How to fight rare diseases with radically open innovation – Open Future

IT WAS a case of doctor heal thyself. When told he would die and given the last rites, a medical student decided to hunt for a cure from his hospital bed. He found one and survived, though not after enduring three relapses that could have claimed him.

Now a doctor in his own right, David Fajgenbaum is pioneering a new approach to fighting rare diseases through an open model of medical innovation. Where the current system of drug discovery relies on a big market to fuel commercial incentives, or random chance that researchers will come together to make a discovery, Mr Fajgenbaum’s “collaborative network approach” overcomes these problems.

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The idea is to scour the world for drugs that have been approved for one use but could have others. Then, it brings together researchers to study how to adapt them, and funds the trials needed to bring them to market. It is a story he tells with a combination of pathos and verve in “Chasing My Cure” (Ballantine, 2019). An excerpt from the book is below, followed by a short interview on collaborative network innovation.

From: “Chasing My Cure: A Doctor’s Race to Turn Hope Into Action; A Memoir,” by David Fajgenbaum (Ballantine, 2019)

Nausea overwhelmed me, partly because of the chemotherapy cocktail that had been slowly dripping into my veins, and partly because of the realization that I was completely alone. I was terrified. This was the fourth time in the last two years that I would approach the precipice of death. This time, I knew that I would die, because the only drug in development for my disease had failed to work. The harsh reality was that the medical community didn’t understand the most basic aspects of my illness—the only thing the medical community “knew” to be true was actually wrong—and the world’s expert in it had run out of ideas and options for me.

Despite the fact that my immune system was consuming all of my energy as it attacked my organs, despite the accumulated toxins and chemotherapy that made my thinking cloudy, I had the most clear and important thought of my young life: I could no longer just hope that my treatment would work. I could no longer rely on the previous research. I could no longer hope someone else, somewhere would perform research that would lead to breakthroughs that could save my life. If I were to survive again—and to survive long term—I had to get off the sidelines and act. If I didn’t start fighting back to cure this disease, no one else would and I would soon die.

I would never get to marry Caitlin or have a family with her. Dr. van Rhee was the foremost expert in the world on Castleman disease—Santa himself— but the foremost expert in the world can only ever know as much as the accumulated knowledge in the world. If the answers have not yet been uncovered, then the foremost expert couldn’t possibly know them. These answers weren’t Google-able, and prayers couldn’t help to find the doctor who knew them. No one knew. Even worse, there were no promising leads being chased. The limits of Dr. van Rhee’s potency were the limits of the world. They were also now my limits, and other patients’ limits too.

My body was dying. I was in overtime. I was spent. But at least I wasn’t on the sidelines anymore. Now I was in the game, and I knew what I had to do. I would simply have to increase the knowledge of the world about iMCD.

My sisters, Caitlin, and Dad were seated around the bed and had listened to Dr. van Rhee’s every word. They all had their hands on their heads and stared down at the floor between long blinks and deep breaths.

I interrupted the silence by saying something that I hadn’t ever voiced before but knew was my only choice. In hindsight, it reminds me of the final promise I made to my mom. “If I survive this, I’m going to dedicate the rest of my life—however long that may be—to answering these unknowns and curing this disease.”

I heard myself like I was Winston Churchill vowing to fight on the beaches, but my pledge to defeat Castleman disease was less than stirring to Caitlin and my family. Those words in the hospital room landed with a polite thud. They each gave a half smile—a kind of smile that I had seen before. The one where they purse their lips and close their eyes. They were just focused on me making it through this relapse. They weren’t interested in heroics. They too knew that we were in yet another overtime, and that the future no longer pertained.

I couldn’t blame them. My family had watched this monster of a disease take me to the brink of death three times. They had also lost some of their optimism eight years before, when our mom’s brain cancer relapsed after one year of treatment on the only promising drug at the time. With no other options, she died a few months later. Here I was, fifteen months after last being ravaged by my disease, and the only promising drug was not working. This was a situation familiar to everyone in that room.

But this was the moment when I realized that I was finally done with the passive kind of hope, the hope that waits for Santa Claus and gets in the way of action. […] I understood that hope on its own is often not enough. […]

Now I had to figure out what actions to take. And, of course, I had no guarantees that I would figure anything out or that my final days would not be spent working in vain to answer the unknowns of Castleman disease. In fact, I expected that my time would probably run out before I could make a meaningful impact for myself and other patients, but I wanted to go out swinging; there was no way to know unless I tried. I would make every second count, and my fourth overtime would be bigger than just me fighting to survive—it would be me fighting to extend survival for the thousands of other patients with my disease.

But first things first: I asked the nurse for a dose of Zofran for my nausea. It’s a lot harder to solve the thing that’s killing you when you want to throw up. Especially when you’re just a lowly medical student. Then I asked Gena if she could get a copy of my blood work. She wiped away her tears and sprang into action, eager to do something, anything that could help her little brother. I needed my test results so I could start studying my disease and also so I could estimate how much time I likely had before I’d be incapacitated by kidney and liver failure—or dead.
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Excerpt from “Chasing My Cure” by David Fajgenbaum, copyright © 2019 by David Fajgenbaum. Used by permission of Ballantine Books, an imprint of Random House, a division of Penguin Random House. All rights reserved.

An interview with David Fajgenbaum

The Economist: Explain your method of innovating around rare diseases.

David Fajgenbaum: Advances for rare or “orphan” diseases occur completely randomly. Organisations raise money, invite researchers to submit proposals describing how they would use the funds, select the best proposals and hope that the results are translated into breakthroughs for patients. This works for common diseases, but not for specific, rare ones where a handful of researchers may apply per grant. It’s like waiting for the stars to align.

When I relapsed on the only drug in development for my disease, idiopathic multicentric Castleman disease (iMCD) in my third year of medical school, I co-founded the Castleman Disease Collaborative Network (CDCN) to pioneer a new “collaborative network approach.” We built a community of over 400 physicians, researchers and patients, invited the community to crowdsource research ideas, recruited the best researchers to perform these prioritised studies and used the data to identify drugs already-FDA-approved for other diseases as potential iMCD treatments.

The Economist: How has that worked out?

Mr Fajgenbaum: I am alive today thanks to our work. Our systematic approach to research enabled the first-ever treatment (siltuximab) and discovery of a treatment for patients who are siltuximab-refractory, like me. Based on experiments I performed on my own samples, I discovered a drug (sirolimus) that was originally developed for kidney transplantation 30 years ago, but no one had ever tried it for iMCD. With no other options, I began taking it and it’s saving my life. Unfortunately, we’re only able to help about half of patients today and each of us could relapse at any time, so we still have a long way to go.

The Economist: How can this model work for other diseases?

Mr Fajgenbaum: Since the funding systems and the hurdles are shared across rare diseases, this model has the potential to have an impact on many more rare diseases. I’m aware of it already being used by a number of rare disease groups and it served as the inspiration behind the Chan Zuckerberg Initiative’s recent “Rare As One” campaign, which is infusing patient-powered principles and resources into dozens of rare diseases. The “collaborative network approach” requires a group of patients or family members who want to help drive forward progress, collaborative physicians and researchers singularly focused on making progress for patients, and disease communities willing to contribute funds, data and samples to research.

The Economist: What’s the biggest obstacle? Does the current system of medical innovation and healthcare fuel this model or discriminate against it?

Mr Fajgenbaum: A critical aspect of our approach is to use the data from our crowdsourced studies to identify drugs already FDA-approved for other conditions that may be effective. Since these drugs are already approved and even generic in many cases, there is less of an incentive for the manufacturers to fund research and clinical trials. And without these clinical trials, insurance companies do not want to cover the cost of the drug in this new use.

This cycle can be broken if clinical trials of these potential agents can be funded independently of the pharmaceutical industry, potentially unlocking treatments that were hiding in plain sight. Castleman disease is diagnosed in 5,000 new patients each year in America, similar to ALS. Though our approach makes every dollar count because it is systematic, highly coordinated and proactive, the biggest obstacle is funding trials.

The Economist: Let me ask a sensitive question: How’s your health?

Mr Fajgenbaum: Though I received my last rites when I was 25 years old and nearly died four more times in the next three years after diagnosis, today marks 70.68 months since my last relapse while I’ve been on sirolimus. The 0.68 is important. I’ve learned that I can’t round up—I may relapse tomorrow and may never make it to 71 months. But I also refuse to round down because my CDCN team and I have worked so hard for every day of remission for myself and other patients with iMCD. This remission gave me time to marry my wife Caitlin and even have a daughter, named Amelia, last year.