Ibrutinib and BTK inhibitors for dummies

Ibrutinib is a relatively new and revolutionary drug that has changed the landscape for treating CLL [it is also used in some other blood cancers]. For many people, it might be the only leukemia drug they ever need. Newly diagnosed folks with CLL all have the chance to live normal lifespans and control their CLL indefinitely taking a pill a day.

Like many great discoveries, ibrutinib was an accidental one. Velcro was created by a Swiss engineer who observed the way burrs stuck to his dog’s fur. Play-doh was a failed wall cleaning paste that kids starting using to mold sculptures. In 1943 a naval engineer dropped a spring he had made to create a horsepower meter and the spring walked away, birthing the slinky. Viagra was a failed heart drug that turned out to help men keep up and at em, and now showing promise with snakes in zoos.

Ibrutinib was a molecule created by a small pharma company founded in 1998 by a radically inventive biologist, Craig Venter . The goal was to create a drug that targeted an enzyme called Bruton’s Tyrosine Kinase (BTK) in the hope to help those with rheumatoid arthritis. The problem at the time with ibrutinib was that it bound too tightly to BTK, covalently they call it, and the conventional wisdom was that was not desirable. If only Venter knew. A company called Pharmacyclics came along in 2006 and purchased the ibrutinib molecule and some other experimental molecules for a pittance. They got lucky and figured out the way ibrutinib bonds was a good thing. The rest is history.

The name “ibrutinib” derives from what it does. The “brut” is for BTK, the enzyme ibrutinib inhibits. What about “inib”? You guessed it. Inib is short for inhibitor. Inhibitor drugs often end in “inib”, Drugs that end in “mab” like rituximab, are monoclonal antibodies.

So how does an inhibitor work? For that, as for with all things CLL, we have to go back to cell biology for dummies. CLL is a cancer of lymphocytes. Lymphocytes are a type of white blood cell which play a critical role in our immune systems. There are two types of lymphocytes, b-cells and t-cells. Think of b-cells as navy seals and t-cells as green berets. Our immune systems are wonderfully complex. B-cells and t-cells fight invaders in very distinct and different ways.

More specifically, CLL is a cancer of our “b-cell” lymphocytes. Somewhere along the way the genetic code in one of our b-cells got corrupted and started cranking out millions of copies of its corrupted self. Normal b-cells fight invaders by seeking them out, studying them and creating antibodies to neutralize them. T-cells go after viruses and bacteria in a different way, with with a potent enzyme that kills infected cells. The “B” in b-cell, now get this, comes from the bursa of fabricius, where b-cells are made in birds. I guarantee you if asked on Jeopardy where the B in b-cells comes from, you would be the only one to get it right. The bird bursa is named after Heironymus Farbricius (that’s a mouthful of a name), an Italian doctor from the 16th century known as the Father of Embryology.

So with that background, lets go back to ibrutinib and BTK. Remember in cell biology for dummies where we talked about molecules on the surface of our cells? They all have different jobs. One very important part of the surface of a b-cell is the b-cell receptor (BCR). The BCR is made of immunoglobulins and sticks out from the surface of our b-cells like a Y. The BCR is what activates our b-cells by sending a signal to the nucleus of the cell, something we do not want with a cancerous b-cell.

To get to the nucleus, that signal has to travel through a path of kinases (enzymes) including the one discovered by Ogden Bruton, hence the name Bruton’s Tyrosine Kinase. BTK is over expressed in CLL. If you can inhibit BTK, you can break the signal that activates the cell.

Think of a inactivated b-cell nucleus as an off light bulb, waiting to be switched on. Think of the b-cell receptor as a switch. Think of BTK as being a power strip receptacle in between the BCR and the nucleus through which the on signal must pass. Ibrutinib binds to the BTK receptacle, interrupting the BCR signal to turn on the cell. When the cell doesn’t get turned on, it dies.

How does ibrutinib work in the real world? Spectacularly as it turns out. At eight years out a large majority of those who took ibrutinib as a first treatment have not had their cll progress! This includes mutated and unmutated cll. It gets better. The response to ibrutinib appears to deepen over time. And ibrutinib also appears to give our green beret t-cells a boost by cleaning out the environment where they live. That is another way of saying ibrutinib can actually restore some part of our immune systems.

There can be side effects for some with ibrutinib, also called off target effects. The target for ibrutinib is BTK in cancerous b-cells. But ibrutinib can impact other cells in an unintended way that causes side effects such as rashes and diarrhea. For most people these side effects are mild to moderate and tolerable. Ibrutinib can trigger afib in some, a more serious side effect.

That is where all the new and improved BTK inhibitors come in. Zanubrutinib and Acalabrutinib are designed to have less off target effects. Notice the “brut” and “inib” in both names? That tells you they are BTK inhibitors.

For first time users, “resistance” to ibrutinib is rare. Resistance occurs when ibrutinib can no longer bind to BTK. But remember when we discussed how ibrutinib bonds covalently to BTK (they share an electron)? Now we have BTK inhibitors in clinical trials like Loxo-305 that can bond non-covalently and can overcome resistance, exciting times indeed.

A drawback for ibrutinib is that it is a continuous therapy. Some argue that a relatively low toxicity pill a day is much better than the risk of more serious toxicity with chemo drugs. What seems most likely in the future is that other drugs like venetoclax will be added to ibrutinib to induce deeper remissions so we can get off all drugs.

So there you have it, ibrutinib for dummies. I am two years out on taking ibrutinib and consider it to be a miracle drug. It never would have occurred to me to inhibit a kinase, who thinks of crazy stuff like that? I am so grateful the world has smart people.

Oh yes, I cant leave you hanging about snakes and viagra. My cajun friend told me his pet snake stopped killing rats in his barn. The only thing that worked on his snake to get him back killing rats was Viagra. As it turns out, drum roll, Viagra cures reptile dysfunction too.

Be safe in these crazy times, it will pass I am sure. And somewhere along the way I am one hundred percent sure one of those smart guys that figured out how to inhibit BTK will find out what makes covid click and create a drug that whacks it.