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>> If X % subjects achieve SVR @ 12 weeks? how will this number hold up thru 24 weeks? Is there a precedent / expectation given past studies that shows a relationship between SVR12 and subsequent SVR(24) data?
also the drug drug interaction data to be presented in the fall for NM283, would not this data be comparable to the VX950 data ie... provide SVR12? <<
My guess is that the VRTX SVR12 will be equivalent to SVR24 , +/- a percent or two. Not everyone here agrees as you'll see if you look at our predictions. I base it on the fact that relapse begins shortly after stopping therapy and the assay ( LOD 10 IU/ml ) that VRTX is using will pick up even low viral load relapsers by Wk. 12.
I don't think we'll get any off-treatment data from the interaction study , just the 12 wks. on-treatment results for viral load. We can compare that to SOC or VRTX 12 wk. on-treatment data , I suppose.
>> Your argument ought to be directed to Congress rather than the FDA. <<
A new law that provides for Accelerated Approval based on marginally sub-standard survival data , with provisions for confirmation before full approval , would make sense.
However , there is no need for such a law now for the FDA to apply the logic to drugs like DNDN. They just have to grasp the logic. Maybe it will take a new law for them to do that.
Clearly they have the authority to approve DNDN with conditions regarding completion of 02B. They just don't have an easy way to explain it when they do , and other companies will rightly wonder WTF FDA policy really is.
>> Explaining something to some people, it is important to do it "easy", in a way they can understand. <<
Go ahead and explain it " difficult " , in a way I may not be able to understand. If I need help , I'll ask.
What you failed to pick up on is my contention that the DNDN survival data is at least as good as the BEST surrogate data , especially for unvalidated surrogates , in predicting the likelihood that future trial data will demonstrate a "true" survival benefit.
On Vectibix , PCYC , DNDN and the FDA
The FDA deserves be on the hot seat right now as other companies ask for a second look at their data , since the lack of logic ( and integrity ? ) in the accelerated approval process is now too obvious to ignore.
This is what they said about Vectibix :
"Although the pivotal trial failed to show evidence of an impact on overall survival, FDA Division of Biologic Oncology Products Director Patricia Keegan noted in her recommendation to approve the biologic that "improvements in [progression-free survival] are generally accompanied by improvement in overall survival."
"Generally" , AKA : "sometimes". Not this time , though , in the case of Vectibix.
The purpose of Accelerated Approval is to get drugs on the market that are very likely to improve survival based on "surrogate data" , with the understanding that they will get full approval only if they subsequently demonstrate the survival benefit.
Now , suppose you had a bunch of NDAs or BLAs to review , with data packages similar to either :
1) The Vectibix data , on PFS.
or
2) The DNDN data , on actual survival.
Which group would have a better chance of eventually demonstrating improved survival ? I'd bet my money on the group "2" drugs , and I'd call the person crazy that said ONLY the group "1" drugs are eligible for Accelerated Approval , the situation that now pertains at the FDA.
Yeah , I hope there's some sweaty brows at the FDA right now as they try to decide what to do with DNDN. Maybe they'll decide that the best decision will be the one that makes the most sense.
In other words , time to start doing things differently.
IDMI up big again today
I think the biotech shorts are now also short on courage. The phrase " binary event " has them peeing their pants.
IDMI up 40% today
(The DNDN effect in play again. IDMI announced date of ODAC AC mtg.)
http://biz.yahoo.com/bw/070403/20070403005818.html?.v=1
IDM Pharma Inc. Announces Oncologic Drugs Advisory Committee Meeting for Junovan(TM) (Mifamurtide) Will Take Place on May 9, 2007
Tuesday April 3, 10:35 am ET
IRVINE, Calif.--(BUSINESS WIRE)--IDM Pharma Inc. (Nasdaq: IDMI - News) announced today that the U.S. Food and Drug Administration (FDA) has scheduled an Oncologic Drugs Advisory Committee (ODAC) meeting on May 9, 2007 at which ODAC will discuss Junovan. IDM has filed a new drug application for Junovan (known as Mepact in Europe) for use in the treatment of patients with newly diagnosed resectable high grade osteosarcoma following surgical resection in combination with multiple agent chemotherapy in the United States and Europe. "IDM's team is looking forward to discussing the clinical safety and efficacy data on Junovan with the members of the ODAC and the FDA review team," stated Jean-Loup Romet-Lemonne, CEO and founder of IDM.
The FDA is seeking the opinion of the ODAC panel for Junovan. The FDA regulations indicate that although the FDA will consider the recommendation of the panel, the final decision regarding the approval of the product is the responsibility of the FDA.
About the Phase III trial with Junovan
The Junovan marketing applications include efficacy and safety data from 678 patients with non-metastatic resectable osteosarcoma, 332 of whom received Junovan, and from 115 patients with metastatic or unresectable osteosarcoma, 39 of whom received Junovan in the controlled Phase III trial conducted by the Pediatric Oncology Group (POG) and the Children's Oncology Group (COG), sponsored by the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI). The biological effects and safety of Junovan are further supported by data from 17 Phase I and II clinical studies performed by Ciba-Geigy in which an additional 248 patients received at least one dose of Junovan.
Junovan (mifamurtide - Liposomal Muramyl Tripeptide Phosphatidyl Ethanolamine MTP-PE) is selectively delivered to macrophages via the scavenger lipoprotein receptor pathway, activating the tumoricidal activity through the cytoplasmic Nod2 receptor. When administered in combination with chemotherapy and after tumor resection to osteosarcoma patients in the Phase III trial, Junovan provided a significant improvement in Disease Free Survival (DFS) (p less than 0.0245) and Overall Survival (OS) (p less than 0.0183). At 6 years, the probability of survival when Junovan is combined with adjuvant chemotherapy is 77% (95%CI:72-83%) compared to 66% (95%CI:59-73%) without Junovan, a clinically meaningful finding in a pediatric population where the longer the survival, the greater the chance that the patient is cured of cancer. Additional survival data from the COG (median follow up of 7.7 years) supports the survival benefit of Junovan in the treatment of non-metastatic osteosarcoma. The most common adverse events include chills, fever, nausea, vomiting, myalgia, headache, tachycardia (fast heart rate), hypo- and hypertension, fatigue and shortness-of-breath, generally mild to moderate in nature and consistent with the activation of monocytes and macrophages by Junovan and the flu-like symptoms that follow cytokine release.
About Osteosarcoma
About 3% of all childhood cancers are osteosarcoma. Because osteosarcoma usually develops from osteoblasts, it most commonly develops in teenagers who are experiencing their adolescent growth spurt. Osteosarcoma is an orphan disease and there are approximately 1000 new cases in the US each year. A similar incidence of the disease exists in Europe. According to the Children's Oncology Group (http://www.curesearch.org/our_research/index_sub.aspx?id=1761), the survival of children with osteosarcoma has remained at 60-65% since the mid-1980s. The standard treatment for osteosarcoma is tumor resection with combination chemotherapy before and after surgery.
About IDM Pharma
IDM Pharma (IDM) is a biopharmaceutical company focused on the development of innovative products that activate the immune system to treat cancer. IDM's lead product candidate, Junovan(TM), (mifamurtide for injection), known as Mepact in Europe, is part of a new family of immunotherapeutic agents designed to destroy residual cancer cells by activating the body's natural defenses. IDM has submitted applications to the FDA and the EMEA, requesting marketing approval of Junovan for use in the treatment of newly diagnosed resectable high-grade osteosarcoma patients in combination with multiple agent chemotherapy. The FDA has accepted the new drug application for substantive review, on a standard review basis, contingent upon our commitment to provide pharmacokinetic data for the to-be-marketed Junovan product. IDM is jointly developing Uvidem, a cell-based vaccine product candidate in Phase II clinical trials for the treatment of melanoma, with sanofi-aventis.
For more information, visit www.idm-pharma.com.
Re : B12 absorption
urche,
I think the idea of the AMGN technology is to use B12 absortion as a transport mechanism for the peptide. Sort of a pro-drug , where the peptide is the drug.
EDIT : Oops, you beat me to it biophud.
Re : Dawson-James
I'd stay away. I heard the name comes from the Dawson Gang / Jesse James , notorious outlaws.
>>> I wonder why more oral peptides haven’t been developed based on this principle. <<<
In many cases it's probably a matter of trading off activity for the stability and oral dosing advantages , at least in the cases where the therapeutic peptide is supposed to mimic a native peptide or protein.
SCLN's SCV-07 is a dipeptide with a D-AA and with oral bioavailability. They're supposed to initiate trials soon , but I don't think they've even announced the indication(s) yet.
Re : entecavir vs telbivudine
On top of all that , telbivudine is priced at a discount to entecavir ( and adefovir ).
Nice rebuttal , dewophile. Thanks for posting it.
>> Certainly, as we move forward assuming that we hear positive response back, we will need some additional funds to build out and the remaining capacity in our manufacturing higher on the staff, but I think to talk about any specifics, we'll cover that after the May 15, date. <<
Sufficient ambiguity there to allow for pre- or post-May 15 financing , IMO.
If they finance before May 15 and Provenge is approved , shareholders will be furious because of excessive dilution as a result of the lower pre-approval share price.
If they finance after May 15 and Provenge is rejected , shareholders will be furious because of excessive dilution as a result of the lower post-rejection share price , and because Provenge was rejected.
If they finance before May 15 and Provenge is rejected , shareholders will be furious because Provenge was rejected.
If they finance after May 15 and Provenge is approved , shareholders will be euphoric.
Conclusion : Finance after May 15 and pray for approval.
>> wouldn’t this be the perfect time to announce a public offering? <<
Friday evening is good for that type of announcement but I'd think it better to wait till Monday , at least , since there's a good chance the share price will settle at a higher level. The basher analysts have weighed in already but there's still some big guns that haven't spoken and will likely come out with upgrades.
If DNDN goes into the PDUFA date without additional financing , you'd have to figure they have supreme confidence in a positive outcome. Or else they're crazy.
Dendreon Crop Stocks Up With New Prostate Cancer Drug
I guess these guys think DNDN is an Ag company. The picture in the article appears to be an "approach" shot of the prostate.
http://www.ecanadanow.com/science/health/2007/03/30/dendreon-crop-stocks-up-with-new-prostate-cancer...
or
http://tinyurl.com/22g5te
DNDN 9:8 vote for approval ??
I've seen it mentioned on MBs that there was a second vote on efficacy besides the 13:4 vote. Is this correct?
P.S. to DNDN longs : The best thing for that hangover is : " Hair of the dog that bit ya ! ".
>> GSK thinks Cervarix is an all-around better drug <<
I think Merck agrees. Looking back , it's the only thing that would explain the ham-handed way Merck handled the Gardasil promotion. Their intent was to get every eligible girl vaccinated before Cervarix becomes best-in-class , then they could produce a more competitive product to be ready for the next generation of eligible patients.
I'd bet money [or an iHub membership ] that Cervarix proves superior.
( I haven't researched it , so it might be a bad bet. The adjuvant might improve the immune response at the expense of injection site reactions or other AEs. )
>> GlaxoSmithKline said in January it was launching a head-to-head clinical trial involving more than 1,000 women to try to prove Cervarix is superior to Gardasil. Glaxo said then it expected to have results from the study in about a year. <<
This is probably why Merck was so aggressive in marketing Gardasil , e.g. mandatory vaccinations , etc. --- which ended up backfiring.
It seems GSK is confident they'll win the head-to-head. The adjuvant must give them the edge.
New thinking needed at FDA re: oncology drugs ?
The jiggering of the efficacy question reflects a commonsense desire by the panel members to express an opinion which would not have been reflected in a yes or no answer to the original question.
What most of them seemed to want was approval , but verification by 9902b. If this was an accelerated approval based on a surrogate endpoint , the model for moving forward would be clear , which makes no sense to me , since that says a surrogate endpoint that MAY predict survival was clearly met , so we'll approve and require follow-on data to see if there is truly a survival benefit. The level of uncertainty about the survival benefit is actually quite high at the time of approval.
In the case of Provenge , the certainty of a survival benefit is much higher than in the case above , though it doesn't meet the gold standard typically required for unconditional approval. Yet the most likely action by the FDA , based on past experience , seems to be an approvable letter pending 9902B. That's just nuts , IMO. It flies in the face of common sense and that's what the panel was saying today.
Call it accelerated approval , conditional approval , fingers-crossed-behind-my-back approval , whatever , just approve the damn thing and any other cancer drugs with data similar to this going forward. In other words , FDA , use some common sense -- like the panel members.
JMHO , FWIW.
>>> A hedge fund in trouble = dumping a lot of their other biotech holdings... Aiming4. <<<
The ones that are in trouble with DNDN are likely short speculative biotechs. They're not likely to short those more , after this. :)
Bigger biotechs they may be holding long could get dumped.
Dew , apparently many panel members were reluctant to vote yes or no on the question as originally phrased and the FDA rep modified it.
I wouldn't be surprised if a hedge fund or two goes bust because of this. What a shame.
Congrats DNDN longs !
CNBC saying now DNDN will EXPLODE tomorrow.
Forget basketball.
The real March Madness is in Gaithersburg at the FDA AC mtg.
I hope the National Guard is standing by in case of a negative vote.
C'mon DNDN !! -- 3-pointer at the buzzer to win by a vote !
GlaxoSmithKline Submits Biologics License Application to U.S. Food and Drug Administration for CERVARIX(R)
http://biz.yahoo.com/prnews/070329/clth041.html?.v=89
Thursday March 29, 2:22 pm ET
New Vaccine Candidate Developed to Protect Against Cervical Cancer - Filing Includes Data from Almost 30,000 Females
PHILADELPHIA, March 29 /PRNewswire-FirstCall/ -- GlaxoSmithKline (NYSE: GSK - News) announced today that the company has submitted a Biologics License Application (BLA) for CERVARIX® (human papillomavirus vaccine, AS04 adjuvant-adsorbed), its cervical cancer candidate vaccine, to the U.S. Food and Drug Administration (FDA). If licensed, the vaccine will be indicated for the prevention of cervical cancer and precancerous lesions associated with the most common cancer-causing human papillomavirus types. For this candidate vaccine, GSK selected a novel proprietary adjuvant system called AS04, intended to enhance immune response and increase duration of protection.
"Today's filing is an important milestone for GSK and reflects our commitment to help prevent cervical cancer, the second most common cancer among younger women," said JP Garnier, CEO of GlaxoSmithKline, one of the world's leading vaccine manufacturers. "We believe that the best possible protection against cervical cancer will include routine screening together with a vaccine designed to provide targeted, durable protection against the most common cancer-causing virus types."
The BLA for the GSK cervical cancer candidate vaccine includes data from clinical trials in almost 30,000 females 10 to 55 years of age and reflects an ethnically diverse population. The submission also contains data from the largest Phase III cervical cancer vaccine efficacy trial to date, which was conducted around the world in more than 18,000 females 15 to 25 years of age.
"We are pleased to submit this file to the FDA," said Barbara Howe, MD, Vice President and Director, North American Vaccine Development Organization, at GlaxoSmithKline. "It includes a considerable amount of data for virus types 16 and 18 that cause 70 percent of cervical cancer cases worldwide, as well as data for other virus types that can lead to cervical cancer. We look forward to presenting study results in the coming months."
The GSK cervical cancer candidate vaccine is formulated with a proprietary adjuvant system called AS04, containing aluminum hydroxide and monophosphoryl lipid A (MPL®). Published data have shown that the GSK cervical cancer candidate vaccine formulated with AS04 provides a stronger and longer lasting immune response compared to the same GSK vaccine composition formulated with a traditional aluminum hydroxide adjuvant.
About Cervical Cancer
After breast cancer, cervical cancer is the second most frequently occurring cancer in women between the ages of 20 to 39 in the United States. The American Cancer Society estimates that in 2007 more than 11,000 women will be diagnosed with cervical cancer and nearly 4,000 will die from this disease in the United States. Furthermore, approximately 2 million precancerous lesions are diagnosed each year in the United States.
The GSK Cervical Cancer Candidate Vaccine Around the World
In addition to the Biologics License Application submitted for CERVARIX® with the U.S. Food and Drug Administration, GSK has submitted a marketing authorization application to the European Medicines Agency, Australia, Canada, and major countries in Asia and Latin America.
About GlaxoSmithKline
GlaxoSmithKline-one of the world's leading research-based pharmaceutical and healthcare companies-is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information, please visit http://www.gsk.com/media .
GSK Biologicals (GSK Bio), one of the world's leading vaccine manufacturers, is headquartered in Rixensart, Belgium, where the majority of GlaxoSmithKline's activities in the field of vaccine research, development and production are conducted. GSK Bio employs more than 1,500 scientists, who are devoted to discovering new vaccines and developing more cost-effective and convenient combination products to prevent infections that cause serious medical problems worldwide. In 2006, GSK Bio distributed more than 1.1 billion doses of vaccines to 169 countries in both the developed and the developing world - an average of 3 million doses a day. Of those vaccine doses, approximately 136 million were doses of combination pediatric vaccines which protect the world's children with up to six diseases in one vaccine.
Alzheimer's vaccine works on mice
http://www.guardian.co.uk/science/story/0,,2045450,00.html
Alzheimer's vaccine works on mice, says Japanese scientist
Justin McCurry in Tokyo
Thursday March 29, 2007
Guardian Unlimited
Scientists in Japan have developed an oral vaccine for Alzheimer's disease that has proved effective in mice, raising hopes that an effective treatment for humans can be found for the fatal condition, which affects millions.
Scientists at the National Institute for Longevity Sciences in central Japan said today that they hope to begin small-scale clinical trials of the oral vaccine later this year.
"We hope the phase one trials go well," Reuters news agency quoted Takeshi Tabira, the institute's director, as saying.
"Animals are able to recover their functions after developing symptoms, but humans are less able to do so. It may be that this only works in the early stages of the disease, when symptoms are light."
The vaccine reduced the amount of amyloid plaques - believed to be the cause of Alzheimer's - and improved brain function when administered to mice that had been genetically modified to develop the disease, Mr Tabira said.
The vaccine works by stimulating the immune system to attack and destroy amyloid proteins in the brain, and the mice suffered no side-effects, such as inflammation or bleeding in the brain.
Tests showed that mental function in the mice returned to near-normal levels three months after they were administered the treatment.
Successful trial on humans would boost attempts to prevent Alzheimer's from becoming a medical emergency in countries with rapidly ageing populations.
The disease affects 5 million Americans, according to the Alzheimer's Association, and a recent report by the London School of Economics and the Institute of Psychiatry warned that 1.7 million people in the UK will have dementia by 2051.
One in 20 people aged over 65 and one in five people over 80 have a form of dementia, with around two-thirds of the total suffering from Alzheimer's.
Thanks , Biowatch. EOM
>>> Not sure in this case, but don't noncrossovers often do worse than crossovers in trials because at the time they were allowed to crossover they were ... (i) dead or (ii) in very bad shape or (iii) simply not fighting as hard as the crossovers for a few extra months of life? <<<
micro,
Almost always , I think , those in group (i) do poorly.
For the other groups , I think it would depend a lot on the nature of the crossover treatment offered. A brutal tx., like most chemos , would probably cause someone who was already feeling very sick to think twice. On the other hand , a relatively benign tx. like Provenge might appeal to the sicker patients even more than those less sick , who might choose to go straight to chemo instead of Provenge.
At least walldiver's numbers stack up in favor of Provenge , whatever the confounding influences might be. Better than having to explain the reverse situation.
I wish all the DNDN longs luck tomorrow , as well as patients and others with an interest in seeing it succeed. My vote would be for a conditional approval like the USDA granted to the canine melanoma vaccine recently. That would serve all interests best , IMO , since Provenge availability would not be delayed , yet confirmatory efficacy data from 9902B would be required to get permanent approval. The FDA should look to the USDA for help on this , if needed. ;)
>> Of course that would ignore dozens of trials where GMCSF did nothing for cancer patients. <<
I'm not saying the DNDN procedure is not working , just that I haven't seen much that convinces me that it's acting in a prostate-specific way as opposed to as a general immune stimulant. If DNDN or others have shown that GM-CFS fused to a non-tumor-specific protein , used in the same ex-vivo stimulation process , doesn't work as well as PAP-GM-CSF against prostate cancer , fine. Cite those studies.
I may not have made myself clear in my point about frozen Provenge. With Provenge , we're talking about a treatment where the MOA is immunological , but beyond that it's poorly characterized. Now you're going to freeze/store/rethaw/infuse a cellular infusion product and assume that no unknown ( read : confounding ) immunogenic species will be generated in that process that will cause it to be different from fresh Provenge. Not a problem if the surrogate marker is the final endpoint , but IMO a bad idea if post crossover endpoints like survival are critical.
>>> The FDA has a long history of allowing x-over in a trial with a surrogate endpoint after each patient has met the surrogate. This is not much different. So I don't understand your point. <<<
I don't have a problem with crossover designs , per se , just when the crossover experimental drug is not the same as the treatment arm experimental drug.
Imagine a situation where the freezing process generates factors in the crossover Provenge that add to efficacy , or add to toxicity , or both. You would have a hard time sorting it all out in a trial like this. If the crossovers had lived twice as long as those who received fresh Provenge , could you tell whether it was due to the freezing or , instead , to the delayed administration ? You'd have a similar problem if frozen Provenge caused patients to die much quicker than the non-crossovers.
There may be no such confounding in these trials but it's still a bad design for pivotal trials in first-in-class drugs , IMO.
Thanks.
I've never been any good at the marketing stuff.
>>> Provenge is the first trial I've seen that did stimulation with GMCSF in treatment arm but not in placebo arm (albeit I haven't looked exhaustively). <<<
The placebo arm , being frozen Provenge ( for crossovers ) , was not a 'true' placebo in these trials and confounds the results in a way that should incentivize the FDA to discourage this type of trial design in the future.
I would have assumed that early on DNDN would have shown that non-tumor-specific proteins fused to GM-CSF did not work , or at least not as well. Now I wonder if they even did the studies.
My choice for a second-generation -- and universal-- product , based on what I've seen so far , would be GM-CSF fused to GM-CSF.
>>> If the immune response is not antigen specific, then Neuvenge = Provenge. <<<
To save on labels , call them all: 'Anyvenge'.
A booster shot would , of course , be 'Revenge'.
>>> On Table 28 / page 116, they clearly show that the immune reaction is to the fused antigen alone. So not to PAP and not to GM-CSF as I first guessed. <<<
Your guess was not bad if you look at the antibody component of immune response-- see Table 31 / p.123
Wouldn't be hilarious if it turned out that the MOA of Provenge was induction of anti-GMCSF antibody ?
I guess they don't need a well-defined MOA to get approved , but these data are not what I expected to see. I always thought the anti-PAP activity was a given.
The AC will probably ask some pointed questions on this topic.
Like you guys , I'd be happy with equal or better relapse rates compared to control , but I'm a little concerned that even if that appears to be the case , there might be a catch.
If you look at the demographics , you'll see that the arms are balanced pretty well in all regards except race. In particular , the NM283 arms have about half the number of African-Americans as the conrol arm. I know that AAs have significantly lower overall SVR rates , but I need to try to find out if this is due to nonresponse or relapse , or some combination of each.
Since each arm will only have 10 or so patients who are HCV-neg at EOT and thus candidates for SVR , one or two patients per arm can swing the relapse rates considerably. Any randomization imbalance against the control arm that adversely impacts relapse rates in that arm could easily make NM283 look better than it deserves.
Maybe we'll get lucky and they'll disclose the demographics of the responding patients ( i.e. HCV-neg EOT )in each arm so there's no confusion.
I'm just hoping to see results that give us some reason to look forward to the naive data at AASLD in the fall.
EASLxpectations ?
Anyone have thoughts about what kind of NM283 SVR rates ( vs. control ) in the nonresponder trial would be considered good or bad by the investment community , including us ?
P.S. 'Relapse rates' vs. control is an equally valid way to look at this question.
The way things are going , IDIX should convert the 'Corporate Leadership' webpage into a wiki , which can then be updated in real time by departing execs.
:(
>> Am I reading this wrong, or does Provenge stimulate a T-cell response against the fusion PAP not native PAP? <<
I suppose the explanation is that the response against the native PAP takes longer to develop ( via epitope-spreading ) , and is seen in only the 0-16 week data. It looks a little dicey , though.
It's reasonable for the response to be stronger against the fusion protein than against the native protein , but I'd expect a significant boost in the native protein response in Provenge-treated patients compared to controls.
After all , patient cancers don't express fusion protein.
>>> What I did not fully expect was that the method of filtering was not prespecified - since Dendreon has kept hammering that it was prespecified. <<<
Does anyone think the DNDN deceptions on such issues , apparently repetitive and well-documented , rise to the level where lawyers begin to salivate ?
If the FDA issues an approvable requiring 9902B completion , will shareholders take it out on Gold & Co.?
Could this be what the shorts are , in fact , betting on ?
Here's a recent ISIS paper that relates structural features of oligos to hepatotoxicity :
(free full-text):
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17182632
Nucleic Acids Res. 2007;35(2):687-700. Epub 2006 Dec 19.
Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK, Hung G, Monia BP, Bennett CF.
Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, CA 92008, USA. eswayze@isisph.com
A series of antisense oligonucleotides (ASOs) containing either 2'-O-methoxyethylribose (MOE) or locked nucleic acid (LNA) modifications were designed to investigate whether LNA antisense oligonucleotides (ASOs) have the potential to improve upon MOE based ASO therapeutics. Some, but not all, LNA containing oligonucleotides increased potency for reducing target mRNA in mouse liver up to 5-fold relative to the corresponding MOE containing ASOs. However, they also showed profound hepatotoxicity as measured by serum transaminases, organ weights and body weights. This toxicity was evident for multiple sequences targeting three different biological targets, as well as in mismatch control sequences having no known mRNA targets. Histopathological evaluation of tissues from LNA treated animals confirmed the hepatocellular involvement. Toxicity was observed as early as 4 days after a single administration. In contrast, the corresponding MOE ASOs showed no evidence for toxicity while maintaining the ability to reduce target mRNA. These studies suggest that while LNA ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity.
>> "Conditional approval" means the product has been shown to be safe and have a reasonable expectation of efficacy in treating melanoma. The designation allows Merial to market the therapeutic vaccine while collecting additional efficacy data to support full marketing approval. <<
I appreciate that the FDA may be more inclined to do this for dogs than for humans ( I like dogs better too ), but wouldn't the 'conditional approval' designation for Provenge make the most sense , all things considered ?
Don't mind me , just thinking out loud , in writing.
The Bar-Heads would have been a better example if they were trying to illustrate the adaptations needed to migrate over the Himalayas. It was like comparing driving up a mountain on a bike versus on a motorcycle. The cranes they showed barely made it flying thru the valleys , much less over the peaks , and they were easy prey for Golden Eagles. Bar-Heads probably cruise easily at 10,000 feet above the altitude limit of the eagles.
Thanks for the info about Delaware law on takeovers. I guess the NVS acquisition of Chiron is instructive in some ways , in that the initial lowball NVS offer was rejected by a hedge fund or two , and NVS had to come back with a considerably higher offer that was considered acceptable. It doesn't rule out the possibility that NVS might be less-than-eager to advance agendas that might boost the share price of IDIX in the months leading up to a takeover bid , however.
I'm just trying to think of reasons why the CFO bailed. If I recall correctly , NVS has some clause in their agreement with IDIX regarding CFO hiring / firing rights. The questions then arise whether he was asked to leave so an NVS-friendly replacement could be named , whether he left because he thought IDIX was likely to remain dead in the water ( or worse ) , in the foreseeable future , or whether he simply found a more desirable position elseware. I'm not suggesting one is more likely than the other , just that I'm thinking about all the possibilities.
A corollary to the " Don't get scammed" rule is : " Figure out what the scam is so you can invest to benefit from it. " :)
OT : BTW , I expected to see your Bar-Headed Geese on the "Planet Earth" series which debuted tonite , but instead they showed a type of crane that migrates over the Himalayas. Not over Everest like the Bar-Heads , though.
Kudos to Discovery Channel for a spectacular series. I can't wait to see the next installment.