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How about selling the Tyzeka rights to GILD ?
Since it now appears likely that any real commercial potential that Tyzeka has is likely to derive from usage in combos with either adefovir or tenofovir , and that's a couple of years away , it seems like a waste for IDIX to fund a marketing and sales operation in the meantime , not to mention the P4 trials. Right now Tyzeka might be worth more to GILD than it's worth to IDIX / NVS. ( I'm assuming in this scenario that IDIX/NVS have decided that valtorcitabine is not going to be Tyzeka's saviour. )
Nothing prevents IDIX/NVS and GILD from collaborating on a combo , of course , but an outright sale of Tyzeka might make more sense for both sides. GILD has an established HBV franchise , while IDIX has no new drug candidates for HBV ( again , discounting valtorcitabine , which they could throw into the deal as a freebie ). A sale would provide cash , greatly reduce cash burn , and allow IDIX to focus on antiviral drug discovery.
Just a thought , but I'm guessing an announcement of a such a deal would be seen as a positive for IDIX.
EDIT : The problem with this may be that GILD wouldn't be willing to pay much for Tyzeka , since they already have the tenofovir plus emtracitabine combo ( Truvada ) , and might not see Tyzeka as much of an upgrade to emtracitabine. Still , combo trials using Tyzeka are already underway and there is at least a chance that results could be surprisingly good and thus make the deal rewarding for GILD.
This is priceless :
http://www.investorvillage.com/smbd.asp?mb=971&pt=msg&mn=149258
Progress
In an attempt to avoid service of process from today from Plaintiff CareToLive Kirsten and Paul Goldberg left town today.
AS the Washington Post said: “in the basement of a house in a tree-shaded Northwest Washington neighborhood from which Goldberg and his wife, Kirsten Boyd Goldberg, publish a newsletter …………"
The true story of the pleaseant tree lined street:
The investigator hired by CareToLive while conducting surveillance on the Goldberg’s home (which doubles as their basement office) was approached by the next door neighbor in this pleasant little tree shaded street where the Goldberg’s home/basement office is located,(these next door neighbors presumably having been advised by the Goldberg’s that here were PI’s in the area attempting to serve legal process upon them). Well the nice lady that lives next door in this nice little tree lined neighborhood did proceed to call the CareToLive investigator a “mother f________! I am not sure which finishing school in Washington DC she learned such language, but it is I guess beside the point.
Last night the Goldberg’s hid in their basement and refused to answer their door to accept CareToLive subpoenas. Today they left town in order to avoid further service (their counsel already acknowledged receipt of faxed subpoenas in this matter). Today they were served by personal process service on their household to a person over age 18.
The Goldberg’s thought they escaped town and avoided legal process.
WRONG!
Apparently their father Boris Goldberg lives with Paul and Kirsten (a household occupant over 18 years of age who can accept service). Our investigator followed Boris as he left the house tonight and he went to a restaurant. When Boris returned home to the Goldberg home/office, where he lives, our investigator said “Hi Boris”. Boris responded with a “hello”.
The CareToLive Investigator then served Boris. At that time panic set in with Boris and he said “I am not Boris and I do not live here”. (as Joey would say heh, heh, heh.) Apparently the Goldberg family is full of three generations of liars. The process server then informed Boris Goldberg that he saw him leave the house earlier, meet others and go out to dinner and then saw him return to his home and served him upon his return home. Boris was then quite speechless.
The investigator got a good laugh out of the laughable attempt by Boris to say that he was not Boris and did not live there (third party sources have confirmed that grandpa Boris does live there).
CareTo Live members. We continue the fight for justice and FDA reform.
>>> NVS clearly thinks the program has value, but big pharmas are not always right <<<
An example with some relevance would be the value NVS placed on NM283 , with the result being they overpaid dearly for the 56% of IDIX they now own. They weren't alone in making that mistake , of course , as I can personally attest. :(
Anyone who made the one-day trade on IDIX from yesterday to today -- my hat's off to ya. I thought about it , but , alas...
FBR has a similar sentiment on IDIX as MS , apparently :
Aug 3 2007 Brief - "Idenix Reports Weak Quarter; Few Drivers Ahead; Stock Unlikely to Move Higher"
Healthcare - (Update - MarketPerform)
Idenix Pharmaceuticals, Inc. (IDIX,chart,profile,sec)
by Jim Reddoch, Ph.D.
http://www.fbrdirect.com/Research/ResearchLib.asp?Ticker=IDIX
I don't have access to the full brief.
Tyzeka seems likely to get some positive mentions at this upcoming Novartis-sponsored satellite symposium :
http://www.sgg-sgvc-congress.ch/program-en.php
Annual Meeting
SASL Swiss Association for the Study of the Liver
Lausanne, Palais de Beaulieu, 27.-28.September 2007
1230-1330
Seoul
Novartis satellite symposium
Darius Moradpour, Lausanne
1230-1355
Seoul
Roadmap for Management of Patients Receiving Oral Therapy for Chronic Hepatitis B
Stefan Zeuzem, Frankfurt
1255-1320
Seoul
Roadmap for Management of Patients Receiving Oral Therapy for Chronic Hepatitis B
Nikolai Naoumov, Basel
1320-1330
Seoul
Discussion
This is the PubMed citation for the same paper :
Clin Gastroenterol Hepatol. 2007 Aug;5(8):890-7. Epub 2007 Jul 13
Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B.
Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane EJ, Jacobson IM, Lim SG, Naoumov N, Marcellin P, Piratvisuth T, Zoulim F.
Stanford University School of Medicine, Stanford, California.
The authors are many of the same group from Stanford who published the '06 treatment algorithm I mentioned in the post this one is in reply to. Some feel their influence doesn't carry much weight compared to , say , the AASLD guidelines , so even if Tyzeka is mentioned favorably , it might not help much. Still , it couldn't hurt.
I just found the site for the conference where Locarnini presented and they have the video , which is a lot better than trying to figure out the transcript.
Also a video and the slides of this :
HBV: Evolving Treatment Paradigms in HIV-HBV Co-Infected Patients
Vincent Soriano, M.D., Ph.D.
and video only of :
Small Molecular Inhibitors of HCV Infection: Agents in the Pipeline
Marion Peters, M.D.
http://www.kaisernetwork.org/health_cast/hcast_index.cfm?display=detail&hc=2234
Canadian '07 HBV Guidelines
Telbivudine gets a favorable mention here ( pdf ) :
http://www.hepatology.ca/cm/FileLib/hepB.pdf
page 11 of pdf , 15c of article :
" Recommendation 22 : Telbivudine is suitable for first-line use in all patients ..."
I guess io_io will be the 'pouncer' this time.
;)
>>> Huh? Entecavir’s sales uptake was far from rapid. <<<
LOL. I was waiting for you to pounce on that.
I concede. I should have said : " This, IMO, goes a long way towards explaining the recent rapid uptake of entecavir."
Since late '05 or so , entecavir sales have been growing exponentially , doubling every 6 months. They can't keep up that pace indefinitely , of course.
My point remains , however , that entecavir is the most attractive drug in a sequential monotherapy paradigm because of the higher hurdle it provides against resistance.
As you've mentioned several times , the general consensus is that combo tx. will likely favor Ns plus Nt combinations , because of better cross-resistance compatibility. For the same reason , when docs choose a monotherapy for a tx.-naive patient , they have to be thinking about what the second drug will be if rescue therapy is required. Whether the first drug they use is an Ns or an Nt ( adefovir , currently , though many are probably using tenofovir off-label ) , the Ns choice is most likely to be entecavir , IMO.
The evolution of combo therapy is still up for grabs , IMO , as many factors besides resistance patterns can come into play.
Some good slides on HBV resistance , etc.
From :
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
International AIDS Society and Australasian Society
for HIV Medicine
7/23/07
Slides (pdf):
http://www.kaisernetwork.org/health_cast/uploaded_files/MOBS103-Locarnini.pdf
Transcript (pdf):
http://kaisernetwork.org/health_cast/uploaded_files/072307_ias_hep_transcript.pdf
( HBV stuff starts on p.18 -- S. Locarnini )
It's a pretty poor transcript but using the slides you can sort of follow along. It covers resistance issues and also co-selection of surface Ag / envelope variants with drug resistance.
Locarnini and his group run the SeqHepB database which now has thousands of HBV sequences from patients who have developed resistance. This sort of data will eventually be used to make treatment decisions as assays for rapid detection of resistant variants become commercially available.
He's a big believer in combo therapy , since it raises the genetic barrier to resistance , and he makes the point that entecavir , which requires 3 or more mutations for resistance , is effectively like a combo tx. , compared to all the other monotherapy drugs which only require 1 or 2 mutations.
from p.39
"...I’m a committed combination therapy person but I have to concede that yes with entecavir in naïve patients you need three mutations to generate resistance then yes, that’s actually a good way to go."
This , IMO , goes a long way towards explaining the rapid uptake of entecavir.
>>> my sense is market expectations are low on valtorcitabine <<<
Agreed. It may be priced-in already. A " no-go " might be considered better news than a " go " , if investors perceive it as a rational move to limit cash burn. It still might be better to announce on Fri. evening , so investors have time to think about it for a bit.
;)
Next shoe to drop ?
This selloff seems extreme to me , even considering the fact that many small biotechs are getting creamed lately. The shorts may know something and the only possibility I can think of is something related to valtorcitabine.
I suppose the plan is to release data at a meeting in the fall , but it wouldn't surprise me if there was a " Friday Evening Surprise " before then , announcing a no-go for valtorcitabine.
Although the rationale for pursuing valtorcitabine may have been strong initially , I wonder if it is today , since valtorcitabine likely selects for the same YMDD mutants that are proving troublesome in terms of cross-resistance to other drugs. A better choice , in retrospect , would have been an Nt rather than an Ns.
Another issue re: YMDD mutants that I've seen mentioned , although only in theoretical terms so far , is the possible adverse effects that could follow in the areas of HBV vaccines and HBV diagnostics. Due to the 'multiple open reading frames' nature of the HBV genome -- and bad luck -- it turns out that YMDD mutations can result in variants in the immune-recognition domain of HbsAg , which , if they persisted and became widely distributed , could result in failure of protective vaccines and diagnostic assays. This whole area of HBV genetics is far from settled but it's something to be aware of.
I'm all out of IDIX now but might be tempted again if things get much worse. I see biotech bargains everywhere I look right now but the charts all resemble falling knives , and I've donated more than my share of blood trying to catch those in the past , so I'm sitting tight.
WSJ.com commentary : "Cancer Regression"
( Edit : Oops ! I see nmstav beat me to it. )
CEO of Pharmacyclics on FDA policy of " Decelerated Approval "
http://www.investorvillage.com/smbd.asp?mb=971&mn=147659&pt=msg&mid=2683253
or
http://online.wsj.com/article/SB118593325021784255.html?mod=opinion_main_commentaries&apl=y
The list of biotech execs who have publicly criticized the FDA recently grows longer. They do so knowing that they risk blowback when their companies must go before the FDA seeking regulatory approvals , which , IMO , adds credence to their arguments.
This line near the end of the article sums it up pretty well , I think :
" Clearly we need to get back to a more context-sensitive regulatory approach for reviewing drugs targeting deadly diseases. That is not to say that rigorous scientific principles should be abandoned. But in medicine, ethical and practical considerations have to play a role too. "
>>> There is no mention in any SEC filing of Baraclude’s endorsement by the group you cited: the National AIDS Treatment Advocacy Group. Nor should there be because NATAP does not have anywhere near the same standing as AASLD in the hepatitis arena. <<<
I don't know if NATAP had anything to do with it or not. That's just where I found the article. This is the PubMed citation :
...
Clin Gastroenterol Hepatol. 2006 Aug;4(8):936-62.
A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.
Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, Tobias H, Wright TL.
Division of Gastroenterology and Hepatology, Stanford University Medical Center, CA 94304, USA. ekeeffe@stanford.edu
...
It looks to me like a bunch of Stanford liver docs. Whoever is behind it , it received substantial notice and is cited often , as I said. I'm not picking sides on which guidelines rule the day , but I'd agree that AASLD ranks near the top.
>>> To reiterate, you claimed in msg #1387 that Tyzeka is deficient and dead in the water because it is not yet included in the AASLD guidelines. I’m saying that your assertion is
BS.<<<
You're having that reading comprehension problem again. The problem I saw was that Tyzeka WAS included in the current AASLD guidelines , and was specifically declared deficient.
New head-to-head data vs. Baraclude could conceivably change things in the monotherapy space , as could some newly-discovered Baraclude SAE , but I'm not counting on it.
>>> Baraclude was not added to the AASLD treatment guidelines for HBV until Feb 2007, almost two years after its FDA approval in Mar 2005.
This blows your assertion that Tyzeka is deficient for not being on the AASLD guidelines right out of the water. <<<
The previous AASLD guidelines were done in 2003 , I believe. Most of these guidelines are updated only when there is a significant change in best practices. However , Baraclude received a positive endorsement in the U.S. prior to the recent AASLD guideline update. The treatment algorithm that was updated in summer of '06 , like the AASLD guidelines , is also cited frequently in discussions of HBV treatment. See :
http://www.natap.org/2006/HBV/072706_01.htm
Baraclude did not suffer from lack of a positive endorsement in the time between launch and the publication of this treatment algorithm because it was so clearly superior to the only other approved HBV Ns , lamivudine.
It also didn't suffer because at no time was there such a damaging disapproval from an organization like AASLD , as has occurred recently re: Tyzeka. Remember , Lok et al. didn't say that there was insufficient data to make a judgement on Tyzeka , they said Tyzeka was " not preferred " and " telbivudine monotherapy has a limited role in the treatment of hepatitis B".
I saw a recent Morningstar report on Smithbarney.com where they project that Tyzeka will capture about 5% of the U.S. and E.U. HBV markets by 2010. I think that's probably about right , plus or minus a percent or so.
I think the door is still wide open as regards combo therapy , however , for the reasons mentioned by dewophile. I don't think monotherapy results will automatically translate to the combo space , and Tyzeka could get a second wind if its antiviral potency adds more to a combo than its resistance rate and profile subtracts. That's all a few years worth of clinical data down the road , however.
Dew , you should read , then think for a few minutes , before you post that someone is out to lunch. Particularly when that someone has EATEN your lunch on issues relating to IDIX and hep antivirals in general , on numerous occasions. In a year or two , I'm guessing that events will show that this occasion follows that pattern.
.....
>Although I expect tenofovir to displace adefovir as monotherapy, I wouldn't be surprised if it [adefovir] hangs on as a player in combos, at a lower price point…<
>>> Adefovir (Hepsera) is more expensive than tenofovir (Viread) and will remain so. GILD cannot charge a premium for Viread in HBV because the Viread price is set by the HIV market. <<<
My point was that if tenofovir displaces adefovir in the HBV monotherapy market , that re-pricing of adefovir at a lower point may allow it to be a viable player in combos , in a manner such that total worldwide HBV sales and profits of the two exceed that which would occur if only tenofovir remained on the market. Mainly I was making the point that adefovir and tenofovir may be more different than one would expect , as regards resistance profiles , and therefore there might be value in keeping adefovir on the market for HBV combos.
....
>…since it seems that the cross-resistance patterns between adefovir and tenofovir might not be as troublesome as one might expect based on structural similarities.<
>>> If you’re suggesting that Viread + Hepsera will be a commonly used combination, I think you’re out to lunch. Extremely unlikely, IMO <<<
That's not what I was suggesting at all , and I think you know it. I was suggesting that if both remain on the market , as suggested above , that adefovir might be part of some combo that could then be followed by a different combo including tenofovir , if resistance to the first combo develops. The reverse might also be true. Right now it's not clear that cross-resistance between tenofovir and adefovir will be as troublesome as cross-resistance between , say , lam and telbivudine.
....
BTW , thanks for reminding me why I continue to post less , and enjoy it more. That's something I don't want to forget.
>>> Tyzeka has a clear edge with pregnant patients and HIV-infected patients (which you forgot to mention in your latest post) <<<
The HIV issue is curious to me also . The quote from the AASLD guidelines I posted were from an addendum added on to the original document sometime after Feb 07. ( I show the pdf doc creation time as 4/30/07 )
I don't quite understand the rec against using Tyzeka for this indication , especially after the discovery that entecavir was active vs. HIV , but there it is.
Here it is again , with some earlier text :
Special Populations
Co-infection with HBV and HIV
We were also informed of a recent case report in which
the selection of an HIV mutant containing the methionine-
to-valine (M184V) substitution was found during
entecavir treatment for chronic hepatitis B in an HBV/
HIV coinfected patient who was not simultaneously receiving
HAART.1 In light of this report, Bristol-Myers
Squibb has advised caution regarding use of entecavir in
this setting. Although the data is preliminary, we agree
with the recommendations in the cautionary letter sent to
all health care providers.
Thus, until further data are available,
we have revised recommendation #33 to read as:
33. Patients who are not on HAART and are not
anticipated to require HAART in the near future
should be treated with an antiviral therapy that does
not target HIV, such as pegIFN-, adefovir, or entecavir.
Caution should be exercised if entecavir is used
in this setting. Although telbivudine does not target
HIV, it should not be used in this circumstance. (II-3)
ANNA S. F. LOK1
BRIAN J. MCMAHON2
1Division of Gastroenterology, University of Michigan
Medical Center, Ann Arbor, MI
2Liver Disease and Hepatitis Program, Alaska Native
Medical Center and Arctic Investigations Program,
Centers for Disease Control, Anchorage, AK
Reference
1. McMahon M, Jilek B, Brennan T, Shen L, Zhou Y, Bhat S, Hale B, Hegarty R, Silicano R, Thio C.
The Anti-Hepatitis B Drug Entecavir Inhibits HIV-1
Replication and Selects HIV-1 Variants Resistant to Antiretroviral Drugs.
Presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 2007.
>>> BUT, if combination therapy gains traction (and it sure looks like all 3 companies think it will based on the series of phase 3/4s out there), then it really will boil down to which nucleoside/nucleotide combo gives the best bang for the buck.. <<<
Agreed. Combo therapies could eventually re-sort the sales leaders in HBV drugs in ways that are hard to predict right now. Substandard monotherapy drugs like lamivudine ( vs. telbivudine and entecavir )and adefovir ( vs. tenofovir ) may even capture surprising market shares. The only downside to using a cheap combo first ( say , lam plus tenofovir or adefovir plus telbivudine ), assuming they provide rapid and sustained viral suppression , is the extent to which the patterns of eventual resistance to the combo hobbles follow-on tx. Although I expect tenofovir to displace adefovir as monotherapy , I wouldn't be surprised if it hangs on as a player in combos , at a lower price point , since it seems that the cross-resistance patterns between adefovir and tenofovir might not be as troublesome as one might expect based on structural similarities.
From the perspective of investing in IDIX , the combo tx. scenario will not fully play out until well after the standstill agreement date passes , while IDIX share price in the more near term seems sensitive to the slow ramp in Tyzeka sales. Having Anna Lok say that Tyzeka has "a limited role in HBV monotherapy" , just a few months ago , suggests to me that Tyzeka sales are likely to disappoint for quite a while yet , and that NVS , should they choose , will be able to buy the balance of IDIX at a price not very far removed from the current price.
>> Did you note the word short in the fifth paragraph of my previous post (#1391)? <<
I did , but I don't think it matters , except possibly in the limited case of pregnant patients , where treatment with Tyzeka would be preferred , even if the intent was to switch to something else after delivery.
You could make the same argument for using lamivudine as first-line , i.e. , what does it hurt to use the cheapest drug first ? For some patients , it works well for quite a while , for the others , just switch them to something else. No worries.
Even a limited period of ineffective tx. could result in generation of resistance mutations that will make subsequent tx. more difficult. Docs won't take that chance knowingly , IMO , at least not in the tort-happy USA.
JMHO.
>> The higher resistance figures in the references you cited are ITT figures, which are irrelevant for the reason mentioned in #msg-14403420: in patients where Tyzeka never works in the first place, it’s immaterial whether it induces strains that are resistant to Tyzeka because these patients will be switched to another therapy. There is no preclinical or clinical evidence I’m aware of that a short regimen of Tyzeka induces resistance to Baraclude or Hepsera. <<
You're way off base here , Dew. Cross-resistance is THE ISSUE that argues against using second-tier drugs first. It's like using a sub-therapeutic dose of an antibiotic against a bacterial infection -- it's worse than no treatment at all because it compromises subsequent therapy.
Tyzeka resistance mutations confer substantial cross-resistance to lam and entecavir. See , for example :
http://www.natap.org/2007/DDW/DDW_16.htm
>>> Perhaps the AASLD guidelines tend to lag behind the state of the art and this is why Baraclude took so long to ramp up despite being clearly the best approved HBV drug during 2005 and 2006. <<<
I agree that lag could be a factor , but I still think that IDIX will take a longer time ramping up than Barraclude because it is not clearly superior to Barraclude , while Barraclude was clearly superior to lamivudine. It will take data from studies out to > 2 yrs. in head-to-head comparisons to change clinical practice appreciably , IMO.
That said , I find it hard to argue for selling IDIX at this price. Of course , I've said that before , wrongly , as it turned out. I'll be compelled to buy more if the price remains depressed later in the year , as the standstill deadline approaches , but I'm laying back for now , as much due to overall market concerns as anything specific to IDIX.
VA monograph on Tyzeka , dated May 2007.
http://www.pbm.va.gov/monograph/Telbivudine.pdf
Worth a look , also. It has a chart near the end showing the VA costs for the various HBV drugs.
Summary conclusions :
"Conclusions
In the phase III trial, telbivudine was noninferior to lamivudine in achievement of Therapeutic and Histological Response in both HBeAg subpopulations. Telbivudine displayed more rapid and potent virologic activity than lamivudine. Lamivudine, at the time of study initiation, was the
appropriate comparative agent; however, it is no longer considered as a first-line agent due to high rates of resistance associated with long-term therapy. The safety profile of telbivudine was similar to lamivudine with the exception of elevations of CK. Genotypic resistance was seen with lamivudine and telbivudine at one year; resistances rates continued to increase at year two. Longer follow-up studies are needed to assess the durability of telbivudine beyond two years. Although not compared in head to head trials, resistance rates seen with telbivudine are likely
higher than with adefovir and entecavir. The VA cost of telbivudine is comparable to adefovir.
Recommendations
Although telbivudine displayed potent virologic activity, the data appear to suggest a higher incidence of resistance to telbivudine than other recommended first-line oral nucleos(t)ide options (i.e. adefovir, entecavir). Due to clinical failures associated with resistance, clinicians are
selecting first-line agents that minimize the development or selection of resistance. Thus, adefovir and entecavir are preferred oral agents for treatment of chronic hepatitis B in
nucleos(t)ide-naïve patients while telbivudine should be considered second-line oral therapy. However, telbivudine as with lamivudine may have a role in certain clinical scenarios such as short-term or combination therapy. Further studies are needed to define the role of telbivudine in combination with nucleotides or peginterferon for the treatment of chronic hepatitis B."
I've been curious about the reasons for the slow uptake of Tyzeka , so I did a little web searching. I came across the recently updated (2007) AASLD Treatment Guidelines for HBV.
pdf at :
https://www.aasld.org/eweb/docs/chronichep_B.pdf
The bottom line is that Tyzeka is clearly relegated to the second tier of treatment options , for almost all patient cohorts. Adefovir , entecavir , and pegifn are listed as front-line , with various qualifications depending on whether patients are naive , lam-resistant , HIV-pos , etc.
Until IDIX can produce data that shows a good head-to-head comparison versus the currently-favored agents ( over several years , probably ) , it's hard for me to see how Tyzeka will ever capture a market share similar to those other drugs. I realize that the AASLD guidelines are not the last word , especially considering the global market , but they carry a lot of weight in the U.S. and probably the EU , as well.
Here's a couple of excerpts from the pdf ( See Table 11 for a summary of tx. recs ):
"Telbivudine is an L-nucleoside analogue with potent
antiviral activity against HBV. Clinical trials showed that
telbivudine is more potent than lamivudine in suppressing
HBV replication. However, telbivudine is associated
with a high rate of resistance and telbivudine-resistant
mutations are cross-resistant with lamivudine.
Therefore, telbivudine monotherapy has a limited role in
the treatment of hepatitis B."
"Patients who are not on HAART and are not
anticipated to require HAART in the near future
should be treated with an antiviral therapy that does
not target HIV, such as pegIFN-, adefovir, or entecavir.
Caution should be exercised if entecavir is used
in this setting. Although telbivudine does not target
HIV, it should not be used in this circumstance."
"In choosing which antiviral agent to use as the firstline
therapy, consideration should be given to the
safety and efficacy of the treatment, risks of drug resistance,
costs of the treatment (medication, monitoring
tests, and clinic visits), as well as patient and provider
preferences, and for women—when and whether they plan to start a family. ...
...In view of the high rate of drug resistance during long-term treatment, lamivudine and telbivudine are not preferred except where only a short course of treatment is planned."
etc.
NM283 = ...
NoMás 283 ???
The next question to consider is : " What price would IDIX shareholders accept from NVS in an acquisition offer ? "
I'm guessing NVS will wait a while before making such an offer -- maybe until after AASLD , where IDIX will have one last chance to convince investors of IDIX' value as an antiviral drug discovery engine.
Then , NVS will offer to buy the balance of IDIX at a premium of 10-15 % to the then-current SP. Large shareholders will protest the lowball takeover attempt , of course , and NVS will then come back with an offer at a 30% premium , or thereabouts , which will be accepted by the BOD and shareholders. This is in line with what happened in the NVS purchase of Chiron.
For those who can time the buy-sell to capture that 30% premium , it will be a great investment. For most of us here , so far at least , not so great.
>>> That is, the explanation is that no such response is necessary; the infusion of GM-CSF-stimulated DCs is enough to stimulate the appropriate T cells. <<<
Exactly , almost. "the infusion of GM-CSF fusion protein -stimulated DCs is enough to stimulate the appropriate T cells"
Provenge = Anyvenge. The GM/CSF-PAP fusion protein is a unique non-self antigen and would be expected to elicit an immune response in a manner similar to other foreign proteins ---like KLH , maybe ? ( That's my guess anyway , in the absence of data suggesting a better explanation for the Provenge MOA. )
See :
http://tinyurl.com/2ma97o
Cancer Immunol Immunother. 2007 Jun;56(6):897-903.
Antigen-independent immune responses after dendritic cell vaccination.
Leonhartsberger N, Ramoner R, Putz T, Gander H, Rahm A, Falkensammer C, Bartsch G, Thurnher M.
Department of Urology, Innsbruck Medical University, 6020 Innsbruck, Austria.
The ability of cultured, antigen-loaded dendritic cells (DCs) to induce antigen-specific T cell immunity in vivo has previously been demonstrated and confirmed. Immune monitoring naturally focuses on immunity against vaccine antigens and may thus ignore other effects of DC vaccination. Here we therefore focused on antigen-independent responses induced by DC vaccination of renal cell carcinoma patients. In addition to the anticipated response against the vaccine antigen KLH, vaccination with CD83(+) monocyte-derived DCs resulted in a strong increase in the ex vivo proliferative and cytokine responses of PBMCs stimulated with LPS or BCG. In addition, LPS strongly enhanced the KLH-induced proliferative and cytokine response of PBMCs. Moreover, proliferative and cytokine responses of PBMCs stimulated with the homeostatic cytokines IL-7 and IL-15 were also clearly enhanced after DC vaccination. In contrast to LPS induced proliferation, which is well known to depend on monocytes, IL-7 induced proliferation was substantially enhanced after monocyte depletion indicating that monocytes limit IL-7 induced lymphocyte expansion. Our data indicate that DC vaccination leads to an increase in the ex vivo responsiveness of patient PBMCs consistent with a DC vaccination induced enhancement of T cell memory. Our findings also suggest that incorporation of bacterial components and homeostatic cytokines into immunotherapy protocols may be useful in order to enhance the efficacy of DC vaccination and that monocytes may limit DC vaccination induced immunity.
PMID: 17106716 [PubMed - indexed for MEDLINE]
Re : SCLN / SCV-07
It's deja vu all over again for SCLN shareholders , it seems.
HCV may well be the best indication to pursue , given the market size and need for a more tolerable and/or safer alternative to ifn , but it's hard to take this seriously coming from SCLN. Implicit Bioscience is going down the same road with a similar dipeptide ( Oglufanide ) and their founder is the co-inventor of Gardisil , so maybe there is something worthwhile going on with these compounds. Structurally they're not that far removed from drugs like thalidomide , imiquimod , CellCept -- i.e., known small-molecule immunomodulators -- and Oglufanide was originally isolated from a thymic extract , so I think the biologic activity is probably real , it's just a question of whether they can pick the right indication , dose and admin. methods , etc. , and then jump thru all the approval hoops.
Oglufanide is in a similar dose-ranging , monotherapy trial in HCV , but they're testing inhaled as well as s.q. administration. SCLN made a big deal over the oral availability of SCV-07 , so I'm surprised they're not trying the oral route as well in this trial.
A 1-log drop in viral load in a week seems like a reasonable goal to me , since ifn as monotherapy would not do much better in these patients , and the ultimate goal is undoubtedly combo therapy with riba and newer direct antivirals , in place of ifn.
>>> obviously I'm one of the few who thinks of this data as largely a positive <<<
I do too , but 'positive' like kissing one's sister is a positive. ( My West Virginia fishing buddies would be saying : " Wow !! That good , huh ?!! " )
This is better than an outright negative interaction study that might have shelved NM283 altogether , but it's a disappointment for those who thought it might lead directly to P3 trials. We're back to dose-ranging P2 studies and all the uncertainty and delays that comes with that.
As a whole , I thought they were more straightforward than usual on the CC , especially Mayer. JP still does the used-car sales pitch too often for my tastes. The statement that 72% PCR-negativity was an all-time high for 12 wks. of triple therapy was one example. If you compare the VRTX Prove-1 results to the IDIX results in any reasonable apples-to-apples way , IDIX doesn't come close.
To give JP some credit , he did say all along that he didn't expect a negative interaction but he didn't convince me and I was more or less expecting the worst , based on the earlier replicon study results.
Ugly chart today , on volume. I thought VPHM might get a bump up today but they're down also , as is VRTX.
Re : HBV therapy duration
I think the idea of 'stopping rules' for HBV treatment is an area of hot debate , since more and more evidence has accumulated that even low-level HBV viremia can lead to complications long-term. eAg seroconversion that is maintained for a number of months is sometimes used as a guide to stop therapy , but it's not foolproof. Viral loads can be high even well after e-seroconversion , and reverse conversion occurs as well. SAg seroconversion is an accepted definition of "cure" in HBV , but it happens rarely with nukes and at only around 6 or 7 % per yr. of ifn therapy , I believe.
There is off-treatment continued suppression of HBV DNA levels that occurs more frequently with ifn treatment than with nukes ( in both e-positive and e-negative ), presumably due to immune mechanisms . SCLN's Zadaxin has considerable rates of seroconversion and HBV negativity occurring after treatment has stopped , again with an immune MOA. With both Zadaxin and ifn the response rates are strongly genotype-dependent.
Clevudine seems to be unusual among the nukes in having high rates of extended off-treatment viral suppression. I don't know what the reason is for that , except that it does have potent antiviral activity and it seems to result in significant reduction in cellular cccDNA levels , according to the company.
Combos of clevudine plus ifn or other immunomodulators , vaccines , etc., would seem to be an obvious strategy , to try to consolidate the off-treatment suppression that occurs with clevudine monotherapy into a complete immune response leading to sAg seroconversion.
Microtubule movie from HHMI
Link in box at bottom of page :
http://www.hhmi.org/bulletin/may2007/chronicle/molecules.html
The chart at this link summarizing the results may be a little better :
http://www.hivandhepatitis.com/2007icr/easl/docs/041707_a.html
On an ITT basis , 70% is the correct figure.
>> seriously, the logic escapes me. <<
Nothing has escaped , because the logic never existed.
One has to know the QoL of the regimen that would replace the Gemzar-containing one on the first leg , as well as the QoL while on the second leg , to make any judgments.
Consider this example :
Patient # 1 : 9 months to progression , 18 months to death ,
9 months of miserable Gemzar-containing chemo followed by 9 months of well-tolerated other chemo.
patient #2 : 6 months to progression , 18 months to death ,
6 months of well-tolerated non-Gemzar chemo followed by 12 months of a different well-tolerated non-Gemzar chemo.
I'd prefer regimen #2 as would most sentient beings.
Why do docs like Gemzar so much ? PFS. A shrinking or stable spot on a scan that makes them feel less impotent about their inability to help their patients live any longer.
Doc : " Good news, Mrs. X ! See that spot ? That's your tumor , and it's gotten smaller since your last scan. My treatment is working ! "
Patient : " " Oh , Doctor ! That's wonderful !! How much longer can I expect to live as a result of this ? "
Doc : " Ahem . Now , uh , let's not get ahead of ourselves. This is still a very serious disease. "
Patient : " Oh. "
It's a form of medical masturbation where , perversely , the patient does all the work and the doc gets the warm , fuzzy feeling.
>> You appear to have been brainwashed by DNDN bulls into believing that survival is the only efficacy metric of consequence in cancer. <<
The thing I like about that statement is that , of necessity , it implies that I have a brain , that could then be "washed". Therefore I'm interpreting it as a well-camouflaged , but nonetheless sincere , compliment. Thank you.
The following passages from the pre-ODAC FDA briefing document have relevance to the Gemzar discussion ( comments in italics are mine ):
EXECUTIVE SUMMARY
Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized 1:1 to receive either Gemzar in combination with carboplatin or carboplatin alone. The
Gemzar/carboplatin combination adds 2.8 months to median progression-free survival (PFS) with no apparent effect on survival at a cost of increased toxicity, mainly anemia, neutropenia and thrombocytopenia, requiring increased RBC and platelet transfusions and increased use of granulocyte stimulating factors and erythropoietic agents. Independently assessed tumor response rates were Gemzar/carboplatin 46.3% and carboplatin alone 35.6%. This trial was conducted entirely outside of the United States and the FDA had no input into its design or conduct.
The main issue is whether adding 2.8 months to median PFS at a cost of additional toxicity with no apparent effect on survival is a sufficient basis for Gemzar approval for this use. Important considerations are that the combination of paclitaxel and carboplatin has been shown to prolong
survival in this setting.( Increased survival ? We mustn't have that !) In addition, a large international gynecologic group (including the NCI, GOG, RTOG and NCIC) at a Consensus Conference on Ovarian Cancer in 2004 indicated that in the setting of second-line chemotherapy for advanced ovarian cancer "progression-free survival does not seem to be a good surrogate for survival". "Progression-free survival data remain of interest but are unlikely to be sufficiently
persuasive to shift practice patterns".
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"It does not appear that differences in post study chemotherapy account for the failure to demonstrate a Gemzar survival effect."
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Quality of Life
Health-related quality of life (HRQL) was assessed using the EORTC QLQ-C30 and the EORTC QLQ-OV28 patient reported outcome (PRO) questionnaires. These HRQL assessments can not be used as the basis of Gemzar approval because the study was not blinded( ! ), the effect of concurrent medications was not assessed( !! ), on some items the carboplatin alone group did better( !!! ) and the effect on "global quality of life," although statistically significant, is not clinically meaningful.
-
RECOMMENDATION
Deferred pending advice of the ODAC.
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-
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As we know , ODAC voted 9 to 2 against approval , but the von E-led FDA , upon reviewing additional information provided by Lilly , could see no reason to deny approval of this wonder-drug. What was the additional info ? Unknown , since it was not made part of the public record. Rumors suggest it was voluminous , however , and was of the " unmarked , small-denomination " variety , whatever that means. The U.S. is in the decided minority , I'm sure , if we're not the only country to have approved Gemzar for this indication.
So , the question for me is : Do I trust more in groupthink , as exemplified by the FDA reviewer quoted above , the ODAC panel , and some current Dendreonites , or do I trust in Dew-think , as exemplified by the scientific genius of Dr. von E ? ( I'm making an assumption as to von E's genius , but a safe one I believe , given the widely-accepted truism that all Bush appointees share this trait , along with the complimentary one of utmost personal integrity. )
What to do ? Hmmm , let me think about it a se... Ok, I've decided. I'm sticking with groupthink. Sorry , Dew.
BTW , Dew , in light of the liberties I took in interpretation of your comment above , and in the interest of fairness and reciprocity , please feel free to interpret my comments in any way that suits you , as well.
Regards , gofish.
>>> In addition, the MOA of Gemzar supports efficacy <<<
Until efficacy of Gemzar is demonstrated in ovarian cancer ( still waiting ! ) , the MOA of Gemzar is much more supportive of causing cancer than curing it ( think about it ) , as is true of most chemotherapy agents and radiation therapy.
Until you have a specific regimen with proof of efficacy using these treatments , all you have is pretty K-M curves on surrogate endpoints , and loads of cash rolling in if you've been smart enough to bribe the right people.
It's hilarious to me how people railed about the possibility that scarce healthcare resources would be used on an untested treatment like Provenge , and how patients might be exposed to risks like CVAs for no reason , but happily accept that the same thing has occurred with Gemzar and other drugs.
Personally , I really have no problem with the Gemzar approval , given the lack of effective treatments for the condition , and I feel the same about AAs in general , for the most part. What is distressing to me is the total lack of logic and consistency in making the approval decisions , with Provenge being the ultimate example. The odds of Provenge providing a survival benefit , based on available data , are much better than the odds for Gemzar in ovarian , which are near zero , based on data on the label.
>> Baraclude is effectively out of the running for Lamivudine-resistant patients. The battle will be between Hepsera, Telbivudine, and perhaps some newer agents. <<
I hadn't heard the news. Based on the statement below from a 10/06 review by Pawlotsky , I assumed entecavir was seeing some usage in lam-resistant patients :
http://clinicaloptions.com/Hepatitis/Treatment%20Updates/New%20Paradigm%20for%20HBV.aspx
Management of Resistance: Implications for Treatment Choice
Source: Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
By: Jean-Michel Pawlotsky, MD, PhD
"One option for patients who develop resistance to lamivudine would be to switch to entecavir, which potently suppresses lamivudine-sensitive variants and also retains activity, albeit reduced, against lamivudine-resistant variants. However, given the risk of selecting additional “secondary” entecavir resistance mutations in lamivudine-resistant strains—which would lead to the loss of benefit from the switch—an alternative strategy is to continue lamivudine and add adefovir as a second drug or to switch to the combination of adefovir plus entecavir. If approved for the treatment of HBV, tenofovir will likely offer a good alternative to adefovir, since it exerts more potent antiviral activity than the 10 mg/day dose of adefovir."
To the extent that the battle is now between Hepsera and Tyzeka ( if it is , in fact ), I maintain that the victor is currently Hepsera based on scientific principles, until IDIX presents data to the contrary.
JMHO.
" Switching Therapy From Lamivudine to Telbivudine Versus Continued Lamivudine in Adults With Chronic Hepatitis B "
How would this study change my thinking ? The question was one of whether telbivudine is superior to adefovir in lam-resistant patients. Only a head-to-head trial will demonstrate that.
I think telbivudine will get some usage here , I just don't think there's anything to suggest it will supplant adefovir , or entecavir for that matter. If a lam-resistant patient is screened for resistance mutations and found to be free of the rtM204I variant that confers resistance to telbivudine , then that patient might be expected to do as well , or better , than if placed on adefovir or entecavir. Alternatively , I'm sure that often a patient is simply switched and followed closely to make sure they're responding. However , a doc can simply switch that same patient directly to adefovir or entecavir and know with near certainty that there will be viral suppression for some time. That's the hurdle telbivudine has to overcome with their studies.
The treatment that makes more sense than any switch to monotherapy using current drugs is simply adding adefovir to lamivudine in lam-resistant patients , since lam is relatively cheap. This way you get the complimentary resistance profiles .
Resistance profiles are not the only factor , of course. Antiviral potency is important too , since resistance mutation frequency is a function of viral load , and antiviral potency is where telbivudine shines. I just think they'll have to demonstrate comparable or superior performance to current drugs before docs make wholesale changes in treatment strategy.
Re : HIV quiz
Just a guess , but I'd think if treatment compliance is good , it's close to a normal lifespan.
>>> However, Tyzeka / Sebivo could take some of the second-line Hepsera business. <<<
I wouldn't expect this to occur. Telbivudine shares the same flaw as entecavir in this regard -- the same mutations that can confer resistance to lamivudine also can result in resistance to these two -- but adefovir / tenofovir have distinct resistance profiles that make them better candidates for follow-on or combos with lam and the others.
New resistance mutations are discovered occasionally so this is a somewhat fluid model , but I believe it's the one that guides treatment decisions currently.
The other advantage that entecavir has is that it's been demonstrated that several mutations are required for "true" resistance , which is why resistance in lam-refractory pts. builds gradually over years. I'm not sure to what extent compensatory mutations are required after the initial resistance mutation to telbivudine before "true" resistance arises , or whether the single mutations are sufficient.
The extra mutation steps are a big deal because they provide a margin of safety. The danger with these patients is in development of resistance that quickly leads to fuminant hepatitis and , often , death. This is less likely to occur suddenly with the higher genetic barrier of multiple mutations.
1-week stopping rule for pegifn/riba
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17457916&...
J Med Virol. 2007 Apr 24;79(6):701-713
Serum levels of anti-NS4a and anti-NS5a predict treatment response of patients with chronic hepatitis C.
Desombere I, Van Vlierberghe H, Weiland O, Hultgren C, Sallberg M, Quiroga J, Carreno V, Leroux-Roels G.
Center for Vaccinology, Ghent University and Hospital, Ghent, Belgium.
In order to understand better the clinical significance and prognostic value of antibody responses to HCV proteins and in search for parameters that may allow the early identification of non-sustained responders to therapy, antibody levels were measured against NS3, NS4a and NS5a at baseline in the serum of 120 patients chronically infected with HCV of genotype 1 that were classified as sustained responders, relapsers, or non-responders to therapy. The capacity of these antibody tests to predict therapy-outcome was evaluated. While no differences were observed in the anti-NS3 responses in these different response groups, anti-NS4a and anti-NS5a antibodies were observed more frequently and at higher titres in sustained responders versus non-responders or non-sustained responders (=non-responders + relapsers). Based on this observation, a combination of test results consisting of 'the absence of NS4a (AA 1687-1718) antibody at baseline and the presence of HCV-RNA exceeding 10(5) IU/ml after 1 week of treatment' was identified which predicts non-sustained response to treatment with 100% certainty. Replacing the HCV-RNA decision limit by a HCV-core antigen level of >15 pg/ml resulted in the same predictive value. The proposed algorithm also holds for patients treated with peg-interferon and ribavirin. In conclusion, in patients with chronic HCV infection, the decision to continue or stop treatment can be made after 1 week of treatment with (peg)-interferon alpha and ribavirin. J. Med. Virol. 79: 701-713, 2007. (c) 2007 Wiley-Liss, Inc.
PMID: 17457916 [PubMed - as supplied by publisher]
Re : memantine for glaucoma
>>> I would ask my ophthalmologist his/her rationale for its use. <<<
It seems he recommended it to mouton because it works in monkeys. I don't know how I'd feel about that.
;)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...
Arch Ophthalmol. 2006 Feb;124(2):217-25.
Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma.
Yucel YH, Gupta N, Zhang Q, Mizisin AP, Kalichman MW, Weinreb RN.
Department of Ophthalmology and Vision Sciences, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. yeni.yucel@utoronto.ca
OBJECTIVE: To determine whether memantine as a treatment for glaucoma prevents neuron shrinkage in the lateral geniculate nucleus, the major target for retinal ganglion cells. METHODS: Sixteen monkeys with right-eye unilateral experimental glaucoma for 14 months were studied and treated with memantine (n = 9) or vehicle only (n = 7). Left lateral geniculate nucleus relay neurons (layers 1, 4, and 6) were examined following parvalbumin immunolabeling. Cell body cross-sectional areas and neuron numbers were assessed using unbiased methods. Memantine- and vehicle-treated glaucoma groups were compared using t tests and analysis of covariance. RESULTS: Compared with vehicle-treated animals, memantine-treated animals showed significantly less mean +/- SD neuron shrinkage in layers 1 (-4.0% +/- 13.9% vs 28.2% +/- 17.4%; P = .001) and 4 (24.9% +/- 10.0% vs 37.2% +/- 12.3%; P = .04). For layer 6, the difference was not statistically significant (34.2% +/- 10.1% vs 45.3% +/- 14.5%; P = .10). Analysis of covariance results showed significantly less neuron shrinkage in the memantine-treated group for layers 1, 4, and 6 (P < .001; P < .02; and P < .04, respectively). This difference was greatest in layer 1. In each of these layers, neuron numbers did not differ significantly between groups. CONCLUSION: Monkeys with glaucoma that were treated with memantine showed significantly less neuron shrinkage in the lateral geniculate nucleus than the vehicle-treated glaucoma group. CLINICAL RELEVANCE: The finding that memantine protects adult visual neurons from transsynaptic atrophy in experimental glaucoma could have therapeutic value. Currently, memantine is being tested in an ongoing clinical trial as a treatment for glaucoma.
Re :Don’t count on tomatoes to prevent PC
The researchers focused on non-Hispanic Caucasian men, as the small number of cases among other ethnic groups was statistically insignificant.( Isn't this data mining ? It sounds like they ignored maybe 20% of the data for some reason. ) They found no significant difference( Was it P=0.06 ? If so , that's significant , in my book. ) between those who had prostate cancer and those who did not in relation to the concentration of lycopene in their bloodstream.
If anyone has a link to the full dataset , I hope they'll post it.
>> The notion that immunotherapy produces late-separating survival curves while chemo produces early-separating survival curves is more spin than science. <<
That's probably true , though I wouldn't be surprised if it becomes more science-like as evidence accumulates since there is a plausible MOA to explain it.
Recognizing a real , meaningful separation in survival curves is the important thing , whether it occurs early or late , when you're talking about drugs for terminal conditions. Optimization , combos , etc. , can increase the spread and move the separation up to earlier time points , but only if the drugs are available to be optimized. What bothers me is the idea that ingrained review methodologies may stifle progress. One thing I'd suggest as a part of every BLA where survival is an endpoint -- a final group picture of Tx. arm survivors vs. control arm survivors , just to keep it real.
On a related note , I sense that a "rebranding" may be occurring with regard to certain chemo drugs which fits in with your comment above. Every week a new paper comes out describing the effects of current chemotherapy drugs on various immune parameters like T-reg depletion , Mac1 vs. Mac2 predominance , myeloid vs. plasmacytoid , cytokine profiles , etc. In a few years they may be calling it ' Chemmunotherapy '.
>> Satraplatin does not produce the same kinds of side effects as cisplatin, carboplatin, and oxaliplatin; hence, the usual platinum “tells” were not even available to the clinicians. <<
I guess we'll see when the briefing documents come out.
Look , I have no reason to think that Satraplatin would be any less effective than other platinum compounds. It's just that others are so comfortable in assuming that's the case without proof . IF there IS a "tell" , then the pain measure is suspect , and you're left with a questionable surrogate endpoint result that's connected to a true clinical benefit by faith , and faith alone.
>> Delay of pain onset is certainly a clinical benefit, and this was the main component of progression in the SPAC trial. <<
Unless my concern about the trial being largely unblinded is baseless , I'd worry about assigning much importance to a subjective measure like 'delay of pain onset' , which would be highly susceptible to a placebo effect , or an investigator bias effect , or both.