Every time I read one of Novogen’s shitty press releases (ASX : NRT) about a new animal study, including today’s latest missive, I get really pissed off. My blood boils. Not just because these are tiny, mostly irrelevant, pre-clinical studies but because their quasi-science content simply betrays the underwhelming nature of the company. I don’t even know how they can ethically justify the animal use for what has been a string of truly marginal experiments that probably wouldn’t even make it into a bottom-tier journal. The problem is that it is all dressed up as progress, designed to keep Novogen’s rabid shareholders excited about the stock.
Aside from the fact that I have been waiting months for a simple toxicology study for NRT’s “flagship” drug (preferably both standalone Anisina, and in combination with their microtubule inhibitor of choice), the company keeps coming out with these utterly rubbish pre-clinical studies that are supposed to keep convincing us that this drug is worth investing in. The drug may in fact be good (unlikely but possible, in the way that it is unlikely but possible that I will have a rampant affair with Liv Tyler one day), but these seemingly regularly timed, incremental and numerically meaningless studies actually don’t do anything to convince an informed investor that this is the case. As far as I am concerned this is just orchestrated science for the purpose of keeping a basic level of noise up, it is the lab equivalent of “make work”, and it’s not even very high quality at that. In fact, if this is the level that the company is currently operating at, there is almost no probability of them hitting their planned 2016 FIH dates for Anisina.
First there is the generally outrageous statement:
US-Australian drug discovery company, Novogen Limited, today announced details of an in vivo proof of concept study that demonstrates their lead anti-tropomyosin drug candidate, Anisina, has the potential to improve the effectiveness of chemotherapy in children and reduce life-long side-effects.
What this pre-clinical study tells us is that a fairly naive neuroendocrine xenograft study using a moderately drug-resistant cell line (more on this in a minute) responded weakly to Anisina alone and one mouse out of five in the highest combination dose group might have had a slightly prolonged response. This study says absolutely nothing about Anisina’s potential effectiveness in children. In fact I would argue that with the limited combination/dose escalation in mice, this experiment doesn’t even reveal anything about the drug’s efficacy in mice. It certainly says nothing predictive about reducing long-term side-effects … side-effects, incidentally that are usually the result of a huge battery of therapeutic modalities given to these very sick kids, not just vincristine.
Now before I write about vincristine, let me briefly comment on disease classification in neuroblastoma because it is quite central to de-bullshitifying NRT’s press release. Although NRT’s press release would have you believe that neuroblastoma is pretty much rife (“it is considered to be the most common solid tumour in children outside the brain”), in fact it accounts for about 6% of cancers in children. We don’t need to specifically focus on infants (<1 year) because although the incidence accounts for more like 50% of cancers at that age, it is 90% treatable in that very young population, and so infants aren’t going to be the clinical development priority for NRT’s drug anyhow. In the US, this means about 700 new cases year and Australia about 50-60 cases a year. Moreover, the disease is stratified into risk groups on the basis of clinical presentation, pathology, imaging (for staging) and biomarkers (particularly MYC gene amplification in high-risk disease patients, and certain mRNAs are getting very interesting as well). These different risk groups have very different predictable outcomes to therapy. Children in low and intermediate risk groups (60% of patients) usually don’t have drug-resistant disease, respond well to treatment, and have a 5-year survival probability of 90-95% (95+% for low risk). About 40% of patients fall into the high-risk category, with a 5-year survival rate of 40-50%.
According to the ASCO guidelines for neuroblasoma (the European SIOPEN guidelines are similar), the standard drugs given to low and medium-risk pediatric neuroblastoma patients are carboplatin, cyclophosphamide and doxorubicin (i.e. 60% of all patients). More recently, etoposide and topotecan have also become part of accepted front-line treatment. Vincristine is not – and hasn’t been – part of the standard of care in this patient population for some time (almost two decades). Children with high-risk disease do receive vincristine in combination therapy, but there is a growing preference to use high dose alkylators in second-line therapy where patients have not responded well to front-line chemo/topotecan, but also including topotecan in combination. One of the reasons (not the only reason … vincristine also has some unpleasant side-effects as NRT constantly notes … but one reason) why vincristine is increasingly not used in front-line therapy in high-risk disease, is because cancer cells rapidly develop drug resistance to vincristine (and doxorubicin) and become even more difficult to treat, and so it may be better as a back-up therapy. Incidentally, this issue of (multi)drug resistance is something that NRT almost never talks about when it harks on about making vincristine “work better”.
If you got lost in the above paragraph, that’s fine. I did too and I wrote the damned thing, but it’s 1:15am and I am not going to change it. The main take-home message is that these sick kids don’t just get given vincristine. They get given, depending on the risk of their disease, a whole variety of drugs in concert as the standard of care, none of which are reflected in NRT’s dinky little experiments. These kids get chemo cocktails (like the ones above, with 4-6 different drugs, with complex and elaborate dosing schedules), but they also get surgery, antibody drugs, radiation (both radipharmaceuticals and external beam radiation) and they even get stem cell transplants. And here you have NRT nonchalantly talking about a combination therapy with vincristine, a drug that simply isn’t used in front-line therapy for the vast majority of these kids, nor representative of the extent of the therapeutic regime needed to treat them effectively.
The funniest thing about all this (if you can find something funny about kids with cancer), is that the NRT press release actually discloses a key piece of information, namely the mouse model. The company used the CHLA-20 cell line to implement its pre-clinical tumour model, and presumably the usual flank model (I am 99% sure this company isn’t sophisticated enough to do an orthotopic model). This moderately drug-resistant cell line is a “patient-derived” cell line that was taken from a cancer patient after treatment with cyclophosphamide, doxorubicin, cisplatin, and teniposide. In other words, NRT is actually testing their “combo” vincristine-Anisina drug in a model that is theoretically representative of the 5% of low/medium risk patients that failed first-line treatment and the 50% of high-risk patients that failed first-line treatment. That’s about ~150 new pediatric patients a year in the US (and about 10-15 in Australia). Notwithstanding that all children deserve to have a happy and healthy life, this is a tiny number of patients, and it represents the total patient reservoir that NRT is going to have to competitively tap into if it is going to run clinical trials for this drug in the representative population.
If that sounds long and difficult to you, especially considering that the company hasn’t dosed a single patient yet – in fact hasn’t even completed (started?) toxicology studies yet – you would be absolutely correct.
If it sounds like a very small commercial opportunity for a new drug, you would be also be correct.
Additionally, there is a huge immunological element to treating neuroblastoma, and so since these types of xenograft studies are performed in immunocompromised mice, they are not representative of either tumour microenvironment (especially if they are flank xenografts) or any type of drug-immune system interaction. They also tend to rely on cell lines that have been in culture for years and so achieving experimental results that are highly reproducible can be difficult (especially if orthotopic models aren’t used). In fact, although CHLA-20 xenografts are fairly common in academic research, the gold standard animal model for testing cytotoxic drugs for neuroblastoma is the TH-MYCN mouse model, which is a genetic model. Therefore, NRT really has done the bare minimum with this pre-clinical study in terms of trying to establish representative drug behaviour in a meaningful model.
In fact, my second “favourite” quote is:
The importance of this study, from a clinical perspective, is that is shows we can dose animals with a proprietary formulation of Anisina in combination with the standard of care and recapitulate in an animal model of neuroblastoma the same effect as observed in a test tube.
Well, Dr. Stehn and Dr. Kelly, I hate to tell you this but you are not in the business of making drugs to treat test-tube cell lines (in fact, we don’t even use test tubes for doing this kind of cell biology so your chosen terminology tells us everything about the intended audience for this press release). You are in the business of treating children, and nothing in what NRT has publicised remotely resembles either the standard of care drug regime for children with neuroblastoma, or the standard of testing of new cytotoxic drugs in animal models of neuroblastoma. This is a very VERY simple experiment, a pretty much second-rate bit of science, and the “clinical” investigators quoted in the press release should be ashamed of themselves for even agreeing to participate in this communication farce.
To conclude, pediatric neuroblastoma is an awful cancer. The good news is that for most children it is highly treatable and in the last two decades, survival of high-risk disease has almost doubled. New drugs such as dinutxumab look genuinely exciting for high-risk/refractory patients and some promising new mTOR/multi-kinase strategies are probably going to genuinely help to close the gap based on the cancer genetics that are increasingly shedding light on how to optimise treatment for these really sick kids. All of this incredibly sophisticated clinical science not only bodes well for children with cancer, but it also illustrates just how shockingly irrelevant Novogen actually is.