Bionomics : Creating innovative stories for serious human diseases.

Bionomics (ASX : BNO) is a company I have watched for a long time as it has gone through many stages of re-invention. It is also a company that I have struggled to motivate any real enthusiasm for, either to praise or criticise, mainly because the company is just so mediocre. Let’s face it the world mostly consists of mediocre companies and therefore this is insufficient reason alone to make a comment. As such, this post has existed in one form or another since February and finally after many requests for commentary (including a good amount of goading and ridicule), I have elected to bite the bullet and capitulate.

In order to keep this short and sweet, I will start by briefly enumerating the “warning signs” that this company exhibits that are seldom discussed by analysts (obviously, because we only have sell-side analysts). I will then write a brief commentary on three of BNO’s product pipeline that I think captures most of the current “value” but also piques most of my skepticism about this company.

Here are the warning signs:

  • Basic drug discovery is expensive and under-capitalised drug discovery companies seldom perform well. This company is not a Forma, it has a fairly ad hoc collection of discovery assets. Although for an early-stage ASX-listed biotech it is relatively well-capitalised, in a “hot” discovery area like GCPRs or ion channels (going through a bit of a renaissance at the moment) I would argue that this company lacks the resources to differentiate itself from its much more grown-up competition.
  • By extension, valuation doesn’t come from platform technologies, it comes from the clinical development of good medicines. It is my personal opinion that BNO’s articulation of its drug discovery platform(s) is not a differentiation, and mostly just a way that the company can continue to capture feeble investor mindshare with “new toys” popping out on a periodic basis, rather than strong clinical results for its established pipeline (which it does not have, as I will discuss). A pipeline, incidentally, that greatly exceeds its financial resources.
  • Small cap companies like this have no business being “vertically integrated”, as is BNO’s claim. It’s just not a meaningful differentiator in an era where almost every facet of drug development can be outsourced, with quality. In BNO’s case, this vertical integration doesn’t seem to have a particularly untoward effect on its burn rate, which probably also infers that its “verticality” is probably not much practical added value, and perhaps mostly just marketing spin.
  • BNO has a track record of subsuming mediocre assets through M&A activities. While I generally have respect for management teams that consider growth strategies other than “organic growth” or “financed growth”, as BNO clearly does, an acquisition “process” is not an accretive event in its own right. I just don’t see any sign of quality in the assets that BNO has acquired. What I have observed of BNO’s M&A strategy is not much more sophisticated than “bigger is better”. Just because an asset has some fleas on it, doesn’t mean its bad. But by the same token, just because an asset once loitered in a pharma lab, or a luminary university, doesn’t mean that buying it (for cheap) automatically creates value for the acquirer.
  • BNO publishes very little of its clinical data. VERY little. Some of the more recent public disclosures of technology (i.e. ASCO posters) do not constitute peer-reviewed publications, though there is an implication in BNO’s communication strategy that these presentations substantiate the science through “luminary attendance” at conferences. Most of the posters that BNO has produced are more like marketing documents than scientific communications, little more than a placeholder at a conference for doing business development. That’s fine by the way, but I just want to be clear about it.
  • BNO’s clinical trial designs are incredibly conservative, verging on scientifically marginal. For example, for its oncology asset currently in Phase II (BNC105) it has never had, as far as I can see, any stand-alone clinical assessment of efficacy other than an initial safety study, which showed no observable anti-tumour effect, and has only ever been meaningfully evaluated in a combination therapy setting. This is notwithstanding that the purported mechanism of action supposedly has potent “dual action” anti-cancer effects in its own rights.
  • Related to the above point, BNO is not especially transparent or clear about the mechanisms of action behind its drugs. The company tends to rely on the use of sensationalist concepts like “attacking cancer stem cells” rather than really scientifically justifying the investment thesis behind its pipeline. It needs to do far better if it wants to earn credibility as a diversified biopharma company.
  • BNO’s claims of efficacy are mostly unsubstantiated. In some cases, ad hoc retrospective analysis of very small clinical trials has yielded statements that are intriguing from a marketing perspective, but are statistically indefensible. In other instances, product positioning claims have been made in advance of sufficient clinical assessment to be able to substantiate those claims. I will address this generalised criticism in the context of individual development programs (below).
  • BNO has a huge intellectual property portfolio that consists of IP that is either very very old, or very very recent. Much of the recent intellectual property seems to reflect sensationalist opportunities to position the company into areas that have a high level of investor and public engagement such as immuno-oncology. There is nothing wrong with this per se, it is BNO’s prerogative to position itself how it sees fit. However, the combination of anti-mitotics with checkpoint inhibitors has been patented to death, and therefore yet another microtubule inhibitor + checkpoint inhibitor patent filing (disclosed as a price-sensitive event no less) is clearly a communication strategy that is not targeted at the sophisticated investor or pharma partner. I also shudder to think at the cost of prosecuting what is a large but probably marginally exciting IP portfolio.

Of course, there are some quite positive things about BNO. They are are, notwithstanding the tendency to “rat pack” mediocre assets for cheap, clearly a transactional company. By any metric, the Merck deal looks pretty darned good for a early-stage collaboration and the company got real up-front money, a true rarity in this space. Of course, the touted numbers had a lot of biodollars tagged on the end, but still – I was impressed. I will not deny it.

However, by the same token there are collaborations that seem to be fairly dormant – like Genmab, where it is hard to see that there a strong fit with Genmab’s current focus. Then there are collaborations like the Ironwood partnership (now terminated, though even the positive spin on termination was impressive), which also had big biodollars involved. Now BNO seems to owe Ironwood a royalty for their “work”, who didn’t actually seem to significantly advance the BNC210 program. If I am mistaken about this, I am happy to be corrected.

But these are all annoying generalisations, now to get specific:

BNC210 – Anxiety/Depression

Anxiolytic/anti-depressant drugs are incredibly hard to develop. I have previously waxed lyrical about the challenges of CNS drug development and will not repeat it here. Plus, with the recent acquisition of Spinifex as a perfect example, there is no reason why a small biopharma company can’t develop an excellent CNS drug if the underlying science is there.

In the case of BNC210, the science simply isn’t there, in my opinion. To date, the company has only published animal data and the quality is not very good. Despite over 160 normal patients being dosed across (apparently) 5 clinical trials, there is no peer-reviewed publication – as far as I can ascertain – of the results. All of the historical trials were mostly small studies, usually single site, and really could only be described as “proof-of-concept”. The currently planned clinical studies (in UK/Europe) have some very sophisticated metrology, such as fMRI, so therefore running a small number of sites is completely understandable. But a male-only population is a bit weird, especially since we know from prior development anxiolytic drugs, that drug metabolism is considerably different between men and women.

When I first started reading about BNC210 I obsessed too much about the biology, I cared too much about the potential of nicotine receptors as a target for depression/anxiety management. But the problem with BNC210 is not the biology, it’s the chemistry. BNC210 is L-Isoleucyl-L-tryptophan, essentially nothing more than a dipeptide of isoleucine and tryptophan, two essential amino acids. Both isoleucine and tryptophan-containing dipeptides are known metabolites of peptide digestion (i.e. “breaking down” of food) and are believed to play all kinds of roles in biochemical signalling (tryptophan-containing dipeptides, for example, may have an important role in regulating obesity and diabetes). The problem with most dipeptides in actual biological systems, is that they are usually a short half-life intermediate metabolites and are very easily cleaved into their fundamental amino acids (i.e. just become cell “food”). In fact, isoleucyl-tryptophan has never been “detected” as an intermediate metabolite in biological systems, which sort of substantiates the idea that this molecule is more likely to become a tasty snack for cells, than hang around and demonstrate a lot of drug potency. As an academic comment, this is probably a good example of where Lipinski rules for drug oral bioavailability probably fall on their face.

As it turns out, the company has known since at least 2008 that the half-life of BNC210 is roughly 6 hours, at least in animal studies. By the way, this particular data point is really …er … tough to find in a peer-reviewed journal. So far I have only been able to find it in a poster given at a conference in Barcelona in 2008, and the “footers” of old press releases (no longer archived by BNO). Usually murine PK is faster than humans, so it may well be that the half-life is somewhat more prolonged in humans. But if it isn’t, then BNO has a major problem because it doesn’t support the proposition of daily oral dosing. By way of comparison, most selective seratonin reuptake inhibitors (SSRIs) have a half-life of between 13 and 45 hours in people (and mice), mostly driven by gender differences in metabolism.

The truth is, all this doesn’t matter. BNO has finished playing with normal volunteers to understand the basic safety of their drug. Unsurprisingly, a dipeptide that is probably naturally – and transiently – produced when you eat a good (or even bad) piece of steak is neither here nor there in terms of safety. BNO is now, approximately 7 years later, doing the proper PK/PD work in humans so eventually I am sure we will see a high-quality peer-reviewed publication of all the great data obtained to date (though someone reading the hype in 2011 would be forgiven for having expected to see it by now). The issue I have is that the management team is already making claims about the drug that they cannot substantiate on the basis of the data they have today. This is a “table” from a recent CEO newsletter:

Deb's Table

Firstly, the inclusion of valium (diazepam) in this table is a bit obnoxious because although it is commonly prescribed for anxiety, it is not the “competitive” product for BNC210, SSRIs are (Prozac a.k.a. fluoxetine is only one such example) – despite previous “published” science to the contrary. Valium is just “table filler” to make BNC210 look good. Not only does BNC210 have insufficient PK/PD data from patients to make virtually all of these claims, I would argue that some of the competitive arguments are also misleading. For example, most SSRIs are also fast-acting (what does that actually mean???), it’s just that many patients are put on a dose-escalation schedule in order to appropriately monitor and risk-manage a patient. SSRIs are also incredibly safe and have drug interaction profiles that are not only excellent, but increasingly well understood. In terms of CYP450 interactions, fluoxetine is probably at the more complex end of the scale compared with, for example sertraline, but any drug interaction issues can be managed proactively and this is usually a low prescription risk.

So to repeat, this table is just a huge generalisation and doesn’t accurately reflect SSRIs as a class. As for an issue like drug withdrawal, until BNO does a long-term usage study, the company has no basis to make this claim. Unless, of course, it already knows that the drug has negligible effect. In which case, that may be a very safe marketing claim to make in the absence of clinical data. I have already addressed the the once-a-day oral dosing issue previously, again insufficient data has been ascertained to make this claim. I would argue until their current Phase Ib/II studies are complete, I don’t see how the company can, in good faith, position the drug in this way. It also doesn’t help that sell-side analysts, such as Tenushree Jain at Bell Potter are willing to throw terms like ‘Blockbuster’ out there without an ability to understand the basic science (though I note, by all accounts, she is a very bright and talented individual and no unkindness is intended).

So I am going to go out on a limb here.

Here is my opinion of this drug. I think it is long in the tooth, and any time I see a company take forever to publish clinical data, I am immediately skeptical. BNO has had plenty of opportunity to substantiate its marketing claims. It hasn’t chosen to do so. It makes claims about the drug that are not reflective of any robust public-domain, peer-reviewed evidence. I am sure that the company knows much more that we do, but when it starts to make serious marketing claims for a drug that has yet to complete PK/PD in patients, I get antsy. But my really controversial opinion about this “drug” is that when it undergoes “gastric metabolism” (i.e. you eat it and your stomach does its biz) it is simply going to become a source of L-tryptophan. Don’t get me wrong, tryptophan is critical for serotonin synthesis and therefore has a fundamental role to play in mood, behavior and cognition. But what it means is this : if BNC210 is to be proven to be an efficacious drug, it should be compared with oral tryptophan.

Ouch!

I think it is unlikely to beat it – notwithstanding that 75% of anti-depressant efficacy in drug studies is attributable to placebo effect. Perhaps then, BNC210 is just the “ultimate” placebo – a placebo with a bit of science behind it (does that make it a drug?). Instead of doing studies to look at the impact of food blocking on dose administration (perhaps already a bit of a hint about how Bionomics may really feel about concerns regarding oral availability of this drug), it may need to ask the question whether its drug is any better than tryptophan-rich food.

BNC105 – Oncology (Small Molecule)

I will admit, that my ire rose a couple of weeks ago when I read about BNO’s “combination therapy” patent with checkpoint inhibitors. When that is the most exciting piece of news that a company has, you know that a program isn’t really all that exciting.

Fundamentally, BNC105 isn’t exciting, especially considering where the overall field of cancer is going at the moment. It is yet another microtubule inhibitor or, as the company prefers to call it, a vascular disrupting agent (VDA). Despite claiming monotherapeutic efficacy (a “one-two punch” at endothelial cells and tumor cells, no less), the Phase I clinical (safety) experience with the drug showed no objective anti-tumor efficacy. Now that’s ok to some extent, the study was a very bog-standard dose-escalating safety study, and efficacy isn’t the main goal. But then again, BNO was clearly hoping to see something because they evaluated treatment response with magnetic resonance imaging (MRI), which is great for looking at changes in tumour   vasculature. Nothing. Nada. Moreover all subsequent clinical work has been in combination with other drugs, which doesn’t exactly send a highly positive signal that this drug is believed to have efficacy in its own right.

I would have expected to see a stand-alone Phase II efficacy study for a drug that is claiming any kind of effect. The fact that BNO didn’t do this, strongly suggests that it internally lacks confidence that this drug has any monotherapeutic efficacy. I also would have possibly tolerated the shift over to combination therapy studies if the trial outcomes hadn’t been so shamelessly hyped. The Phase I/II study was in a very small number of ovarian cancer patients, in combination with carboplatin and gemcitabine, followed by “maintenance therapy” of BNC105 as if to somehow imply that after whacking the patient with a nasty dose of gemcitabine, the follow-on monotherapy with BNC105 was the magic bullet! In a study design like this, there could be absolutely no claim of efficacy attributed to the drug, because neither the study design nor the patient statistics warrant it. This is awful clinical science.

This is the clinical science equivalent of trialing a gun control case in Texas.

Even worse was the Phase II renal cancer announcement in March of last year. The DisrupTOR-1 trial was intended to compare BNC105 combined with Everolimus (Afinitor), with Everolimus alone. The results presented by the company demonstrated that there was no difference in PFS between treatment arms. The company did take the position that a sub-population analysis hinted at efficacy (though given the number of patients, not with statistical significance) and subsequent biomarker work suggests a patient profile that is likely to be a responder, based on 6 month progression profiles. The challenge is that BNO has no data to substantiate whether this profile predicts a responder to Everolimus or Everolimus+BNC105. To be honest, I no longer really understand where this is going.

To conclude, this is a drug that has been reinvented a number of times. It started off as a VDA, then it became sexy to accentuate an mTOR potentiating effect (in combination) and now it is obviously a potential combo therapy for checkpoint inhibitors (presumably due to some fundamental cytotoxicity, rather than anything cleverer). Despite all these incarnations and guises, the fundamental reality is this: there is simply no evidence that this drug does anything useful, either as a monotherapy or a combination therapy. There is plenty of slick positioning that makes this drug look a lot more exciting than it really is.

BNC101 : Anti-LGR5 mAb

I will try to keep this one short. It’s also probably the yukkiest one from an investor perspective because it is a biologic, and it costs serious $$$s to do the front-end development. We’ve known for a couple of years now that BNO is writing some pretty hefty checks to Lonza. We are also reminded incessantly that this asset basically came from Biogen Idec (via Eclipse and Dyax), which somehow implies a quality mAb/target. That may be true, but it is far from obvious to me. I also don’t particularly like it when a small molecule company takes on a biologic because the development skills required of the “fully vertically integrated” company are rather different.

But I am willing believe that BNO has the talent and capital to make it happen. So let’s park that issue for now.

LGR5 (aka GPCR49), the target that BNC101 “hits”, is part of the family of receptors called G-protein coupled receptors (GPCRs) and there is no doubt that this is a hot target space at the moment. There are many GPCRs that remain unexplored and even undiscovered. Indeed, that this part of the mystique of this target arena. However, we have known about LGR5 for almost two decades, including normal tissue expression of the target. Notwithstanding any potential anti-cancer effect, LGR5 is highly expressed in a wide range of non-cancerous tissues, including mundane and ubiquitous things like muscle tissue, presumably part of the reason why Eclipse never got any traction for this drug. This normal expression profile is problemetic when dosing a patient with a biologic targeting LGR5, because although it might be over-expressed in certain cancer stem cells (it is), you are probably going to have a hell of a protein sink when administering this drug. What this means is that all the normal tissues act like a big sponge and suck up the dose, so in order to deliver the drug to where you want to, it could mean huge doses overall. This in turn means a higher risk of toxicity (biologics are usually safer but dose still matters), shorter circulation half-life (impacts drug administration regimen) and cost (more material = more $$$s).

But even this aside, it’s not immediately evident that LGR5 is a good target for a cancer drug. A biomarker? Yes, almost certainly. A drug? I am not so certain. Part of the problem is that LGR5 expression seems to be the result of a co-regulatory gene in the Wnt / β-catenin (“pronounced “wint”) pathway, a fundamental regulatory pathway that is implied in both stem cell regulation and cancer proliferation. This pathway is incredibly complex, to the extent where anytime I have ever attended a scientific presentation on it, my eyes start to glaze over in about 3 minutes (and I will accordingly try not to bore you here). There is no doubt that LGR5 seems to be a good diagnostic biomarker for cancer stem cells, particularly in certain cancers like colorectal cancer. However there are conflicting views about whether targeting LGR5 is a particularly strong therapeutic concept, with the prevailing view that  LGR5 overexpression is part of an important tumour suppressing mechanism and, sort of non-intuitively, may actually increase cell adhesion (i.e. prevent metastasis). Certainly, there are more promising parts of Wnt to hit with a drug than LGR5. Therefore hitting LGR5 with an antibody, thereby suppressing LGR5, might not necessarily give the desired effect in patients.

To be clear, I am not completely negative about BNC101, I just don’t see the right level of science in the decision-making and I am not sold on an asset just because it has some big names in its commercial lineage. There is no doubt that recent poster presentations show an impressive anti-tumour effect, and this deserves acknowledgement. It’s just that these models are sort of naive and might not be capturing the regulatory role of LGR5 signalling in the “intact” tumour environment (let alone the effects of normal tissue expression). To be clear, even a patient-derived xenograft is almost certainly not going to demonstrate native CSC behavior in an animal model.

Concluding remarks

I have elected not to spend time talking about the melanoma program (BNC420) which is a neat story but seems to just ignore the fact that melanoma is known to have many different metastatic mechanisms. Notwithstanding BNO’s impressive success in engaging with Merck, I am not going to bore you with commentary about the probability of success of an Alzheimer’s drug (0%), let alone a CNS drug (<5%). They could be beautiful molecules but all it means is those particular assets are at the speculative end of the spectrum when trying to work out what this company is really worth.

Upside really.

In short, this is a company that is commercially aggressive and has shown that it can play with the big boys. At first blush, it does a lot of things well, including promoting itself. However the science is fundamentally weak and the lack of visible clinical data to substantiate the company’s claims is a real concern. Let’s hope that this is something that the management team recognises as an area for improvement in the future. Only when that improvement happens, and not before, will the company be able to justify its current market cap.

 

 

 

 

 

 

4 thoughts on “Bionomics : Creating innovative stories for serious human diseases.

  1. I read with interest the blog on Bionomics. Unfortunately much of my interest arose from some incorrect assumptions, and insufficient and precise information. So, in an effort to get some things back on track (rather than having a go at the blogger) I have chosen to tackle the imperfections in the blog in a somewhat serial fashion.

    The blogger talks about the lack of transparency on mechanism of action of the drugs but indicates in the case of BNC210 that he has not investigated its target/MOA. That maybe isn’t the best way to tackle this subject.

    It appears that the blogger is describing a spurious structure of BNC210. On the facts available to me he does not have the correct structure. It is not a di-peptide.

    Bionomics has many peer-reviewed publications and poster presentations, including at least one reporting the latest BNC105 Phase II trial. The blogger should make himself aware of these publications as they will always be the most reliable sources of technical information. Even the posters are bound to be factual – nobody will want to stand in front of them if they aren’t. On the other hand, I’m sure we all understand that a lot of clinical data from a large number of companies never gets published due to confidentiality and company policy reasons.

    The Forma Therapeutics comparison doesn’t cut it for me. Bionomics has a strong and well-developed ion channel drug discovery platform for Neuroscience. Its targets, voltage and ligand gated ion channels, are the third most drugged family of targets. Very few companies have been able to be successful in the space in which Bionomics has carved out its success. Importantly Big Pharma is buying those that have been, for example, Convergence. I doubt that it is a stretch that one day one of Bionomics’ licensing partners will see it is cheaper to buy the company than continue to pay the milestone and royalty payments in the licensing agreement.

    When the blogger says valuation doesn’t come from platform technologies, it comes from the clinical development of good medicines it makes me stop to think. Bionomics is coming up with great ideas for targets and indications, developing good molecules using rational focused drug discovery, partnering early with the experts (Merck for example) and in this way it gains access to significant resources that smaller biotech companies cannot afford or imagine. They can also use the more clinically experienced and resourced companies to take the compound into later stage Phase II and Phase III. In a nutshell, Bionomics takes a novel small molecule, runs it through pre-clinical development, puts it into early stage clinical studies and then looks to find a partner for the later stage clinical development. That makes sense to me and it looks just like any sensible drug development program.

    The blogger doesn’t seem to like Bionomics’ ‘vertical integration’. The value that I perceive in this is that Bionomics’ acquisitions have enabled it to reduce the cost of its programs and those companies are generating a revenue stream for Bionomics. So, consequently, Bionomics can do more drug discovery and drug development work without increasing their cash burn. That isn’t wasteful M&A. That’s good business!

    I reckon there was a lot to like about the Ironwood deal (even if it did end prematurely) and Ironwood must have liked it when they signed on too. From my readings, Ironwood invested millions of dollars in Bionomics and BNC210 during the 2 year collaboration and partnership. The mechanism of action for BNC210 was clearly defined during this period, large amounts of clinical trial material was manufactured. Toxicology studies were performed in rats and dogs to prepare for what could be up to 12-week long Phase II studies, an IND was filed and a phase I study examining pharmacokinetics of BNC210 in a capsule was run under the IND. Ironwood seems to have done a reasonable amount of work.

    I’m not sure what the blogger’s complaint about the current Phase II BNC210 trial is. It is a single site trial, where one of the machines is, so in this case it isn’t surprising. I’m not sure about it being a male-only population in the fMRI trial. I think Bionomics has indicated that females can be recruited into the trial but generally speaking gender isn’t so relevant at this stage (it is, of course, when teratogenicity work is done).

    I liked the concept that the blogger put forward about the molecule being possibly bioavailable from steak. It conjured up the thought that only vegetarians would be taking Valium or Prozac. However, I think the blogger hasn’t got the right structure for BNC210 so that thought didn’t last long.

    The blogger wields a big stick on the table of comparisons that was found in a newsletter. The table represents the benzodiazapenes comparison, which is fair (contrary to the blogger’s opinion) as these are in almost all cases the first line therapy before antidepressants (SSRIs/SNRIs) are prescribed or have taken their effect. There are black box warnings on most antidepressants around suicidality and other effects like serotonin syndrome which can be life threatening. Sexual dysfunction is a debilitating side effect that interferes with patient compliance. The discontinuation syndrome is very unpleasant, makes ceasing the drugs a lengthy and difficult process and transitioning from one drug to another is also difficult for this reason among others. This withdrawal syndrome has been the focus of a law suit recently where the Cymbalta discontinuation side effects were reported to occur in 2% of patients but actually occur in ~45% of patients.

    The final points that need to be made about the the blogger’s remarks is that Merck’s ability to choose good programs and partner with good molecules or a really good company has been shown, time and time again, to be ‘on the money”. The blogger also needs to realise that the AD compound is not disease modifying but symptomatic treatment, and the other program is for pain, a hugely successful area for biotechs at the moment.

    On the basis of the above remarks it is a very harsh judgment to call Bionomics ‘mediocre’, blogger. I don’t think that people of the caliber of Richard Hargreaves or Frank Yocca would be amongst their scientific advisors if their science wasn’t up to par. On the other important measures, such as the size of several licensing deals or market cap, Bionomics is much more than ‘mediocre’ and on any relative measure IMHO it is probably well ahead of 98% of the Australian biotech sector.

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    • I read with interest the blog on Bionomics. Unfortunately much of my interest arose from some incorrect assumptions, and insufficient and precise information. So, in an effort to get some things back on track (rather than having a go at the blogger) I have chosen to tackle the imperfections in the blog in a somewhat serial fashion.

      Great. I love serial. “The Blogger” is reading… by the way, I hate being called a blogger. My name is “Chris”.

      The blogger talks about the lack of transparency on mechanism of action of the drugs but indicates in the case of BNC210 that he has not investigated its target/MOA. That maybe isn’t the best way to tackle this subject.

      I did. I made all reasonable efforts to find the details of this drug, including – but not limited to – the usual online chemical resources (i.e. Chemspider), google searches, PubMed, the company’s own repository of “poster” presentations, etc.

      It appears that the blogger is describing a spurious structure of BNC210. On the facts available to me he does not have the correct structure. It is not a di-peptide.

      Point me in the right direction, and I am happy to fix it.

      Bionomics has many peer-reviewed publications and poster presentations, including at least one reporting the latest BNC105 Phase II trial. The blogger should make himself aware of these publications as they will always be the most reliable sources of technical information. Even the posters are bound to be factual – nobody will want to stand in front of them if they aren’t. On the other hand, I’m sure we all understand that a lot of clinical data from a large number of companies never gets published due to confidentiality and company policy reasons.

      I don’t believe that made any statements to the contrary, except that you should know that a poster is not a peer-reviewed publication. I am also not generally all that interested in pre-clinical journal articles. Please point me to the publication (not a poster) that summarises the BNC105 clinical data, and I will be happy to review it.

      Although my enthusiasm will be low – because the company has not demonstrated WHATSOEVER that BNC105 has any clinical efficacy (including their posters). I should also note that any company that elects not to publish data for “confidentiality or policy” reasons is a shonky, unethical and utterly crap company. That is not even a point of contention.

      The Forma Therapeutics comparison doesn’t cut it for me.

      I was using a platform company example, not a specific technology. But ok.

      Bionomics has a strong and well-developed ion channel drug discovery platform for Neuroscience. Its targets, voltage and ligand gated ion channels, are the third most drugged family of targets.

      All true. Though you would be amazed at what infrastructure is really required to do this properly. Bionomics spend is not even close.

      Very few companies have been able to be successful in the space in which Bionomics has carved out its success.

      By what metric is Bionomics “successful” for you?

      Importantly Big Pharma is buying those that have been, for example, Convergence. I doubt that it is a stretch that one day one of Bionomics’ licensing partners will see it is cheaper to buy the company than continue to pay the milestone and royalty payments in the licensing agreement.

      Good, well – I suppose one of us is into spurious optimism. It isn’t me. So it must be you.

      When the blogger says valuation doesn’t come from platform technologies, it comes from the clinical development of good medicines it makes me stop to think.

      Good!

      Bionomics is coming up with great ideas for targets and indications, developing good molecules using rational focused drug discovery, partnering early with the experts (Merck for example) and in this way it gains access to significant resources that smaller biotech companies cannot afford or imagine. They can also use the more clinically experienced and resourced companies to take the compound into later stage Phase II and Phase III. In a nutshell, Bionomics takes a novel small molecule, runs it through pre-clinical development, puts it into early stage clinical studies and then looks to find a partner for the later stage clinical development. That makes sense to me and it looks just like any sensible drug development program.

      This is no longer the reality of drug development, particularly the congested areas that Bionomics operates. If a company really has a game-changer, it must be prepared to finance it into Phase III, especially in the completely ‘non-sexy’ areas that Bionomics operates.

      The blogger doesn’t seem to like Bionomics’ ‘vertical integration’. The value that I perceive in this is that Bionomics’ acquisitions have enabled it to reduce the cost of its programs and those companies are generating a revenue stream for Bionomics. So, consequently, Bionomics can do more drug discovery and drug development work without increasing their cash burn. That isn’t wasteful M&A. That’s good business!

      The “financial contribution” of Bionomics corporate structure is negligible relative to the cost of doing business. I am glad you are excited by those ROCs, I am not.

      I reckon there was a lot to like about the Ironwood deal (even if it did end prematurely) and Ironwood must have liked it when they signed on too. From my readings, Ironwood invested millions of dollars in Bionomics and BNC210 during the 2 year collaboration and partnership. The mechanism of action for BNC210 was clearly defined during this period, large amounts of clinical trial material was manufactured. Toxicology studies were performed in rats and dogs to prepare for what could be up to 12-week long Phase II studies, an IND was filed and a phase I study examining pharmacokinetics of BNC210 in a capsule was run under the IND. Ironwood seems to have done a reasonable amount of work.

      That is a neophyte viewpoint of “partnering”. When a grown-up company does “partnering”, if the partner abandons the asset and relinquishes their commercial duties, the “partner” doesn’t still get a piece of the action. This deal structure is nothing short of ridiculous and is not even remotely industry-standard. But thank you for your opinion. It’s like saying that when you break up with someone you still have sexual visiting rights.

      I’m not sure what the blogger’s complaint about the current Phase II BNC210 trial is. It is a single site trial, where one of the machines is, so in this case it isn’t surprising. I’m not sure about it being a male-only population in the fMRI trial. I think Bionomics has indicated that females can be recruited into the trial but generally speaking gender isn’t so relevant at this stage (it is, of course, when teratogenicity work is done).

      Gender is ALWAYS relevant – women tend to metabolise psychoactive drugs far more quickly than men. But fair enough.
      I don’t believe I complained about this – I acknowledged that single/small numbers of sites were reasonable given that no every hospital has an fMRI facility.

      I liked the concept that the blogger put forward about the molecule being possibly bioavailable from steak. It conjured up the thought that only vegetarians would be taking Valium or Prozac. However, I think the blogger hasn’t got the right structure for BNC210 so that thought didn’t last long.

      Oh good, well, please send me to the journal article that elucidates the structure and I will happily correct. By the way, if a guy like me can’t work out the structure, then perhaps I am either 1) completely stupid (possible) or 2) Bionomics needs to do a better job. NONE of the posters for BNC210 on the bionomics website elucidate the structure.

      The blogger wields a big stick on the table of comparisons that was found in a newsletter. The table represents the benzodiazapenes comparison, which is fair (contrary to the blogger’s opinion) as these are in almost all cases the first line therapy before antidepressants (SSRIs/SNRIs) are prescribed or have taken their effect.

      Bullshit. This is factually incorrect. What decade are you living in?

      There are black box warnings on most antidepressants around suicidality and other effects like serotonin syndrome which can be life threatening. Sexual dysfunction is a debilitating side effect that interferes with patient compliance. The discontinuation syndrome is very unpleasant, makes ceasing the drugs a lengthy and difficult process and transitioning from one drug to another is also difficult for this reason among others. This withdrawal syndrome has been the focus of a law suit recently where the Cymbalta discontinuation side effects were reported to occur in 2% of patients but actually occur in ~45% of patients.

      Cymbalta is a different beast, it is an SNRI. Most modern SSRIs are very good drugs. Your information is incorrect and incomplete.

      The final points that need to be made about the the blogger’s remarks is that Merck’s ability to choose good programs and partner with good molecules or a really good company has been shown, time and time again, to be ‘on the money”. The blogger also needs to realise that the AD compound is not disease modifying but symptomatic treatment, and the other program is for pain, a hugely successful area for biotechs at the moment.

      Merck is a mostly average company. I chose not to make any comment about the AD drug because I could find absolutely no information about it. Perhaps you have insider knowledge that I don’t. Unless I am mistaken, I believe I fully acknowledged and even positively commented on the Merck deal, so what is your point?

      On the basis of the above remarks it is a very harsh judgment to call Bionomics ‘mediocre’, blogger.

      Nope, it is pretty much a mediocre company.

      I don’t think that people of the caliber of Richard Hargreaves or Frank Yocca would be amongst their scientific advisors if their science wasn’t up to par.

      Possibly. I don’t believe I commented on any of the programs that either of these gentleman are involved with. I have met Richard several times, I agree he is a bright guy. Merck’s deal may be a good deal but it does not vindicate the rest of the company. So, again, what did I say that was contrary to your point?

      On the other important measures, such as the size of several licensing deals or market cap, Bionomics is much more than ‘mediocre’ and on any relative measure IMHO it is probably well ahead of 98% of the Australian biotech sector.

      Market cap is irrelevant. Other than the Merck deal, it has no significant deals at present. It does a poor job of publishing its clinical data. I stand by my assertions.

      Thank you for reading, Martin Soust – aka “Barry White”.

      Like

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