I’m all for company re-branding and re-invention, and Invion (ASX : IVX, née CBio) has done plenty of that. However, you also hope that when a company has a second-lease of life, that it does something worthwhile. It’s sort of the corporate equivalent of surviving a major heart-attack and deciding with the clarifying hindsight of the cardiac recovery ward that it’s time to kick the deep-fried foods, cut back on the booze and maybe get a personal trainer. In the case of Invion, that epiphany really hasn’t happened. CBio’s strategy for a failed Phase II study of XToll was 1) re-brand 2) do more of the same 3) bring in a few extra assets with fleas on them. Oh, and bring in some of the usual ASX biopharma geezers to govern the company.
All great news for shareholders, I am sure …
In fact, XToll hasn’t gone away, it’s still kicking around as INV-103. This is a recombinant form of HSP10, a heat shock protein that is highly involved in both anti-autoimmune functions and tumourigenesis. HSP10 exerts anti-inflammatory activity by inhibiting Toll-like receptors (TLRs), a critical part of the link between acquired and innate immunity that is a rich target space for autoimmune diseases. Certain TLRs have been shown to be very interesting drug targets (e.g. TLR4, 7 & 9) and a significant amount of TLR research is being done in the field of Crohn’s disease, arthritis and lupus. “XToll” had a very small Phase IIa study in rheumatoid arthritis (RA) which, despite a generally positive “interpretation” in a Lancet publication actually failed it’s end-point.
RA drug development is a hugely congested and challenging space, and certainly not a place for a marginally capitalised company. The main problem with XToll in the RA setting was that the clinical trial was probably not structured or powered sufficiently to actually demonstrate a meaningful outcome. As usual, it was underfunded, on-the-cheap and possibly not even well enough thought out. Certainly the clinical trial design looked pretty academic. However, now the company has abandoned RA and moved on from one disease for which it is incredibly difficult to empirically assess drug response, to another disease that is tough to even clinically characterise, namely Lupus. The INV-103 trial design for lupus (specifically systemic lupus erythematosus or SLE) looks similarly anaemic, and so far – admittedly at a tiny dose – hasn’t yielded much. Also always a little dodgy to see a company that has to raise a bit more money to finish a clinical study. But now that the company is dosing at what is likely to be a “therapeutic” dose, maybe the future results will be more interesting. Certainly it looks like the baseline dose level for the SLE study was the top dosing level from the RA study, but now that we are talking about moving from 10mg to up to a 300mg dose, it sort of suggests that this is a drug “concept” where mechanism of action still isn’t clearly understood. I am not even going to address the potential tumorigenesis aspects of this drug (i.e. long-term it could actually increase the risk of cancer, depending on how it is delivered).
The second asset (INV-104) is a “proposed” inhalable form of leukotriene receptor antagonist (LTRA), zafirlukast. This is an asthma prevention drug that is marketed by AstraZeneca as Accolate, but is now off-patent. I’m not going to spend too much time talking about this asset because it is fundamentally stupid and irrelevant. Nobody develops an inhaled version of a drug unless there is a targeted or beneficial bioavailability (i.e. in an acute disease setting) or unless inhalation dramatically improves or eases compliance (i.e. the inhalable insulin story, which has been incredible to watch and is a real case study in everything that can go wrong with developing and commercialising an inhaled drug). Actually the fundamental bioavailability of zafirlukast isn’t even understood and so, actually, Invion is proposing to spend what will end up being significant financial resources on repackaging and understanding the pharmacology of a generic drug that works perfectly “ok” as an oral administration. There are several oral LTRAs that are marketed, they all work “ok” with a variety of dosing schedules. Not only is there not, in my opinion, a business case for this “project”, but Invion doesn’t currently have the financial or execution chops to develop the product. Inhaled drugs are hugely expensive and complex to develop, especially for a drug that is proposed for long-term use.
Onto the “flagship” asset – INV-102. Another generic drug, nadolol (marketed by Pfizer as Corgard), is being proposed for treatment of … well… let’s call it “airway diseases” (wait … that’s what Invion calls it). Nadolol is just a non-selective beta blocker (one of several available) that is most commonly prescribed for hypertension and angina. The whole beta blocker story in congestive heart failure (CHF) is really fascinating because for the longest time it was believed that beta blockers would be damaging rather than beneficial and it took absolutely decades to turn the idea around, but now beta blockers are a hugely important drug class in managing heart disease. Currently, beta blockers are generally contra-indicated for patients with asthma / COPD, but Invion proposes to apply the same reasoning for the use of beta blockers in the CHF space, to COPD, on the basis that prolonged low-dose administration in the chronic disease setting confers significant patient management benefit. Indeed very nice pre-clinical models support this thesis, as does some initial (limited) clinical experience in asthma patients.
Incidentally, I actually really like this clinical science and some seriously beautiful work has been done in the academic setting.
The problem is the commercial strategy. Developing a new drug for long-term use for asthma is a long journey, even more challenging for a cheap, widely available generic drug that is already extensively prescribed off-label. Fortunately, although this research continues, (thankfully for shareholders) through funding by the US National Institutes of Health (NIH)*, the company now articulates aspirations for using this drug to treat “smokers cough” during smoking cessation on the basis that the discomfort and burden of cessation-induced bronchitis is actually a complicating factor to successfully quitting. Well, to be accurate, not bronchitis but (according to the widely-acclaimed patent application) mucus hypersecretion a.k.a. phlegm. Not only does this application seem to sort of contradict the general thesis of INV-102 (as it is a fairly short-term therapy) but it’s hard to even imagine that this class of “patients” even exists. How do you control for all the recovery factors – including intermittently falling off the wagon – for someone who is trying to stop smoking? Even something as simple as seasonality? Do you only run these clinical trials in the summer? Does catching a bit of ‘flu negate the data? Honestly, when I read the exclusion criteria and I see “referred for smoking cessation without serious commitment to quit” as a point of exclusion, I start to suspect that there is going to be fair amount of pop psychology around this study. I could sort of get the asthma idea, but smoking cessation something I don’t really understand and frankly, I can’t find any clinical evidence to back up the idea that this would even work.
So what do we have in this company?
- We have an anti-autoimmune drug that may or may not work (probably not) and is basically already classed as a failure (by the way, lesson to all those companies that brand their drugs early – XToll is a case in point as to why you don’t brand a drug until it is clinically demonstrable).
- We have a generic LTRA that is possibly going to get reformulated from a oral drug that works fine, to an inhaled drug that will likely cost a pile to validate.
- We have a generic beta blocker that is already widely prescribed off-label being re-purposed to help “quitters” manage their mucosal excretions. By the way, as a side-note, I am not a big fan of companies that claim to have re-purposed generic drugs with application patents because they normally are not very robust ventures. In the case of Invion’s smoking cessation patent there is fairly ancient medical literature around the use of beta antagonists to control mucosal secretions in other disease settings, such that one reasonably “skilled in the art” (of phlegm?) would have considered it to be a fairly obvious concept. Even if it gets granted, challenging it probably wouldn’t be too hard.
Hmmmm. Not much to really like, is there? Phlegmatic even…
Awesome Photo Credit: Ryan McGuire. http://www.gratisography.com/
* Noting that none of the $4m-odd number oft-flounted about by Invion seems to go to the company and seems to be an multi-site academic R01 grant (#1U01AI095050-01).