The Past Marches On

Many years ago (about a decade…), when I was at the biotechnology company Allelix Biopharmaceuticals (acquired by NPS), I worked with Dr. Dan Drucker at Toronto General Hospital (TGH; now part of The Toronto Hospital) to develop derivatives of the hormone GLP-2. Dan had discovered that GLP-2 has a powerful effect in stimulating the development of intestinal epithelium cells, i.e. the lining of the gut. I remember being there when he ‘opened up’ some experimental mice – you didn’t even need to take a measurement to see the marked difference in the bowels of the experimental mice versus the controls as the differences were so significant.

Dan had indications from earlier experiments that one of the glucagon family of hormones had this effect, and he had tried various elegant engineering experiments to determine which one. As the Allelix research director I had sponsored a collaboration with Dan and provided him with synthetic samples of these hormones. Near the end of the collaborative period, with little success, Dan decided to take the simple, direct approach – he simply gave series of injections to mice with each of the hormones – which is when GLP-2 ‘jumped’ out.

That period was one of the most exciting in my professional career. Dan had new results almost every day that he e-mailed to me and I kept designing and sending him new samples to test. I’d e-mail him at 1:00am and he’d respond at 1:30am! We were having fun and were driven. In drug development you want to find a new approach to treating disease. Here we had a powerful effect by a natural hormone. We wanted to know if there was any disease that we could effectively treat and if we could make a more effective version of the hormone.

I made literally dozens of derivatives of GLP-2 and passed them on to Dan. Experiments looked at the minimal size of the hormone and the critical regions. We were also very interested in improving the activity of the hormone. That family of hormones are quickly inactivated by an enzyme (DPP-IV) that chops-off one end. By testing different ends we were able to make versions of GLP-2 that resisted that degradation and were therefore several times more potent, i.e. you could get the same effect with less hormone. Besides improving the economics of the drug it gave Allelix a proprietary product – a key requirement in commercial drug development. Of the dozen of so patent applications in my name that were made over the years, the only issued patent that I bothered to frame and hang on my office wall was one for those derivatives of GLP-2.

There are lots of diseases involving the intestinal lining. But the most obvious one to look at was Small Bowel Syndrome (SBS) – a condition where patients have had to have large portion of their intestines surgically removed and must be maintained on intravenous feeding, often for the balance of their lives, which may be significantly shortened.

Why these reminiscences? While NPS has been testing one of my derivatives (ALX-0600), which they subsequently called Teduglutide, over many years, they just announced that they have initiated pivotal Phase 3 clinical studies on patients with SBS. If these studies are successful they will be a giant step closer to getting approval for the drug and being able to make a meaningful difference in peoples’ lives.

It’s been years since I worked on the project, and literally dozens of other people have contributed, but it’s still something I recall fondly and am especially proud of.

No comments:

Post a Comment