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PolyMedix, Inc. Message Board

  • mulletman99 mulletman99 Feb 6, 2013 1:06 PM Flag

    Aegis Capital released a 3 page write-up on PYMX today

    They initiated coverage on Cubist, but included a 2-3 page write-up on the science behind 30063 and discusses the phase 2 data.

    This was written by the head of healthcare equity research
    at Aegis Capital.

    PolyMedix – Defensin Mimetics (Brilacidin / PMX-30063)
    PolyMedix, a micro-cap company, is currently in the process of developing a member of
    the arylamide derivative chemical class. Company scientists selected this compound
    using a rational drug design process based on the firm’s proprietary algorithmic platform,
    which employs coarse-grained resolution of the behavior of bacterial cell membranes to
    identify agents that can mimic the action of host defense proteins, particularly defensins.
    The defensins are small, cysteine-rich cationic proteins found in both vertebrates and
    invertebrates. They have also been reported in plants. They are active against bacteria,
    fungi and many enveloped and non-enveloped viruses, and consist of 18-45 amino acids
    including six (in vertebrates) to eight conserved cysteine residues. The three-dimensional
    structure of one such defensin is shown below.
    Figure 11: Structures of Human Beta-Defensin (HBD-2)

    Immune cells contain these defensin peptides in order to assist in killing phagocytized
    bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most
    defensins function by binding to the microbial cell membrane, and, once embedded,
    forming pore-like membrane defects that induce efflux of essential ions and nutrients.
    The bacterial cell then swells and subsequently lyses as large fragments of the membrane
    that once kept it intact starts to flake away. PolyMedix’s small molecule defensin
    mimetic antibiotics mimic the activity of host defense proteins. Host defense proteins are
    part of the innate immune system. In the human body, host defense proteins primarily
    exist in the respiratory tract, the urogenital tract, the gastrointestinal track and the
    epidermal tissues under the skin, all locations where microbial pathogens first enter the
    human body, and represent a first line of defense against bacterial attack. Host defense
    proteins act rapidly against bacteria, unlike other parts of the immune system that take
    longer to work. These proteins employ a simple, yet highly effective bactericidal
    mechanism by targeting bacterial membranes and disrupting them. At low doses, these
    antimicrobial proteins associate in membranes causing membrane thinning and formation
    of transient pores leading to membrane permeabilization and leakage of cellular ions and
    metabolites, which results in the killing of the bacterial cell. At higher doses, they cause
    generalized disruption of the bilayer structure of the membrane, leading to the complete
    breakdown of the bacterial membrane and leakage of cellular contents, which results in
    the killing of the bacterial cell.

    Currently-marketed antibiotics act on specific molecular targets in bacteria and many
    must enter the bacterial cell to work. Bacteria can become resistant to antibiotics via
    multiple pathways, but these generally manifest in one of the following two ways:
     genetic mutations that modify the molecular targets of the antibiotics themselves
    (target modification), rendering these targets invulnerable to the antibiotic in
    question; or metabolic responses that cause the cell to pump out foreign agents (efflux pumps),
    preventing the antibiotics from accessing the molecular targets.

    In contrast, host defense proteins physically disrupt the cell from the outside. The
    mechanism of action of the host defense proteins makes it difficult for bacteria to develop
    resistance because of several reasons:
    - defensin proteins do not have to enter the bacterial cell to work;
    - these agents act quickly, killing bacteria within minutes of exposure, thereby limiting
    the bacterial response time; and
    - in order to develop effective defenses, the bacteria would have to alter the structure
    of its cell membrane, which is a highly complex multi-step response that would
    likely reduce the ability of the newly mutated bacteria to grow and survive in a
    natural environment due to the changes that would occur in the membrane’s ability
    to transport essential nutrients and wastes into and out of the bacterial cell.

    It has been documented in many studies that susceptible bacteria do not readily develop
    resistance to host defense proteins under experimental conditions that readily permit the
    development of resistance against conventional antibiotics. Furthermore, bacteria remain
    sensitive to the host defense proteins despite hundreds of millions of years of evolution in
    which bacteria have been exposed to host defense proteins’ antimicrobial mechanism of
    action. Another favorable attribute of host defense proteins is that they selectively target
    bacteria and not mammalian cells, by recognizing the differences in the composition of
    bacterial and mammalian cell membranes. The outer surface of bacterial cell membranes
    is more negatively charged than mammalian cells. Bacterial cell membranes also lack
    cholesterol, an essential component of all mammalian membranes. Host defense proteins
    specifically target membranes that lack cholesterol and have a high degree of negative
    electrical charge. Therefore, they selectively attack bacterial cell membranes while
    mitigating harm to mammalian cells.

    Accordingly, PolyMedix developed PMX-30063, the firm’s lead defensin mimetic
    antibiotic, and other novel small molecule defensin mimetic antibiotics in order to
    specifically mimic the actions of host defense proteins. PMX-30063 and the firm’s other
    defensin mimetic antibiotics are completely synthetic, which make them easier and less
    expensive to produce than full-length proteins. PolyMedix’s small molecule compounds
    demonstrate activity in animal models of systemic infection, activity that was lacking in
    others’ past attempts to develop natural host defense proteins. These defensin mimetic
    antibiotics may be developed in a variety of formulations, including injectable, tablet and
    topical, for a wide range of antibiotic applications. Preclinical experiments have
    demonstrated that PMX-30063 and its derivatives have several fundamental advantages
    over various existing antibiotic classes.

    - Broad-spectrum activity, including efficacy against resistant strains. By acting
    on bacterial cell membranes, the PolyMedix antibiotic candidates are expected to
    have efficacy against a broad range of Gram-positive and Gram-negative pathogens.
    In vitro testing has confirmed potent bactericidal activity against multiple different
    types of bacteria, including resistant strains. PolyMedix scientists have shown the
    cell-killing capability of the firm’s lead antibiotic against hundreds of different
    strains and species of S. aureus, including nearly 100 drug-resistant strains. The
    antibacterial activity of the company’s defensin mimetic antibiotics has also been
    demonstrated in animal models of systemic infections.
    - Lower likelihood for the development of drug-resistance. It is very difficult for
    bacteria to develop drug resistance to natural antimicrobial host defense proteins
    because these proteins act on bacterial membranes rather than on a single, mutable
    molecular target, such as an enzyme. Because PolyMedix’s defensin mimetic
    antibiotics are designed to have the same mechanism of action as host defense
    proteins, we anticipate they will have a similar lower likelihood of developing
    bacterial resistance compared to conventional antibiotics. This reduced likelihood of
    bacterial resistance has been shown in laboratory serial passage experimental studies.
    - Potentially faster acting than other antibiotics. In time-kill studies, PolyMedix’s
    defensin mimetic antibiotics act quickly when bacteria are exposed to them. The
    firm’s scientists observed bactericidal activity in a matter of minutes after exposure
    to these defensin mimetic antibiotics. In contrast, many currently marketed drugs
    can take hours or even several days to show effect.

    We believe that the PolyMedix antibiotic candidate represents a particularly intriguing
    agent because it has thus far demonstrated comparable anti-infective efficacy to Cubicin
    in a Phase 2 trial that was recently conducted by PolyMedix, and because it also invokes
    a mechanism of action that may allow it to evade the evolution of resistance. This
    differentiates PMX-30063 (brilacidin) from other next-generation antibiotics. The Phase
    2 study of PMX-30063 in skin and skin structure infections reported results in April
    2012. The study was conducted at 21 sites in Canada, Russia and the Ukraine. The trial
    enrolled 215 patients across four dosing arms. Three arms were given low, medium, or
    high doses of PMX-30063 (0.4mg/kg on day one followed by 0.30mg/kg daily for four
    days; 0.75mg/kg on day one followed by 0.35mg/kg daily for four days; or 1.0mg/kg on
    day one followed by 0.35mg/kg daily for four days) plus two days of placebo for a total
    of seven days. The fourth arm was administered daptomycin daily for seven days (per
    label recommendations). Top-line results were as shown in the table below:

    Table 4: Phase 2 PMX-30063 Clinical Cure Data
    Day 3 Clinical Response Low Dose Medium Dose High Dose Daptomycin
    Per Protocol 85.0% 71.4% 89.7% 74.5%
    modified Intent-To-Treat (mITT) 81.4% 67.6% 77.8% 74.5%
    Intent-To-Treat (ITT) 79.6% 68.5% 75.9% 74.5%

    While the data did not indicate the presence of a true dose response, they clearly show
    evidence of drug antibacterial activity and favorable clinical cure rates vs. an active
    comparator. The per-protocol cohorts were defined as those patients who received 80%
    of study drug, were culture-confirmed for S. aureus infection, and who were assessed
    (161 out of a total 215 patients enrolled). The modified ITT population encompassed all
    patients with confirmed S. aureus infections (172 of 215 subjects). At this juncture,
    PolyMedix is planning to resume Phase 2 testing of brilacidin to refine the dosing
    regimen in order to confirm evidence that the drug could be effective after only one or
    two days of dosing, which would confer a substantial convenience advantage and
    potentially avoid any cardiac side effects, primarily hypertension, which were observed
    in the first Phase 2 study at the medium and high-level doses of the drug.

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    • Nice post mullet. What mullet posted was just the analysts comment on one of cubist competitors_pymx. The essense of the very large report on cubist was that it was initiated with a neutral rating. And the sole reason given was that they rely too much on just one drug and that drug may be becoming off patent protection by 2017. He also noted that cubist has an aggressive development program to get much needed diversification and they have 1 billion dollars in cash for same.
      If you read between the lines he is saying pymx would be a great addition to cubist pipeline. I dont think cubist can not buy pymx or let anyone else buy. Price here is dependant on multiple bidders. But, from here at least a double since MidCap will accept nothing less than 18 mil.
      Long timers here may not want to here this, but pymx is a great buy here.

    • How about a write-up on the financial position ?

      In consideration, the Borrowers have granted the agent, for the benefit of the lender, a security interest in the Borrowers’ intellectual property. The amendment further provides that in the event that the Borrowers consummate one or more transactions which result in at least $18,500,000 in aggregate net proceeds to the Borrowers, the agent and lender will release the security interest in the Borrowers’ intellectual property. Except as expressly modified by the amendment, the loan and security agreement, as amended by the first amendment, remain in full force and effect in accordance with its terms and conditions. No assurance can be given that the Borrowers will consummate any transaction or that the net proceeds from any transactions will be sufficient to obtain the release of the security interest in the Borrowers’ intellectual property.

 
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