Also posted on the Yahoo ISIS Board.
Over the past week, Potted and his brother ( FlowerBasket ) have been reviewing Alnylam’s RSV research program, and are awaiting this Friday’s webcast on RSV (Respiratory Syncytial Virus Infection). http://biz.yahoo.com/cc/0/90460.html . . . For those unfamiliar with Alnylam, they are STILL working on an effective SYSTEMIC DRUG DELIVERY SYSTEM for their numerous RNAi-based drugs ( 7 or 8), however their RSV drug program utilizes a unique aerosol delivery, which has shown promise in earlier trials. . . . and this could potentially be the FIRST RNAi-based drug from Alnylam on the market! . . . BUT (and there had to be a but!) . . . a review of the current RSV research now shows some “telltale” signs that Alnylam’s RSV program may well be in deep TROUBLE - - IMO! . . . Here’s Potted’s reasoning.
1) On the much ballyhooed initial release of Alnylam’s RSV results, in which NO DATA were presented, one could have counted the words “Proof-of-Concept” (POC) literally a dozen times throughout the article! . . . While POC is important, that lingo ( POC ) is generally reserved for early clinical and pre-clinical research, NOT for a completed Phase II candidate going into Phase III registration. . . So Potted questions . . . Was Alnylam fearful of using STRONGER language for what the results really show?
2) Alnylam reports, “Top-line results show that ALN-RSV01 was safe and well tolerated and demonstrated statistically significant anti-viral activity.” . . . Well . . . to be successful when going after a virus . . . one NEEDS nearly complete KNOCK-DOWN of the virus! . . . say 90% or more just to be in the ball game! . . . So Potted questions again . . . Does “demonstrated statistically significant anti-viral activity” mean nearly complete knock-down of the virus? . . . Potted thinks . . . NO! . . . This is a key reason why Stan abandoned the Antisense viral work years ago at ISIS! . . . the “bar of viral destruction” is set so high that it is very difficult to achieve such a high level with current RNA technology! ( perhaps Regulus has more of a role here! ) . . . and anything less with viruses is considered TOTAL FAILURE!
3) Part of the Alnylam study protocols for RSV even had FlowerBasket scratching his basket! . . . “The study was performed using ALN-RSV01 or placebo administered intranasally for five consecutive days -- two days prior and three days after viral inoculation.” . . . So Potted & Basket question . . . Why was the drug given BEFORE the viral inoculation? . . . as this scenario could NEVER play-out in the real world! . . . Imagine being diagnosed with the virus, and then being told that the new drug will work ONLY if you were already taking it! . . . And Potted again questions . . . Are the viral loads controlled ONLY when the drug is initially present upon infection? . . . Just too many QUESTIONS here - - IMO!
So from the above, Potted and Basket both conclude that there may be some BIG PROBLEMS with Alnylam’s RSV program! . . . that is if one equates SUCCESS with having a marketable RNAi-based drug for RSV! . . . but knowing Alnylam . . . they will likely MODIFY the definition of trial success! ( they always do! ). . . and they will shout “PROOF-OF-CONCEPT!” over & over again! . . . and will PROCLAIM the often-used words . . . “Just More Optimization Needed!” . . . and . . . “It’s Just Around the Corner!” . . . and the crazed Alnylam investors will shout, “GO ALNYLAM!” . . . and the DREAM lives on! . . . and the stock price RISES! . . . well . . . MAYBE! . . . and MAYBE NOT!
Go to the Head-of-the-Class with ISIS!
The Potted ones don't seem very well informed. Their Point 2 is clearly false. Portion of viral load is directly related to severity of RSV disease. Even a partial reduction of viral load yeild clinically relevant results. This has been in the published literature for years.
Do your own DD but unfortuantely the "potted one" and his brother seem to be highly uninformed.
The Journal of Infectious Diseases 2005;191:1861–1868
© 2005 by the Infectious Diseases Society of America. All rights reserved.
Respiratory Syncytial Virus Load Predicts Disease Severity in Previously Healthy Infants
John P. DeVincenzo,1,3,4,5
Chadi M. El Saleeby,1,3,6 and
Andrew J. Bush2
Departments of 1Pediatrics and 2Preventive Medicine, University of Tennessee School of Medicine, 3University of Tennessee Graduate School of Health Sciences, 4Le Bonheur Children’s Medical Center, 5The Children’s Foundation Research Center, and 6St. Jude Children’s Research Hospital, Memphis
Background. Elucidating the relationship between viral load and respiratory syncytial virus (RSV) disease severity is critical to understanding pathogenesis and predicting the utility of antivirals.
Methods. Previously healthy, naturally RSV-infected infants <24 months old not treated with ribavirin, passive antibody, or corticosteroids were prospectively studied (). Viral loads were measured by fresh quantitative culture from nasal washes collected at a single time point shortly after hospitalization.
Results. The subjects’ mean age was 112.1 days, and the mean estimated gestational age at birth was 38.38 weeks. RSV load decreased with longer durations of symptoms before specimen collection (). Male subjects had higher RSV loads than female subjects (). Significant independent predictors of longer hospitalization were congenital anomaly (), lower weight on admission (), and higher nasal RSV load (). A 1-log higher RSV load predicted a 0.8-day longer hospitalization. Lower weight and higher RSV load were also independently associated with respiratory failure ( and , respectively) and requirement for intensive care ( and , respectively).
Conclusions. In previously healthy infants, higher RSV loads measured at capturable time points after symptom onset predict clinically relevant measures of increased disease severity.
Jac . . . Potted stands by his previous claims that the results reported by Alnylam, "Subjects receiving ALN-RSV01 experienced a 38.1% reduction in infection rate as measured by plaque assay (P less than 0.01)." . . . were NOT good enough! . . . and represent TROUBLES for Alnylam going forward!
And Jac . . . the RNAi Therapeutics Blogger (normally a strong supporter of Alnylam) goes one step further, suggesting that some of the RSV viral reduction may not be due gene-blocking at all! . . . ( oh! . . . such blasphemy! ) . . . "The problem with calling the results a definite proof-of-concept for RNAi in humans is that this program targets a virus, and it is well documented that particularly unmodified siRNAs can have profound antiviral effects independent of their gene silencing activity, i.e. by inducing cytokine responses. However, I acknowledge that Alnylam and their clinical collaborators have done almost all humanly possible to (statistically) exclude the influence of various parameters such as inflammatory cytokines on the antiviral efficacy, although it is not clear e.g. when and where these markers were measured" . . . http://rnaitherapeutics.blogspot.com/search?updated-min=2008-01-01T00%3A00%3A00-08%3A00&updated-max=2009-01-01T00%3A00%3A00-08%3A00&max-results=18 . . . Now Jac . . . Potted won't go there! . . . but many technical RNAi "experts" will! . . . Looks like both You and Alnylam may have a bit more "explaining to do!"
Go to the Head-of-the-Class with ISIS!
you seem to think a lot of whats going on at alny is far from completion.whats the connection between alny and sirt? some of the directors are on both of these revolutionary companies. could these companies be more hype and promoting than real? are these scams being perpertrated by academias best? just an inquiry for the time being.
This RNAi will be public domain before a viable delivery is achieved.
Great target but no means of delivery = $$ expensive science project.
Potted, I disagree with you on mipomersen but I've got to agree with you that ISIS has them beat on this one!
Gpy . . . Merck and Roche likely under-estimated the RNAi drug-delivery problem - - just like Alnylam! . . . but ISIS never under-estimated it! . . . Stan ( at ISIS ) had commented at one time of the difficulty with the double-stranded structures. . . that's likely why ISIS, when initially developing their technology, decided on a SINGLE-STRANDED (SS) RNA technology. . . NOT double-stranded (RNAi). . . and developed their "patent estate" with SS Antisense!
The prices paid for the technology will look like small potatoes IF a systemic drug delivery system is defined shortly (say less than 5 years) . . . but if this process drags on! . . . and on! ( say more than 10 years and no more clarity! ) . . . then it will be called BUST!
A good description of Antisense, the science, the technology, and the drug therapeutic programs are on the ISIS web site: http://www.isispharm.com/research_technology.html
Actually . . . the Antisense mechanisms are easier to grasp than RNAi! - - IMO!. . . just another elegant mechanism to "block" genes!
Go to the Head-of-the-Class with ISIS!
This Phase II was in effect a first tentative step.
The main issue is it is clear nasal delivered RNAi is not as good as inhalational delivered RNAi for RSV.
Thus the pivotal Phase II in naturally infected individuals (to occur first half of this year) will use inhalational delivered RNAi which is delivered extremely well (better than had been expected from animal data) in man (results presented late last year).
I anticipate the dose and PK after inhalational administration of ALN-RSV001 will be optimized so that you will see absolute (100%) reduction in viral titer after dosing is complete without (of course) the need for pre-administration of ALN-RSV001 which is not therapeutically relevant in the real-world.
ALNY RSV Data already released at the WSJ and on the ALNY web site!
http://online.wsj.com/article/SB12042582... . . . and on the Alnylam web site - - where more data statistics are given . . . http://phx.corporate-ir.net/phoenix.zhtm...
Depending on measurements used, ONLY ABOUT A 20% to 40% reduction in viral infection rates! - - Statistically significant . . . YES! - - - BUT in Potted's view. . . NOT GOOD ENOUGH! . . . NOT ENOUGH KNOCK-DOWN OF THE VIRUS! . . . And as Alnylam will likely say, "More Optimization Needed!" . . . Here are the key findings. . .
Subjects receiving ALN-RSV01 experienced a 38.1% reduction in infection rate as measured by plaque assay (P less than 0.01).
Similar reductions in infection rate were obtained with other measurements of viral infection, including RT-qPCR, spin-enhanced culture, and RSV antigen assay.
The overall infection rate by any of these measures showed a statistically significant anti-viral effect for ALN-RSV01 (P less than 0.025).
Treatment with ALN-RSV01 also resulted in nearly a doubling -- a 95% increase -- in the number of subjects who remained free of infection (P less than 0.01); 12 of 42 subjects receiving placebo were uninfected as compared with 24 of 43 subjects treated with ALN-RSV01.
Measurements of viral dynamics showed consistent trends favoring an ALN-RSV01 treatment effect, including viral AUC (area under the curve), viral load, peak viral load, duration of viral shedding, and mean daily viral load.
In this relatively small study, there were no significant difference in clinical symptoms.
ALN-RSV01 was found to be safe and well tolerated.
It appears that ALNY has an "Inhalation Study" following later this year . . . where results are expected to be much better!
Go to the Head-of-the-Class with ISIS! . . . Potted Right Again?