An Overview of Pharmaceutical Innovation

So our mid-semester for this unit is on Wednesday, and some of my friends kindly pointed out to me that this special lecture from the first week is likely to be examinable. The lecturer confirmed it as well. Guess I'll have to look over it then :P

This lecture is relatively short, but it doesn't come with a nice little lecture outline slide, so I'll have to actually make some decisions and decide what to include. Le sigh.

Drug Development

Drug development can be classified into three broad stages:

1. Discovery Phase- The phase in which the drug is "discovered." This starts by figuring out what you want to target and figuring out if the target is "druggable" (i.e. able to be targeted by a drug). Next up is the selection of a "lead compound" (that's the "lead" that rhymes with "bead", not the periodic table element) that might be able to bind to the drug, and then some optimisation to make it bind better or otherwise give it better pharmacokinetic properties. This gives you your "candidate drug."
2. Development Phase- The phase in which the drug is trialled and tested. This starts off with some preclinical development, in which some of the technicalities (like how to administer the drug) are sorted, and then the actual clinical trials and so forth.
3. Commercialisation Phase- The phase in which the drug is approved and commercialised, ready to make the drug companies some $$$.

Of course, in real life it isn't always that simple. In this post I'll cover three drugs that were discovered in different ways: omeprazole, paclitaxel and flecainide.

Omeprazole

Omeprazole treats gastro-oesophageal reflux disease (GORD), also known as GERD in North America (since they leave out the O in "oesophageal"). I've blogged about GORD/GERD here. As mentioned in that previous post, there are drugs to treat GORD. These include histamine receptor blockers (as histamine leads to acid production, as noted here) and proton pump inhibitors (PPIs). Omeprazole, produced by the UK company Astra, is one of the latter.

There were several obstacles in omeprazole development. The first test compounds that they used were not very efficacious. Also, another company managed to make some histamine blockers, filling the GORD treatment niche and putting pressure on Astra to come up with something different. Later on, however, Astra found another compound that was promising, but it was patented in Hungary, further halting development until the patent was found to have expired. This promising compound still wasn't what the company was looking for, as it had serious thyroid and vascular toxicity issues in the animal models that they tested. Eventually, however, promising human trials of omeprazole helped its development to come to fruition. In the early 1990s, omeprazole reached "blockbuster" status (i.e. it was a popular drug).

Paclitaxel

Paclitaxel is a drug that treats ovarian cancer. This lecture had a lot of random facts about ovarian cancer, and I doubt we have to remember them in that much detail, but here they are anyway. The categories of ovarian tumours include serous, mucinous, endometrioid, clear-cell, transitional and squamous cell, with serous being the most common. Ovarian cancer can also be subdivided into benign, intermediate and malignant.

Paclitaxel works by binding to β-tubulin. β-tubulin is an important component of microtubules, which form the spindles during cell division. Now, the slides don't say, and I didn't exactly take great notes from this lecture, but I'm guessing that that's how paclitaxel works: by inhibiting the spindles which would normally help a cell to divide. (This random abstract I found on PubMed seems to agree.)

Paclitaxel is derived from the Pacific Yew. Just like omeprazole, paclitaxel's development was also fraught with challenges. In the beginning, this compound wasn't seen to have much activity in tumour cell lines, so nobody really cared about it until President Nixon declared a "War on Cancer." It was then found that paclitaxel actually had an effect, but there was another problem: it was poorly soluble in water, and solubilising agents could be toxic. Eventually they figured out that they could solve this problem by using slow infusions. Yet another problem that paclitaxel development faced was a shortage of the Pacific Yew: it grows slowly and was endangered. Later on, however, chemists figured out how to produce it by using plant cells in vats, solving that issue.

Flecainide

Flecainide treats cardiac arrhythmias, which I've written about here. At first, dysrhythmic drugs had serious side effects. An example of this was procainamide, which had a very narrow therapeutic window. Flecainide is actually a fluorinated analogue of procainamide.

Once again, there were several challenges in flecainide development. For starters, they weren't really sure how it worked or what it targeted: they were mainly just testing it to see what would happen. Also, flecainide was slow to produce, which made the whole process slower. Eventually, though, flecainide was released as the first intentionally produced antidysrhythmic drug.