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Pannobhaso
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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.
  • HCV Patient Dosed 29 comments
    May 29, 2014 12:47 AM | about stocks: BNIKF

    In recent weeks, there has been some controversy spread on various forums about Benitec's (OTCPK:BNIKF) management deliberately rejecting patients for enrollment in their HCV TT-034 clinical trial. This false information has grown out of frustration with the four month delay in dosing. Some of the supporters of this view have continued to push this line despite management's statements to the contrary.

    This argument can now be put to bed because today the company has announced that the first patient in the TT-034 trial has now been dosed. This is a groundbreaking moment for the company as this is the first systemically administered, in-person, ddRNAi drug to trialed in the world. The management team at Benitec and a the medical team at Duke Medical deserve some credit for this achievement.

    The progress of the patients will be monitored and reported on by an independent team.

    The next milestone will be reached when the first safety results are known. It is anticipated that the first two cohorts will only produce safety data, efficacy results will only be known when the results from the later cohorts are available.

    For Benitec longs, the light at the end of the tunnel has just gotten a lot brighter.

    Themes: HCV, TT-034, Benitec Stocks: BNIKF
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Comments (29)
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  • GreenGrowthGeek
    , contributor
    Comments (639) | Send Message
     
    Let's hope that the trial proceeds now without further delays. I also here rumblings of an up listing in the U.S market. The worm is turning.
    30 May, 12:55 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » http://bit.ly/1hDRSf4

     

    GGG I think this is what you are referring to.
    30 May, 02:15 AM Reply Like
  • brama66
    , contributor
    Comments (61) | Send Message
     
    What will be interesting is if the first two patients show a reduction in viral load as well. If that's the case, it could be assumed by many observers of the stock that the technology indeed works without the full therapeutic dose. Findings like that could cause the share price to move earlier. Of course, that is all hypothetical. However, there have been scientific suggestions that given the mechanism of action, this could be a possibility.
    Either way, the first patient is dosed, and we are a step closer to a one-shot cure. All benitec has to do is achieve their goal with TT-034 of a one-shot, pan-genotype cure, charge half of what gilead is charging, and they will sweep the rug out from beneath Sovaldi. Price will be extremely less of an issue, and both benitec shareholders, benitec, and hep c sufferers will all benefit.
    31 May, 02:12 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » Hi brama,

     

    "All benitec has to do is achieve their goal with TT-034 of a one-shot, pan-genotype cure, charge half of what gilead is charging, and they will sweep the rug out from beneath Sovaldi. "

     

    I would add a word of caution here, if I may. We are all optimistic about TT-034 but it still has a long way to go, even if it is successful, before we say that it will sweep the rug from beneath Sovaldi (and others). There is no doubt in my mind that a well priced, one-short treatment for HCV will have great potential in the market, however, to be the market leader we have to consider a couple of issues first.

     

    TT-034 relies on the AAV8 vector so even if the current trial is hugely successful, those patients who already have the AAV8 antibodies in their system will not be able to the treated with TT-034. To treat these patients a different vector must be tested.

     

    The FDA is also being very strict about not administering TT-034 to fertile females. Until new trials are approved where the impact on germline cells is tested and proved to be safe or non-existent, then, even if the current trial is successful, I cannot see the FDA approving TT-034 to treat females of childbearing age. (ddRNAi is only supposed to work in somatic cells but I think the FDA will want to see lots of data before it supports this assertion.)

     

    The time taken to achieve all this will be a factor in determining TT-034's market share.

     

    On the other hand a hugely successful TT-034 clinical trial will just about guarantee that there will be major interest in Benitec's other pipeline products, such as Tribetarna. This interest will, in my opinion, be the real source of medium term benefit to shareholders.
    31 May, 05:18 AM Reply Like
  • brama66
    , contributor
    Comments (61) | Send Message
     
    So Panno, i have a few questions then.

     

    1. What would cause someone to already have AAV8 antibodies?

     

    2. I'm still confused about why it can't be used on fertile females. Are they thinking it would effect ovums? Is so, why would that not apply to all men considering we produce sperm pretty much for most of our lives? Or are they thinking about the possibility of a woman being pregnant while treating with TT-034? If so, wouldn't concurrent pregnancy tests rule that out?

     

    Sorry, I'm still new at understanding some of the mechanism of action of AAV8 or viral vectors. Thanks for your robust and informative reply, btw!
    31 May, 10:56 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » Hi brama,

     

    AAV's are naturally occurring viruses so there are some people who have already come in to contact with them and retained antibodies to one or more serotype. As TT-034 uses AAV serotype 8, patients with the AAV8 antibody will likely have an immune response to the vector, which could cause complications. Changing the vector would change this outcome but that new vector would need to be tested in the clinic before it could be made available for general use.

     

    This is the reason why those being treated with non-therapeutic doses cannot be re-treated. The first treatment will likely cause AAV8 antibodies to be produced, greatly increasing the chance of an immune response with a second treatment.

     

    In the case of the first treatment, the hope is that the virus will have done its work with no immune response or before any immune response occurs and this is part of the observations being carried out. However, even if no immune response is noted, the effect of the TT-034 vector will be a little like that of a vaccine against AAV8; the body will be ready for AAV8 next time around, killing it off and thus intercepting and disrupting any treatment.

     

    With regard to point two: Males in the current trial are required to provide semen samples which will be tested to prove that the new genetic material has not made its way into their sperm.

     

    The extra difficulties in harvesting ova, timing, invasiveness, etc., mean that no childbearing capable females are included in the current trial. This means that the current trial will not be able to establish that the new genetic material does not make its way in the ova. An additional trial will be required to establish this.

     

    In all the animal testing that has been carried out with various modes of RNAi therapies, I think there has only been one case (and not corroborated) where the new genetic material made its way into a second generation and that was with some type of worm. However, the FDA will have to be certain that this does not occur before they tick this box.

     

    I hope that his answers your questions.
    31 May, 10:15 PM Reply Like
  • brama66
    , contributor
    Comments (61) | Send Message
     
    Yes, absolutely. Totally makes sense now. Thanks!
    1 Jun, 02:09 AM Reply Like
  • georgejjl
    , contributor
    Comments (3) | Send Message
     
    Do not forget the Tacere/Benitec hepatitis C trial with TT-034 is not the first human trial to use Benitec's ddRNAi technology.

     

    Calimmune has a human trial using Benitec's ddRNAi technology to silence the CCR5 gene to cure HIV.

     

    The Calimmune trial has been ongoing for almost one year and they are treating patients in the second cohort of three cohorts currently.

     

    Calimmune

     

    In March 2012, Benitec Biopharma announced the execution of a non-exclusive licensing agreement with US-based biotech company Calimmune for the use of ddRNAi in the area of HIV/AIDS world-wide. The agreement covers the application of ddRNAi to target up to three key viral and cellular genes identified as significant therapeutic targets to inhibit HIV/AIDS infection.

     

    Calimmune’s approach to the application of ddRNAi to HIV/AIDS is highly innovative and has been developed with core technology from the lab of Dr David Baltimore, a Nobel Laureate in the area of HIV/AIDS. Benitec Biopharma is proud to be involved in this program through the provision of the license to Calimmune.

     

    Calimmune’s approach involves extraction of T cells from HIV patients, ex vivo silencing of the gene that codes for the CCR5 receptor protein and is associated with low HIV loads, and re-injecting the modified cells, thereby conferring resistance to HIV. In its Phase l/ll clinical trial of the treatment, Calimmune is about to complete enrolment of the first cohort. Read Calimmune’s latest presentation.

     

    - See more at: http://bit.ly/1iHYzwT

     

    http://bit.ly/1iHYxFh

     

    Good luck and GOD bless,

     

    George
    1 Jun, 07:31 AM Reply Like
  • georgejjl
    , contributor
    Comments (3) | Send Message
     
    Regarding the possibility of natural AAV8 antibodies in some patients treated with TT-034

     

    "...Among the most commonly used AAV vectors, antibodies to AAV5, carrying one of the least-conserved capsid sequences,61 and to AAV8 are among the least prevalent...."

     

    "...Some of the proposed strategies to overcome the limitation of humoral immunity to AAV, which could be used alone or in combination, are summarized in Table 1.65-71 Switching serotypes seems unlikely to succeed because of the high degree of cross-reactivity of NAb across AAV serotypes. Conversely, some promising results have been obtained with pharmacologic and physical (plasmapheresis) modulation of anti-AAV NAb titers, and the use of catheters followed by saline flushing has been explored in the setting of AAV vector gene transfer with some promising results...."

     

    "...In more than 15 years of clinical experience with AAV, there have been no observations of clinical events related to AAV integration. Continued monitoring in clinical trials, and ongoing laboratory studies, should help to define and reduce this long-term risk of AAV vector administration...."

     

    http://1.usa.gov/1iI4Zfs

     

    Good luck and GOD bless,

     

    George
    1 Jun, 08:33 AM Reply Like
  • georgejjl
    , contributor
    Comments (3) | Send Message
     
    See the number 2 exclusion criteria for the TT-034 trial.

     

    http://bit.ly/1iI9xCx

     

    Remember that the primary goal of the current trial is to prove that TT-034 is safe and a secondary goal is to test to see if it is efficacious. I truly believe that both goals will be achieved in this trial.

     

    Later a much larger trial will be performed on a broader population of patients with hepatitis C infections.

     

    http://bit.ly/1iI9xCx

     

    Good luck and GOD bless,

     

    George
    1 Jun, 09:20 AM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » Hi George, thanks for your contribution. I will make a couple of points to clarify the above.

     

    It is true that TT-034 is not the first test of ddRNAi. That honor went to Benitec and the City of Hope with their HIV trial. However, both the CoH and Calimmune trial have one major difference to the TT-034 trial and that is the transfection of hematopoietic stem and T cell was ex vivo, no foreign matter was directly injected into the patients. This is a significant difference.

     

    On the other hand, there have been literally hundreds of gene therapy trials (even though the FDA has yet to approve a single product for the market) and ddRNAi should really be seen as being in the same family of products as these gene therapies. In the case of the AAV8 Hemophilia trial, no restrictions were placed on childbearing age women, unless they were actually pregnant. This seems a little inconsistent unless no transfer of genetic material to germline cells was already established in a previous trial.

     

    Which brings me to TT-034's next trial. Assuming all goes well with the current trial, a Plla trial is planned. At that time some of the restrictions imposed on the current trial may be removed as a Plla trial should include a broader section of the HCV population. With the right protocols in place, women of childbearing age and those with a BMI>30 may be included.

     

    Management has always said that they believe the real value of TT-034 will be realized after a Pll trial has results. If these current restriction are overcome in the Pll trial, then I think they are spot on.

     

    With regard to the AAV8 vector. This was the vector chosen by Tacere and Pfizer. It seemed like the best option at the time and may well be proven to be so. However, there is a possible contradiction in Benitec strategy here. The HBV program is supposed to piggyback on to the success of the HCV program. The HBV treatment will simply have a different target. However, Benitec has licensed the AAV5 vector from uniQure to deliver its HBV ddRNAi molecule. If the AAV8 vector proves efficient, would they really want to make a change for the HBV treatment? The AAV5 license seems as though it could just be a backup strategy.

     

    So, the issue of childbearing age women being treated could be resolved in the next trial and there seems to be a backup plan for AAV vector if serotype 8 is not efficient.

     

    1 Jun, 10:11 AM Reply Like
  • brama66
    , contributor
    Comments (61) | Send Message
     
    Panno, aside from the medical side of Benitec, do you have any insight as to what the ADR and 1:5 reconsolidation means for shareholders? Obviously, this seems like a major step forward in possibly listing on the Nasdaq, but is this a relatively good thing for shareholders for the stock to reconsolidate?
    1 Jun, 03:28 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » I am glad you used the word re-consolidation rather than reverse split as I don't see this as a traditional reverse split. The announcements in the press say that the terms are 1 ADR for every 5 Ordinary Shares. So, while the number of ADR's held by a shareholder may be one fifth of their current shareholding, those ADR's still represent the same number of Ordinary Shares so if you sold one ADR you would get five times the price of a single Ordinary Share.

     

    Where it becomes interesting is whether or not this change will break the price nexus between the Australian and US markets. The increase in price in the US should make the stock more attractive to institutional investors. Being a sponsored program should also make it easier for brokers to trade in Benitec stock. (I know a number of people on this forum have mentioned that their regular broker could not help them purchase stock.) Both of these factors could improve the liquidity of the stock in the US and this may have a positive effect on the price of the ADR's.

     

    Each holder will have to make up their own minds as to whether or not they want to convert BNIKF holdings to BTEBY but on face value I see this as a positive move.
    1 Jun, 09:06 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » This page may be useful.

     

    http://bit.ly/1kyIA40
    1 Jun, 10:07 PM Reply Like
  • pga2003
    , contributor
    Comments (30) | Send Message
     
    Safety is primary study goal, efficacy is secondary goal. It would seem that a $5 plus listing after ADR will significantly ready the company for Nasdaq's minimum SP requirement for the future. (They still need a larger MC.) The pipeline is vibrant, execution is a must.
    1 Jun, 05:51 PM Reply Like
  • petethepanzer
    , contributor
    Comments (937) | Send Message
     
    it will be well over a year before we see an efficacy cohort since viral load is 5000/cell and based on the monkey rna levels you can clearly see that you need to produce the rna in the thousands which means that efficacy data will be in 2H 2015

     

    the most valuable thing in their pipeline is the vegf drug since a single intravitreal injection will be equivalent to a lifetime of vegf injections and this data will be in 2016
    1 Jun, 07:32 PM Reply Like
  • petethepanzer
    , contributor
    Comments (937) | Send Message
     
    pannobhaso are you going to reply to my comment
    1 Jun, 11:33 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » I was not aware that a reply was required. I thought this was just your opinion. Specifically, what would you like me to respond to?

     

    The timetable for TT-034? Assuming recruitment gets back on track and all cohorts can be filled on time, indicative efficacy results from Cohort 3 should be available about April 2015.

     

    I am not sure what you mean by your second paragraph. I am assuming you are referring to the AMD treatment but, as no trial dates have be set for this, I am not sure what data you are expecting in 2016.
    Now that we have our own lab, I am confident that the team will fast track the AMD program and so it could be ready for the clinic in 2015. However, I do not believe that we will have enough capital to fund a trial without doing a deal beforehand or raising capital again.

     

    I have expressed my own view that I think the NSCLC program will be the important short to medium term program. A clinical trail for this is supposed to start in Europe at year's end but more likely Q1 2015.
    2 Jun, 02:42 AM Reply Like
  • petethepanzer
    , contributor
    Comments (937) | Send Message
     
    i disagree cohort 3 will not produce efficacy results considering 5000 virons per cell and the rna produced in the money models of hep c in the presentation you could expect cohort 4 to provide efficacy

     

    it will take nine months just to do the first three cohorts and then it will take three-five months for the second last cohorts considering its 10 weeks after first patient and between cohorts

     

    you could guess most of the actual value creation is sometime in 2016
    2 Jun, 06:04 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » The company has frequently stated that the "value creation" for TT-034 will be during /after the planned Plla trial so I am not sure what point you are making here. The Plla trial will clearly be a 2016 proposition.
    2 Jun, 09:14 PM Reply Like
  • brama66
    , contributor
    Comments (61) | Send Message
     
    Panno, I thought I heard Peter French say in an interview that cohorts *might* be dosed sooner if safety and efficacy are demonstrated. But I also understand that the FDA criteria is pretty much set in stone. Do you think earlier dosing of further cohorts might be possible if safety and efficacy can be demonstrated?
    2 Jun, 09:33 PM Reply Like
  • joe2302
    , contributor
    Comments (3) | Send Message
     
    as to the adr- my understanding is that the issuer will/may charge a yearly maintenance fee to hold the adr as that is customary. The stock now held as BNIKF tracks BLT and i was told there is no worry as to holding it as is as there is no maintenace fees or conversion fees to concern myself with.
    Had to go to the international trading desk of the broker to get the info.
    Don't know is this helps but hope it does.
    2 Jun, 10:34 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » Joe, not converting BNIKF to BTEBY is an option that the company has left open but I think all EXISTING BNIKF holders should ask themselves one question, "What is going to be best for me when I want to sell my shares?"

     

    I say this because existing holders have already bought the shares and converting them is not compulsory, so the only other action to consider is a possible future sale.

     

    If most holders convert to BTEBY then the future volume of trade in Benitec may well be through that ticker. Right now there is an average daily trade of 140,000 BNIKF shares. Before the beginning of this year there would not be that many shares traded in a whole week. If volume dwindled on BNIKF, how easy would it be to sell ones holdings?

     

    On the other hand, if one thinks that the BNIKF daily volume is only going to have a slight drop off, then why pay an annual fee if there is no immediate benefit?
    3 Jun, 06:55 AM Reply Like
  • joe2302
    , contributor
    Comments (3) | Send Message
     
    my thoughts exactly-and as i have no crystal ball, i guess i will wait till the end of june to see what/if anything happens.

     

    and thanks for your insight.
    5 Jun, 06:44 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » Hi brama, I think that the dosing regime will remain as approved by the FDA. What good safety and early efficacy results will do is give a green light to the team to start planning for the Plla trial. Without these results planning for the next stage of the program will be a waste of time.

     

    I do agree with petethepanzer that cohort 4 results will be the ones that the company is relying on for efficacy but, as I stated, cohort three should give an indication of what can be expected.

     

    I expect the market to react positively when these results are known but any increase in the pps will only be sustained if a deal is done for one or more of the pipeline programs. ISIS and Alnylam got their high market caps not because they had good trial results but because they managed to on-sell their technology (money in the bank). I am hopeful that the NSCLC program will be that bait that big pharma bites on.
    2 Jun, 10:39 PM Reply Like
  • petethepanzer
    , contributor
    Comments (937) | Send Message
     
    if theres no immune response against the vector then the mouse model essentially proves the gene silencing effect since murine cells are not much different then our own this would be cellularly conserved ability

     

    http://bit.ly/1p2JjQt

     

    the only question is did they select the right strands that silence the hepc virus and get fully coverage of all possible mutants they wrote a seperate paper on this itself

     

    benitec could be the next gilead though if you are willing to hold it for around five years
    2 Jun, 11:52 PM Reply Like
  • omcdac
    , contributor
    Comments (66) | Send Message
     
    Do u think Benitec will like Alnylam Pharmaceuticals, Inc in 5 years. $60/ Stock ?
    9 Jun, 11:05 PM Reply Like
  • omcdac
    , contributor
    Comments (66) | Send Message
     
    Pannobhaso, you are amazing witter and teacher.
    rnai.technology is right place for you about reading and writing about RNAi
    9 Jun, 10:57 PM Reply Like
  • Pannobhaso
    , contributor
    Comments (107) | Send Message
     
    Author’s reply » I have been asked again if I think that the safety results from cohort one "may" gives us a sneak peak into the efficacy of TT-034.

     

    I know we would all like to know about efficacy sooner rather than later but, for the first cohort to show efficacy, the transduction rate in humans would have to be better than both the murine and NHP models. This very unlikely. The pre-clinical data does not support the notion that the first cohort, or even the second cohort, "may" indicate efficacy. For an "indicative" efficacy assessment a vg/cell >5,000 is required. To get to this level the very minimum dose will be administered in cohort 3 but the reality is that cohort 4 (as pointed out by petethepanzer above) is more likely to be the one that we can look to for efficacy.

     

    These comments are in line with the company's view as presented in a number of different presentations.

     

    Sorry to disappoint those hoping for a surprise but I think you will be disappointed if you think that Benitec will present anything other than safety results for cohorts 1&2.
    22 Jun, 11:23 PM Reply Like
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