Novogen : BBB Antics (Part III)

I decided to tone-down the title of Part III of my rant about Novogen. Not because their recent announcement about TRXE-009 is not “bad behavior”, it is. It’s just not as bad as Graham Kelly’s informal chit-chats on HotCopper, in my opinion.

My goal in life is to be critical when warranted, but not to be unreasonable.

In my previous post on Novogen (item #9) I had indicated that I would deal with the blood-brain-barrier (BBB) issue separately as I was already violating any basic accepted principles of a blog entry on the basis of length number of issues addressed in a single post. Apologies. I hope I didn’t lose anyone because there are some serious problems with the claims being made by Novogen in these “informal” forums and, in my opinion, they are worth understanding. Even if you don’t like my arguments, it’s worth taking a step back and looking at the bigger picture of what this company does in terms of communication strategy.

On the topic of “BBB”, the first point I would like to make is fundamentally investment-related so if you don’t like science you can tune-out after this paragraph. One of the great reasons why oncology drugs have a different (i.e. lower) investment risk profile than “traditional” CNS drug application areas (Alzheimer’s, stroke, epilepsy, psychiatric conditions) is because they are generally easier to develop. The brain is a tough organ to dose and the failure rate is much higher as a consequence. We also generally don’t tolerate the same risk/side-effect profile in CNS disorders as we do in oncology and so although Novogen’s intention to hit brain mets/cancers (like glioblastoma) may be an admirable one, it significantly changes the risk profile of an oncology drug program and this needs to be understood by investors. This also means they need to be especially careful about their public claims if they are going to engage sophisticated investors for the long-haul (no more announcements that you killed a few glioblastoma cells in an in vitro assay, or a rat flank model, please). And it will be long-haul, because Novogen’s aspirations for TRXE-009 implies at least a 2-3 year longer development period than the average oncology drug – and possibly longer if the goal is pediatric patients where the risk-reward equation is quite a bit tougher, even in the oncology setting.

At the most basic level, what irritated me about Novogen’s announcement was the fact that BBB penetration is only a tiny part of the issue of dosing the brain. It is absolutely true that a relatively small percentage (3-5%) of drugs cross the BBB without any transport modification (for example, making small molecules more lipophilic or using transporter/bi-specific strategies with biologics) and it would appear that Novogen’s NADH oxidase-targeting small molecules probably don’t intrinsically cross the BBB, at least at a sufficient rate (more on that in a minute). It is therefore entirely reasonable to use a delivery strategy like a lipid “particle” or “shell” to facilitate transport and this is an increasingly well understood technology strategy for a wide range of molecules. But it also has to be understood that such strategies not only increase the complexity of drug manufacture and formulation, but they also increase the complexity of understanding the more tricky parts of brain-targeting drugs, like pharmacokinetics and metabolism.

This leads to the fundamental reason why Novogen’s claim of a “major milestone” is fundamentally bullshit. It is not enough for a drug to simply cross the BBB. The drug has to have sufficient tissue penetration to be efficacious. The brain is not a homogeneous mass it is actually highly compartmentalised. A drug needs to have the pharmacokinetics (in “layman” terms – the “uptake” and “clearance” and general “staying power”) to be efficacious. And – especially  in the case of a drug that is “lipidised” – understanding metabolism is critical because it will be a function of both the drug itself and the drug delivery technology that is employed. If Novogen had claimed not only BBB transport of TRXE-009 but also shown (preferably in a peer-reviewed publication rather than an obnoxious press release) that the kinetics and metabolism was promising as well (preferably in some larger mammals too), it would have been somewhat less irritating.

But only somewhat.

I say “somewhat” because Novogen simply hasn’t done enough work to make the glowing claims that it has. At the most basic level, it is extremely tough to measure BBB transport effectively in pre-clinical models. To even make the claim of a drug crossing the BBB requires much more robust science than a couple of rat experiments. Not only that, but pre-clinical models (particularly in small animals like mice and rats) have not been shown to be strong predictors of drug performance in patients, precisely because the traditional notion that permeability was sufficient to achieve efficacy (i.e. Novogen’s claims) is inadequate. As I have stated above, the brain is heterogeneous and pharmacokinetics/metabolism is far more important to ultimate drug efficacy once basic BBB permeability has been established. It’s also important to understand that choosing the pre-clinical model carefully is critical as there is even variability in BBB permeability rate between different strains of animals. I remember quite “fondly” a few years ago a pharma collaboration I was involved with where a radiolabeled construct had totally different BBB transport between different mice strains – a huge headache for translational decision-making.

Moreover, in the case of a “CNS” targeting drug, the target itself matters more than ever. It is not enough that the target is simply present in the disease/site of interest. Because of the challenges of getting the drug into the brain, any off-target drug behaviour can have a disproportionate impact on efficacy. NADH oxidase is an interesting target, but it is not cancer-cell specific and in the treatment of cancers of the brain, may have some additional challenges. For example, NADH oxidase will have a much higher target availability in the presence of phagocytosis, so deciding how to time treatment relative to standard-of-care treatments like radiation, will be important.  Intrinsically NAD(P)H oxidases are highly involved in a wide range of normal CNS processes so off-target effects of TRXE-009 in the brain (and even impact on the BBB itself) may be a more significant issue than is currently articulated by Novogen

Lastly, to finally illustrate the sort of general rubbish nature of this announcement, there is an additional snag. You see, brain cancers are particularly tough when it comes to drug delivery strategies because the BBB may already be partially breached – or more specifically, the “Brain-Tumour Barrier” (BTB) is partially breached because the “tight junctions” of the tumour vasculature have been lost due to the formation of “leaky” blood vessels. Very good research has been conducted that demonstrates the heterogeneity of BBB integrity that can result from brain mets (for example, breast cancer mets) and this in turn had a major impact on the role of drug efficacy. Not only that, but BBB “breach” characteristics are different for CNS metastatic disease, than for diseases that originate in the brain (such as glioblastoma) and so Novogen’s “sweeping” claims of being able to target both types of patients with a little bit of brain permeability data is pretty underwhelming.

To conclude, Novogen’s announcement of a major milestone is simply rubbish, and wasn’t worthy of the reward of a stock-price bump. Not only do I tire of press releases in advance of robust, peer-reviewed data, which in my mind only serves to reinforce the negative perception that companies like Novogen do the bare minimum in order to be able to justify a juicy soundbite. But the truth is that grown-up companies don’t put this kind of information out there because it is at best, speculative of efficacy, and at worst – misleading.

The people at Novogen aren’t stupid and the company has a sufficient balance sheet to do things properly. With it’s NASDAQ ADR ticker it also has to appeal to the US investor, which is (apparently) a slightly higher bar than the home crowd Down Under.

Time to grow up.

 

Photo Cred : The Wizard of Oz (1939). “if I only had a brain…” Er… yes.

2 thoughts on “Novogen : BBB Antics (Part III)

  1. Pingback: Novogen : Unacceptable Behaviour (Part II) | The Long Tail

  2. Pingback: Bionomics : Creating innovative stories for serious human diseases. | The Long Tail

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