Erratum? BNC210

Firstly, in the interest of being positive, congratulations to Bionomics (ASX : BNO) on all the recent positive coverage on the Merck relationship. No matter how you feel about the company, its prospects, or the way it goes about doing things, it’s pretty impressive to have a major-league pharma partner like that. Of course, it is somewhat less impressive when your major development partner also becomes a significant shareholder (consentually, no less), but perhaps I will save that perspective for another day.

Per my earlier promise, I would like to review my commentary on BNC210 from back in July. Not many of my opinions have changed about this company (and in my view, the near-term economics of the Merck deal was “baked” into the share price already, otherwise it’s pretty hard to justify the market cap) but I have had dribs and drabs of intelligent people reach out to me over the past few months and tell me that I am just plain wrong about the identity of BNC210. In some ways I am relieved to hear it, because honestly – it just didn’t make sense. Sigh… you know the world is going rapidly downhill when one can no longer rely on basic databases like ChemSpider…

As such, I am compelled by the basic standards of decency to clarify that based on the information I have been given and subsequent sniffing around, BNC210 is likely to be described in US patent application 2015/0166534 “Novel Anxiolytic Compounds.” The “general” formula in the abstract describes a fairly large library of compounds but I am guessing it is probably the first example in “Table 1” on page 25 given the comparative efficacy in the different models.

Ok, that’s fixed. Phew! I feel a weight off my shoulders…

Except that I would still like to point out a few simple things. What kind of a company lets so many public domain inaccuracies remain uncorrected? Moreover, this is a company that still does not talk very much about the mechanism of action (MoA) or the efficacy basis of BNC210. It’s possible that there are defensible commercial reasons for this (notwithstanding that the patent is reasonably well written) but when a company is spruiking a CNS drug for an incredibly tough area like anxiety/depression – literally an ocean of failures – there really needs to be some elucidation as to why the higher investment risk is justified. The fact that the MoA is not really disclosed on the BNO website after all these years (and all those press releases!) and that the structure and other data has not been disclosed in any peer-reviewed publication (as far as I can see) continues to raise a red flag for this skeptic.

But then again, if Merck is snaffling up shares and obviously has information the average retail punter doesn’t have, then maybe that’s really all you need to know about whether BNO’s tech is any good or not.

5 thoughts on “Erratum? BNC210

  1. On 16 September BNO released positive results of their Phase 1 trial of BNC210.

    They explained its mechanism of action as being a “negative allosteric modulator of the a7 nicotinic acetylcholine receptor”.

    They said their findings seemed to demonstrate that mechanism of action because BNC210 significantly reduced the effect of nicotine, as measured by EEG.

    Non-smoking subjects were given nicotine nasally and their responses were measured by EEG.

    13 subjects responded to the nicotine in a dose-response way and it turned out that 12 of those 13 had received the increasing doses of BNC210, rather than placebo. (Since 42 subjects received the increasing doses of BNC210, this means that 30 didn’t show a dose-response effect; and 11 of the 12 placebos also didn’t show the dose-response effect)

    This sounds like good news to me, if in a decent subgroup of cases anxiety leads to stimulation of the a7 receptor and BNC210 blocks that to some extent, without causing any annoying cognitive dysfunction.

    I don’t know if I understand the logic behind this correctly, as I thought nicotine was supposed to have a calming effect. Or maybe that only happens once you’re addicted to it! Maybe for novice smokers it stimulates you!

    Good onBNO if this is good support for their anti-anxiety drug.

    So why did Ironwood hand it back?

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    • Hi Anne,

      … always appreciate the detailed commentary. Thanks!

      I’m aware that the target is is the a7 nAChR, that’s not the issue. The descriptor “negative allosteric modulator of the a7 nicotinic acetylcholine receptor” describes how the molecule interacts with the target but doesn’t explain the proposed mechanism of action of the drug. “Negative allosteric modulation” (or, put another less wonkish way – allosteric inhibition – or just “inhibition”) means that the drug interacts with the receptor indirectly and my reduce (or “block”) the ability for the receptor to be “hit” or “modulated” by another molecule. Hence the partially-successful nicotine blocking study.

      We’ve known for probably 10-15 years that nAChRs are an interesting target for anxiety (because, as you sort of imply, smoking is a form of self-medication for anxeity – and yes, nicotine is a stimulant) but there is a lot of complexity in this receptor class because they regulate a huge number of physiological process and so there are – depending on the exact characteristcis of the drug – multiple potential mechanisms of action around these targets, depending on how they interact. The a7 receptor also seems to be an odd choice (I will caveat that I am not a neuroscientist so I am happy to be corrected).

      My hypothesis is that the MoA is not fully understood or difficult to understand (the Phase I data sort of supports that as there are clearly multiple mechanisms at play). CNS drugs are incredibly difficult to develop and unless the effects are able to be clearly understood, it’s challenging to summon the courage to invest.

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    • PS: I should also note that your statement of “without causing any annoying cognitive dysfunction” is probably inaccurate given that the study was very short-term. a7 nAChR is implicated in long-term memory formation – that would be the bigger concern, not short-term cognitive impairment. a7 receptor is also highly expressed in the spleen where it appears to play a role in promoting immune response, an additional potential headache for long-term use of the drug (i.e. increased risk of infection, cancer) and also makes the drug harder to dose the patient for a CNS application.

      Again – if I am wrong – happy to be corrected by a reader.

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      • And thank you, Chris, for your detailed response!

        In the 2014 poster, which is a pdf listed on BNO’s website under CNS research, the mechanism of action is described as follows:

        In vitro studies have shown that BNC210 is an antagonist of the a7 nicotinic acetylcholine receptor (a7 nAChR). It inhibits rat and human a7 nAChR currents (in stably transfected cell lines) induced by acetylcholine, nicotine, choline and the a7 specific agonist PNU-282987, with IC50 values in the range of 1.2-3μM. BNC210 does not displace alpha-bungarotoxin binding and its inhibitory effects are not influenced by the concentration of acetylcholine used (EC20 or EC80), suggesting that the modulation is via an allosteric site.

        Chris, I know it’s poster info and not (yet) a peer-reviewed paper, but assuming the info is all good, do you think the results they generated after performing their various acts of “menace” on their rats demonstrated a clear and logicial mechanism of action?

        Also in my reading, I read that in Nov 2014 BNO borrowed $US10m from Silicon Valley Bank to advance their research into BNC210, hoping to get it to an attractive enough point to attract another well-moneyed partner. They have to pay back this loan 30 months after taking it out.

        That’s impressive: I don’t know what interest Silicon Valley Bank is charging, but they obviously thought BNO is a good bet for paying the money back by mid 2017.

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      • Nope. And judging from the way you framed your question, neither do you.

        And yes, it was a strange financing. Debt financing to develop an early-stage asset is quite unusual.

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