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>> anyone have info handy on what percent of the HBV market HIV/HBV coinfection encompasses <<
I'd like to see a good summary of the coinfection problem as it applies to the major markets as well ( HBV/HIV , HCV/HIV, HBV/HCV, HBV/HCV/HIV -- I think that's all of 'em , unless we look at genotypes ).
I looked around some and found things like 6-10% of HIV patients are coinfected with HBV , but it varies widely by region / other factors. Things like sharing needles by drug users changes the ratios of coinfected patients dramatically. The HCV naive vs. nonresponder cohorts would likely show different coinfection rates also.
If you use the following worldwide incidence figures (ballparks only) you can get an upper limit for the total numbers of HBV or HCV patients coinfected with HIV , but it would say nothing about the ratios in any given market(s) :
HIV: ~ 40 mill.
Chronic HBV : ~ 400 mill.
Chronic HCV : ~ 200 mill.
If anyone finds a good source of data we should put it in the RMF.
>> this PJ report seems "rather convenient" <<
The timing is suspicious , I'd agree. Who knows what the motivation might be. I'd much prefer that we got all relevant info on a company from the company itself , in a timely manner , rather than see it leaked out by those in the market with "contacts" that we don't have access to.
I know , I'm dreaming.
>>> PEG and NM283 @ 48 weeks was already shown to have a significantly higher SVR than SoC <<<
Not SVR , but HCV-negativity @ 48 wks. was superior. The PJ report suggests that once off-treatment , NM283/pegifn patients relapse at a higher rate (maybe much higher ? ) than SOC patients.
This doesn't surprise me that much , given that the value of riba in SOC is not because of the incremental benefit it adds in direct antiviral activity , but rather the reduced relapse rates it yields ( i.e higher SVR) , probably due to immunomodulating effects ( Th1-biasing ).
IDIX was no doubt tripped up by the early replicon data showing no benefit of riba addition. It was still a blunder , IMO , not to plan for riba tests in humans from the start , just to cover all the bases. Now they'll be flying blind , or nearly so , into P3s with a meager database to base them on.
The ultimate outcome could still be good -- maybe spectacular. No one knows what the triple therapy will show , and if they get more rapid viral load reductions ( vs. SOC ) with riba adddition it will translate to higher SVR rates , IMO.
I think the implication is that the only way they can get to P3 is with triple therapy , and that IDIX might decide to go to the P3 based on the outcome of the current study alone.
I've been wondering why we've never heard anything about SVR rates from past studies of NM283. Now we know -- there weren't any.
If IDIX wants to do a dose-optimizing P2 triple therapy study they better do it pronto. They're going to wake up one morning to find VX950 the new SOC , with the higher approval hurdle that goes along with it. If things are as gloomy as PJ suggests , I bet IDIX will give serious consideration to waiting for VX950 approval , then run the combo polymerase-protease trials that everyone is expecting.
Bummer.
OT : Try saying the title of my last post five times , real fast.
I can't do it , but then again , I only speak well in writing.
Two Genes Identify Early-Stage Lung Cancer Patients with Excellent Prognosis
Zosia Chustecka
Medscape Medical News 2007. © 2007 Medscape
February 21, 2007 – Among patients with early-stage non–small-cell lung cancer (NSCLC) undergoing potentially curative surgery, the coexpression of 2 gene proteins identifies a subgroup with an excellent prognosis, researchers from the Lee Moffitt Cancer Center in Tampa, Florida report in the February 22 issue of the New England Journal of Medicine.
The 2 genes, both involved in DNA synthesis and repair, are the regulatory subunit of ribonucleotide reductase (RRM1) and the excision repair cross-complementation group 1 (ERCC1). About 30% of the patients investigated (55 of 184) had high levels of both gene markers, and clinical records showed that they had an excellent outcome.
Patients who have high expression of these 2 gene proteins do not need to receive adjuvant chemotherapy, as "almost all of these patients are truly cured by surgery," senior author Gerold Bepler, MD, PhD, commented to Medscape.
Adjuvant chemotherapy is given to most patients with completely resected lung cancer, usually immediately after surgery, Dr. Bepler explained. The aim is to prevent disease recurrence, which occurs in about half the patients. "However, this treatment has resulted in an approximately 10% improvement in patients' survival, meaning that many patients get chemotherapy after surgery without getting a benefit, and some will even be harmed by this."
Testing for the 2 gene markers can identify patients with high levels of expression who do not need to undergo chemotherapy, Dr. Bepler said. "The test is relatively easy to do and can be performed on standard specimens," he added. However, the test is not yet approved by the FDA, and "the finding should probably be confirmed in a large cooperative trial."
For their study, Dr. Bepler and colleagues developed a process for automative quantitative determination of the RRM1 protein in routinely processed histologic specimens. They also measured expression of ERCC1 and another protein, the phosphatase and tensin homolog (PTEN), but found that this third marker was not correlated with survival.
The researchers comment that analysis of RRM1 has been technically difficult in the past, but the system they developed allows gene-expression analysis of both RRM1 and ERCC1 that is "objective, reliable, and reproducible."
Same Markers Predict Poor Response in Advanced Cancer
The same 2 gene markers have previously been shown to predict which patients with advanced NSCLC have a poor response to chemotherapy with gemcitabine and platinum compounds.
"RRM1 and ERCC1 are important in controlling the 'integrity' of the DNA during cell doubling," Dr. Bepler explained. "We already know that chemo does not work well in patients with high expression of both genes, because chemo works by causing DNA damage, which is fixed by these genes." Hence, patients with low levels of these genes have a more aggressive cancer and benefit most from chemotherapy, he said.
Both potential uses for the 2 gene markers are highlighted in an accompanying editorial, written by Adi Gazdar, MD, from University of Texas at Dallas. "Knowledge of these 2 gene markers could affect 2 major aspects of the management of NSC lung cancer: the selection of patients with resected early-stage tumors who do not require adjuvant therapy, and the selection of patients who are not likely to benefit from conventional chemotherapy for advanced cancer," he says.
N Engl J Med. 2007;356:800-808, 771-773.
http://tinyurl.com/3bud87
Protocol for Factor VIIa Reduces Costs, Increases Off-Label Use
Martha Kerr
Medscape Medical News 2007. © 2007 Medscape
February 21, 2007 (Orlando) — Guidelines devised and implemented at the University of Michigan Health System in Ann Arbor for the appropriate use of recombinant Factor VIIa have resulted in an increase in off-label use of the drug. Despite this, there has been a decrease in the number of doses given, resulting in a significant cost-savings with this expensive drug, researchers announced here this week at the 36th annual meeting of the Society of Critical Care Medicine.
"We instituted guidelines, including appropriate dosing, because the literature is wide-ranging on what the recommended dosing is," principal investigator Dina A. Mohammad, PharmD, told Medscape. "Another reason for the need for guidelines is that we have seen a shift in use of Factor VIIa, with an increase in off-label use."
Dr. Mohammad pointed out that "Factor VIIa is being used more often for bleeding that is not related to hemophilia, despite the fact that there aren't many controlled trials of off-label use of Factor VIIa. This increase in off-label use has resulted in significant increases in healthcare expenditures." She estimated the cost of Factor VIIa as approximately $0.85/µg.
The Factor VIIa guidelines were implemented at the University of Michigan Heath System in October 2005. A retrospective and ongoing review of patterns of use of Factor VIIa in the 12 months prior to and 8 months postimplementation was conducted by Dr. Mohammad and colleagues.
In the year prior to implementation of the guidelines, 70 adult patients received 277 doses of Factor VIIa, with an annual cost of $1.8 million. Postimplementation, 146 patients received 185 doses, for an annual expenditure of $1.3 million.
The total number of patients receiving Factor VIIa increased from 5.8 patients per month before the guidelines to 12.1 patients per month after implementation. But the total number of doses given per month decreased from 23.1 to 14.9.
Appropriate use of Factor VIIa was 91% before the guidelines were instituted. Off-label use increased afterward, but its use for hemophilia decreased to 72%.
The total number of doses given for hemophilia decreased from 23.1 to 15.4 doses per month. At the same time, the number of doses for nonhemophilia indications increased from 6.3 to 14.9 per month. Nearly all off-label use of Factor VIIa was related to bleeding associated with cardiothoracic surgery, with the number of doses used in that setting increasing from 1.9 to 8.1 doses per month after guideline implementation.
Total annual expenditures decreased $500,000 with Factor VIIa guidelines in place, despite the increase in off-label use of the drug.
"Factor VIIa use carries a heavy cost-burden," Dr. Mohammad said. "It is a significant expenditure."
"Factor VIIa is the number-one expenditure for hospital pharmacies because it is so expensive," meeting participant Ernest Alexander, PharmD, from Tampa General Hospital in Florida, asserted.
"We have adopted similar guidelines — it has resulted in $100,000 a year [in savings] with just this intervention," Dr. Alexander said. "If it is administered as ordered, that's 6 doses at a total cost of $90,000. With our guidelines, we got away with a cost of about $2,000 a patient, for a total annual cost of about $70,000."
"The reason [for the cost savings] is dose control," Dr. Alexander said. "We are currently conducting a prospective evaluation [much like Dr. Mohammad's] to determine just what the savings is with use of the guidelines.
"What we really need is a gatekeeper, such as a hematologist," Dr. Alexander said. Dr. Mohammad agreed, noting that a gatekeeper reviews every case for which Factor VIIa is prescribed at the University of Michigan. "Our hematologists support the use of Factor VIIa guidelines.
"The main conclusion here is that guidelines for the appropriate use and dosing of Factor VIIa are necessary," Dr. Mohammed said, with Dr. Alexander in strong agreement.
Dr. Mohammad and Dr. Alexander report no relevant financial relationships. The research was not commercially supported.
SCCM 36th Annual Meeting: Poster 549. Presented February 20, 2007.
http://tinyurl.com/2chopo
Baraclude blemish ?
I suppose the solution to this problem is to only use entecavir in combo with HAART in co-infected patients. Cross-resistance with HIV drugs is another criterion of HBV drugs that may determine market share.
Hepatitis Meds May Be Linked To Drug Resistant HIV Canadian Health Agency Warns
by The Canadian Press
February 21, 2007 - 9:00 pm ET
note from Jules Levin: A poster at CROI, the HIV conference upcoming Feb 25, 2007, will be presented by a researcher regarding the finding discussed below.
(Ottawa) The manufacturer of the antiviral drug Baraclude says the drug may be linked to the development of a treatment-resistant strain of HIV in one patient with the disease.
Baraclude, the brand name for the drug entecavir, has been authorized for use in Canada since June 2006 for the treatment of adults with active chronic hepatitis B infection.
But in an advisory issued Wednesday, Health Canada said the drug's manufacturer informed the federal department that a U.S. patient _ infected with both HIV and hepatitis B _ became resistant to one of the more commonly used HIV medications while taking Baraclude alone.
The report is one of three from the United States submitted by Bristol-Myers Squibb Canada concerning HIV patients who experienced a decrease in their human immunodeficiency virus levels while using Baraclude, despite not being treated with HIV drugs.
To date, studies do not suggest that Baraclude has any activity against HIV. Drugs which have effects against HIV may be associated with an increased risk of developing treatment-resistant forms of the infection.
Canadians taking Baraclude should consult their physicians if they have any questions or concerns, said Health Canada, which will provide any warranted safety recommendations for the drug once a review is completed.
For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcv
>>> Is this something that puts you at a higher risk while you are taking them that stops when you stop the meds, or does it increase your lifetime risk even after you stop taking the meds? <<<
My guess is that there would be some cumulative risk that goes with years of even marginally higher BP and/or pulse rate , but I think the real risk is in the older adult population who remain on the meds and you get the added effects of age-related factors.
They also failed to mention an obvious benefit of the ADHD drugs--Compared to untreated patients , patients on ADHD drugs who had a heart attack or stroke were more likely to seek prompt medical care because they didn't get distracted.
HCV Testing Advised for Patients Who Received Blood in NICU Before 1992
( Sheesh , am I naive or what? I've assumed all along that our first-class medical care system would have begun notifying tranfusion recipients who were at-risk for HCV exposure many years ago. )
http://tinyurl.com/yvbveg
By Megan Rauscher
NEW YORK (Reuters Health) Feb 20 - It would be prudent to screen people for hepatitis C virus if they received a blood transfusion in a neonatal ICU before July 1992, conclude investigators from Anchorage, Alaska, in a report in the February Archives of Pediatrics and Adolescent Medicine.
The authors note that the risk of HCV from a transfusion is now low, but it was potentially significant before 1992 when blood banks introduced screening with the second-generation HCV antibody enzyme immunoassay.
As part of a general HCV look-back and notification program, the researchers identified 1,797 persons who received transfusion(s) in one NICU between January 1975 and July 1992. Of these, only 651 (36%) had a locatable and recent mailing address and were sent a notification letter.
HCV testing was carried out in 216 (33%) of the 651 persons sent a notification letter. Seven of the tested individuals (3%) were found to be positive for HCV antibody, with six having confirmed HCV infection (RNA positive).
"These persons, aged 13 to 26 years, were unaware of their serostatus prior to screening under this program," first author Henry H Cagle from the Alaska Native Tribal Health Consortium told Reuters Health.
When asked if they were aware of having received a blood transfusion while in the NICU, 75 of 147 responders (51%) said that they were not.
The cost for personnel and data collection/management was conservatively estimated to be $105 per person sent a notification letter, for a total program cost of $68,355.
This look-back and notification program, Cagle said, "required a large commitment of both personnel and financial resources, which resulted in a relatively low yield of at-risk persons located and tested for hepatitis C. These findings should be considered before implementation of such programs in other locales."
Similar to CDC recommendations, "we advocate that healthcare providers provide counseling and hepatitis C testing, as appropriate, for all patients with a history of blood transfusion or NICU stay before July 1992," Cagle concluded.
Dr. Maureen M. Jonas from Children's Hospital Boston notes in a related editorial that primary care providers "need to be reminded that there are, no doubt, young patients in their practices with unrecognized HCV infection."
Furthermore, "Simply asking patients whether they have a history of blood transfusions is not enough, especially when those transfusions may have been administered in the newborn period," she continues.
"As Cagle and colleagues have indicated, it may be most prudent and cost-effective to be alert to this risk and to test all individuals aged at least 14 years who had been treated in a NICU for HCV as they are recognized," Dr. Jonas writes.
Arch Pediatr Adolesc Med 2007;161:125-130, 202-203.
FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events
( A little late in the game for this , IMO. Is it really a surprise when drugs that reliably raise pulse rate and BP increase the incidence of CVD / stroke ? )
ROCKVILLE, Md., Feb. 21, 2007-The U.S. Food and Drug Administration (FDA) today directed the manufacturers of all drug products approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) to develop Patient Medication Guides to alert patients to possible cardiovascular risks and risks of adverse psychiatric symptoms associated with the medicines, and to advise them of precautions that can be taken.
"Medicines approved for the treatment of ADHD have real benefits for many patients but they may have serious risks as well," said Steven Galson, M.D., Director, Center for Drug Evaluation and Research (CDER). "In our ongoing commitment to strengthen drug safety, FDA is working closely with manufacturers of all ADHD medicines to include important information in the product labeling and in developing new Patient Medication Guides to better inform doctors and patients about these concerns."
Patient Medication Guides are handouts given to patients, families and caregivers when a medicine is dispensed. The guides contain FDA-approved patient information that could help prevent serious adverse events. Patients being treated with ADHD products should read the information before taking the medication and talk to their doctors if they have any questions or concerns.
ADHD is a condition that affects approximately 3 percent to 7 percent of school-aged children and approximately 4 percent of adults. The three main symptoms are inattention, hyperactivity, and impulsivity. People with ADHD may have difficulty in school, troubled relationships with family and peers, and low self-esteem.
An FDA review of reports of serious cardiovascular adverse events in patients taking usual doses of ADHD products revealed reports of sudden death in patients with underlying serious heart problems or defects, and reports of stroke and heart attack in adults with certain risk factors.
Another FDA review of ADHD medicines revealed a slight increased risk (about 1 per 1,000) for drug-related psychiatric adverse events, such as hearing voices, becoming suspicious for no reason, or becoming manic, even in patients who did not have previous psychiatric problems.
FDA recommends that children, adolescents, or adults who are being considered for treatment with ADHD drug products work with their physician or other health care professional to develop a treatment plan that includes a careful health history and evaluation of current status, particularly for cardiovascular and psychiatric problems (including assessment for a family history of such problems).
As part of the Agency’s ongoing regulatory activity, in May 2006 the FDA directed manufacturers of these products to revise product labeling for doctors to reflect concerns about adverse cardiovascular and psychiatric events. These changes were based on recommendations from the FDA Pediatric Advisory Committee and the Drug Safety and Risk Management Advisory Committee. To help patients understand these risks, an additional part of this revised labeling process is the creation of a Patient Medication Guide for each individual product.
The medicines that are the focus of the revised labeling and new Patient Medication Guides include the following 15 products:
Adderall (mixed salts of a single entity amphetamine product) Tablets
Adderall XR (mixed salts of a single entity amphetamine product) Extended-Release Capsules
Concerta (methylphenidate hydrochloride) Extended-Release Tablets
Daytrana (methylphenidate) Transdermal System
Desoxyn (methamphetamine HCl) Tablets
Dexedrine (dextroamphetamine sulfate) Spansule Capsules and Tablet
s
Focalin (dexmethylphenidate hydrochloride) Tablets
Focalin XR (dexmethylphenidate hydrochloride) Extended-Release Capsules
Metadate CD (methylphenidate hydrochloride) Extended-Release Capsules
Methylin (methylphenidate hydrochloride) Oral Solution
Methylin (methylphenidate hydrochloride) Chewable Tablets
Ritalin (methylphenidate hydrochloride) Tablets
Ritalin SR (methylphenidate hydrochloride) Sustained-Release Tablets
Ritalin LA (methylphenidate hydrochloride) Extended-Release Capsules
Strattera (atomoxetine HCl) Capsules
The draft Patient Medication Guides for each product can be found at:
http://www.fda.gov/cder/drug/infopage/ADHD/default.htm.
For more information please visit www.fda.gov.
>> Expansion of indications for Cell-Cept <<
Have they looked at use as an antiviral ? VRTX had an IMPDH inhibitor in development for HCV but has stopped work on it - not sure why. I know it had some activity in combo with ifn/riba and the following abstract suggests similar activity in HIV.
(free full-text available)
http://tinyurl.com/23b3vm
"In vitro combination of amdoxovir and the inosine monophosphate dehydrogenase inhibitors mycophenolic acid and ribavirin demonstrates potent activity against wild-type and drug-resistant variants of human immunodeficiency virus type 1."
The new HCV antivirals might provide a niche for some previously discarded drug candidates , as part of novel combo txs.
OT : Last comment by me also. My suspicion is that regardless of whatever other design peculiarities exist , e.g., locks with pumping system , etc. , the bridge is probably designed to hold a full load of water , to the brim or to overflow ports.
Flooding downpours , tsunamis , glacial melt , whatever , on the canals on either end and on the bridge itself , combined with the possibility of power / pump failures , would flood the entire structure and require a design that could support this maximum volume of water.
So , again , given this overflow capability , any number of floating objects could be supported as well , limited only by their ability to float ( i.e. draft-limited ). More stringent limitations on allowed vessels might be imposed for a variety of reasons , but not because Archimedes was nuts (even if he was ).
I think Dew is on the right track but maybe was not clear about what he meant ( rare for him ).
Presumably the bridge is designed to hold a full load of water up to some overflow point , such as might be reached during heavy rains. Thus , any number of floating objects would not add to the weight maximum , since they would displace the equivalent weight in water and any excess would run out the overflow.
>> VRTX: I guess we won't be seeing VX-950 on the market in 2008. What was the scenario that the CEO saw this happening? This always confused me. <<
I think the idea was to use efficacy and safety data from the P2 trials along with additional safety data from the proposed P3 trial to support the NDA in '08. The P3 could not be finished at the time of filing if it's a normal 72-week trial.
I suppose there's still a chance this could happen if all the stars align , and I think Boger is still holding to this timeline for filing. I doubt they could market before '09 even if this works , however.
>>> All that assures is that Cox methodology per se was mentioned in the statistical analysis plan. It does not imply that the way DNDN conducted the Cox analysis was pre-specified.<<<
My own reading of the document statement would be that the analysis was prespecified , meaning the complete method and details of the analysis as would be understandable to someone knowledgeable in the field.
Of course , I'm assuming that Fair Disclosure also means unambiguous disclosure. Yeah , right.
In this case I think the statement was carefully crafted so as to convey whatever definition they needed it to convey , then or in the future , depending on the circumstances.
Like the crash in share price last spring , we probably won't know the reason for the current move until well after it's over. I'd speculate that it's a combination of doubts about VX950 being "the answer" along with reduced concerns about NM283 SEs and/or ability to combine it with riba.
Since IDIX was north of $20 based on what was then perceived to be a stronger competitive position vs. VX950 , then to the extent that IDIX is seen as reclaiming that position we might move considerably higher. The riba interaction data is key , IMO.
Tyzeka sales will be a slow slog but I think that's been built-in to SP for awhile. I think it will take additional data , whether formal trials or investigator-initiated stuff , that clarifies the benefit of Tyzeka in various cohorts re: cross-resistance , combo usage , HIV coinfection , etc. , before Tyzeka can really claim its rightful mkt. share. I'll be interested in the combo studies with pegifn , which I believe are ongoing now. Progress on valtorcitabine would be nice , too , since a fully in-house combo would be advantageous , obviously.
I still see IDIX as low risk here , but the upside is a crapshoot that's dependent on IDIX marksmanship.
Bottom line -- I don't have a clue.
Re : IDIX >>> The company is out of the penalty box and skating once again. <<<
I like that , except now all I can think about is thin ice.
Re : >>> my prediction, IDIX climbs to $10+ by March 2nd earnings call... <<<
Nice call.
Re : VRTX at BioCEO
If I heard correctly , Alam said that combos of protease and polymerase will not be on the market for 'many years' , but said that proof-of-concept studies may begin as early as '07. I think he also said that VRTX work on combo studies would not begin in earnest until after NDA filing for VX950.
The IDIX non-presentation at BioCEO was a smashing success , apparently. (Silence was golden , so-to-speak.) :))
Re : DNDN & NIH meeting
Here's the link to the replays ( scroll down ; two separate 'events' ) :
http://videocast.nih.gov/PastEvents.asp?c=998
>>> Part of this goes back to one of the key precepts of modern pharmacologic design: get as close to the ultimate effector of a particular pathway as possible. I think most physicians are firm believers in this concept. <<<
I'm not really trying to imply that I have insights into the future value , or lack thereof , of FVIII inhibitors vs. other approaches. However , it's easy to think of examples where the key precept described above has been ignored , and will be ignored going forward , and for good reasons.
One example , appropriately , is hemophilia which is treated with FVIII , not something closer to the ultimate effector(s) of clotting.
Another example that we'll likely see going forward is in anti-TNF therapy for things like arthritis and psoriasis. The current use of anti-TNF mabs fits the key precept and as a result , some patients die ( with itchless skin and pain-free joints! ) from severe infections or cancer because a vital immune mediator has been clumsily blocked . Targeting the dysregulated TNF production further back on the signalling 'tree' , on a more individualized basis , may allow pain-free joints and a fully-functional immune system to coexist.
Thanks rfj and Dew for the explanations. I can see how FVIII would not be considered the optimum target , I just wasn't getting the idea that it was an unlikely target altogether.
I can still imagine future scenarios where targeted interventions in the cascade "tree" are made based on individual differences ( determined by rapid biomarker tests , for example ) with a role for many drugs with different MOAs. The idea , it seems to me , would be precise control of the tree and , thus , the coag/anti-coag balance. A choice between a blood clot that destroys your brain and a bleed that destroys your brain ain't much of a choice but , unfortunately , it's one people are making today.
Still don't get it. Total lack of FVIII causes bleeding episodes in hemophiia . I'm assuming bleeding is more of an anticoagulation-type event than a coagulation-type event. If you wanted to promote anticoagulation , you might think of partially inhibiting FVIII.
>>> FVIII is an unusual place for an anticoagulant to intervene in the cascade. <<<
I'm curious about why you think so. Given the FVIII / hemophilia connection , it strikes me as an obvious place to intervene.
I haven't followed this area , but it would seem logical to have separate drugs that can intervene in all three pathways - intrinsic , extrinsic , and common - for maximum flexibility , no ?
re : GNVC >>> ." Immunologic work now suggests that reovirus exposure is "educating" the immune system to recognize and kill the same cancer cells that were attacked by reovirus. "If you can teach the immune system to recognize cancer cells," says Coffey, "it may be possible to fight off the disease for much longer than we originally anticipated." <<<
Although the GNVC non-replicating adenoviral vector is not oncolytic per se , I think we'll begin to hear more about the combined immune-activating benefit that results from the action of the TNF transgene together with the likely immune reaction to adenoviral 'body parts' released from/around the injected tumor sites. The vector could be acting as a built-in TLR agonist or similar adjuvant. The MOA for TNFerade ,especially against distant metastases , hasn't been fully elucidated yet but my guess is it's not all due to the transgene.
Nice run by GNVC recently but IMO it's still a good bet at this price , based on the pancreatic data alone.
NCI/NIH Video link
http://videocast.nih.gov/
The link above says there will be an archive available in PastEvents ( wherever that is ) for on-demand viewing. The title to look for is : "Bringing Therapeutic Cancer Vaccines and Immunotherapies Through Development to Licensure".
I only caught bits and pieces myself and will probably try to listen to the archive version too. If I find a separate link , I'll post it.
I'd like to think that FDA policies are reasonable enough so that combo therapy trials of new HCV antivirals could move ahead unimpeded , and I agree that the odds of a particularly nasty interaction are low and would likely be discovered early.
However , in the final panel discussion yesterday it was very clear to me that the concerns I outlined are real among the drug development community ( which formed the bulk of the audience ) , and are likely impeding progress in certain cases , at least. There was much talk about getting a "safe harbor" assurance from the FDA , and the FDA response was , basically , " Don't hold your breath."
The issues were much more complex than we've discussed here , and include legal liability issues as well as regulatory vulnerability issues , and in the cancer immunotherapy area it involves the use of , for example , adjuvants like IL-12 that will never be approved on a stand-alone basis.
Overall , it's just becoming clear to me that the regulatory mechanisms are not working efficiently and fixing it will require more than a tweak here or there.
Of course , I feel that way about government in general. )
Let the Revolution begin !!
>>>> IMHO we will likely see combos of oral HCV inhibitors planned this year. I suspect when both compounds are in PHIII, there is sufficient data to analyze the potential combo risk. Some of the potential candidates still have very good safety profiles. And given some of VRTX's recent results, I think they are now highly motivated to look at other non-approved drugs in a win-win-win (VRTX-partner-patient) type situation. <<<<
I hope you're right about this , but after listening to the FDA folks yesterday I'm inclined to agree with Dew that they will delay for fear of jeopardizing their ongoing
"monotherapy" registration trials.
Imagine these two hypothetical scenarios for an examination of a VX950 / NM283 combo. Let's say VRTX and IDIX are both well into their P3 registration trials , they both have seen excellent safety and efficacy in the monotherapy trials , and both expect to get approval and capture significant market share. However , both also recognize that a combo of VX950 plus NM283 could represent a win-win for them as a tx. for nonresponders or as a way to eliminate or reduce the need for ifn and/or riba or further shorten tx. times. They've done the preclinical combo work and some short-term P1 studies , and now they're starting a sizable P2 to optimize the combo regimen. A few hundred patients have been treated with the combo , and large numbers of serious AEs are occurring , including some deaths. Oh-oh. What will the FDA say ? Well , the combo trials will stop for sure , and that's perfectly reasonable , but out of concern for "patient safety" the FDA will also stop the monotherapy trials since one of these drugs is a killer and they don't have any idea which one it is. They need more toxicology studies , more time to elapse to detect AEs in previously treated monotherapy patients , etc. Both drugs are dead in the water , indefinitely , and the FDA is viewed by many as having averted a possible disaster. They're basking in the glow.
Now , in scenario 2 , VRTX and IDIX wait until the monotherapy drugs are approved , knowing that aggressive clinicians will do the combo anyway as it's an obvious way to try to deal with difficult patients. The same rate of serious AEs and deaths
occurs as in scenario 1 , above , but due to poor postmarketing surveillance and lack of interest at the FDA , the realization of a problem occurs more gradually and with more uncertainty. What does the FDA do now ? They send out a notice recommending against the combo usage ; they require a warning in the labels for both drugs , and monotherapy sales of both drugs live happily ever after.
IMO , many sponsors would see the above scenarios as a reasonable depiction of the current operation of the FDA : anal-retentive about safety before approval , and largely relieved of that burden by the approval "flush".
If the FDA was consistent with their actions regarding drug safety both before and after approval , and had good systems for post-marketing surveillance , then it would be in the drug sponsors' interests to do such combo studies ASAP , rather than gaming the system as they do now.
JMHO.
Re : HCV combo trials
After listening today to the NIH workshop on cancer vaccines / immunotherapy , I'm inclined to agree with Dew that combo studies in HCV won't happen until the individual drugs are approved , if then. The questions to the panel today largely focused on this same issue , i.e. cancer trials using combos of unapproved drugs , and the FDA reps dodged and weaved ( "You CMA , I'll CYA ." ) , leaving the question unanswered , and the problem unsolved. If the reluctance exists among sponsors to do these studies for cancer , where the tolerance for SAEs is much higher , then surely it exists in spades for an indication like HCV.
The FDA could largely solve this problem by simply announcing with conviction that combo studies done post-approval ( of the relevant monotherapy drugs ) will be just as likely - or unlikely - to result in withdrawal of the original approval(s) as they are to result in a failure to approve in the first place , so sponsors may as well get busy with the combo registration studies concurrently with their monotherapy registration studies.
The FDA will never do this of course , because pulling drugs from the market post-approval makes it look like they missed something during the approval process. This also explains their long-standing reluctance to enforce collection and reporting of post-marketing safety data.
All-in-all , my respect for the FDA took a dive today. We need a do-over on the entire drug approval process , IMO.
>> i am concerned that there had been an indication where this agent might cause chrons disease. Gi-5005 is modified through dna to produce a substance found in the hepatitis c virus. <<
I'm not sure I understand the question. Are you concerned about a connection between Crohn's disease and HCV ? That's not the reason for the exclusion criteria in this trial. Crohn's patients , probably due to leaky guts , develop immune responses , including antibodies , to many gut flora including yeast. The concern is , IMO anyway , that the yeast vector would aggravate Crohn's by further stimulating the anti-yeast response.
alpha-glucosidase inhibitors for HBV
I meant to post this here :
http://www.investorshub.com/boards/read_msg.asp?message_id=16834501
alpha-glucosidase inhibitors for HBV
( We discussed this previously re: HCV , with concern about the wisdom of inhibiting such a vital host process. This abstract suggests that intermittent treatment may be a way around this problem. }
1: Antivir Chem Chemother. 2006;17(5):259-67.
alpha-Glucosidase inhibitors have a prolonged antiviral effect against hepatitis B virus through the sustained inhibition of the large and middle envelope glycoproteins.
Simsek E, Lu X, Ouzounov S, Block TM, Mehta AS.
Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, PA, USA.
Previous work has shown that the secretion of enveloped hepatitis B virus (HBV) DNA and the HBV middle envelope protein (MHBs) are sensitive to glucosidase inhibition. Here, it is shown that HBV DNA secretion remains depressed after the removal of the glucosidase inhibitor and long after glucosidase function returns to normal. For example, glyco-processing and the secretion of alpha-1 anti-trypsin returned to normal within 3 h of the removal of the glucosidase inhibitor. In contrast, the secretion of HBV did not return to normal for more than 7 days after the removal of the inhibitor. Consistent with the inhibition of HBV virion secretion, the levels of HBV L and HBV M proteins were also reduced by treatment with the glucosidase inhibitor and remained reduced for 7 days after compound withdrawal. The implications of the prolonged antiviral effect against HBV and the use of glucosidase inhibitors as antiviral agents are discussed.
PMID: 17176630 [PubMed - in process]
http://tinyurl.com/23wnpj
( The link below is to the home page of one of the authors above , and offers a rationale for an immune-mediated benefit of tx. with AG inhibitors.)
"Our theory about how HBV and other chronic viruses that use glycoprotein oligomerization for their morphogenesis, escape cellular proteasomal mediated degradation and antigen presentation, has been significantly advanced, too. With Drs. Mehta, Philip, Norton and post doctoral fellows Drs. Simek and Gomathinayagam , we have shown that pharmacologically directing HBV proteins to mis-fold and become degraded in the proteomes can lead to their “super-presentation” by the cell immune (MHC-1) system. They used a glucosidase inhibitors we developed to accomplish this."
http://tinyurl.com/ypej58
Vertex Nears Hit or Miss
By Adam Feuerstein
Senior Writer
2/6/2007 1:19 PM EST
www.thestreet.com/_yahoo/newsanalysis/biotech/10337045.html
or http://tinyurl.com/2wbwz9
Vertex Pharmaceuticals (VRTX) is pushing ahead with an aggressive drug development plan that, if successful, will drastically improve how hepatitis C is treated across the world -- and make boatloads of money for the company and investors in the process.
If Vertex stumbles, however, the blowup will be spectacular, even by biotech standards.
The drug in question is called telaprevir. Vertex is in the midst of an ambitious phase II clnical study program that will yield crucial data over the next 10 to 12 months.
Most importantly, we'll soon know whether: 1) telaprevir can shorten treatment time for most hepatitis C patients to as little as three months, compared with about a year for current treatments; and 2) whether telaprevir can boost cure rates for hepatitis C patients to 70% to 80% or higher from about 50% today.
If the telaprevir pill can achieve all that, the drug might easily generate $2 billion to $3 billion in revenue and could double or even triple the value of Vertex shares, which closed Monday at $32.52. Likewise, the downside risk is eye-popping: Wipe telaprevir off Vertex's map, and the stock could head quickly back to the teens.
While Vertex has other drugs in the oven, the company's near-term fortunes are tied tightly to telaprevir, which is why investors need to pay attention to the outcomes of these ongoing clinical trials, which the company has dubbed PROVE 1 and PROVE 2.
But first, here's why the drug has generated so much excitement already.
Telaprevir is designed to attack hepatitis C by inhibiting the protease enzyme, one of the key enzymes used by the virus to make copies of itself. This "direct antiviral" approach differs from current hepatitis C drugs, which work by boosting the body's immune system to tamp down and eliminate the virus.
A weekly injection of alpha interferon (Schering-Plough's (SGP) PEG-Intron or Roche's (RHHBY) Pegasys) combined with daily oral doses of a generic drug ribavirin is the current standard of care for hepatitis C patients. A normal treatment course for Type 1 hepatitis C (the most prevalent form) takes 48 weeks to complete. But only about half of patients are cured, and the side effects can be difficult to tolerate, including flulike symptoms, anemia and depression.
Vertex believes that adding telaprevir to the current standard of care will increase cure rates and shorten the length of treatment. Early clinical data have backed that view, although final proof will only come from longer studies in more patients. That's what Vertex intends to do with its PROVE 1 and PROVE 2 studies, which are being run in the U.S. and Europe, respectively.
For now, let's focus on PROVE 1, since that's the study that will soon yield some important data. The study has enrolled 260 patients spread across four arms:
Arm 1: 12 weeks of telaprevir plus 12 weeks of alpha interferon and ribavirin (which I'll now refer to by its shorthand, PEG-IFN/RBV)
Arm 2: 12 weeks of telaprevir plus 24 weeks of PEG-IFN/RBV
Arm 3: 12 weeks of telaprevir plus 48 weeks of PEG-IFN/RBV
Arm 4: A "control" or comparison treatment of 48 weeks of PEG-IFN/RBV (no telaprevir).
The most important data coming from this trial will be "cure" rates, defined as the number of patients in which the level of hepatitis C virus becomes undetectable, as measured by a highly sensitive blood test. In medical parlance, this is known as the rate of "sustained virologic response," or SVR, and it is typically assessed six months after the end of treatment.
In PROVE 1, all patients have completed their 12 weeks of telaprevir dosing. Arm 1 patients are off treatment altogether (having also finished their 12 weeks of PEG-IFN/RBV), while patients in Arms 2, 3 and 4 continue to get PEG-IFN/RBV.
Vertex's stated intent is to use medical meetings as the forum for the release of clinical data, as opposed to simply issuing press releases. The first likely opportunity, then, is the European Association for the Study of Liver Disease, being held April 11 to April 15 in Barcelona. At this meeting, we're likely to get an interim update on treated patients, which will include some shorter-term measure of SVR, or cure, rates.
Looking further ahead, expect additional data at the Digestive Disease Week conference May 19 to May 24 in Washington, D.C., and the American Association for the Study of Liver Disease annual meeting Nov. 2 to Nov. 6 in Boston. (Mark your calendars.)
Vertex's stock has been weak since December, when shares were trading above $44, in part because the release of the first slug of data from PROVE 1 proved a bit disappointing to some and also raised the specter of unacceptable toxicity.
After 12 weeks of treatment, Vertex reported that 88% of patients on a telaprevir-containing arm had undetectable levels of the hepatitis C virus in their system, compared with 52% of patients in the control arm. But when these results were adjusted for the 9% of patients who dropped out for adverse events, the undetectable rate in the telaprevir arm was reduced to 80%, below the 90%-plus rate that many investors were expecting at this stage of the trial.
A higher-than-anticipated dropout rate due to toxicity was also a bit unexpected, raising concerns that telaprevir, despite its high efficacy, might have safety issues. Specifically, some anecdotal reports of severe skin rash in patients taking telaprevir raised alarm bells on Wall Street, although Vertex has vehemently denied that any such problems exist.
Vertex believes that the data generated by PROVE 1 and its sister trial in Europe, if positive, will be enough to form the basis of an approval filing with the Food and Drug Administration in the middle of 2008. The company does plan on running a phase III trial, starting in the second half of 2007, to add to the drug's safety database.
If Vertex can hold to this aggressive time line, telaprevir could be on the market by early 2009.
Additional clinical trials of telaprevir are also under way, including studies in hepatitis C patients who have failed or responded poorly to current treatment.
Few doubt that telaprevir is a real drug or that it will increase cure rates for hepatitis C patients -- but by how much? And will the drug's benefits outweigh its risks? The answers to these questions are still unknown but will come fairly soon from data generated in the PROVE 1 and PROVE 2 studies.
Only after that data are released will investors be able to answer the risk/reward question for considering Vertex shares.
>> If the FDA saw a serious—perhaps life-threatening—problem in a combination trial, they could place a clinical hold on all VX-950 development until they sorted it out. Is this a risk VRTX will be willing to take? <<
Given the longstanding unmet need for an effective treatment for nonresponders , I would expect the FDA to be relatively accomodating in this situation. I can imagine a conversation where the FDA agrees that any new , unexpected SAEs in the combo trial will be assumed to be due to the combo and not to VX950 , assuming a good monotherapy database , of course , and subject to change based on postmarketing safety data. Absent this sort of up-front understanding , however , I agree that VRTX would be wise to wait on the combo trials.
BTW , Alam's CC answer to Werber's ITT question sounded like the ramblings of a madman. I bet Alam's eyes were spinning in circles. No wonder he wanted to take it offline.
The VRTX halo is showing some corrosion.
re : Lupus Drugs
I think we'll soon see some INDs popping up from COLY , ANDS and the like for TLR antagonists for lupus , TLR-7 in particular.
Interesting - if true - comments on VX950
Starting at msg#1532 on iVillage VRTX :
http://tinyurl.com/yvym9g
It might not be a mistake. I'm with Ameritrade and they often refer to me as Butthead , too.
I must admit , though , 'Smack My Ass , Call Me Sue' IS an unusual name for a bank.
MedInsight Announces Clinical Trial Results of Low-dose Naltrexone; Potential Breakthrough for Crohn's Disease Patients
DOVER, Del., January 30, 2007 /PRNewswire-USNewswire/ -- The forthcoming edition of the American Journal of Gastroenterology (early release now online) reports the results of a successful clinical trial using low-dose naltrexone (LDN) to treat Crohn's disease.
In 1982, Dr. Ian Zagon and Dr. Patricia McLaughlin at Hershey Medical Center, Penn State University College of Medicine, discovered that naltrexone - approved by the FDA in 1984 for treating substance abuse - also triggers the production of higher levels of naturally occurring opioids (also known as endorphins) when used at a fraction of the usual dose. This prompted Dr. Zagon and his team to research the application of naltrexone in treating various other conditions.
In 2004, Moshe Rogosnitzky, director of research at MedInsight Research Institute, presented evidence to Dr. Zagon that increased endorphin levels could have a beneficial effect in treating Crohn's disease. As a result of this information, Dr. Zagon and Dr. Jill Smith, Professor of Gastroenterology at Hershey Medical Center, launched a preliminary clinical trial using a low dose of readily available naltrexone.
Backed by seed funding from Penn State University, the results of the clinical trial demonstrated the treatment to be remarkably effective. Eighty- nine percent of treated patients experienced significant improvement in their symptoms, and two-thirds experienced remission.
"This is a novel, yet effective, approach to treating a common disease," says Dr. Smith. A follow-up controlled trial, sponsored by the Broad Medical Foundation and the National Institutes of Health, has been launched by Drs. Smith and Zagon to confirm the results of the first study.
Dr. Zagon, study co-author, is also encouraged by the findings. "I am delighted to see this study published," says Dr. Zagon. "Although it is a preliminary investigation, and its findings need to be verified by controlled studies, it points to the efficacy of low-dose naltrexone in treating patients with Crohn's, a devastating and debilitating disease."
Co-author Moshe Rogosnitzky agrees. "Once the results of this study are confirmed," he says, "we will have perhaps the safest and so-far most- effective overall treatment for Crohn's disease."
Ironically, the low cost of LDN treatment - less than $100 per month - could prove to be a disadvantage. At that pricing level, few drug companies have the incentive to invest the funds necessary to obtain FDA approval for this new indication.
Nevertheless, Dr. Smith remains confident. "We have already been approached by biotech companies with an interest in licensing this therapy," she says. "Because naltrexone is already approved for other uses, it should be a relatively inexpensive process to obtain FDA approval for its use in Crohn's disease."
About MedInsight Research Institute
The MedInsight Research Institute is a US-based 501(c)3 charitable organization co-founded by Moshe Rogosnitzky of Israel and Dr. David Youlton of the UK. Its mission is to alleviate the suffering of those afflicted by life-threatening or chronic medical conditions. It does so by providing comprehensive scientific reviews of data regarding commercially unsponsored medications, long-lost therapies, and specialized tests that enable the personalization of medical treatment. The MedInsight web site, which will make all its work public and freely available, will be launched later this year.
Source: American Journal of Gastroenterology, Online Early, February 2007
http://www.medadnews.com/News/Index.cfm?articleid=410404#
Re: VRTX
( This is apparently from a Prudential report , courtesy of gladpick on YMB. Sorry if it's old news.)
pru part 1 -target $45-overweight (Not rated) 29-Jan-07
11:23 am 1/10/07: VRTX: TELAPREVIR EFFICACY DATA IS LIKELY TO BE PRESENTED AT EASL
• We met the management team in San Francisco and gained some insight to the clinical progress of telaprevir (VX-950, TVR).
• Management suggested that the next set of TVR data is most likely to be presented at a medical meeting, possibly the
European Association for the Study of the Liver (EASL) in Barcelona, Spain from April 11 to 15. Previously it was assumed that the three-month SVR data from about 20 patients would be communicated to the Street in a press release form.( Have they postponed the release because they want to create a bigger buzz at the EASL venue , or are they praying for better data from the ongoing trials because the currently available data doesn't look so hot ?)
• In addition to previously announced clinical trials of TVR, the company also announced that it will initiate a clinical
trial in genotype 2 and 3 HCV patients, an exploratory trial in which TVR is used twice a day without rotonavir boosting and trials in special patient populations, such as HIV/HCV co-infected patients.
• Management felt very confident about its goal of achieve a SVR of 75% or better in the ongoing Phase II trial, initiating a
Phase III in ’07 and filing an NDA in ’08.
• Based on a listing on ClinicalTrials.gov, Schering-Plough is planning a new Phase II trial of its protease inhibitor, SCH 503034 (SCH), in previously untreated HCV patients with genotype 1 (Study P03523). The initiation of this trial signals a shift of strategy on SCH 503034 by Schering-Plough. Previously, the company has been focused on developing the drug for HCV patients that have failed interferon-based treatments.
• Because SCH 503034 is a close competitor to Vertex's telaprevir, we thought it might be useful to compare the designs of Phase II trials of these two drugs.
• The biggest difference between P03523 and two telaprevir trials (PROVE1 and 2) is the treatment duration involving the experimental drugs: for SCH it is 24 weeks as the shortest and 48 weeks as the longest; and for telaprevir it is all 12 weeks.
• We think there are plus and minus of both trial designs. Ultimately, the success of a regimen will depend on efficacy (SVR), safety, treatment duration and convenience in that order. Assuming both drugs will succeed in its respective Phase II and III trials based on current designs and be launched, telaprevir has the advantage of treatment duration over SCH 503034. A shorter treatment duration could also mean better safety and patient compliance.
http://tinyurl.com/39j4dw