This month, we’ll get topline from a BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) phase III in phenylketonuria (PKU). The drug is a promising candidate to treat an as yet incurable condition, and has performed promisingly in early stage clinical trials, but the soon to be reported phase III comprises a much wider scale patient population, and the indication in question is a notoriously difficult condition to consistently treat. If BioMarin can bring some promising efficacy results to the table, however, the company could be looking at an overhaul of its current PKU drug, Kuvan, and in turn, a boost to its PKU derived revenues. Here’s a look at the science behind the drug, and what it might mean for BioMarin and PKU sufferers going forward.
First, let’s look at the condition itself. Outside of the medical space, and of course its sphere of sufferers, PKU isn’t a particularly well known disease. For those not familiar with it, it’s caused by a mutated (and in turn, defective), or complete absence of phenylalanine hydroxylase (PAH). PAH is the enzyme responsible for breaking down an amino acid called phenylalanine (phe). Those reading may have seen the phrase “contains a source of phenylalanine” on food and drink packaging. PKU is the reasoning behind this labeling. The only current way to avoid the impact of a build up of phenylalanine in the body, which includes things like brain damage, slow growth, dermatitis, among others, is to avoid consuming the amino acid altogether (or at least in a vastly reduced fashion), and so food and drink companies are required to notify consumers if their products contain it.
An additional impact of PAH not breaking down phenylalanine is rooted in the fact that the breaking down of the latter turns it into tyrosine – another amino acid which is responsible for protein synthesis. In healthy humans, Tyrosine is what’s called non-essential – i.e. the body produces it naturally. In PKU patients, the lack of PAH makes it essential, meaning a patient must actively consume tyrosine t make up for their body’s lack of ability to synthesize it.
So how does BioMarin’s drug work? The drug, called PEG-PAL, is an injectable phenylalanine ammonia lyase (PAL) that, as the first three letters of its name suggests, is pegylated. If a drug is pegylated, it just means the active compound (in this case, the PAL) is coated in poly ethylene glycol, which essentially protects the drug from our immune system. This makes it both more effective, and longer lasting (i.e. in an extended release sense). PEG-PAL breaks down phe into harmless components, but does not convert it to tyrosine, so this element of the condition must still be maintained through diet.
So how did the drug perform in trials to date, and and should we be looking for in the upcoming topline? We’ve done a bit of digging, and found two contrasting trial blogs from patients that underwent PEG-PAL treatment as part of the phase III in question. Of course, these are not representative of the trial as a whole, but they offer some insight pre-release.
The first, a female based in Omaha, reported high efficacy (phe levels reduced to 6 from mid twenties, which is in line with normal levels) and minimal side effects – the odd dermatology issue, a couple of headaches etc. The second, another female, this time based in Texas, while also reporting a similar efficacy, reported more severe adverse events, including debilitating joint stiffness, signs of anaphylaxis, and golf ball size swellings across her body). What does this mean? That the safety and tolerability side of the trial will be under close scrutiny by the FDA if the drug gets to an NDA phase. Reduced phe levels is the primary endpoint, so any discernible advance towards this endpoint can be considered positive on release. We’ll be looking closer at the secondaries, however, to see if the case of the second patient is isolated, or at least not representative of a wide subset.
When’s the data scheduled for? All we know at this stage is that the company expects to publish before the end of the month. This means anytime between now and the end of next week, assuming everything goes to plan. When we get the data, we’ll dissect it and update our bias. One to watch.