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A researcher into gene silencing as a technology for improving the lives of those suffering from incurable diseases. Benitec Biopharma is my primary investment in this technology as ddRNAi offers one-time treatments for a broad range of these diseases.
  • TT-034: Not A Binary Outcome For Benitec 17 comments
    Jul 4, 2014 7:03 AM | about stocks: BNIKF, BTEBY

    On May 29, 2014 Benitec Biopharma (OTCPK:BNIKF, OTCPK:BTEBY) announced that patient dosing had commenced in the clinical trial of its lead compound for the treatment of Hepatitis C (HCV), TT-034. The trial's protocol demands that the first patient in each dosing cohort (of which there are five) be treated and monitored before the rest of the cohort can be dosed. In the case of the first three cohorts the dosing and monitoring period is six weeks. In the case of the fourth and fifth cohorts the dosing and monitoring period is ten weeks. The remaining patients in each cohort have the same dosing and monitoring periods. The protocol also dictates that the independent Data Safety Monitoring Board (DSMB) reviews the safety data from each of the first patients in each cohort before approving the dosing of the remaining patients. The protocol also dictates that the safety data for all patients in a cohort must be reviewed before approval can be given for dosing of the following cohort.

    If everything went smoothly i.e., all the patients were screened and dosed on time and the DSMB met immediately after the dosing anniversaries mentioned above, then the first three cohorts would each take 12-13 weeks from first dosing to assessment and the last two cohort would each take 20-21 weeks.

    The trial is now at a stage where the first patient in the first cohort (of two patients) will, in the next few days, reach the six week anniversary and the DSMB will be able to review the safety data.

    As we are so close to this first milestone I thought that I would remind shareholders of the consequences of the outcomes for TT-034.

    The company has committed to releasing data on each cohort as dosing progresses. This means that, if a second patient is dosed next week, after the DSMB meets (assuming it meets on time), then shareholders can expect to receive news about the first cohort in the third week of August. The company may elect to announce the dosing of the second patient before then. This would be a good sign regarding the issue of safety as such an announcement would confirm the DSMB approval.

    In my opinion, the first announcement will only give an indication of the safety of TT-034 and safety is the purpose of the first cohort. Should no or inconsequential adverse events be recorded, then the second cohort will be approved. While this would cause a positive announcement, the market reaction may remain subdued as it may already expect that TT-034 will present no safety issues at this low dose. The market could instead be waiting for efficacy results to be tabled before it gets excited?

    If safety was a major concern at this stage, then the trial would likely be put on hold by the FDA. This would be a significant setback to Benitec, however, it would not be the end of the world. The reason that this would not be the end of world is because the company has other pipeline products and management had the foresight to raise sufficient capital to progress one or more of these to the clinical trial stage. The results for TT-034 or therefore not binary i.e., good results mean we press on, poor results mean we fold, for Benitec. It is true that poor results would have a negative impact on the company's share price but, in the long run, this could be recovered if, for example, a trial of Tribetarna for Non-Small Cell Lung Cancer (NSCLC) was to prove safe and efficacious. The trial for Tribetarna can be funded from within the current capital available to the company and, as it targets a different gene compared to TT-034 and it does not use the AAV8 vector, the results for TT-034 will be irrelevant to the commencement of this NSCLC trial.

    If the safety data was poor and this result was because of the AAV8 vector, then this would have implications for Benitec's Hepatitis B (HBV) program. However, this too has a different genetic target to TT-034 and Benitec has the option to use the AAV5 vector which it has licensed from uniQure instead of the AAV8 vector. Again, this means that poor safety data from TT-034 would not scuttle the HBV program but it may set it back in time as adjustments are made.

    What about efficacy? If safety does not impress the market then will the first cohort announcement contain a surprise in terms of efficacy?

    I am on record as saying that the pre-clinical data does not support this notion, however, anything is possible. If pre-clinical data was the only criterion for a successful treatment for HCV, then HCV would have been cured years ago and the 95% failure rate of clinical trials would not be the norm. The fact is that the symptoms of HCV can occur when the percentage of infected hepatocytes is very low (different studies show varying percentages). If the first patient had such a low percentage and the TT-034 vectors were lucky enough to encounter most of these cells, then who knows what could happen in terms of viral load reduction. This is why we have clinical trials and why the results from one patient are unreliable.

    As far as comparing the trial data to the Non-Human Primate data is concerned, the first dose administered to cohort one is well below even the lowest dose administered to NHP's, let alone the therapeutic levels. The minimum dose administered to NHP is the same as that to be given to cohort two. So it is not until cohort two that any comparative efficacy data can be studied. I still think cohort three will give the first real indicative level of success when compared to NHP data and cohorts four and five will, hopefully, prove to be therapeutic.

    In summary, positive safety results will see the trial go marching on, which may or may not rev up the market. Negative results will see a short term reduction in the share price but management has been prudent enough to have in its pocket a very sound alternative plan, which is funded and does not rely on what happens with TT-034. Indicative efficacy results for TT-034 are not likely to be seen until cohort three has completed its monitoring stage but anything is possible; after all, this is the first in human trial of this kind of technology and so there really is no precedent.

    Disclosure: The author is long BNIKF.

    Additional disclosure: This article is not intended to be investment advice. Each reader should do their own due diligence.

    Stocks: BNIKF, BTEBY
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Comments (17)
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  • brama66
    , contributor
    Comments (172) | Send Message
     
    "Indicative efficacy results for TT-034 are not likely to be seen until cohort three has completed its monitoring stage but anything is possible; after all, this is the first in human trial of this kind of technology and so there really is no precedent."

     

    Oh, to be able to set precedent. That would be exciting to behold!

     

    Great blog as usual, Panno!
    4 Jul 2014, 02:55 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » Congratulations to the guys and gals over on investorshub for maintaining a pinned folder on due diligence for Benitec. In addition to Benitec's own website, this is a good place for new investors to get a feel for the company and the technology.
    5 Jul 2014, 09:57 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » I have been asked to qualify how the NHP data can relate to efficacy when monkeys are not affected by HCV.

     

    It is true that humans and, to some degree, chimps are the only species which suffer from HCV and this makes the study of the disease difficult. In an effort to improve the way scientist study HCV replication replicon models were developed where cell cultures could be used to mimic in vivo viral replication. While these models are not perfect they do represent the best available way of pre-clinically testing the efficacy of drugs designed to prevent HCV replication.

     

    In the case of TT-034 a replicon model was used to determine the dosing levels required to eliminate the virus in liver cells. Having determined the appropriate dosing levels, these where then tested in NHP's for safety. The results showed that at the therapeutic levels predicted by the replicon model, there were no safety issues with TT-034. This means that there is a direct link between the dosing levels of the NHP and the efficacy predicted by the model.

     

    A paper published on TT-034 says: " The results of in vitro replicon experiments demonstrated potent anti-HCV activity of each of the shRNA expression constructs. The ability to approximate the levels of shRNA required to inhibit HCV replicon activity, as well as quantify the level of shRNAs produced in NHPs, suggest that clinically feasible doses of TT-034 administered to patients should be sufficient to confer therapeutic benefit. Yet, the numbers of shRNA species required for inhibition of HCV on a per cell basis may actually be even lower than suggested by the transient replicon experiments (Figure 6); the adenovirus shRNA expression vector delivered to replicon containing cells is nonintegrating and thus was diluted amongst daughter cells as a result of cell division while in cell culture. The ability to use a shRNA approach with a vector which confers long-term expression in vivo results in durable expression; indeed, data from our unpublished IND enabling studies demonstrates persistent shRNA levels out to 180 days, the duration of the experiments in the murine and Cynomolgus models (data not shown). Furthermore, it is important to note that while the replicons produce hundreds or thousands of copies of the HCV genome per cell35,36 chronically infected human hepatocytes harbor only 5–7 copies/cell on average.33,37 Finally, the process of RNAi is catalytic; one active species loaded into the RNA-induced silencing complex can result in multiple rounds of degradation."

     

    It also says: " These data predict that the product will be safe and efficacious in clinical testing."

     

    I hope that this clarifies the matter for those interested.
    8 Jul 2014, 04:44 AM Reply Like
  • Cyndia
    , contributor
    Comments (4) | Send Message
     
    I think i have to correct you sir, or I need correcting. You wrote: " The trial's protocol demands that the first patient in each dosing cohort (of which there are five) be treated and monitored before the rest of the cohort can be dosed."

     

    When I look at the dosing schedule, starting as early as cohort 2, they are doing "Sequential and Parallel 1+2" dosing and continuing on through cohort 5.

     

    So, in cohort 3, patient 1 is dosed, then (presumably) a week later the other 2 within cohort 3 are dosed and so on through cohort 5. What do you think? Also, will they be starting the UCSD trial after this one is completed, assuming everything goes well? Thank you and thanks also for keeping us interested investors up to date with your articles.

     

    Cyndia
    9 Jul 2014, 07:00 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » Thanks Cyndia, you are correct in saying that the dosing is sequential and parallel for cohorts 2-5. What this means is that the first patient for each cohort is dosed and monitored then, after the monitoring period and safety being established, the remaining patients in the cohort can be dosed in parallel. The gap between the first and remaining patients in cohorts 2/3 will therefore be a minimum of six weeks and the gap between the first and remaining patients for cohorts 4/5 will be a minimum of ten weeks, not one week.

     

    I hope that his clarifies the matter for you.
    9 Jul 2014, 10:17 PM Reply Like
  • bioseeker2011
    , contributor
    Comments (46) | Send Message
     
    The May 29, 2014 ASX announcement issued by the company included a table but made no reference to "parallel" enrollment nor, for that matter, did the company's June 11 roadshow presentation. Furthermore, the clinicaltrials.gov trial listing also does not disclose this information. Can you please provide a public source for your information?
    10 Jul 2014, 10:43 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » Please see table on page 16, column five for details. This table is also shown in the RAC presentation.

     

    http://bit.ly/1ngiB2z
    11 Jul 2014, 09:53 PM Reply Like
  • brama66
    , contributor
    Comments (172) | Send Message
     
    So, Panno, this means then that the trial will actually end sooner than what most maybe originally thought?...since most thought it was all going to be sequential...including myself. Nice catch. I missed that.
    12 Jul 2014, 09:55 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » The latest ASX announcement also explains how this will work and how future trial announcements will relate to the dosing regime.

     

    http://bit.ly/1zsOFub
    12 Jul 2014, 09:12 PM Reply Like
  • brama66
    , contributor
    Comments (172) | Send Message
     
    So, Panno, if I'm reading and calculating that right, if everything goes without a hitch, the trial will be completed in 76 weeks roughly, correct? So we are expecting the trial to be completed by mid-November-ish of 2015?
    13 Jul 2014, 01:15 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » If everything went without a hitch then the end of Nov 2015 could be achieved. I think the more likely outcome is Jan 2016 because of the number of reviews required of the DSMB, each of which could add a week or more to the timetable.

     

    What I am hoping is that the data from cohort four will be sufficient to allow the company to plan for the next trial, a Pllb trial. This would allow them to get a lot of the planning and preparation done while cohort five is still awaiting results.

     

    The company has always maintained that it needs to be in a Pllb trial before it can do a deal on TT-034 and so the sooner we can get to that stage, the better.

     

    As we are also going to be running a NSCLC trail in 2015, the timing of "doing a deal" is going to be critical as we start to see our cash burn rate increase over the next twelve months.

     

    I am hearing that the AMD program has some interest and, now that we have our own lab, I would expect that program to advance quickly through the pre-clinical stage. As I understand it, the two scientist we have just hired to work in our lab are two that worked on the AMD program for Tacere before Benitec took over, so they have hit the floor running.

     

    It is also possible that a deal could be done on this program while it is still in pre-clinical development. A deal could happen anytime and any deal would see the pps take off This is why I am long on Benitec rather than a trader.
    13 Jul 2014, 02:56 AM Reply Like
  • brama66
    , contributor
    Comments (172) | Send Message
     
    Oh wow. Yeah, I have not sold any shares since jumping in. Ever since I discovered benitec back in 2012, I was a firm believer once I saw the NHP result of TT-034. I can't wait to see what happens mid 2016! Thanks, Panno.
    13 Jul 2014, 11:06 AM Reply Like
  • bioseeker2011
    , contributor
    Comments (46) | Send Message
     
    Using the schedule the company just released, the absolute earliest the trial can end is January 2016 BUT for this to happen the second and third patients in cohorts 2-5 would need to start in parallel on the very day the DSMB gives the go-ahead for the next cohort. Considering the company was off by almost a year on the IND filing and by more than 3 months on the first patient dosing, I think there is ZERO likelihood the trial ends in January 2016.
    13 Jul 2014, 11:39 AM Reply Like
  • brama66
    , contributor
    Comments (172) | Send Message
     
    Yeah, I realized I wasn't taking into effect ANY reviews between cohorts. Nor does it take into account the assumption that next patients are lined up and waiting. But since we are long, and it's the tech that I truly believe in, I could care less if it takes an extra month or two. As long as they do things right, and the tech is proven, benitec shareholders will not be disappointed, in my opinion.
    13 Jul 2014, 05:51 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » It has been pointed out to me that there is a rumor doing the rounds that no efficacy data of the remotest kind can be gleaned from any of Benitec's TT-034 pre-clinical studies. This may be someone's opinion but it would NOT be the view of the scientific community.

     

    In my post above I have explained how Tacere (now a Benitec subsidiary) and Pfizer used the accepted replicon standard for pre-clinical determination of therapeutic levels of anti HCV replication drugs and how these levels were tested for safety in mice and NHP's in order to determine an appropriate trial dosing regime.

     

    Without this process how would anyone know what levels to dose in the trial? If efficacy had not been forecast in the pre-clinical work why would anyone even bother to run a trial, let alone invest in the company running the trial? Why not dose at levels ten times higher than the current doses, just to be sure of hitting the target?

     

    Common sense tells us that the scientists behind TT-034 believe it will be efficacious and at the levels being tested in the clinical trial. The quotes in my post above show this to be the case. Furthermore, when Pfizer was involved and leading the research their scientists had this to say: "Following administration of PF-05095808 (now referred to as TT-034) or corresponding synthetic shRNAs, sequence-specific antiviral activity was observed in HCV replicon and infectious virus systems."

     

    http://1.usa.gov/1raoBPG

     

    Pfizer recently conducted further research to into the active mechanism of TT-034's shrna viral replication inhibition and concluded: "Our studies have revealed unexpected complexity in both shRNA maturation and siRNA activity supporting further studies on the basic processes governing Dicer-dependent RNAi agent processing and siRISC bioactivity. However, our results have also demonstrated an on-target mechanism of action for TT-034 against both the (+) and (−) strands of the HCV RNA genome. Coupled to its established safety in rodents and nonhuman primates and its apparent capacity to suppress HCV from resistance development, these findings justify progression of TT-034 to the clinic to investigate its potential benefit for the treatment of chronically infected HCV patients."

     

    http://1.usa.gov/1raoBPI

     

    Clearly, Pfizer's scientist as well as Benitec's own strongly disagree with the assertion that there is no pre-clinical data supporting the efficacy of TT-034.

     

    Furthermore, the trial protocol was reviewed by the NIH, Recombinant DNA Advisory Committee and received unanimous support. Now why would such eminent scientists lend their support if they thought that the efficacy model did not stand up to scrutiny?

     

    http://1.usa.gov/1raoC5W

     

    As I have said previously, the real results for both safety and efficacy will only be known when trials have been conducted in humans but to suggest that the pre-clinical data is useless is either misguided or malicious but it is not true.
    10 Jul 2014, 04:04 AM Reply Like
  • hindmost
    , contributor
    Comments (128) | Send Message
     
    What I don't get, is why Pfizer pulled out if it all looks (looked) so good. Comment?
    19 Jul 2014, 09:01 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (242) | Send Message
     
    Author’s reply » Hindmost, I have covered this point in a previous blog post. In short, Pfizer closed its plant in Sandwich, UK (for cost saving reasons) and ALL the programs that were being developed there. This action was NOT specific to TT-034.

     

    For Pfizer, I think this is going to be a case of throwing out the baby with the bathwater.
    19 Jul 2014, 10:26 PM Reply Like
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