Apaziquone (which Spectrum is referring to by trade name EOquin) is what’s called an indolequinone. It is a bioreductive prodrug, which means it remains inactive until it reaches its target location, and a chemical analog of the above mentioned, and well established. chemotherapeutic agent mitomycin. The cells that make up the inner surface of the urinary bladder are a type of cells referred to as hypoxic, which just means they are deprived of oxygen. When the drug comes in to contact with a hypoxic cellular environment, it is converted to active metabolites by intracellular reductases. The active metabolites alkylate DNA and initiate a process called apoptotic cell death. For those not familiar with apoptosis, it’s the process through which cells die. It generally involves a break down of the cell membrane, which allows the intracellular material to leak out of the cell, followed by a clean up process involving white blood cells – specifically, macrophages. In healthy cells, apoptosis takes place at a pretty regular rate, and it’s the standard process through which cells remove themselves from our system on expiry. Cancerous cells don’t initiate apoptosis naturally, and this leads to the excessive proliferation associated with the disease.
Jumping back to the currently used treatments, the above mentioned meta analyses that hint at efficacy for epirubicin and mitomycin when used as intravesical chemotherapy agents immediately post-surgery suggest a reduction in recurrence of somewhere between 5-15%. The standard accepted number is 12%. To put this another way, if a surgeon flushes a patient with either epirubicin or mitomycin once he or she has removed the tumors from the patient’s bladder, evidence suggests that patient has a 12% smaller chance of fresh bladder cancer tumors forming than they would otherwise have without the intravesical chemotherapy.
There are a few things to note here.
The first, that 12% is not that high. Especially in a low grade severity cancer, a reduction of 12% is not enough to warrant SOC status for these off labels. The second is that the 12% figure is an optimistic estimate. The third, that many physicians don’t use intravesical chemotherapy post resection, for the simple reason that they don’t class the 12% figure as providing any meaningful clinical benefit. This latter point, clinical benefit, is very important for the purposes of this discussion, and it’s something we’ll come back to.
So, Spectrum Pharmaceuticals, Inc. (NASDAQ:SPPI) conducted two pivotal trials designed to underpin its registration application, both of which were pretty much exactly the same. Both investigated the efficacy of the drug in patients with TaG1-2 grade tumors, wit ha single administration immediately post resection, comparing an active arm and a placebo arm on a circa 1:1 ratio. The table below shows the results of these two trials.
The primary endpoint of both trials was disease recurrence, defined as any histologically-confirmed bladder cancer, within the 2-year study period. Both trials failed to demonstrate a reduction in disease recurrence with apaziquone at 2 years. The 2-year rate of recurrence was lower for apaziquone-treated than for placebo-treated patients in both trials. Again, however, there are a few important points to note here.
The first is that the difference between the two arms, in both trials, is just 6.6% and 6,2% respectively. This is far lower than the generally accepted 12% benefit established by way of meta analysis, and is at the very low end of the above mentioned 5-15% spectrum of benefit. The second key point is that the p-values for both trials were way above the generally recognized stat sig value. For an outcome to be considered stat sig, or to put this another way, for us to be able to say that the result seen came about on the back of the input (in this instance, the apaziquone treatment) a p-value of less than 0.05 is required. Anything above this translates to statistical insignificance – essentially, the inability to say that the treatment caused the result. If a trial is non stat sig, any endpoints past the primary are rendered useless.
So how can Spectrum be hoping for an approval based on two failed trials?
