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PolyMedix, Inc. Message Board

  • john_j_england john_j_england Jan 21, 2011 11:18 PM Flag

    discussion from another forum

    Polymedix:

    I've spent the last 2 weeks reading papers from the company in regards to their antibiotic platform and the work appears solid to me (given my limitations in this field). The publications are even in relatively decent journals.

    Anyone know of any red flags?
    ************************************
    Phase 2 data is due this quarter on the antibiotic and this is really the first actual efficacy study of the drug in infected patients so this is a big event to watch for the company to see if they can show PoC. Most of the comments have been cautiously optimistic on the drug but the first real sign of proof will come with this data.

    I had some general questions about the MoA of the drug under item 2 of #msg-48713859 and David Miller got a response direct from the company that he posted in #msg-48778970. I also posted some questions/potential concerns regarding safety (liver elevations/tingling) in item 1 of that post that David also responded to in #msg-48774984. Not sure if you have any comments on side effects.

    What are your thoughts on the other half of the PYMX story, the potential replacement for Protamine that they are developing?

    All told, seems like an interesting company and valuation doesn't exactly look expensive. I have them at least on my watch list but I need to see a little more before I would consider them
    ********************************
    Polymedix and defensins - Is this a mimic of human defensins? If so this sounds like one of the all time worst ideas I've ever heard. "Hey, lets take a natural immune fighter from humans and use it by itself, without the normal combo with other defense mechanisms. Over the next decade we'll do 3 or 4 more and then we can watch micro-organisms develop resistance piecemeal to natural human defenses that they would never develop in nature."
    ************************************************
    I was a bit concerned about the SIT/SBC titers shown (in the 2-4 range) in their ICAAC poster. Not a red flag exactly, but likely a caution flag. I have no great confidence that their doses are big enough here, and so I view their trial as no slam dunk.

    I wish they were developing an oral drug for thrush and oral infections - the Lua papers in Molecular Oral Microbiology I thought were very impressive.

    This technology belongs in a big pharma in my view. Someone who can take a dozen of their antibiotic drug candidates into wide-ranging development rather than trying to bootstrap things on a shoestring.

    ***********************
    The one red flag that I can come up with is that their efficiency is reduced by increasing ionic strength. They become weak at the physiological ionic strength of blood. So this could be one cause for concern.

    Of course this type of nucleation and elongation / polymerization sequence can be "sped up" by increasing the concentration of the monomers, so perhaps the doses used will overcome this concern.

    http://investorshub.advfn.com/boards/read_msg.aspx?message_id=59015121

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    • Some of the more informed comments are from David Miller of Biotech Stock Research. I was tipped off to PYMX from his newsletter.

      He posts on iHub regularly...

      http://investorshub.advfn.com/boards/profile.aspx?user=62662

      and you can sign up for his tweets here...

      http://twitter.com/#!/BiotechStockRsr

      BSR is the best bio-newsletter I've found. It's not cheap @ $695/yr but it's worth it.

    • I worked on phase 3 clinical trials for cancer drugs.
      The list of side effects were ginormous; the side effects were almost as bad as the disease; the percentage of people experiencing those side effects was large. Yet, the FDA approved the drugs and the patients were happy to receive them.
      If I were to have MRSA eating away at me and the doc said that they could give me a drug that would cause some minor/temporary peripheral neuropathy and might damge my liver a bit; I would say shoot me up with the PYMX drug doc; I'll only have one beer tonight. - cheers
      p.s. Your liver can heal itself.

    • Regarding PYMX...


      Quote:
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      With respect to the numbness/tingling, it was indicated that the effect was seen out to 10 days post treatment in certain instances. Is that cause for any type of concern? That seems strange that there would still be a numbness/tingling sensation out to 10 days post treatment. Even though this doesn't appear to be a concern now, I wonder if this could be signs of a more worrisome side effect that might occur in a longer duration, or different type of, study. Any thoughts are appreciated here.
      --------------------------------------------------------------------------------



      The drug likely won't be dosed longer 1x/day than 7-14 days, so cumulative tox is unlikely to be much of a problem beyond the 10 doses we've already seen. The big test for both side effects is to see if they worsen in actual patients. Remember, the drug hasn't been in infected patients yet.


      Quote:
      --------------------------------------------------------------------------------
      I understand that PMX-30063 is patterned after human defense proteins. How has PMX-30063 been designed to succeed where natural human defense proteins fail? Is it simply a matter of PMX-30063 being many fold more potent than natural human defense proteins or is there some major structural difference that leads PYMX to believe that PMX-30063 can succeed against bacterial infections where natural human defense proteins fail?
      --------------------------------------------------------------------------------



      This is a good question. Again, while this looks really promising there is no data in real patients yet. We initiated formal coverage on the company back in January. The biggest issue is that the programs are very early with little data in actual patients for either drug, but especially the antibiotic. Patience and patients, as a wise man I know once said, will reveal whether they indeed have something here.
      Unless otherwise indicated, this is the personal viewpoint of David
      Miller and not necessarily that of Biotech Stock Research, LLC.
      We're on Twitter at BiotechStockRsr

      • 2 Replies to john_j_england
      • Regarding PYMX...


        Quote:
        --------------------------------------------------------------------------------
        With respect to the numbness/tingling, it was indicated that the effect was seen out to 10 days post treatment in certain instances. Is that cause for any type of concern? That seems strange that there would still be a numbness/tingling sensation out to 10 days post treatment. Even though this doesn't appear to be a concern now, I wonder if this could be signs of a more worrisome side effect that might occur in a longer duration, or different type of, study. Any thoughts are appreciated here.
        --------------------------------------------------------------------------------



        The drug likely won't be dosed longer 1x/day than 7-14 days, so cumulative tox is unlikely to be much of a problem beyond the 10 doses we've already seen. The big test for both side effects is to see if they worsen in actual patients. Remember, the drug hasn't been in infected patients yet.


        Quote:
        --------------------------------------------------------------------------------
        I understand that PMX-30063 is patterned after human defense proteins. How has PMX-30063 been designed to succeed where natural human defense proteins fail? Is it simply a matter of PMX-30063 being many fold more potent than natural human defense proteins or is there some major structural difference that leads PYMX to believe that PMX-30063 can succeed against bacterial infections where natural human defense proteins fail?
        --------------------------------------------------------------------------------



        This is a good question. Again, while this looks really promising there is no data in real patients yet. We initiated formal coverage on the company back in January. The biggest issue is that the programs are very early with little data in actual patients for either drug, but especially the antibiotic. Patience and patients, as a wise man I know once said, will reveal whether they indeed have something here.
        Respond | No replies

        **************

        PYMX part 2... From the horse's (company's) mouth on your #2 question:

        "The natural defensins don't fail. In humans they are used as a barrier and not as a systemic response. The barrier works well until bacteria get inside the body and we can't mount a systemic defense against them. Below are two papers which include more information. "

        Zasloff et al, Nature, v415, pg 389-395. January 24, 2002
        Tossi et al, Biopolymers, v55, pg 4-30. July 2000

      • PYMX - 4/7/10 Call Re PMX-30063 Phase 1b Results

        1. There was mention of no serious adverse events found in the Phase 1b study, although there was some degree of liver elevation and a numbness/tingling side effect. It sounded like the liver elevations were minimal and well below the 3x upper limit threshold that normally gives cause for concern. With respect to the numbness/tingling, it was indicated that the effect was seen out to 10 days post treatment in certain instances. Is that cause for any type of concern? That seems strange that there would still be a numbness/tingling sensation out to 10 days post treatment. Even though this doesn't appear to be a concern now, I wonder if this could be signs of a more worrisome side effect that might occur in a longer duration, or different type of, study. Any thoughts are appreciated here.

        2. I have just a general question myself on the MOA for PMX-30063 for Biomaven or any others that closely follow this program. I understand that PMX-30063 is patterned after human defense proteins. How has PMX-30063 been designed to succeed where natural human defense proteins fail? Is it simply a matter of PMX-30063 being many fold more potent than natural human defense proteins or is there some major structural difference that leads PYMX to believe that PMX-30063 can succeed against bacterial infections where natural human defense proteins fail?

        3. PYMX is in discussions with pharmaceutical companies with respect to the partnering of PMX-30063. PYMX hopes a decision on whether the drug will be partnered or whether PYMX will go it alone in Phase 3 will be reached by the end of this year.

        4. I noted several questions from David Miller around the 44 minute mark of the presentation. David, since I know you read and post here: (1) Were your questions related to safety, among other things, adequately addressed? (2) Any comments on the numbness/tingling out to 10 days? (3) What are your thoughts with respect to PMX-30063 and with PYMX itself generally? Do you like the risk-reward of the stock here?

    • Don't worry Richard I think I hold the record for missteps. Great post. Thanks. Brock

    • *****************************************************
      Well the PYMX compounds kills bacteria in the same way that natural defensins do, but PYMX claim (with justification based on what I can tell) that their defensin mimics are both more potent and more selective (i.e. the concentration needed to kill bacteria vs. the concentration needed to damage human cells) than natural defensins.

      The main point of the PPYMX drugs is they do not engender resistance - multiple passes of less-than-lethal concentration have no effect on MIC, unlike any other known antibiotic. The reason for this is that these molecules kill bacteria by physically damaging the bacteria cell wall - that's not something that a bacteria can easily mutate to avoid. The normal resistance mechanisms (efflux pumps etc.) simply never come into play.

      So engendering resistance is not an issue here at all in my opinion. Safety and efficacy are the issues.

      ********************************************************
      I think this MoA will prohibit oral versions of these antibiotics: they kill bacteria too well. It is not a good idea to clear all the bacteria from the gut. That leaves, however, a large arena for use.
      ****************************
      I agree that the serial passage data is a first step in proving that you aren't inducing Armageddon. But then note that:

      a) Serial passage data for some micro-organisms vs some anti-biotics looks a LOT better than others. And their drug's serial passage data is all staph-aureus. However if they tried the same test against the 100 most widely variant strains of microbes living around humans I'd bet 10,000:1 they'd find a few that didn't have that comforting flat curve. One good place to look would probably be the gut. And of course microbes swap spit every once in a while. Also note - there are bacteria with resistance to defensins.

      b) I would guess that the serial passage data for an antibiotic introduced long ago generally looks a lot worse than when the drug was first released. Unless they are completely confident in their bacterial lines haven't picked up anything. So the comparison isn't entirely fair.

      In toto I would still strongly suggest this is playing with fire - of the type on the surface of the sun. Maybe it's safe. But I sure wouldn't bet against mother nature - at least without one heck of a lot of data. Accordingly I'll bet another 10,000:1 that 20 years after this drug is introduced (and I surely hope it isn't) that resistance is cropping up.

      ***************************************************
      I discussed the Polymedix compounds with a friend of mine who is perhaps the leading public figure in the field of bacterial resistance - he expressed no long-term safety concerns. His view is that what PYMX is trying to do is hard, but it's a promising direction.

      I agree that there are some current bacterial defenses to defensin (in particular Bacterial Defensin Resistance Protein, MprF) - not surprising as that's a battle that's being going on for millennia, way predating human antibiotics. There are some rare resistance mechanisms to Polymyxin B and colistin which are the current last-resort antibiotics most closely approximating the PYMX MOA.

      It would be stupid to say that you could never get resistance, but it's clearly much less of an issue than with traditional antibiotics. And with dangerous new resistant strains like NDM-1 emerging all the time, I'd be happy to have an alternative to conventional antibiotics. (I have a high degree of confidence that NDM-1 would be susceptible to the PYMX drugs).

 
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