrolled till the last minute and then needs 3 months to go through the program that means the data won't be locked until sometime in February at the earliest and to wait 5 to 6 months to get the data analyzed is normal. Heck it took them almost 5 months to analyze the phase 2 data
and that was only 900 patients..........
sorry, evidently you don't have a sense of humor. I was basically accusing you of being able to look into the future or being a time traveler. I knew you weren't either
the guidance as you say is full enrollment by 11/07. I think enrollment is going faster but we can leave it at november. I think they will bust their butts to get the data quicker than 5 or 6 months. the endpoints are simple and it shouldn't take that long. It should go 3 months less but there is nothing for me to chill out about. I wasn't excited
reason not to date a felon
2. Prison hepatitis C poised to infect U.S.
Comment | Forward to a friend
According to public health experts, hepatitis C-positive convicts leaving prison could pose a huge threat to the general population over the next several years, making it one of the biggest upcoming health threats the system will face. Right now, only 2 percent of the general population is estimated to carry hep C, but roughly 40 percent of the 2.2 million U.S. prison population is project to be infected. This happens, largely, because disease is spread by high-risk behavior common in prison, such as needle sharing, getting prison tattoos and body piercing. Infected patients risk liver failure or liver cancer, but prisons seldom screen for hep C, avoiding the $9,500 annual cost per patient of treatment for the disease. Now, public health officials are warning that if the problem isn't stemmed in prisons, convicts exiting prison will spread the infection throughout the population, creating a staggering burden for the larger healthcare system.
MCU/MPH.to - Medicure - MC-1 Lead drug candidate for cardiovascular reperfusion is in PH 3 trial /w 3000 patients.
Expect full enrollment Nov/07 with Data by August /08.
This drug has zero side effects, zero competition, and No Partnership yet with Big Pharma as of 4/31/07.
since you know they won't have a partner at 4/31/07 can you also tell me what their stock price will be on that date. Better yet all stock prices and your answer doesn't have to be limited to life science stocks.
The data will be out way before August. That August date is probably when they would have their nda filed by
window dressing was the wrong term
I should have said mark up the portfolio
I own ymi but i wouldn't call it a rally
It was about 1.50 all day and then it looks like someone bought a couple of hundred thousand shares with a minute to go.
window dressing or new coming?
If there is an announcement on monday someone can easily get checked by the sec to see who bought the block. It would be pretty dumb
good post
I didn't have the patience
dorb data is better than genta or alth data
if it is low risk of harm in an immanently fatal disease the bar for proof of efficacy is (and should be IMO) lower. You can see that this was the issue by the penultimate question - which was about risk of harm.
If you believe this then you should own dor biopharma dorb
conjuchem PC-DAC(TM):Exendin-4 Phase I/II Multiple-Dose Study Preliminary Results Demonstrate Safety and Efficacy at Once-Weekly Dosing
Monday March 26, 4:30 pm ET
- One Month Study in Seventy Type 2 Diabetes Patients -
MONTREAL, March 26 /CNW/ - ConjuChem Biotechnologies Inc. (TSX:CJB - News) today announced positive preliminary results from its Phase I/II multiple-dose clinical study for the treatment of Type 2 diabetes using the Company's proprietary PC-DAC(TM):Exendin-4. Results from the study demonstrated that PC-DAC(TM):Exendin-4 was generally well tolerated and, when administered once-weekly at each of the dosing levels tested, lowered blood glucose.
ADVERTISEMENT
The Phase I/II trial, a randomized, double-blind, multiple-dose study, evaluated safety and tolerability of PC-DAC(TM):Exendin-4 in patients with stable Type 2 diabetes. Pharmacokinetic and pharmacodynamic parameters were also evaluated. All patients were on stable doses of metformin with HbA1c levels between 7.0% and 10.6%. The trial enrolled 70 patients at 7 centers in the U.S. and Canada with patients randomized to one of four parallel treatment groups: 1 mg (n(equal sign)18), 2 mg (n(equal sign)17), 3 mg (n(equal sign)17) or placebo (n(equal sign)18). Sixty-nine patients received 5 doses over a one month period. The product is a highly soluble liquid formulation injected with a 30 gauge needle.
Reductions in mean fasting plasma glucose (FPG) were statistically significant in all treatment groups versus baseline and placebo over the five-week treatment period (FPG was measured Days 1 and 7 post-dosing). The average reductions from baseline values for the 1 mg, 2 mg, and 3 mg treatment arms were -9% (baseline 154 mg/dL), -11% (baseline 172 mg/dL), and -7% (baseline 170 mg/dL), respectively, versus -1% (baseline 158 mg/dL) in the placebo group. The reductions were statistically significant versus baseline (p(less than)0.005 for all cohorts) and versus placebo (p(less than)0.005 for 1mg and 2 mg cohorts, p(less than)0.03 for the 3 mg cohort).
HbA1c improved in all three treatment groups with median HbA1c decreasing 0.5%, 0.8%, and 0.6% in the 1 mg, 2 mg, and 3 mg groups at the end of the five-week period, decreasing 0.7%, 0.6%, and 0.7% at day 49, and decreasing 0.7%, 0.8%, and 0.9% at the end of the study period (day 63) versus baseline. The placebo group declined 0.35% at five weeks, 0.3% at day 49, and 0.2% at the end of the study period. The reduction for the pooled treatment groups was statistically significant versus placebo at day 49 and at the end of the study period (p(less than)0.03, ANCOVA).
There was no statistically significant effect on weight in the treatment cohorts versus baseline or placebo at the end of the 35-day treatment period.
The drug was generally well tolerated. The most common side effects during treatment included headache occurring in 3 out of 18 placebo patients (17%) and 15 out of 52 treated patients (29%) and nausea which was reported in 3 out of 18 placebo patients (17%) and 11 out of 52 treated patients (21%). There were no cases of drug-related vomiting in either the 1 mg or 2 mg cohorts; vomiting occurred in 5 patients in the 3 mg cohort, none of which led to patient drop-out. There were no skin reactions in the 2 mg and 3mg treatment groups; skin reactions were reported in 4 placebo patients and 1 patient in the 1mg cohort. Generally low-level antibodies were detected in 11 out of 52 treated patients (21%). There were no drug-related serious adverse events during the study.
Commenting on these preliminary results, Thomas Ulich, M.D., ConjuChem's Executive Vice President of Research and Development, stated: "These encouraging results provide evidence that long-term once-weekly administration of PC-DAC(TM):Exendin-4 can be therapeutically useful for control of glycemia in patients with Type 2 diabetes. In particular, the study demonstrated that treatment with 2 mg of PC-DAC(TM):Exendin-4 was very well tolerated and effective in lowering blood glucose levels."
ConjuChem intends to submit the study results for presentation at a scientific meeting in 2007.
In conjunction with the multi-dose results, ConjuChem also reported that ongoing product development programs including manufacturing process improvements are expected to be completed in 2007 in time to be included in a Phase II study, which is planned for initiation by year-end.
About PC-DAC(TM):Exendin-4
Exendin-4 is a Glucagon-like peptide-1 (GLP-1) homolog and an agonist for the GLP-1 receptor. Exendin-4 decreases glucagon and increases insulin secretion in a glucose-dependent manner. Exendin-4 may stimulate beta-cell proliferation, restore beta-cell sensitivity to glucose, delay gastric emptying, and increase peripheral sensitivity to glucose. The clinical utility of Exendin-4 is somewhat limited by its relatively short half-life in plasma. Developed with ConjuChem's proprietary PC-DAC(TM) technology, PC-DAC(TM):Exendin-4 is a modified Exendin-4 analogue that is covalently bound to recombinant human albumin (Recombumin(R), provided by Novozymes Delta Limited). The preformed albumin-peptide conjugate has a much longer half-life than the peptide alone. The product is a highly soluble liquid formulation that is injectable in a small volume with a small gauge needle.
Conference Call
The Company will be hosting a conference call with management to discuss these results on Tuesday, March 27, 2007 at 8:30 a.m. EDT. The call will be audio-cast live and archived for 90 days at www.conjuchem.com. A taped replay of the call will be available by telephone on March 27, 2007 through Tuesday, April 3rd, 2007 at midnight. To access the replay, dial 416-640-1917 or 877-289-8525 and enter access code 21224642.
About ConjuChem
ConjuChem, developer of next generation medicines from therapeutic peptides, is creating long-acting compounds based on bioconjugation platform technologies. When applied to peptides, the Company's systemic DAC(TM) and PC-DAC(TM) Technologies enable the creation of new drugs with significantly enhanced therapeutic properties as compared to the original peptide.
Detailed descriptions of the Company can be viewed on the Company's website www.conjuchem.com.
Forward-Looking Statements
Some of the statements made herein may constitute forward-looking statements. These statements relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause ConjuChem's actual results, performance or achievements to be materially different from those expressed or implied by any of the Company's statements. Actual events or results may differ materially. We disclaim any intention, and assume no obligation, to update these forward-looking statements.
For further information
Lennie Ryer, CA, Vice President, Finance & CFO, ConjuChem Biotechnologies Inc., (514) 844-5558 ext 224, ryer@conjuchem.com
Michael Polonsky, Investor Relations, (416) 815-0700 ext. 231, (416) 815-0080, mpolonsky@equicomgroup.com
--------------------------------------------------------------------------------
Source: ConjuChem Biotechnologies Inc.
I think some biotech ceos should take alxn's ceo on a ride in a car and explain to him that the whole industry will have a problem if he proceeds with that price.
if he can't understand it they should leave him in the car when it goes over a cliff
I guess you should repeat the higlighting of important info even if it is old news, not everyone has the memory that you have or reads every post
I am not saying coprexxa is better for ipf than intermune's drug.
there isn't enough data, but their small phase 2 trial showed about the same efficacy as pirfenidone did in their small trial without the side effects.
It will also be approved first. if people with IPF have absolutely nothing because now they won't even get a doctor to prescribe actimune, they would probably try coprexa if they get the data published in a peer reviewed journal at the proper time.
you are correct I have never said they can take the data they have now and go into a phase 3 trial. If they get a nice sized phase 2 trial going they could have data on that way before pirfenidone is approved
it is more a risk reward kind of thing. Without the actimune sales intermune would be trading at 12 dollars or less. The analysts actually raised the target saying there is less risk because they are terminating actimune trials and sales. Actimune was bringing intermune cash flow, its failure shouldn't increase the price target, but thats what analysts do.
the isis drug
from the article you sited
Elevations in liver transaminases (ALT) were observed in this high-dose cohort; five of the eight patients dosed at 400 mg/week, including all four patients with undetectable levels of apoB, experienced modest ALT elevations at or above three times the upper limit of normal (3xULN). No patients experienced ALT elevations greater than 5xULN; the maximal ALT observed was 241 IU/L. Importantly, no patients evidenced liver chemistries that would suggest risk of liver injury (extremely high ALT or ALT elevations together with elevations in bilirubin greater than 2xULN). The mild increases in ALT at the 400 mg/week dose likely reflect extreme lipid-lowering activity, not toxicity
I am surprised you didn't comment about this. I don't believe the drug could get approved or a partnerhip deal signed with the alt elevations observed. The company says they don't believe it is liver toxicity.
They have a really long way to convince most people of that.
estriol
Pipex (a terrible name) has the US commercial rights to the drug
Pirfenidone
pirfenidone has a huge side effect issue which makes it even difficult to do a placebo controlled trial. You know who is on the drug because the side effects tell you
are they getting better because they are on the drug or because they know they are on the drug
corky ipf
Tetrathiomolybdate therapy protects against
bleomycin-induced pulmonary fibrosis in mice
GEORGE J. BREWER, MATTHEW R. ULLENBRUCH, ROBERT DICK, LEOVIGILDO OLIVAREZ, and
SEM H. PHAN
ANN ARBOR, MICHIGAN
Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson’s disease,
produces an antiangiogenic effect by reducing systemic copper levels. Several
angiogenic cytokines appear to depend on normal levels of copper for activity. In
both animal tumor models and in cancer patients, TM therapy has proved effective
in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic
and inflammatory cytokines are also subject to modulation by the availability of
copper in a manner similar to angiogenic cytokines. As a first step in evaluating
whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we
studied the effects of TM on a murine model of bleomycin-induced pulmonary
fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin,
a surrogate marker of systemic copper levels. Significant decreases in systemic
copper levels were associated with marked reduction in lung fibrosis as
determined on the basis of histopathologic findings and a biochemical measure of
fibrosis. The protection afforded by TM was also reflected in significantly reduced
bleomycin-induced body-weight loss. In the next phase of this work, we will seek to
determine the mechanisms by which TM brings about this therapeutic benefit. (J Lab
Clin Med 2003;141:210-6)
Abbreviations: CTGF _ connective-tissue growth factor; SEM _ standard error of the mean;
SPARC _ secreted protein, acidic and rich in cysteine; TGF _ transforming growth factor; TM _
tetrathiomolybdate
Pulmonary fibrosis, idiopathic or otherwise, is
commonly progressive and essentially untreatable,
with a fatal outcome.1,2 It is clear from a
rather wide body of work that the underlying mechanism
involves dysregulation and overproduction of certain
cytokines.1-5 A central mechanism appears to involve
continued overproduction of TGF-_, which could
in turn increase the production, activity, or both of
CTGF.6-12
Bleomycin, when given to cancer patients, produces
pulmonary fibrosis in about 3%.13 On the basis of these
observations, a mouse model of pulmonary fibrosis has
been established in which intratracheal instillation of
bleomycin uniformly produces pulmonary fibrosis.4,6,9-
12,14 This model is thought to be a model of human
pulmonary fibrosis. The hypothesis that TGF-_ is central
to pulmonary fibrosis has been validated by studies
showing that inhibition of TGF-_ by pharmacologic
means or by antibodies greatly reduces the pulmonary
fibrosis produced by bleomycin or other methods of
lung injury in the mouse.8,12
In previous studies by members of our group, it has
From the Departments of Human Genetics and Pathology, University
of Michigan.
Supported by National Institutes of Health grants HL28737,
HL31963, and HL52285. The University of Michigan has recently
licensed the antiangiogenic uses of tetrathiomolybdate to Attenuon,
LLC. Dr. Brewer and Mr. Dick have equity in this company.
Submitted for publication July 19, 2002; revision submitted October
4, 2002; accepted November 18, 2002.
Reprint requests: George J. Brewer, MD, Department of Human
Genetics, University of Michigan Medical School, 4909 Buhl, Ann
Arbor, MI 48109-0618; e-mail: brewergj@umich.edu.
Copyright © 2003 by Mosby, Inc. All rights reserved.
0022-2143/2003 $30.00 _ 0
doi:10.1067/mlc.2003.20
210
been shown that copper-decreasing therapy with TM, a
copper-specific agent, can prevent, at least for a time,
the growth of many types of advanced and metastatic
cancers through an antiangiogenic mechanism.15-19 The
hypothesis underlying this approach is that one or more
copper-containing or copper-binding angiogenic promoters
(eg, vascular endothelial growth factor, fibroblastic
growth factor, angiogenin, angiotropin, SPARC,
or others) require higher levels of copper to be active
than are required for basic cellular needs for copper.
15,19 We hypothesize that use of the anticopper drug
TM drops the patient into an “antiangiogenic window”
of copper levels in which angiogenesis is inhibited but
copper deficiency is not severe enough to cause side
effects.
As we examined the series of cytokines involved in
the pathogenesis of fibrosis, it appeared to us that one
or more of them had a high probability of sharing the
copper dependency of the angiogenic cytokines discussed
above and that copper-decreasing therapy with
TM might abrogate the development of pulmonary
fibrosis. In this work, we have shown that TM therapy
does indeed inhibit development of pulmonary fibrosis
in the bleomycin mouse model.
METHODS
Mice. Female CBA/J mice, 8 to 10 weeks old, were from
Jackson Laboratories (Bar Harbor, Maine). At the start of the
experiments, the mice weighed 21.4 _ 1.7 g (mean _SD).
Bleomycin treatment. We administered bleomycin on day
0 by means of endotracheal instillation through the oral cavity
after exposing the mouse’s airway by pulling its tongue. Each
mouse received 0.001 units/gm body wt of bleomycin (Bristol-
Myers, Evansville, Ind) in 30 _L sterile saline solution.
Control mice were administered an equal volume of sterile
saline solution.
TM treatment experiments. TM was given in 0.25 mL of
water once daily by means of intragastric gavage in the doses
and times indicated in the various studies.
Three experiments were carried out. Experiment 1 comprised
four groups of five to seven mice each. Group 1
received bleomycin, group 2 was a saline control, group 3
received bleomycin and TM therapy, and group 4 was a
TM-therapy control. (All groups started with seven mice, but
two mice from group 1 died before the end of the experiment
as a result of the illness produced by bleomycin, and one
mouse each from groups 3 and 4 died as a result of technical
problems encountered during TM gavage.) The mice in
groups 3 and 4 were started on TM therapy at a dose of 0.7
mg/day, 7 days before the administration of bleomycin, and
were continued on this dose throughout the study until being
killed at day 21, except for a 3-day period (days 9-11 after
bleomycin) when they were each given a dose of 1.2 mg
TM/day. We temporarily increased the dose to ensure that
copper concentrations would be adequately decreased in this,
our first experiment.
Experiment 2 was a TM dose-response study comprising
five groups, each containing four bleomycin-treated mice.
Group 1 was a control, given bleomycin but no TM. Each
mouse in groups 2 through 5 received an identical load dose
of 1.2 mg TM/day for 3 days before the administration of
bleomycin. Groups 2 through 5 were administered 0.3, 0.5,
0.7, or 0.9 mg of TM/mouse/day, respectively, until the mice
were killed at day 21. Eighteen mice that received no bleomycin
were divided into five groups and given either no TM
(as in group 1, above) or loading doses and varying doses of
TM (as in groups 2 to 5, above) and served as controls for TM
therapy.
In experiment 3, the starting times for TM treatment varied.
Twenty-one mice were divided into five groups of four to five
mice each, all of which received bleomycin. Group 1 mice
received no TM. Mice in groups 2 through 5 received a 4-day
loading dose of 1.2 mg TM/day, then 0.9 mg/day until being
killed at day 21. However, starting times of TM treatment
were varied, beginning 5 days before the administration of
bleomycin in group 2, then beginning 4, 7, and 14 days after
the administratino of bleomycin in groups 3, 4, and 5, respectively.
Eighteen mice that received no bleomycin were divided
into five groups and given either no TM (as in group 1,
above) or doses of TM and starting times comparable to those
in groups 2 through 5, above, and served as controls for TM
therapy.
Copper status. In the presence of TM therapy, copper
status can’t be assessed by direct measurement of serum
copper because of the accumulation of a tripartite complex of
TM, copper, and albumin that turns over slowly, causing the
serum copper to be increased even though availability of
copper is decreasing. However, we have found that serum
ceruloplasmin is a good surrogate marker of copper status15
because the liver secretes this copper-containing protein into
the blood at a rate dependent on copper availability. We
monitored copper status by assaying serum ceruloplasmin on
the basis of its oxidase activity20 in blood from the tail vein.
To avoid excessive bleeding, one mouse from each group was
bled at each time point; mice were rotated so that different
mice were bled. A ceruloplasmin assay was conducted in each
mouse when it was killed.
Hydroxyproline assay. We assessed the extent of fibrosis
by assaying hydroxyproline content of whole-lung homogenates
at the time of sacrifice, as previously described.21 Hydroxyproline
was expressed as micrograms of hydroxyproline
per mouse lung (the lung tissue included both lungs).
Microscopic evaluation of the lungs. For structural evaluation
of fibrosis, we inflated lungs with formalin after killing
the mice. After overnight fixation, the lungs were embedded
in paraffin. We prepared sections for Hematoxylin-and-eosin
staining, as well as for Masson trichrome staining for the
evaluation of collagen deposition.21
Statistical analysis. For comparisons of means, we used
analysis of variance, followed by Scheffe´’s test for multiple
comparisons when appropriate. For the dose-response and
varying starting times for TM studies, we also used regression
analysis to evaluate statistical significance.
J Lab Clin Med
Volume 141, Number 3 Brewer et al 211
RESULTS
Experiment 1. As shown in Table I, at the time of
killing, the mean body weight of bleomycin-treated
animals (group 1) was significantly less than that of
saline solution–treated controls (group 2). TM treatment
protected against some of the bleomycin-induced
weight loss (Table I), as shown by the lack of a significant
difference in weight between the bleomycin/TM
(group 3) and saline solution (group 2) means. TM
alone (group 4) tended to produce some weight loss in
experiment 1 (Table I). The mean hematocrit of bleomycin-
treated animals (group 1 of Table I) was significantly
increased compared with that in the other three
groups.
The mean ceruloplasmin level of bleomycin/TM
mice (group 3 of Table I) was about 55% that of
bleomycin animals (group 1), and the two were significantly
different. TM alone (group 4) resulted in a mean
ceruloplasmin concentration about 80% that of saline
controls, but this difference was not statistically significant.
The hydroxyproline results of experiment 1 are also
shown in Table I. Therapy with TM almost completely
abrogated fibrosis as measured by this assay. Bleomycin
treatment (group 1) produced a highly significant
increase in hydroxyproline compared with that seen in
saline solution–treated controls (group 2), but we noted
no significant difference between the TM-treated bleomycin
mice (group 3) and the saline-solution group 2,
and the means were very close. The mean values between
bleomycin-treated (group 1) and bleomycin/TMtreated
(group 3) animals were highly significant. In
this experiment, TM alone seemed to have some effect
on increasing hydroxyproline levels, an effect that
wasn’t borne out in experiments 2 and 3.
The results of lung histopathologic study from experiment
1 bear out the hydroxyproline results (Fig 1).
Although scattered patches of fibrosis and inflammatory
cells were found in the TM-treated bleomycin
animals, these were substantially smaller, with lesser
degrees of cellular infiltration compared with those in
the animals treated with bleomycin alone. Masson’s
trichrome–stained sections revealed much less collagen
deposition in the TM-treated group than in the mice
given bleomycin only (data not shown).
Experiment 2. Experiment 2 was a dose-response
study. The overall data on weight, hematocrit, and
hydroxyproline levels at the time of sacrifice are shown
in Table II. Scheffe´’s’ correction for multiple comparisons
showed that the relevant means were not significantly
different from one another, except as noted in
Table II.
We monitored weight throughout experiment 2 (Fig
2), and although the means at the time of death are not
significantly different, it is clear from the data shown in
Fig 2 that TM in doses of 0.5 mg/day on up protected
against bleomycin-induced weight loss, similar to the
results in experiment 1.
Additional analysis of the hydroxyproline data of
experiment 2 is shown in Fig 3. Regression of the
hydroxyproline values against TM doses of 0.3 to 0.9
mg/day yields a highly significant F statistic. In this
experiment, hydroxyproline levels were not affected by
TM treatment alone (Fig 3), in contrast to experiment 1.
The ceruloplasmin data of experiment 2 were separately
analyzed (Table III). All of the means of the
bleomycin TM groups are significantly different than
those of the bleomycin control at the time of killing, but
they do not show much dose-response effect. Dose
response of TM on ceruloplasmin may be better appre-
Table I. Data from experiment 1 at time mice were killed
Treatment parameters Bleomycin Saline solution Bleomycin/TM TM
N 5 7 6 6
Weight (g) 18.6 _ 1.4 24.0 _ 0.04 21.2 _ 0.8 20.4 _ 1.0
Hematocrit 55.0 _ 2.7 44.8 _ 0.2 39.7 _ 2.6 44.1 _ 1.0
Ceruloplasmin (IU) 25.3 _ 2.8 22.7 _ 1.1 13.9 _ 3.3 18.1 _ 3.4
Hydroxyproline (_g/lung) 252 _ 16 156 _ 9 162 _ 12 193 _ 5
Statistical analysis (P values) comparisons Weight Hematocrit Ceruloplasmin Hydroxyproline
Bleomycin vs saline solution .001 .004* .001 .005* .183 .90* .001 .001*
Bleomycin vs bleomycin/TM .06 .32* .001 .001* .01 .06* .001 .001*
Bleomycin/TM vs saline solution .16 .62* .001 .004* .06 .38* .674 .980*
TM vs saline solution .002 .07* .24 .99* .1 .70* .018 .119*
*P value with Scheffe´ ’s correction for multiple comparisons.
J Lab Clin Med
212 Brewer et al March 2003
ciated after examination of the individual mouse data
during the course of the experiment, in which the 0.9
group shows low levels, the 0.3 group relatively normal
levels, and the 0.5 and 0.7 groups intermediate levels.
Experiment 3. In experiment 3, the starting time of
TM was varied. As shown in Fig 4, the sooner TM was
started, the more effective it was in protecting against
hydroxyproline accumulation. Regression of hydroxyproline
levels against the day therapy was started
(days _5 to _14) gave an F statistic of 21 (P _ .05).
Because the number of animals in each group was
relatively small, we combined the data on the postbleomycin
TM groups (days _4, _7, and _14), then
compared the mean with that of the bleomycin control,
which yielded a significant t-test result (P _ .05). As in
experiment 2, we detected no effect of TM alone on
hydroxyproline levels (Fig 4). Overall hydroxyproline
values were lower than those in experiments 1 and 2
because of the use of younger animals, weighing 10%
to 20% less.
DISCUSSION
It is clear from the data presented here that TM
therapy has a major protective effect against the lung
damage and illness produced by intratracheal bleomycin
instillation in mice. Bleomycin treatment causes
much weight loss, but this is protected against by an
adequate dose of TM (Table I, Fig 2). The bleomycininduced
illness produces hemoconcentration by day 21,
probably a result of the animals’ not drinking adequate
water; this is also protected against by TM (Tables I
and II). Bleomycin also causes pulmonary fibrosis,
Fig 1. Effects of TM on histopathologic findings. Lung sections from bleomycin-treated mice (left) and mice
treated with bleomycin plus TM (right) mice were stained with hematoxylin and eosin, then photographed at a
magnification of 40_ (upper), 400_ (middle), or 1000_ (lower).
J Lab Clin Med
Volume 141, Number 3 Brewer et al 213
measured by levels of hydroxyproline, and TM therapy
strongly protects against hydroxyproline accumulation
(Table I, Fig 3). The therapeutic and protective effects
of TM are dose-dependent, as shown in Figs 2 and 3.
TM can be started after the inflammatory damage is
well under way14,21 and still provide benefit, as shown
in experiment 3 (Fig 4). As late as days 4, 7, and 14
after bleomycin administration, TM initiation is still
beneficial.
The main mechanism of action of TM is to decrease
systemic copper levels. That TM worked in this study
to decrease copper availability, as planned, is shown by
the reduced ceruloplasmin levels in the experiments
(Tables I and III). Possible mechanisms by which decreased
copper levels could be therapeutically effective
against the bleomycin damage—in increasing order of
likelihood, in our judgment — are:
(1) Effects of TM on decreasing direct copper interactions
with bleomycin. This seems unlikely; in experiment
3, TM was effective when started several days
after bleomycin-induced injury.
(2) Possible antioxidant effects of TM, countering the
oxidant-damage effects of bleomycin. This seems unlikely
for the same reason given above.
(3) An effect of copper depletion on a copper-dependent
enzyme, such as lysyl oxidase. We measured lysyl
oxidase in the lungs in one experiment and found no
effect of TM (unpublished data). We believe the copper
deficiency isn’t sufficiently severe to affect copperdependent
cellular enzymes, but study of this possible
mechanism should continue.
(4) Effect of TM on proangiogenic cytokines. We
know that many proangiogenic cytokines are copperdependent,
as discussed in the Introduction, and we
Fig 2. Mean weights for mice in each group at several time points
during experiment 2 and at the time they were killed (21 days). The
bleomycin group showed severe weight loss, but TM protected
against weight loss in a dose-dependent manner, with the 0.9-mg dose
being fully protective.
Fig 3. Relationship of excess hydroxyproline (a measure of fibrosis)
to TM maintenance dose in experiment 2. Closed squares, mean
values of four mice given bleomycin and treated with varying doses
of TM, ranging from 0 to 0.9 mg/day during the maintenance phase
of therapy. Open triangles, mice that were not did given bleomycin
but received the maintenance doses of TM indicated. Regression of
the hydroxyproline data (closed squares) on TM doses ranging from
0.3 to 0.9 mg/day provided an F statistic of 14.8 (P _ .002).
Table II. Data from experiment 2 at the time mice were killed
Treatment
Bleomycin
(n _ 5)
Bleomycin/TM 0.3
(n _ 4)
Bleomycin/TM 0.5
(n _ 4)
Bleomycin/TM 0.7
(n _ 5)
Bleomycin/TM 0.9
(n _ 5)
Weight (g) 17.6 _ 0.68 19.5 _ 1.76 21.5 _ 0.87 20.8 _ 1.02 22.4 _ 0.87
Hematocrit (%) 55.0 _ 0.71 46.3 _ 0.25 47.3 _ 0.63 44.3 _ 2.75 42.5 _ 1.32
Hydroxyproline
(_g/lung)
217 _ 7.8 232 _ 3.7 197 _ 15.1 172 _ 22.0 157 _ 14.5
Data approved as mean _ SEM.
Weight: None of the means was significantly different than other means, with Scheffe´ ’s correction for multiple comparisons.
Hematocrit: The means of the bleomycin TM 0.7 mg, bleomycin TM 0.9 mg, and all the saline-solution and saline-solution TM groups were
significantly different than the mean of the bleomycin group with Scheffe´ ’s correction for multiple comparisons.
Hydroxyproline: None of the means of the bleomycin TM groups was significantly different than the bleomycin mean, with Scheffe´ ’s correction
for multiple comparisons. The means of the saline-solution control and the saline-solution TM 0.5 were significantly different than that of
bleomycin.
J Lab Clin Med
214 Brewer et al March 2003
have unpublished evidence that some of these are inhibited
by TM therapy. Angiogenesis may play some
role in the mouse model of bleomycin-induced lung
injury, although it seems unlikely that it plays a central
role. However, antiangiogenic effects of TM may contribute
to TM’s therapeutic effect.
(5) Inhibition of inflammation through inhibition of
proinflammatory cytokines. We know from unpublished
work in a mouse model of liver inflammation
that TM inhibits inflammation. The finding in experiment
3 that TM administration started relatively late
(days 4, 7, and 14) after bleomycin instillation still has
a significant effect in inhibiting fibrosis (Fig 4) argues
against suppression of inflammation as the sole effect
of TM. TM started on day 4 wouldn’t reduce copper
levels to the therapeutic area until about day 7, by
which time all or most of the inflammatory stimuli are
peaking. TM started at days 7 and 14 would not get
copper levels into the therapeutic range until well after
inflammation and inflammatory stimuli would have
subsided.
(6) Inhibition of fibrosis through inhibition of the
profibrotic cytokine pathway. As discussed in the Introduction,
the possibility of copper dependence of this
pathway was the reason we initiated this study. Several
candidate cytokines may be inhibited in this pathway. It
is known that SPARC is one stimulus for TGF-_ expression,
22,23 and SPARC is known to be copper-dependent.
24 SPARC-null mice demonstrate marked mitigation
of bleomycin-induced fibrosis.23 TGF-_ itself
interacts with heparan molecules, some of which are
known to be copper-dependent.25 Finally, CTGF is rich
in cysteine,10 suggesting that it binds copper and is
dependent on copper for activity. We think it most
likely that a combination of antiangiogenic, antiinflammatory,
and antifibrotic effects are involved. These
possible mechanisms are under investigation.
Irrespective of the pathway, or the molecular mechanism,
involved, the fact that TM therapy can so markedly
inhibit fibrosis in this model raises the exciting
possibility of using this approach to preventing and
treating pulmonary fibrosis in patients. The data of
experiment 3, shown in Fig 4, indicate that TM therapy
is effective after injury, which supports its potential
efficacy in the clinical situation. The possibility of early
clinical trials is enhanced by the fact that this drug has
already seen considerable experimental use in human
subjects with Wilson’s disease26,27 and cancer15,19 and
has proved remarkably safe. The only side effect of
copper-decreasing therapy with TM in cancer has been
overtreatment, which leads to easily reversible bonemarrow
depression. The use of serum ceruloplasmin as
a surrogate to monitor copper status in the clinical
situation has proved effective, reliable, and easy to
use.15
It has not escaped our attention that the profibrotic
pathway involving TGF-_ and CTGF is central to
pathologic fibrosis in many organs besides the
lungs.7,10 A partial list includes liver cirrhosis, renal
interstitial fibrosis (often a final common pathway for
many types of renal damage), systemic sclerosis (frequently
complicated by pulmonary fibrosis), keloid,
hypertrophic burn scarring, and excessive fibrosis in
various parts of the intestinal track in some patients
after disease or injury. If TM treatment is effective in
treating pulmonary fibrosis, there are obviously a host
Fig 4. Hydroxyproline data from experiment 3. TM-treated mice
were given a loading dose of 1.2 mg for each of 4 days, then 0.9
mg/day. Closed diamonds, mean hydroxyproline data at the time
mice were killed (day 21) from four mice in each group, except for
day _7, which had five mice, all treated with bleomyci, and all
treated with TM at varying starting times. Closed squares, mean
values from four mice given bleomycin only; open circles, mean of
four mice given saline solution only. Open triangles, means of three
or four mice given no bleomycin but administered TM at varying
starting times as controls for the bleomycin/TM mice. Regression of
the four data points shown by the yielded a significant F statistic (P _
.05). The data from the bleomycin/TM groups given TM post bleomycin
instillation (_4, _7, and _14 days) were pooled and the mean
compared with the bleomycin mean by the use of Student’s t test and
found to be significantly different (P _ .05).
Table III. Ceruloplasmin values of bleomycin and
TM-treated animals during experiment 2
TM maintenance dose
(mg/day)
Ceruloplasmin values
Day 8* Day 14* Day 21†
0.0 20.8 30.2 22.8 _ 2.8
0.3 20.3 23.6 5.4 _ 2.7
0.5 14.4 10.6 4.5 _ 2.7
0.7 12.6 15.5 4.7 _ 2.2
0.9 0.6 3.7 1.8 _ 0.7
*Data at 8 and 14 days are from single mice.
†Data from 21 days are at the time mice were killed and represent
the mean _ SEM of four to five mice in each group. At the time of
death, the mean value of each bleomycin/TM-treated group was
significantly different from the mean of the bleomycin group (no
TM treatment) with Scheffe´ ’s correction for multiple comparisons.
J Lab Clin Med
Volume 141, Number 3 Brewer et al 215
of other diseases of excessive fibrosis and/or inflammation
in which TM therapy should be evaluated.
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J Lab Clin Med
216 Brewer et al March 2003
I really don't think anything will help him if he is on the respirator
the only thing might be
http://www.mitechnews.com/articles.asp?Id=4563&sec=105
Tetrathiomolybdate (TM) for ipf
Dr. Brewer at the u of michigan may have some drug because I believe he has some wilson's patients on it
but I am not sure that he is diagnosed correctly i don't think nhl becomes IPF
Interstitial pneumonias are a confusing and frustrating set of diseases both for the treating physician and for the diagnostic pathologist. One source of the confusion has been the lack of overlapping terms that treating physicians and pathologists use. For example, idiopathic pulmonary fibrosis (IPF) is a clinical term describing a slowly progressive, chronic interstitial pneumonia. Since many of the interstitial pneumonias, including UIP, DIP, and NSIP, fall under this category, it is a non-specific term. Most pathologists who are experts in lung pathology use the terms IPF and UIP to mean the same disease process. To complicate matters even further, European clinicians utilize the term cryptogenic fibrosing alveolitis for IPF. Pathologists also share in the confusion. Terms that were commonly used by pathologists just a few years ago have also undergone an evolution. Bronchiolitis obliterans with organizing pneunomina (BOOP) is no longer used because it has been considered a mixture of terms. Lymphocytic interstitial pneumonia (LIP) is now considered a lymphoproliferative disease. Giant cell interstitial pneumonitis (GIP) is now considered a hard metal pneumoconiosis.
P.S. HAD BAD EXPERIENCE WITH CORNELL PARTNERS AND MANIPULATION OF STOCKS
you are right, cornell is the worst
IDIX Announces Resignation of Chief Financial Officer
Tuesday March 20, 4:05 pm ET
CAMBRIDGE, Mass., March 20 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX - News) today announced that David Arkowitz, chief financial officer and treasurer, has resigned effective March 30, 2007 to pursue an opportunity at another life sciences company. David Blanchard, Idenix's vice president of finance, who has been with Idenix since 2000, will serve as interim chief financial officer with responsibility for finance and information technology until a national search for a new chief financial officer is complete.
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"Over the past three years, David has played an integral role in the establishment of the essential infrastructure and key governance and business processes to support Idenix's growth as a public company and the commercialization of our first product," said Jean-Pierre Sommadossi, chief executive officer and chairman of Idenix. "We are thankful for his contributions and wish him success in his new endeavor."
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and HIV. For further information about Idenix, please refer to http://www.idenix.com.
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