The Currently Incurable Scientist: RRx-001 and the Impact of One CRC Patient-Chemist
My most recent The Currently Incurable Scientist column published this week on the Fight Colorectal Cancer website. It explains in layman’s terms the mechanism of action & the very unique and promising preliminary clinical profile of an experimental drug called “RRx-001” in early clinical trials including a randomized Phase 2 trial (NCT02096354) for metastatic colorectal cancer (CRC).
As usual, I wanted to use my personal blog not to simply repeat the information in The Currently Incurable Scientist column (for all of that very interesting information, read the column!). Instead I wanted to use my personal blog to offer a “Director’s Cut” focused more on the fascinating human interest story behind RRx-001’s discovery and development, as well as drug discovery in general. Let’s just say it is neither a typical drug molecule nor a typical drug discovery/development story – and some aspects of the story are both very surprising and inspirational.
A Short Recap on Why I Think RRx-001 is Such an Interesting Experimental Drug
- Turning genes on which tell a cancer cell to grow when it shouldn’t be growing
- Turning genes off which normally would tell a cancer cell to stop growing or die
- Turning genes off/on which help the tumor evade the immune system
- Turning genes off/on which cause tumors to become resistant to chemotherapy
RRx-001 uniquely impacts a number of epigenetic pathways with intriguing end results, at least in preliminary clinical trial data. RRx-001 appears to resensitize tumors in multiple CRC patients to previously failed FOLFIRI chemotherapy – and it appears to do this with a very benign side effect profile.
Its Phase 1 clinical trial data was recently published in the journal Lancet Oncology, along with an accompanying commentary. In addition to the Lancet Oncology Phase 1 trial publication, two case reports on CRC patients from this trial have also been published. Most recently, preliminary Phase 2 data has also been publicly presented. RRx-001 appears to continue to show a similar profile in the early days of its current randomized Phase 2 CRC clinical trial, potentially confirming the Phase 1 trial observations.
Possibly even more exciting, as an untested (yet!) scientific hypothesis, I am very curious how many cycles of FOLFIRI –> RRx-001 –> FOLFIRI –> RRx-001… could potentially be done in a continuous loop fashion. If that kind of “continuous loop” treatment protocol worked in a significant number of patients, it could potentially transform standard of care for Stage IV CRC patients and significantly extend survival. At this point it is only a scientific hypothesis but I am crossing fingers it might work in eventual clinical testing!
Serendipity, Intuition, Persistence and the Impact of One CRC Patient-Chemist
The back story of where RRx-001 came from and its path to development for CRC (and now multiple other types of cancer) is one of the most unique I have personally heard in modern drug discovery. A longer version of the story is on the developing company’s website. My goal is to present some of the information from that source and use it to illustrate some common aspects of drug discovery: 1.) Serendipity 2.) Intuition 3.) Persistence 4.) the impact of a scientist serving as a molecule’s champion – in this case a CRC patient-chemist.
RRx-001’s Origins – Serendipity and a VERY Intuitive Open Mind
Prof. Mark Bednarski was initially a Chemistry professor at a top University, the University of California at Berkeley. He also was diagnosed with early-onset CRC shortly after his 33rd birthday. His CRC diagnosis transformed his life and afterwards Prof. Bednarski went to Medical School at another top University (Stanford) and eventually he became a professor of Radiology there.
RRx-001, in terms of becoming a potential cancer drug, was born in all places, on the ski slopes of Utah. By chance, Prof. Bednarski met another chemist on the ski slopes, a chemist from ATK Thiokol, a defense and aerospace contractor which designs and manufactures e.g. rocket fuel and military-grade explosives. As often happens when two chemists meet, even if they work in different chemistry sub-fields, chatting about research ensued. As they chatted, structures related to RRx-001 were drawn in the snow and Prof. Bednarski was intrigued… Yes they were meant to be explosives but his nimble scientific mind and intuition also envisioned that their very unique chemical structures could potentially have medicinal value as well.
The structures were so unique that most drug discovery medicinal chemists (including me) would not have made that potential therapeutic mental leap. That is actually saying it too mildly – at least speaking for me, I would have run away as fast as possible if it were proposed to me as a drug. I tend to run away from things that look like chemicals from the explosives/rocket fuel industry! 🙂
How Unique Were the Chemical Structures?
Keep in mind, these chemicals were designed by a maker of explosives and rocket fuels… they were not originally intended to be potential medicines. And their structures show that design background. For my chemist readers, I pasted the structure of RRx-001 below.
For this blog’s audience, I won’t go into the chemistry details of why a compound like RRx-001 does not look like a traditional medicine but I will say that no structure like it is usually allowed in pharmaceutical & biotech compound testing collections. Why? For the basic logical reason that as I mentioned… it looks like chemicals from the explosives/rocket fuel industry! Chemists also would not be fans of that bromine (the “Br”) atom sticking off the end – but I’ll save you from hearing a chemistry lecture today why… 🙂 By the way once again, serendipity rears its head… this kind of chemical structure would cause worries of toxicity – but thus far based upon early testing, RRx-001 appears to have an abnormally benign clinical toxicity profile compared to most cancer drugs! No nausea. No hair-loss. No fatigue. No low blood counts. Nothing similar to standard chemotherapy or prior epigenetic drugs’ side effects.
An important note: RRx-001, although chemically related to explosive and rocket fuels – is itself non-explosive. So don’t worry… no cancer patients are exploding when it is being dosed! The chemistry term for it is a “synthetic intermediate” which means a chemical that is generated on the path towards synthesizing a desired design goal. That is what makes Prof. Bednarski’s intuition so incredible – and it also shows the power of a scientist from outside of drug discovery looking at potential medicines with fresh eyes.
Initially, Prof. Bednarski observed the potential of a chemical like RRx-001 to possibly be useful to selectively damage cancer cells during radiation therapy. Along those lines he collaborated with his colleague and company co-founder Dr. Susan Knox, a practicing radiation oncologist. Upon subsequent testing over the years by an ever growing group of fellow scientists, the unique structure of RRx-001 was found to also impact epigenetic pathways, as mentioned at the top of this post, which opened up its potential use to a much broader cancer patient population than ever originally intended!
Persistence and Being a Molecules Champion
Drug discovery is hard. Very hard. I was quoted in Ken Burn’s adaption of the Emperor of All Maladies as saying something along the lines of “Chemists need to be eternal optimists, because 99.99 percent of what you do fails.” Your chemistry often fails to make your target compound. If that works, the compound fails in in vitro testing. If that works, the compound fails to adequately enter & survive in the blood stream after being dosed to an animal. If that works, the compound fails to show efficacy in an animal model. If that works, the compound fails to pass toxicity testing. If that works, the compound fails to adequately enter & survive in the blood stream when dosed to a human. If that works, the compound fails to be safe in humans. If that works, the compound fails to have efficacy in patients in clinical trials. Believe it or not, that is actually an over-simplification of all the ways that a potential drug can fail before it can become a medicine! Drug discovery is one of the hardest endeavors attempted by humans – but the potential end result of really making a difference against unmet medical needs in real people’s lives also make it one of the most rewarding possible!
With all the possible ways to fail lined up against it – a potential drug needs at least one “champion” who believes in it and pushes it forward against the headwind of all that potential failure – as long as data indicates that it can possibly still make it to the finish line and become a medicine! That job, of being a champion, is very tough to do in the best of circumstances. To push forward a strange drug molecule, sourced from an explosives manufacture no less, takes the strongest molecular champion possible. Prof. Mark Bednarski was that first champion for what is now a molecule being tested against multiple tumor types (including CRC with preliminary signs of success) in five parallel clinical trials.
Prof. Mark Bednarski passed away on February 18, 2006 after a 14 year battle with CRC. He was only 47 years old.
Many scientists and others have worked on the development of RRx-001. Quoting the Lancet Oncology commentary “RRx-001 is a member of a new class of panepigenetic modifying drugs called dinitroazetidines that look exceptionally promising in early clinical development”. There are still a lot of unknowns as it undergoes additional clinical testing to attempt to confirm the early safety and efficacy profile. If it successfully becomes an approved drug for Stage IV CRC patients, RRx-001 would be the best example I personally have seen of serendipity, intuition, persistence and the impact of one Patient-Chemist. Thanks to a member of the CRC patient community itself, Prof. Mark Bednarski.
Disclaimer: My oncologist is the PI of one of the RRx-001 clinical trial sites.