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Toxic and death spiral converts
Thanks, David and XRYMD, for the primer on financing.
Given that info, would the Resverlogix deals in 2007 constitute "death spiral convertible" financing and is it bad for the company? It would seem to fit the definition in that the company had to initially accept a much higher interest rate and then paid off the creditor with additional shares. The company has undoubtedly been shorted this year too---even management says so.
On the other hand, the share price seems to have stabilized in $12-14 range over the last month, up considerably since August. This suggests to me the shorters either were only modestly successful or have not yet made their full assault.
Urche
Resverlogix death spiral convert
The deleterious effect of that convertible is obvious in retrospect, but I'm curious as to the general feeling about it among shareholders when it was originally announced.
David,
I think you are referring to the two financings done in 2007 as convertible debentures. The first one, as originally announced on Jan. 2, didn't strike me as toxic with 8% interest rate on the notes and conversion price of $10.40 ($13 for associated warrants). The shares were trading at $14-15 at that time.
But then things got complicated and hard for me to understand. Over the course of the year there was another financing of similar size and at least 3 PR's announcing changes to the terms. These terms sounds more toxic with interest rates rising to 13-14% but I admit that I haven't taken the time and I'm not I could understand the end result even if I took the time.
So, David, what is your understanding of the convertible financing and why do you refer to it as a "death spiral convert"? Sounds like something that Spock and Scotty surely could figure out a strategy to save the day.
Regards,
urche
Sembiosys
Yes, I also am not aware of any other SBS holders on this board (or elsewhere in the world).
And to follow up on an earlier thread, I just used an Etrade limit order ($2.85) for SMBGF.pk which took about a week to go thru. Don't know if it'll be as liquid as a sale, but so far there seems to be no need for a $Canadian account as long as one is content with owning shares of a Canadian company denominated in $US which suits me fine.
urche
HDL isn't just "good cholesterol"anymore
Anyone interested in HDL, apolipoprotein A1, and lipid profile therapeutic strategies will find this article from Cleveland Clinic Journal of Medicine interesting:
Shortcut to: http://www.ccjm.org/PDFFILES/Ansell10_07.pdf
I won't paste it here because it is several pages long and has some good tables and drawings.
But generally the article is about the concept that HDL is a heterogeneous group of particles not only in terms of size but also function. Even HDL, the reputed good cholesterol, in certain people and in certain disease states (such as sepsis), can become oxidative and pro-inflammatory.
I learned from the article that there are even a small handful of tests that are not commercially available but purport to measure the qualitative aspects of HDL, which may be more important than the level of HDL used in current clinical practice. Of course, this relates to the torcetrapib disaster, which publicized in big dollar terms how boosting HDL isn't in itself necessarily a worthwhile goal.
The article was written by Benj Ansell who has a holding in Bruin (I believe still a private company) which has done exciting work with D-4F. However, after reading the article, I am more comfortable with my long time holding of Resverlogix and very recent nibble into Sembiosys, both speculative plays trying to develop clinically useful forms of ApoA1. My own hunch is that ApoA1 holds more promise therapeutically than HDL mimicry or enhancement.
I'm off to buy some eggnog.
Turnaround for 2008
I would support CAMH, Response, Javelin, Momenta as beaten down and poised for major movement depending on outcome of near term events. In the case of Momenta, there is a collar (cash) that should prevent it being a worst of 2008 contender. Spectrum wouldn't go on my list just because it has enough in its pipeline to keep it away from the best or worst ends of the scale.
Although it probably only has about 5 private shareholders left (including Randy and I), Cobalis may also qualify. At 6 cents per share, it is more likely to be zero or a buck at the end of the year than anywhere in between. CBLS, BTW, had the distinction of adding the letter "e" to its ticker this week.
Giving Thanks
Although it has been all I can do to read most of this board, much less participate recently, when I do finally have an opportunity to catch up, this board is inspiring. The enduring collective knowledge, adherence to a code of civility, and occasional wry humor are much appreciated. Thanks to all who participate.
urche
Canadian companies
Stuck holder, thanks for sharing those companies off my radar screen. I have no knowledge of them, but here are a few others to consider.
1)Like Dew, I am following Sembiosys (SBS.to) with keen interest.
2)Response Biomedical---$125 M market cap with important news about FDA approval (or not) of a heart failure test expected any day. It also has its fingers into some infectious disease tests, esp staph and flu. Moving nicely today so something may be breaking.
3)Cryocath---I just sold my position, but only to take some gains to the sideline.
4)Resverlogix---Almost unbelievably, like SBS , also based in Calgary, and doing promising very early development with ApoA1.
Urche
Satraplatin RIP
To make a Halloween metaphor, that news puts another nail in the coffin of my biotech blunders and adds to my never ending befuddlement. Time after time it seems the lesson is always to expect the unexpected.
Spectrum was one of my first biotech investments in 2002, almost solely on the promise of satraplatin and the reputation of its scientific head, Luigi Lenaz. I also was attracted by the model of developing some generic, Indian produced drugs to help defray development costs. Until today I thought that there was no more sure drug destined for approval than satraplatin. It had the advantages of oral bioavailability, similar mechanism to approved platinum drugs, and, presumably, similar efficacy. So, it seemed to me it was just a matter of time before the survival data and almost perfunctory approval.
Of course, Spectrum had lots of wild swings during the ride and my investment has done very well for me, my current position being essentially "free" shares. No complaints there.
But, this biotech investment world continues to demand constant diligence, humility, and respect for the unexpected.
Urche
thanks for sharing.
ASPREVA
I can't say I am disappointed even though the price is only about 15% above yesterday's price. Since the lupus program failed, Aspreva didn't have much to look forward to other than acquiring something with its large cash stash or be acquired. I was wondering how I was going to unwind this holding. Now I know and it's time to look for another undervalued Canadian company.Any suggestions?
No staph question.
I was more interested in pro-BNP which will not be marketed by 3M. Staph seems to be in the headlines these days, however, so maybe we'll see some collateral benefit.
Response in November?
Admittedly impatient to learn about the FDA's decision re NT-pro BNP, I recently called the company for info. It turns out that there indeed have been some amendments and delays to the application. But it may be a good thing in the long run. In august Response submitted additional info which may substantiate the claim that the pro-BNP test is in some ways SUPERIOR rather than equivalent to existing tests. That would be a big deal, IMO, and worth the additional wait. So, the 90 day clock restarted ticking in Aug. But a decision is not necessarily expected by Nov. because the 90 day figure is just a guideline, not an FDA mandate. I expect the next few months to be more than interesting for Response. The 3M flu test may get approval during this flu season (early 2008?) as well.
Patiently,
Urche
Health Vault and Quality Systems
Evidently Quality Systems (QSII) is one of those partners eager to get into bed with Microsoft. QSII, the producer of NextGen, the EMR widely used in physician offices across the country, wasted no time with this announcement:
NextGen ChartMail(SM) to Become Interoperable with Microsoft HealthVault
NextGen Healthcare, a wholly owned subsidiary of Quality Systems, Inc. (NASDAQ: QSII) and leading provider of fully integrated ambulatory healthcare and connectivity solutions today announced support for HealthVault, the newly launched consumer health platform from Microsoft Corp.
NextGen Healthcare’s ChartMail allows health care providers to send personal health records directly to patients in a secure, authenticated manner. Its interoperability with HealthVault, when completed, will allow the data to be uploaded into Microsoft’s new platform, giving the patient more options when managing their health information.
Peter Neupert, Corporate Vice President of Microsoft’s Health Solutions Group said, “NextGen Healthcare is clearly an industry leader, and Microsoft is proud to work with them in the development of interoperable applications that will enable consumers to make better choices regarding their health by arming them with information and putting them in control of their health records.”
Dronedarone results ? relevant to Cardiome
These results look pretty good to me and, therefore, I think the competition is more significant for Cardiome which is also developing an oral drug for prevention of recurrent atrial fib. This abstract is from Medscape.
Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.
N Engl J Med. 2007; 357(10):987-99 (ISSN: 1533-4406)
Singh BN ; Connolly SJ ; Crijns HJ ; Roy D ; Kowey PR ; Capucci A ; Radzik D ; Aliot EM ; Hohnloser SH ;
Cardiology Division, Veterans Affairs Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA. bsingh@ucla.edu
BACKGROUND: Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects. METHODS: In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428 [ClinicalTrials.gov] ) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376 [ClinicalTrials.gov] ), we evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter. RESULTS: In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (+/-SD) ventricular rate was 117.5+/-29.1 beats per minute in the placebo group and 102.3+/-24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6+/-31.9 and 104.6+/-27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group. CONCLUSIONS: Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.
radiation with virtual colonoscopy
Question for Bob or xrymd: I think I heard the radiation delivered with standard CT of the abdomen and pelvis is on the order of equivalent to 100 chest xrays. If so, it would be hard to make a case justifying such a test for screening without a lot of informed thought. Do you know how much radiation is needed for virtual colonoscopy compared to a standard CT of abdomen and pelvis? Has anyone run the data to predict how many cancers would be CAUSED by regular virtual colonoscopy screening?
OT Etrade and foreign stocks
E*Trade has a new foreign-market online-trading system for stocks in six countries including Canada. Has anyone here used it? "
I have used it for some trades in Canada. You need to set up a new "global" account and then buy the foreign currency you need to trade. Once set up the system seems to work very well.
That's interesting and something I'll explore.
Thanks.
It is easy to get frustrated or burned trying to buy thinly traded pink sheet stocks traded mainly on Canadian exchanges. For examples, Resverlogix and Sembiosys have such low volume with the pink sheet tickers and such wide spreads that it's hard to buy thru Etrade. Somedays there are zero shares traded and you usually have to call for a quote.
I would assume there is a commission for exchanging the currency first, and then a brokerage commission and perhaps even additional fees for the global account. So it may have too much frictional cost to be worthwhile for a casual trader.
Urche
CEO announcement
Jeezum I feel out of the loop. I was not aware that Radvak had resigned (if that is what happened).
But this looks like a very strong move on the part of Response, to hire a CEO who was a honcho at Quidel, a company I keep on my radar as one of Response's closest and much larger competitors.
I am still surprised at how long the FDA is taking to make its pro-BNP decision.
Anyone have an idea what to expect over the next few months?
urche
Press Release Source: Response Biomedical Corp.
Response Biomedical appoints S. Wayne Kay Chief Executive Officer
Wednesday September 12, 8:30 am ET
VANCOUVER, Sept. 12 /CNW/ - Response Biomedical Corporation (TSX-V: RBM, OTCBB: RPBIF) today announced the appointment of S. Wayne Kay as Chief Executive Officer (CEO). Mr. Kay was also appointed to the Company's Board of Directors.
Mr. Kay is a former President, CEO and Director of Quidel Corporation, a leading global company in the discovery, development, manufacturing and marketing of rapid diagnostic solutions at the point-of-care (POC) in infectious diseases and reproductive health. During his tenure he designed and managed a strategy responsible for building and sustaining unprecedented market leadership of rapid influenza testing (from an approximately 2 percent to 49 percent market share). He was also responsible for significantly improving the financial performance of the company during his tenure. Since leaving Quidel in 2004, Mr. Kay served as an executive advisor to the management and boards of several early stage companies, mainly in the San Francisco and San Diego areas. He also served as an executive advisor to one of the US's most successful blue-chip healthcare/life sciences venture capital funds, Kleiner Perkins Caufield and Byers.
"We are very excited to have attracted such an experienced, proven executive to lead Response Biomedical," said Dr. Richard Bastiani, Chairman. "Wayne has a wealth of experience in the diagnostics industry, and particularly in POC, and has a proven acumen for building strong teams and executing on strategy. He led Quidel through a strong expansion phase in their history and his many years experience will be invaluable to lead the Company, as we begin our expected rapid growth phase."
"I am very pleased to be joining Response Biomedical at this exciting time in the evolution of the Company," said Mr. Kay. "With partnerships in place with Shionogi & Co. Ltd. and 3M Company, we are poised for strong growth. I look forward to leading the execution of our cardiovascular partnering strategy, as well as the scale-up in manufacturing, the launch of the new RAMP(R) Reader and the regulatory approval of three products, all anticipated in the next few quarters. These are the building blocks which I believe will significantly enhance shareholder value."
Dr. Bastiani continued, "On behalf of the Board of Directors, I'd also like to take this opportunity to thank Bill Radvak for his many years of dedicated service to the Company."
As part of Mr. Kay's compensation package, he has been granted options to acquire 1,500,000 common shares of the Company, subject to vesting requirements. The options are exercisable at a price of $1.07 per common share.
About Response Biomedical
xolair is about the only drug to compare
Randy,
The only other treatment I can think of that might lower IgE would be allergy shots (desensitization).
But maybe I wasn't clear about the statistical analysis. I would have liked to see an analysis (P values) that quantifies the likelihood that the difference in IgE levels between Prehistin and placebo was due to drug effect. The raw numbers seem to indicate a significant difference, but i found it odd that there was no P value.
urche
Unclear what this means
Here is the PR, rather oddly written, I think. It is notable for lack of any statistical analysis of the differences in IgE levels in the study arms, instead relying on the raw numbers. So we are left to guess or try to figure out for ourselves if the results are statistically significant. Of course, the IgE levels were not primary prespecified endpoints, so the data is good for hypothesizing and speculation, not basis for scientific claims.
Press Release Source: Cobalis
Allergy Patients Treated with PreHistin Had Rise in Ragweed IgE Antibodies Blunted During Pollen Season
Monday August 27, 6:57 pm ET
IRVINE, Calif.--(BUSINESS WIRE)--Cobalis Corp. (OTCBB:CLSC - News), a pharmaceutical company specializing in anti-allergy medications, today reported that seasonal allergy patients who received PreHistin had on average less ragweed IgE after the treatment than those who received placebo.
This is important because IgE is a key chemical mediator in allergic reactions. Developing a drug that can safely reduce specific IgE levels is a goal of drug companies.
These findings - along with the previously reported 250% average increase in blood cobalamin levels and the established safety of PreHistin - are testament to PreHistin's marketability to the over 50 million Americans with allergies.
The research
1,551 ragweed allergy patients received either 3.3mg of PreHistin twice daily for 42 days or placebo. Blood samples were taken from patients before and after treatment, that is, pre-seasonally and during the ragweed pollen season. The samples were analyzed by chemiluminescent immunoassay at Medtox Labs.
The results demonstrated changes in serum ragweed specific IgE levels from pre-treatment to post-treatment (in kU/mL): The average for the 737 PreHistin patients went from 6.27 to 7.68 (an increase of 1.41), while the average for the 735 placebo patients went from 6.34 to 9.20 (an increase of 2.86), a difference of 1.50 between the groups. IgE levels in allergic individuals generally increase during the allergy season. PreHistin blunted this expected seasonal rise in IgE.
Similar supporting studies in humans and mice
"The current anti-IgE results tend to replicate earlier findings that cobalamin treatment prior to the allergy season can affect the amount of ragweed specific IgE levels in humans. Allergy patients in the Pacific Northwest were given 15 mcg cyanocobalamin IM for 15 days (n=27) or placebo (n=34). Blood samples were collected prior to the treatment and approximately 10 months later during the next season. Chemiluminescent lab assays showed reductions in the ragweed specific IgE levels for the active group and increases for the placebo group," said Ernest Armstrong, chief scientific officer.
Funada, et al, reported serum IgE content was significantly higher in cobalamin-deficient mice than in the controls, and that IgE levels in the cobalamin-treated group showed a tendency to recover to control levels. In allergic mice, the serum IgE and pulmonary histamine concentrations were significantly lower in all cobalamin-administered groups than placebos. (International Journal Vit Nutr Research, 71 (1):p 60-65 January, 2001).
What is IgE?
Antibodies help to capture unwanted invaders. People who have allergies have an antibody called Immunoglobulin E, or IgE. Each type of IgE has specific "radar" for one type of allergen - ragweed, dog, cat, mold, etc. When the specific IgE comes in contact with such an invader, it causes the release of histamines and the symptoms of an allergic reaction: sneezing, nasal congestion, wheezing and coughing.
The existence of IgE antibodies is common to all forms of allergic disease, including: allergic rhinitis "hay fever," asthma, atopic dermatitis, urticaria, and other allergic reactions.
Studies have shown that IgE levels, and the prevalence of allergic disease, are now higher in children than in their parents. This problem is worsening over time around the world.
money tv
Anyone have access to this piece on MoneyTV?
http://biz.yahoo.com/iw/070810/0289003.html
"Cobalis Corporation (OTC BB:CLSC.OB - News) President Chas Radovich reacted to a filing to invoke involuntary bankruptcy"
It would be interesting to know what Chas has to know publicly at this time.
CAMH
I really don't intend to prolong this discussion or further my reputation as a curmudgeon. I can accept the conclusion that current evidence suggests TWA testing has "implications for risk stratification and health policy".
Where I think we can agree to disagree is that I don't see how the results published so far can be applied by an INDIVIDUAL patient and an INDIVIDUAL doctor. With non-ischemic cardiomyopathy and a negative test, I think we can say the results could be used to avoid unnecessary AICD insertion. Other than that, I don't think we can say the test has the specificity or sensitivity to answer the critical questions it is supposed to address.
My mind really is open, believe it or not.
Urche
Don't know what you are talking about,
and I am a subscriber who thinks the money is well worth it.
CAMH
99% negative predictive value would be a compelling statistic in favor of making TWA testing standard of care.
I believe you cite that statistic based on the ALPHA study reported earlier this year.
http://tinyurl.com/yoknyl
The ALPHA study (Prognostic Value of T-Wave ALternans in Patients with Heart FAilure Due to Nonischemic Cardiomyopathy) enrolled 446 consecutive patients with NYHA Class II or III non-ischemic cardiomyopathy and left ventricular ejection fraction (LVEF) less than or equal to 40%. On the primary endpoint (cardiac death and life-threatening arrhythmias) an abnormal MTWA test had a Hazard Ratio of 4.01 (p=0.002), or four times the risk than a normal MTWA test. The 12-month negative predictive value of the test was reported to be 98.7%, indicating that patients with a negative test result are at very low risk of sudden cardiac death. For patients with LVEF less than 35%, the Hazard Ratio and negative predictive value were 4.28 (p=0.004) and 99%, respectively.
Note that this study was in patients with non-ischemic cardiomyopathy. I believe that about 75% of cardiomyopathy is ischemic, at least in the developed world. As far as I know, we don't yet have phase III results of a prospective study in the ischemic cardiomyopathy population. From this PR (http://tinyurl.com/2e887j), it appears that the results will be no better than EP testing, the current standard of care.
"The positive and negative predictive values of a MTWA-directed strategy and that of an EP test alone were essentially identical," said Costantini. "This is most important, as the clinically relevant question today is not who should receive an ICD, but who is unlikely to benefit from ICD therapy. The use of a non-invasive approach to help us answer this question represents a significant step forward."
IF TWA is similar to EP testing, that is pretty good, obviously, but no where near 99% negative predictive value.
I am predicting that the negative predictive value for the typical patient with ischemic cardiomyopathy will be significantly lower, perhaps low 80's. My feeling is that will be low enough to make the test not acceptable as standard of care for a literally life and death decision.
CRYO/ CYT.to
Jonmarin, I am interested enough in Cryocath that I bought a small amount, enough to stimulate more research. I think it sounds like a good technology with reasonable patent protection and a very large and growing market, patients with atrial fibrillation/flutter.
After watching the company for a while, the news that they sold their surgical device unit, thereby becoming more focused on the ArcticFront device, was enough to convince me to buy.
Does anyone have information on differences between the Cryocath and Cryocor devices? Also, other than BSX is there any other competition for cryotherapy devices in arrhythmia control?
I am already overweighted in Canadian companies---- and SemBiosys is looking awfully interesting, too.
CRYO, CYT.to, with a touch of DNDN
Regarding CryoCath and its deal with Boston Scientific, here is an article from Heart.org (which requires registration so I won't post a link).
This article may have limited relevance since the CryoCath device apparently will not be developed further by the company. Instead BSX will be using some of their technology. But, what I find interesting is the color provided on the reasons for panel members' votes and the seemingly onerous conditions placed on the approval. CRYO holders should be relieved that BSX has spared them the agony of becoming DNDN REDUX. I particularly appreciate the courage of Dr Sharon-Lise Normand (see bold passage).
Cryoablation catheter for atrial flutter gets thumbs-up—with conditions—from FDA advisory group
June 28, 2007 Shelley Wood
Gaithersburg, MD - The FDA's Circulatory System Devices Advisory Panel has voted 8 to 2 in favor of recommending approval of the CryoCor Cryoablation System for the treatment of atrial flutter. Those yes votes, however, came with near-unanimous agreement on a set of conditions pertaining to labeling, training, and postmarket approval studies.
"At least the majority of the panel believes there is an important clinical need for this device," committee chair Dr William H Maisel (Beth Israel Deaconess Medical Center, Boston, MA) summarized after the vote. "It has been said by many people on the panel that this is about the patient. For me as a practicing clinical electrophysiologist, I'm glad that I might have this tool on the shelf to pull out in certain cases."
The cryoablation device works on the same premise as a radiofrequency (RF) ablation device, with the aim of blocking electrical conduction in myocardial tissue; instead of RF current, the cryocatheter delivers extreme cold from the tip of the ablation catheter. As the sponsor, CryoCor Inc, showed today, the pivotal study of its device was a prospective, nonrandomized, multicenter, single-arm study conducted at 24 US sites; a total of 160 out of 187 patients had the cryoablation catheter inserted.
For much of the day, panel members grappled with the fact that while the totality of the data supported the acute and long-term safety and efficacy of the device, the pivotal trial did not include a comparator group and, more damning, did not meet its end points for chronic effectiveness and safety as set out in the objective performance criteria (OPC) for the study. The seven-day serious adverse-event rate in the study was 6.25%, with a 95% upper confidence bound of 11.19%, yet the prespecified goal for this end point was 2.5% with an upper confidence bound of 7%. Similarly, chronic effectiveness was 81.6% with a 95% lower confidence bound of 74.7% in the pivotal trial, yet the prespecified chronic effectiveness goal was 90% with a lower confidence bound of 80%.
Science vs subjectivity
One of the dissenting votes came from Dr Norman S Kato (Cardiac Care Medical Group, Encino, CA), who stated he was voting no because the sponsor had failed to satisfy the OPC that had been mutually agreed on with the FDA at the outset. "To basically ignore the criteria at this point would be to allow a panel decision or an FDA decision to occur that really wasn't evidence based but was subjective," Kato said. "I believe this is a slippery slope of modifying the success criteria by which these devices are compared. If there were a dispute about the OPC, that would be one thing, but in this situation both the FDA and the sponsor agreed on the criteria. . . I would hope that in the future device companies would use a lot more scientific rigor and evidence to prove safety and efficacy, as opposed to coming back and having this line moved around."
The other no vote came from statistician Dr Sharon-Lise Normand (Harvard School of Public Health, Boston, MA), who agreed with Kato that the panel was setting a poor precedent. "Subjective opinion, I feel, has caused a lot of the votes today, and I'm very concerned about that for patients. I think the public good is at stake here: the data tell us that the safety is twice as bad and the efficacy end point wasn't met," she argued. "I can tinker with it in a thousand different ways and come up with an answer I would like to have, if I wanted that answer, but I have 25 years of experience looking at scientific evidence, and clearly the data do not support approval of this device."
But other panel members argued that the company had gone out of its way to examine the safety data and suggested that the collected adverse-event data might have been boosted by events that had nothing to do with the cryocatheter. Moreover, the OPC were selected on the basis of RF ablation studies for other types of arrhythmia and were not necessarily applicable in this setting, they argued.
"I'm very uncomfortable with deviating from the previously agreed-upon OPC, but on the other hand, I think that the basis of those OPC was experience with supraventricular arrhythmias," Dr Adam Lottick (St Vincent's Hospital, Bridgeport, CT) stated, explaining his yes vote. "If I were determining the OPC that we would be using based on our current understanding of flutter, I think that these criteria would be met."
Likewise, Dr Clyde Yancy (Baylor Heart and Vascular Institute, Dallas, TX) argued that the benefits in this case likely outweigh the risks. "My vote was yes because, ultimately, we are here to serve patients, and I didn't see a very strong signal that this was harmful or dangerous, and I saw sufficient evidence to suggest it was likely beneficial," he explained. "On the aggregate, the PMA [premarket approval application] is not especially strong, but I don't see any reason to restrict good-faith physicians from having access to a different technology to attempt to help their patient population."
Several panel members were intrigued by the albeit-limited data suggesting that cryoablation is a less painful procedure than RF ablation. Several acknowledged that this attribute would be a welcome addition to the EP lab, particularly if the need for or intensity of sedation could be reduced. Dr David Slotwinder (Long Island Jewish Medical Center, New Hyde Park, NY) confessed to his fellow panel members that he has used a different cryoablation catheter, off-label, for the treatment of atrial flutter almost "exclusively" for the past few years and that the difference in pain perception is "remarkable."
"I want to express to the panel how important a benefit, I think, the reduction in pain is with cryo," he commented.
Conditions for approval
Panel members were keen to have any niggling concerns ironed out as conditions for approval. They unanimously voted in favor of a condition that would require labeling changes to clarify that the device should be used in the right atrium, not the left, and that full details on the types of patients included in, and results from, the pivotal trial be included in the label.
They also voted with nine in favor and one abstention to a condition requiring an "in-person" training program in the use of the device for physicians and associated staff.
In a third, hotly debated condition for approval, panel members recommended that the company be required to conduct a postmarketing registry study, including a comparator arm, examining near-term safety, long-term adverse events, and clinical effectiveness. While almost everyone agreed on the need for a rigorous postmarketing study, the panel was divided as to whether the registry should be restricted to people in whom the data were originally acquired, or in a wider "real-world" population that included off-label use, including patients with heart failure (HF) or recent MI.
Yancy, in particular, insisted that an all-comers registry study, postapproval, should not be a stand-in for a randomized clinical trial in patients excluded from the existing studies. He made what he called a "strong plea" to the sponsor to specifically and prospectively study its device in patients with HF.
"My experience using a denominator of patients with HF is that they don't do very well with RF ablation, and I don't know how they do with cryoablation. I'm concerned that without some strong provisos focused on that patient population and without some forward-looking cryo/HF experience, we face the very real risk of hurting a very vulnerable patient population."
Several panel members also gently chided the FDA for permitting a company to put together a PMA based on a relatively small, single-arm study. While this might be appropriate in some experimental situations, in which a suitable comparator group could not be found or ethically justified, such a group could be easily identified in this case, they suggested.
CAMH
"Putting the currently available studies of microvolt TWA in LV dysfunction in perspective, it can be concluded that the predictive efficacy of the test is largely dependent on the patient population studied."
I am becoming more convinced that TWA testing measures something consistently with validity that is close to or a little better than clinical judgement (based largely on EF and history of ventricular arrhythmia), and/or EP testing which has never been much of a gold standard.
Applied to a population, the test seems to have some validity. At the risk of sounding like a curmudgeon, I remain skeptical that TWA testing is going to enjoy a role as standard of care for testing INDIVIDUAL cardiac patients.
urche
CAMH
I doubt this is news, but this article on T wave alternans is a good summary and reasonable viewpoint, IMO. Bold emphasis is mine.
Value of TWA test for primary-prevention-ICD screening varies by patient risk status
Jul 3, 2007 Steve Stiles
New York, NY - Microvolt T-wave alternans (TWA) testing (Cambridge Heart, Bedford, MA) can help identify patients who qualify for a primary-prevention implantable cardioverter-defibrillator (ICD) who are at low risk of ventricular arrhythmias, but its predictive value is better in some such patients than others, a prospective study suggests [1].
In particular, those who are device-eligible based on low-LVEF criteria but who also have nonsustained VT (NSVT) or syncope can be more reliably risk-stratified by the combination of TWA and electrophysiologic (EP) testing, conclude the study's authors, led by Dr Daniel J Cantillon (Cornell University Medical Center, New York, NY). Their report is scheduled for the July 10, 2007 issue of the Journal of the American College of Cardiology.
For such patients in the study, who had cardiomyopathy of either ischemic or nonischemic origin, the two tests together were more predictive than either alone, according to the authors. But, as coauthor Dr Sei Iwai (Cornell University Medical Center) told heartwire, the event rate associated with a negative TWA test by itself was high enough to question the safety of withholding primary-prevention device therapy.
Apples and oranges?
In the analysis of 286 adult patients with an LVEF <35% referred for EP testing due to NSVT or syncope, TWA testing was performed during atrial pacing in the course of a standard EP study. The technique differs from the more traditional approach of noninvasive TWA testing during exercise stress, complicating comparisons of the current TWA study with most others.
Iwai observed that there is support in the literature for both forms of TWA testing in risk stratification, although they tend to yield different predictive values. Exercise, unlike atrial pacing performed in an EP lab, greatly alters autonomic tone and catecholamine levels, "so you can't say the ways are comparable, and that's a bit of a limitation in the study."
The more important message, however, is that TWA testing probably has to be combined with another risk-stratification strategy, like EP testing, to identify patients like those in the study as at low enough risk to safely avoid receiving ICDs, Iwai said. In the current analysis, a negative result on both the TWA test and the EP study was associated with an 85% two-year rate of survival free from sustained ventricular arrhythmia.
Other findings
The results of TWA testing and EP testing were discordant in 49% of patients, "highlighting the fact that, although TWA and EP studies can both be used to potentially risk-stratify patients for sudden cardiac death, they identify different patient population sets," the authors write.
Number of subjects with each combination of positive and negative TWA and EP test results (and two-year arrhythmic event rate)
Finding
Negative TWA test (n=90), n (%)
NonnegativeTWA test* (n=196), n (%)
Positive EP study (n=115)
29 (28)
86 (33)
Negative EP study (n=171)
61 (15)
110 (35)
*Nonnegative tests=all positive plus all indeterminate tests, according to convention. TWA=T-wave alternans; EP=electrophysiologic
To download table as a slide, click on slide logo below
Without adjustment for potential confounders, a negative TWA result significantly predicted arrhythmia-free survival, with a hazard ratio (HR) of 2.33 (p<0.01) compared with only 1.27 (p=0.21) for a negative EP study. The HR for TWA testing remained significant in an analysis that controlled for age, sex, QRS duration, LVEF, NYHA class, ischemic vs nonischemic etiology, and subsequent ICD implantation.
In an accompanying editorial, Dr Thomas Klingenheben (JW Goethe University, Frankfurt, Germany) points out that EP testing has different predictive values in ischemic and nonischemic cardiomyopathy [2]. So findings based on the current study's mix of etiologies—in 75% and 25% proportions, respectively—don't necessarily apply to the majority of ICD candidates, who have ischemic disease.
For that group, Klingenheben notes, there are data from the Alternans Before Cardioverter-Defibrillator (ABCD) trial, which compared noninvasive TWA with EP studies in patients with ischemic disease, NSVT, no prior ventricular tachyarrhythmias, and an LVEF <40%. ABCD was presented at the American Heart Association 2006 Scientific Sessions and reported by heartwire at the time.
"In that study, both tests were equivalent in predicting appropriate ICD shocks or arrhythmic death, and their negative predictive values were 95%, rising to 98% if both tests were combined," Klingenheben notes. Those numbers are much higher than the 79% negative predictive value observed for TWA testing in the current study's ischemic patients, who had additional risk factors, he observes. "Putting the currently available studies of microvolt TWA in LV dysfunction in perspective, it can be concluded that the predictive efficacy of the test is largely dependent on the patient population studied."
I would have said Pfizer also,
having acquired the IP when they bought Esperion.
Could it be the Italian researchers that discovered the community that had the mutation and did the genetic research?
urche
rest of abstract
For some reason I couldn't get the entire abstract to post. sorry about that. If anyone wants the abstract or article, send me a private email.
urche
Article in major journal
Recent activity may be partly fueled by late June publication of the IMPROVE-CHF study. I don't think this is new news, but acceptance by academics and clinicians is always helped by publication of result in a reputable journal. The article cites Roche as sponsor. There is an accompanying editorial generally positive about the importance of the test, at least for its potential to contribute cost-effectively to decision making within the Canadian health care system. Applicability to the US and comparison to the more commonly used BNP tests in US remain open and relevant questions.
Here is the abstract from Circulation, Journal of American Heart Association:
N-Terminal Pro–B-Type Natriuretic Peptide Testing
Improves the Management of Patients With Suspected Acute
Heart Failure
Primary Results of the Canadian Prospective Randomized Multicenter
IMPROVE-CHF Study
Gordon W. Moe, MD; Jonathan Howlett, MD; James L. Januzzi, MD; Hanna Zowall, MA; for the
Canadian Multicenter Improved Management of Patients With Congestive Heart Failure
(IMPROVE-CHF) Study Investigators
Background—The diagnostic utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure has been
documented. However, most of the data were derived from countries with high healthcare resource use, and randomized
evidence for utility of NT-proBNP was lacking.
Methods and Results—We tested the hypothesis that NT-proBNP testing improves the management of patients presenting
with dyspnea to emergency departments in Canada by prospectively comparing the clinical and economic impact of a
randomized management strategy either guided by NT-proBNP results or without knowledge of NT-proBNP
concentrations. Five hundred patients presenting with dyspnea to 7 emergency departments were studied. The median
NT-proBNP level among the 230 subjects with a final diagnosis of heart failure was 3697 compared with 212 pg/mL
in those without heart failure (P
Clinical / Regulatory / Litigation Calendar
[Please keep entries up to date! See updating procedure at the end of this post.]
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: Cobalis
ACHN – See GILD
ADLR – Approvable letter for Entereg issued 11/6/06 requesting safety data due in 2Q07.
AMLN – Phase-3 LAR results: 2H07; Byetta monotherapy results: 2H07.
ANDS – ANA975 for HCV placed on hold 6/26/06 due to preclinical safety issue; human trials expected to resume at end of 2007 following FDA analysis of animal tox study.
ANOR / AOM.TO – pivotal AMD3100 results any day.
ASPM – Interim data from BRITE trial in depression: scientific conference in 2Q07.
CLSC - Top line results for two phase 3 Trials of Prehistin deemed inconclusive due to low symptom scores in treated and control arms. No further studies announced, possible OTC launch based on prior phase 3 study.
COR – CX-717 tox data submitted to FDA 4/18/07 requesting removal of dosing limitations; reply estimated by mid-July.
CRME - IV RSD1235 NDA refiled, PDUFA Oct 19, 2007.
CYT.TO - Initiated pivotal A-fib trial Oct/06. Complete enrollment 2nd/half 07. Results 2nd half 08.
DDSS – Tramadol NDA: second approvable letter received 5/31/07. New clinical trial likely.
DNA – resubmission of Avastin in breast cancer Q3 07, Avastin adjuvant CRC interim look Q4 07, Rituxan in Primary Progressive MS Ph III Results Q1 08
DNDN – Provenge 9902b study: interim analysis (~180 deaths) 2H08; final analysis (360 deaths) 2010.
DORB – OrBec NDA in GVHD: PDUFA date 7/21/07. (Advisory panel recommended against by 7-2 vote on 5/9/07.)
GILD – Viread NDA submission for HBV: 4Q07.
GILD – GS9190 polymerase inhibitor for HCV: data from phase-1: 3Q07.
GPCB – Satraplatin NDA to ODAC 7/24/07; PDUFA date mid-August. SPARC trial final OS data: fall 2007.
GTCB – ATryn EU launch for HD: July 2007.
GTCB – ATryn DIC program in EU: start of ph-2 (by Leo Pharma) any day.
GTCB – ATryn ph-3 for HD in U.S.: complete enrollment 3Q07, report data 4Q07, submit BLA 1Q08.
GTCB – Merrimack MM-093: results of phase-2 extension trial in RA: late 2007.
GTOP – Final MyVax results Dec 07.
IDIX – NM283 P2 “drug interaction” study: full data at medical conference at AASLD (top-line results were released 6/12/07); new P2b to test anti-emetic regimens to start 2H07.
IDIX - File IND for IDX102 and/or IDX184, 2nd generation HCV nucleosides in 4Q07.
IDIX – Tyzeka P3 in decompensated liver disease: enrollment complete in 1Q07 (75% complete as of 9/27/06);
P3b early viral kinetics (12 week) study, telbivudine vs entecavir, data 4Q07; P2 data for valtorcitabine plus telbivudine 4Q07.
IDIX - IDX899 enters dosing range P1/2a 1H07; human study 4Q07; data on IDX-899 4Q07; first human data in Feb 08 (CROI).
IMCL –
1) Erbitux in NSCLC: OS in 1st-line FLEX study 2H07.
2) Erbitux in 1st-line CRC: CAIRO2 (capox/bev/cet) top line results 2H07
ISA.TO-European psoriasis P3 results 2008. Phase 2B 6&12 month renal results 2008. Phase II/III Uveitis results 2008.
ITMN –
1) ITMN-191 Phase-1B Trial Initiation Q3 2007
PK data for ITMN-191: Q4 2007
2) Pirfenidone - CAPACITY Trial Enrollment Completion May 2007
CAPACITY Trial Top-line results Late 2008 (72 week treatment period)
JNJ: CoStar (CONR) data from U.S. pivotal trial: March 2007 at ACC
LBPFF – see DDSS
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.
Merrimack: see GTCB
MS.TO - Complete enrollment in pivotal Secondary Progressive MS trial this year, interim results mid 2008, trial results in 2009.
Novocell – see SRDX
NRMX, NRM.TO – North American Alzhemed trial complete Jan 07, results to follow. European Alzhemed trial complete 1H08 (?). Kiacta (Fibrillex) received an approvable letter on 8/11/06.
NVS – Tifacogin: enrollment complete 1H07 (#msg-15157973).
PHRM – See GPCB.
POZN – Trexima FDA response date: 8/1/07.
RPRX
Proellex
*Uterine Fibroids Phase 2 (U.S.) Full Phase 2 data (mid-2007)
*One year extension data (4Q2007)
*Initiate pivotal trials (YE2007)
*Initiate U.S. Phase 2 (mid-2007)
Androxal
*Male Secondary Hypogonadism Non-pivotal Phase 3 (U.S.) Full non-pivotal Phase 3 data (3Q2007)
*Initiate first pivotal Phase 3 (around YE2007)
SGP – Ph-2 data for SCH 503034 in HCV: 2H07
SPPI – See GPCB.
SRDX - Novocell phase-1/2 trial in type-1 diabetes: late summer 2007 (enrollment complete 8/30/06).
SYMD- Synthemed-Circulatory System Devices Advisory Panel has been scheduled for September 19, 2007 for Repel CV.
TH.TO -Complete enrollment confirmatory TH9507 HIV Associated Lipodystropy trial 3rd qtr/07, final results 1st qtr/08.
VPHM – HCV-796 500mg phase-2 trial: 4-week data 3Q07, 12-week data 4Q07.
VRTX – Telaprevir: PROVE-1/PROVE-2/PROVE-3 phase-2 timetable: #msg-12267294; start phase-3 by end 2007.
VRUS – Ph-3 Clevudine for HBV: start phase-3 3Q07; Ph-1 R7128 for HCV: 14-day data 4Q07.
ZGEN – rThrombin FDA response date: late October 2007.
--
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news
That's not the news I was hoping for!
There was some interesting trading at end of day.
Looks like some speculators were fooled into a losing bet when the trading halt was announced.
Right after the trading halt was announced on TSX around 3:30 pm, the shares of RPBIF skyrocketed more than 20% in US.
http://finance.yahoo.com/q/bc?s=RPBIF.OB&t=1d&l=on&z=m&q=l&c=
I was hoping this would be news that FDA has approved Response's BNP test. If that news is coming soon, those shares bought for $1 today will look like a sweetheart deal. OTOH, if FDA approval is not forthcoming, the company will look smart for having raised $12M while conditions were good.
Urche
ASTHMA
ONCO, It was you who brought up asthma:
"they have the patent for b-12 and asthma remember"
Let's move on.
Urche
asthma
Onco, show me the data.
As far as I know the first Phase III study measured allergic rhinitis symptoms.
This is from the Cobalis website:
PREHISTIN™ PHASE III CLINICAL TRIALS
Cobalis commenced Phase III Clinical Trials for PreHistin™ in November 2004, when the Company engaged its first Phase III study with four arms and 714 patients during the Mountain Cedar allergy season in central Texas. The primary endpoint of the study was reduction in Total Nasal Symptom Score (TNSS). In July 2006, Cobalis began two twin 10 week pivotal trials with 1551 patients designed to determine the efficacy and safety of 3.3mg of PreHistin BID versus placebo in seasonal ragweed sufferers, with the primary endpoint being the TNSS for weeks 4, 5 and 6. Data from the Mountain Cedar study were used to design the pivotal ragweed studies and are expected to support the results from these pivotal trials in a New Drug Application to the FDA. The Company anticipates announcing the results of the pivotal Phase III ragweed trials by early Spring 2007. If these trials are successful, the Company intends to seek FDA approval to market PreHistin as an over-the-counter allergy medication for seasonal allergic rhinitis.
Phase III trials are conducted to provide data for statistical evaluation of efficacy and safety, with an end result of FDA approval for specific marketing claims and required packaging disclosure and documentation. Government regulation in the US is a significant factor in the production and marketing of new drugs. The FDA must approve all new OTC and prescription drugs, which includes any new use for a substance, even if previously used safely for a different purpose. In the US, companies are subject to rigorous requirements in order to engage in human clinical testing to, in turn, gain approval of a drug.
The primary indication being studied is the reduction of the symptoms of seasonal allergic rhinitis (outdoor allergies or hay fever).
Supplemental Indications Timetable
Cobalis may sponsor clinical research for approval of additional indications.....
Consider conducting clinical trials for gaining FDA approval of supplementary
indication of atopic asthma
they have the patent for b-12 and asthma remember
But do they have enough evidence of efficacy in asthma to make a labeling claim?
buy or not?
I don't plan to buy more stock in this company until I hear a business plan. I haven't heard anything except speculation that they may launch OTC this year. I know there is already competition with sublingual B12, so I would like to know what Cobalis can offer as a niche or marketing advantage. I think the initial phase III study is sufficient to make some claim that it helps allergy symptoms, but I don't know if that is the plan.
Who would be the distributor and marketing partner is also important. So, I might miss a great buying opportunity waiting for those answers, but better than sending good money after bad.
urche
ASPV
This news obviously diminishes if not kills the chances for Cell-cept to be approved for lupus nephritis. Less risk now, less potential gain. So, Aspreva's value becomes easier to figure---pretty much based on its huge cash horde and positive cash flow until its patent protection runs out in 2008 or 2009.
IMO, any upside will depend on two potential developments:
1) Significant off label use in lupus nephritis. After all, the data seems to show that Cell-cept is at least as beneficial as cyclophosphamide, the standard of care, though not superior. Since it is already an approved drug and reportedly enjoying significant off-label use, the data will probably increase use off label.
2) An answer to the question of what the company will do with all that cash (probably > $300 million and growing) burning a hole in their pocket.
Urche
The lights are on and phones working....
Despite the sentiment voiced here that the company is no longer responsive to phone calls, I did get thru easily and was told that they are trying to talk to all investors. But, don't expect answers to the types of questions being asked repeatedly here.
No real significant news to me except for confirmation that a second CRO has been hired, obviously an unanticipated expense that has caused some employees to once again opt to defer paychecks in order to pay the CRO. The company believes that the data has not been analyzed in any way that would prevent a valid audit, and that they are in accordance with FDA guidelines for such an audit. So, there is still a sense of hope and no bridges burned. FWIW, the idea of launching without FDA approval is only one of many options if the phase III studies turn out to be inadequate for approval.
So, back to waiting.
20,000 shares, mostly well aged, avg price about 1.50
I sold some trading shares after last financing and haven't found the enthusiasm to get back in.
I am still holding strong on my remaining shares.
urche
A classy response, Geoff. Well done.
CAMH---still skeptical but not closed minded. I did talk to two of the cardiologists at my hospital and they remain ready to embrace T wave alternans if it gets substantiated. But for now, they admit that they continue to put ICD's in pt's who don't need them and wish they had put ICD's in pt's who have sudden cardiac death.
Regards,
Urche