Lessons for biotech and phar­ma from a doc­tor who chased his own cure

Af­ter be­ing struck by a rare dis­ease as a healthy third year med­ical stu­dent, David Fa­j­gen­baum be­gan an ar­du­ous jour­ney chas­ing his own cure. Amidst the hus­tle of this year’s JP Mor­gan con­fer­ence, the dig­i­tal tri­als plat­form Med­able part­nered with End­points Stu­dio to share Dr. Fa­j­gen­baum’s sto­ry with the drug de­vel­op­ment in­dus­try.

What fol­lows is an edit­ed tran­script of the con­ver­sa­tion be­tween Med­able CEO Dr. Michelle Long­mire and Dr. Fa­j­gen­baum, and it is full of lessons for biotech ex­ec­u­tives charged with bring­ing the next gen­er­a­tion of med­i­cines to pa­tients.

Event host­ed at Co­vo San Fran­cis­co. Pho­tog­ra­phy by Jeff Ru­mans.

David Fa­j­gen­baum:

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Hey guys, I’m David Fa­j­gen­baum. It’s such an hon­or to be here with all of you, to share the stage with Michelle, and to be a part of what will hope­ful­ly be a great evening shar­ing my jour­ney fight­ing Castle­man dis­ease. I’ll al­so share some lessons that you guys can take back to the work that you’re do­ing in biotech and phar­ma.

You see me sit­ting here be­fore you and I look healthy and I feel healthy. And I guess tech­ni­cal­ly I am healthy right now. But my jour­ney has been long, and it’s been tough.

David Fa­j­gen­baum, MD, MBA, MSc, FCPP

In Ju­ly of 2010, I was train­ing to be­come an on­col­o­gist in mem­o­ry of my mom who had passed away just a few years be­fore from can­cer. I made a promise to her that I would ded­i­cate my life to fight­ing can­cer. I was halfway through med­ical school on that jour­ney.

A few weeks lat­er, I went from be­ing to­tal­ly healthy to ex­pe­ri­enc­ing mul­ti­ple or­gan sys­tem fail­ure.

My liv­er, my kid­neys, my bone mar­row, my heart and my lungs be­gan to shut down. And over the course of just a few weeks, I was hos­pi­tal­ized. I was ad­mit­ted to the in­ten­sive care unit. I had a reti­nal he­m­or­rhage which made me blind in my left eye. I gained 70 pounds of flu­id and drift­ed in and out of con­scious­ness. I was on a feed­ing tube. I was get­ting blood trans­fu­sions dai­ly.

I went from be­ing this to­tal­ly healthy med­ical stu­dent to hav­ing what I would write in med­ical records: MSOF. And I re­mem­ber be­ing in mul­ti-sys­tem or­gan fail­ure and think­ing, when I was a med­ical stu­dent I just kind of so lack­adaisi­cal­ly write MSOF and I had no idea what it re­al­ly meant. When I was in MSOF it was a fright­en­ing time, and all with no di­ag­no­sis.

Af­ter 11 weeks I had a lymph node biop­sy per­formed and that biop­sy came back with a di­ag­no­sis of Castle­man dis­ease. Castle­man’s is a rare im­mune sys­tem dis­or­der where the im­mune sys­tem be­comes hy­per ac­ti­vat­ed – it at­tacks and shuts down the body’s vi­tal or­gans.

About 5,000 pa­tients are di­ag­nosed each year in the US with Castle­man dis­ease. So, it’s about as com­mon as ALS. Most of you guys in here, prob­a­bly every­one, has heard of ALS. I’m not go­ing to ask you to raise your hands if you’d heard of Castle­man dis­ease be­fore this. It’s a poor­ly un­der­stood dis­ease. It’s al­so a dis­ease with very lit­tle aware­ness.

But, with the di­ag­no­sis came hope. Two days be­fore the di­ag­no­sis came in, I was so sick that my doc­tors didn’t think I would sur­vive.

But I was di­ag­nosed with Castle­man’s, I was treat­ed with chemother­a­py. Fi­nal­ly, I got enough chemo – I got a com­bi­na­tion of sev­en dif­fer­ent chemother­a­py agents – to where I was feel­ing well.

And you might say, well, chemo made you feel well? I was so sick, I ac­tu­al­ly felt bet­ter with every dose of chemother­a­py.

Thanks to the chemother­a­py, I was able to leave the hos­pi­tal af­ter months and months of hos­pi­tal­iza­tion and start to re­al­ly re­cov­er. I was able to go back to med­ical school and re­al­ly hope that Castle­man dis­ease was in my rearview mir­ror. I was on an ex­per­i­men­tal drug called Ce­tux­imab, the first drug to ever un­der­go a ran­dom­ized con­trolled tri­al for Castle­man dis­ease. But un­for­tu­nate­ly, I re­lapsed on that drug – the on­ly drug in de­vel­op­ment.

I had a con­ver­sa­tion with my doc­tor where he ex­plained to me there were no more drugs in de­vel­op­ment. I asked him, “Well, what oth­er tar­gets are there? There must be cell types or sig­nal­ing path­ways, some­thing else to go af­ter.” And he said, “No, there are none.”

And that’s when I turned to my dad, my sis­ters and my girl­friend Kate­lyn, and I promised them, I said, “I’m go­ing to ded­i­cate the rest of my life, how­ev­er long that may be, to try­ing to iden­ti­fy a treat­ment and maybe even a cure one day for this dis­ease.”

And for me there were a cou­ple of paths for­ward. The first was to be­gin to con­duct lab­o­ra­to­ry re­search at the Uni­ver­si­ty of Penn­syl­va­nia where I was in med­ical school. The sec­ond was to cre­ate a foun­da­tion called the Castle­man Dis­ease Col­lab­o­ra­tive Net­work (CD­CN), with the goal be­ing to ac­cel­er­ate re­search on a glob­al scale.

Through the CD­CN, we’ve been able to make a lot of progress. We’ve raised and in­vest­ed about a mil­lion dol­lars in re­search. Now it’s about $1.5 mil­lion in re­search over the last sev­en years. And from the 1.5 mil­lion we’ve put in, about $7 mil­lion in ex­ter­nal fund­ing has gone to­wards Castle­man’s re­search. So re­al­ly about a sev­en-ex­tra turn on the amount of dol­lars that go to­wards Castle­man’s re­search. And some re­al­ly im­por­tant break­throughs, a new drug that’s un­der­go­ing clin­i­cal tri­als, di­ag­nos­tic treat­ment guide­lines. Lots of progress.

Af­ter I’d got­ten en­gaged to get mar­ried, I had my fifth dead­ly flare of this dis­ease and I spent an­oth­er month in the hos­pi­tal. Cer­tain­ly, we did not think I would make it. But when I did sur­vive, I re­al­ly dove in­to my da­ta. I went back in­to the lab and re­al­ly dove in­to ex­per­i­ments to try to find some­thing, maybe some­thing that al­ready ex­ist­ed, a drug that’s al­ready FDA ap­proved that could maybe help me.

And based on the ex­per­i­ments I did on my sam­ples, I got a sig­nal that sug­gest­ed that the mTOR path­way, a crit­i­cal path­way in­volved in T cell ac­ti­va­tion, VEGF pro­duc­tion, cell pro­lif­er­a­tion, that it may be hy­per­ac­tive in my sam­ples.

And so, I de­cid­ed to do a fi­nal ex­per­i­ment. This is a nor­mal lymph node on the top of the screen. I want­ed to con­firm: Is mTOR re­al­ly ac­tive in my sam­ples? This is just a nor­mal con­trol. Blue stains pos­i­tive for nu­clei. So, it’s kind of just back­ground stand­ing. Brown is pos­i­tive for mTOR ac­ti­va­tion, PSX. You can see there’s a lit­tle bit of brown in a nor­mal lymph node. There’s some mTOR ac­ti­va­tion.

And then this is my lymph node and it was just strik­ing the amount of brown mTOR ac­ti­va­tion in my lymph node tis­sue. And there’s a drug that tar­gets the mTOR path­way called sirolimus. It was de­vel­oped 30 years ago for kid­ney trans­plan­ta­tion, had nev­er been used in Castle­man dis­ease. And so, I start­ed tak­ing it. To­day marks 70.27 months since my last re­lapse since start­ing that med­ica­tion.

To­day’s 70.27 months. And I say 70.27 be­cause I know that I can’t round up. I don’t know if I will re­lapse to­mor­row and if I will ever make it to 71 months. But I al­so refuse to round down be­cause we worked re­al­ly hard for the 0.27 months. I’m go­ing to take every frac­tion that I can get.

I’m sure many of you guys are think­ing about, well how is sirolimus help­ing oth­er pa­tients? I end­ed up fin­ish­ing up med­ical school and then busi­ness school and start­ing a fac­ul­ty po­si­tion at Penn where I’ve ded­i­cat­ed my en­tire ca­reer in life to study­ing Castle­man dis­ease.

And what I found is the ex­per­i­ments that sug­gest­ed siroli­mas might work for me have al­so re­vealed in­creased mTOR sig­nal­ing in oth­er Castle­man’s pa­tients. And we’ve be­gun to give the drug off la­bel.
The drugs have been giv­en about to 20 pa­tients with my dis­ease. About eight of them, I think the ex­act num­ber is eight, have re­spond­ed. So, the drug does not work for every­one with Castle­man dis­ease, but it’s a mean­ing­ful re­sponse ear­ly on. We have a tri­al where we hope to en­roll 24 pa­tients in a for­mal clin­i­cal tri­al to un­der­stand how well this drug works, but we still are re­mind­ed there is work ahead.

Some­times so­lu­tions can be hid­ing in plain sight. So, this drug that I’m on was de­vel­oped 30 years ago for kid­ney trans­plan­ta­tion. It had been sit­ting in my neigh­bor­hood phar­ma­cy that I’d been walk­ing past. Dur­ing all those years when I was back and forth in and out of the hos­pi­tal, it had al­ways been there, but no one had thought to try it. How many drugs are there al­ready out there that are just wait­ing to be found?

Michelle Long­mire, MD, Co-founder and CEO at Med­able

Michelle Long­mire:

I’d love to hear about what it re­al­ly takes to bring some­thing like this in a world where we’re not al­ways will­ing to

ad­mit how lit­tle we know in try­ing to bring about some­thing new to of­fer pa­tients. And then there’s the pub­lic per­cep­tion ver­sus the re­al­i­ty of your con­di­tion in terms of what will they have to of­fer, where you re­al­ly are to­day in med­ical re­search and new ther­a­pies.

David Fa­j­gen­baum:

Ab­solute­ly. Thank you for ask­ing that ques­tion, Michelle. I think that it’s not some­thing that we re­al­ly want to talk about. I think that in med­i­cine, doc­tors and med­ical stu­dents, we al­most don’t like to talk about how lit­tle we know. These are stats that you guys prob­a­bly all know, but there are 7,000 rare dis­eases out there with 95% not hav­ing a sin­gle FDA ap­proved ther­a­py. That’s shock­ing in this day and age. The first way you fix a prob­lem is ad­mit­ting you have a prob­lem. Right? I think that there’s prob­a­bly some val­ue to us ad­mit­ting that we have work to do.

And then, you made a great point about pub­lic per­cep­tion. I think that we see head­lines that talk about the break­through, but we don’t see a head­line that says “100,000 ex­per­i­ments failed to pro­duce a drug to­day”. But every day that’s what hap­pens. And that’s not to dis­cour­age us. That’s not to say we shouldn’t keep try­ing. That’s to say we ac­tu­al­ly should keep try­ing and we should try even hard­er.

So, to an­swer your ques­tion as to how we fix this prob­lem, I think that there are a cou­ple themes from my ex­pe­ri­ence that I think could be help­ful. One is around col­lab­o­ra­tion and how – I didn’t talk too much about the CD­CN – but re­al­ly I think I’d say our se­cret in­gre­di­ent to the progress that we’ve made is that we’ve lever­aged the en­tire physi­cian and re­search com­mu­ni­ty to help to pri­or­i­tize what re­search should be done. We call it crowd­sourc­ing, but it’s just ba­si­cal­ly get­ting every­one’s in­put, pri­or­i­tiz­ing what should be done, and then go­ing out and get­ting the best peo­ple to do it. It’s about get­ting every­body’s in­put. There are physi­cians who don’t have any re­search ex­pe­ri­ence who are go­ing to be able to pro­pose great ideas be­cause they are in the clin­ic with the pa­tient; there are re­searchers who don’t have any clin­i­cal ex­pe­ri­ence who can share things with physi­cians be­cause they spend all day, every day work­ing with those pa­tients’ cell lines.

Michelle Long­mire:

How do we re­al­ly bring ex­perts to­geth­er to solve a hard prob­lem? I think what’s so re­mark­able, you went out and you did that your­self. I’d love to hear about what you’ve learned through the Castle­man Dis­ease Col­lab­o­ra­tive Net­work and get­ting ex­perts to­geth­er and get­ting those in­sights to­geth­er.

David Fa­j­gen­baum:

I’ve def­i­nite­ly learned that it’s not easy to do. We’ve got­ten a lot of peo­ple to work to­geth­er, but it has not been easy. And I’m get­ting 34 ex­perts to­geth­er to agree on, for in­stance, a di­ag­nos­tic cri­te­ria, you could get 34 dif­fer­ent di­ag­nos­tic cri­te­ria from these 34 ex­perts. And un­for­tu­nate­ly, that’s just the way it is. And so, it’s not easy to get every­one to work to­geth­er, but it’s so valu­able when you’re able to.

Ear­ly on we had a hard time get­ting some of the biggest names in our field on board with what we were do­ing. Be­cause what we were say­ing was that we want­ed to get away from a world where the hand­ful of ex­perts in a par­tic­u­lar rare dis­ease have all of the pow­er. They have all the sam­ples, they have all the pa­tients, they get all the grant mon­ey. We want a world where any­one and every­one who has a good idea can con­tribute that idea and then we find the best per­son to do the work, whether they’re a KOL or not. But right now, the KOLs are the ones with the sam­ples. And you can’t do re­search if you don’t have those sam­ples. And so, you can’t get those to the best re­searchers un­less you fig­ure out a way around this.

David Fa­j­gen­baum, MD, MBA, MSc, FCPP

And so, we cre­at­ed a com­mu­ni­ty where, like I said, it was very in­clu­sive. Any­one and every­one can be a part of it. So many “non-KOLs”, like doc­tors who treat pa­tients with Castle­man dis­ease, they got en­gaged, start­ed pro­duc­ing re­al­ly great ideas. We start­ed pub­lish­ing pa­pers to­geth­er.

Then all the KOLs start­ed com­ing in and want­i­ng to be a part of it. I think that it’s an im­por­tant les­son. With­in bio­phar­ma we like to go to the top of the moun­tain and get those key peo­ple. But there’s some lessons about get­ting – maybe they’re not the KOLs, but they’re the next tier. Get them in­volved. Then the KOLs would get in­volved.

And then an­oth­er thing that’s re­al­ly been es­sen­tial is that be­fore the KOLs got in­volved, be­cause they had all the sam­ples and the da­ta, we would have been com­plete­ly… our hands would have been com­plete­ly tied to do re­search un­less we fig­ured out an­oth­er way to get sam­ples and da­ta. And so, we cre­at­ed a nat­ur­al his­to­ry study where pa­tients any­where in the world can en­roll on­line. So, no mat­ter where you’re treat­ed, whether it’s by a KOL or some­one else, you can en­roll on­line, and then we can get your med­ical records and ex­tract the med­ical records in­to a data­base.

All of a sud­den, all of these pa­tients that were… I don’t want to make it seem too dra­mat­ic, but kind of held hostage by their treat­ing physi­cian, who had their sam­ples and their da­ta. Now those sam­ples and da­ta are freely avail­able. And the same thing that we did with med­ical da­ta, we al­so did that with sam­ples. And so, I think just mak­ing it pa­tient-cen­tric is key.

Michelle Long­mire:

Yeah. It seems like the more aware we are, the more we can dri­ve more pa­tient-dri­ven de­ci­sion mak­ing, or where we

Michelle Long­mire, MD, Co-founder and CEO at Med­able

can have more pa­tient em­pow­er­ment.

David Fa­j­gen­baum:

I agree.

Michelle Long­mire:

And one of the things that stands out about your study and about your sto­ry is, what if you hadn’t been a med­ical stu­dent?

David Fa­j­gen­baum:

I know.

Michelle Long­mire:

What af­fect­ed the de­ci­sion? I’d love to hear how you think about a world where not every pa­tient can al­so be­come a med­ical stu­dent.

David Fa­j­gen­baum:

I think that I men­tioned ear­li­er how chal­leng­ing this whole jour­ney has been, cer­tain­ly emo­tion­al­ly chal­leng­ing for my fam­i­ly and I. But al­so, just ob­jec­tive­ly, it was not an easy road for me at all. And I was a med­ical stu­dent at Penn. I’m the son of a doc­tor. I was in Philadel­phia at this med­ical cen­ter, I had all the ac­cess you could pos­si­bly have. And it was a very tough jour­ney. And there were many times where it very well just could have end­ed that day.

So, to your point, think about peo­ple who aren’t in the mid­dle of med­ical school, who don’t have a fam­i­ly mem­ber in med­i­cine, who aren’t in a big aca­d­e­m­ic cen­ter hos­pi­tal. That’s when you re­al­ize that we re­al­ly have a lot of work to do.

What I hope is that ex­pe­ri­ences like mine, these kinds of N equals one, where you’re able to go from no treat­ment to a treat­ment, I think the most im­por­tant thing is then tak­ing that next step in the work that we’re try­ing to do, which is re­peat­ing the same ex­per­i­ments in oth­er pa­tients, un­der­stand­ing how this N equals one could be­come N equals many and ex­pand that di­rec­tion.

I think when we think about drug de­vel­op­ment we go from de­vel­op­ment for a dis­ease, fig­ure out who with­in the dis­ease that drug works for and then per­son­al­ize the ther­a­py with­in that dis­ease. And I think that our ap­proach is kind of the op­po­site, where you start out by find­ing some­thing that works in one per­son, then you fig­ure out what por­tion of the pop­u­la­tion it works in. And that’s where it be­comes a lit­tle bit more sus­tain­able be­cause it’s not sus­tain­able to do this on a one off for every­one. It’s sus­tain­able if you do this in one pa­tient, and then you start ask­ing the ques­tion: How many oth­er peo­ple could this help?

Michelle Long­mire:

An­oth­er re­al­ly neat po­si­tion you’re in is you must be one of the few in po­si­tions out­side of hy­per­ten­sion and di­a­betes who lives with the con­di­tion you treat your pa­tients for. And I’d just love to hear how you think about that and how liv­ing in this con­di­tion has shaped the care that you give to pa­tients.

David Fa­j­gen­baum:

Yeah, I think you’re prob­a­bly right. I’m sure every­one in this room has been touched by dis­ease in some way, and that’s part­ly what dri­ves you to do the work that you do. So, we all have some­thing per­son­al, but I think to your point, it’s a lit­tle dif­fer­ent when you feel your port on your chest that you get chemo through.

David Fa­j­gen­baum, MD, MBA, MSc, FCPP

But I think, for me, be­ing on both sides of the fence has def­i­nite­ly made me bet­ter on both sides. As a pa­tient, I think that I un­der­stand the lim­i­ta­tions of a physi­cian in the way that maybe I wouldn’t have un­der­stood oth­er­wise. And all of us that are in med­i­cine and work in biotech, we’re al­so all pa­tients, right? If we’re not a pa­tient yet, we’re go­ing to be a pa­tient at some point in the fu­ture. But all of us as pa­tients, I think we have as­sump­tions about the way the health­care sys­tem works. As­sump­tions about how bril­liant or not bril­liant a doc­tor is, how good or bad he or she is. But I think that it’s made me re­al­ize kind of the hu­man side. And I make mis­takes all the time. So, I guess that means my doc­tors can make mis­takes all the time. And I think that cer­tain­ly has helped me.

From the med­ical side, I think that it’s giv­en me an un­der­stand­ing of what it’s like to deal with ill­ness in ways that maybe I wish I didn’t know, frankly. But I think that it is im­por­tant be­cause pa­tients know their dis­ease bet­ter than any­one else.

Michelle Long­mire:

You’ve had some in­cred­i­ble break­throughs around drug dis­cov­ery. What do you see as the biggest bar­ri­er to hav­ing the most im­pact in your mis­sion and your work?

David Fa­j­gen­baum:

I think that my sto­ry and the rea­son I’m here is re­al­ly pred­i­cat­ed on the fact that some­one de­vel­oped this drug, Sirolimus, years ago that had al­ready gone through FDA ap­proval, and on the ex­per­i­ments I was able to do us­ing a new tool to un­der­stand bi­ol­o­gy.

To look in your rearview mir­ror at old drugs and say, well back when this drug was de­vel­oped, these tools didn’t ex­ist to be able to probe bi­ol­o­gy the way they do to­day. What I re­al­ly think we need to do bet­ter – and I’m a huge pro­po­nent of this – is let’s use all these brand-new tools to bet­ter un­der­stand dis­ease bi­ol­o­gy. And let’s ask ques­tions about drugs that al­ready ex­ist. Drugs that were de­vel­oped 20, 30, 40, 50 years ago, how can they help pa­tients to­day?

I think the biggest bar­ri­er to that is frankly in­cen­tives and the fact that if that drug was al­ready de­vel­oped, and it’s al­ready gener­ic, you might be able to re­for­mu­late it but even if you do, then you could not pre­vent peo­ple from writ­ing pre­scrip­tions for the old gener­ic ver­sion. So there just are not fi­nan­cial in­cen­tives that ex­ist.

And you guys in this room, and those peo­ple who are in oth­er rooms that are part of JP Mor­gan, you guys are the peo­ple that can help think through so­lu­tions to that. You can be very cre­ative around ways that you could ac­tu­al­ly in­cen­tivize re­pur­pos­ing ex­ist­ing drugs.

For me, in the work that I’m do­ing, we are so fo­cused on pa­tient im­pact that it doesn’t re­al­ly mat­ter if the drug’s gener­ic and off patent and all of that, be­cause we’re go­ing to do tri­als. We’re go­ing to get – whether it’s go­ing to be pri­vate­ly fund­ed or fed­er­al­ly fund­ed – we’re go­ing to get mon­ey to do the tri­al so that we can see if this drug is go­ing to save lives of Castle­man’s pa­tients. Every dis­ease doesn’t nec­es­sar­i­ly have ac­cess to the cap­i­tal to do that kind of stuff.

Tri­als are very ex­pen­sive. Tri­als can be cheap­er done in cer­tain ways. But I think that fig­ur­ing out how we in­cen­tivize re­pur­pos­ing is crit­i­cal.

Michelle Long­mire:

Def­i­nite­ly. What you’re ba­si­cal­ly say­ing is we need to know why a drug could ex­ist and how it will work with­in the cur­rent re­al­i­ty. It’s about say­ing: Here’s a crit­i­cal path­way of this dis­ease, and here’s some­thing that we think could work in that path­way.

One of the in­ter­est­ing com­ments that you had ear­li­er when we were talk­ing was that you re­ceive an email a day from a physi­cian some­where in the world who has a pa­tient with Castle­man Dis­ease and doesn’t know how to treat that pa­tient. I would love to hear how you man­age that with physi­cians who are in coun­tries where they may not have ac­cess the drug, and how you loan them your ex­per­tise and pro­vide that glob­al­ly to peo­ple who treat pa­tients.

David Fa­j­gen­baum:

I’m re­al­ly ex­cit­ed that we’re work­ing on a scal­able so­lu­tion. The so­lu­tion as of right now is me writ­ing man­u­al emails to peo­ple who reach out to me. That’s not scal­able. We used to have a plat­form on a web­site called GHD On­line, and it was a place where physi­cians and re­searchers could post chal­leng­ing cas­es. It was a place where any­one could post any ideas. The idea was that physi­cians in low re­source coun­tries could ask ques­tions of physi­cians in high re­source coun­tries.

We were for­tu­nate that that web­site, they gave us some space, and so we had a Castle­man dis­ease part of the web­site. And so, when peo­ple would send me a ques­tion, I would send them to GHD On­line. They would post it to our com­mu­ni­ty. The com­mu­ni­ty would re­spond di­rect­ly to that per­son. And the nice thing about that is that you’re ed­u­cat­ing the com­mu­ni­ty along the way.

GHD On­line ac­tu­al­ly shut down about a year ago. And so, we’re in the process of build­ing our own kind of cus­tom ver­sion of this. Ac­tu­al­ly, we’re part­ner­ing with the Chan Zucker­berg Ini­tia­tive, so just down the street. CZI has sup­port­ed us to build out this tool where physi­cians, pa­tients and re­searchers – the pa­tients will be sep­a­rate from the physi­cians and re­searchers – but physi­cians, pa­tients, re­searchers, will be able to post clin­i­cal cas­es that they’re deal­ing with and al­so re­search ideas. We’ll use this same place where we’re post­ing re­search ques­tions and clin­i­cal ques­tions to al­so iden­ti­fy and pri­or­i­tize high-im­pact re­search stud­ies.

I mean in med­i­cine it shouldn’t just be one doc­tor email­ing one doc­tor, and that’s it. It re­al­ly should be made in­to a com­mu­ni­ty where the whole com­mu­ni­ty con­tin­u­ous­ly learns from each case.

Michelle Long­mire:

So, of the var­i­ous things you’ve done – from dis­cov­er­ing that Sirolimus could be used to treat Castle­man Dis­ease to cre­at­ing a com­mu­ni­ty to de­vel­op­ing Castle­man Dis­ease Re­search Net­work – what is the thing that you could point to and say, I think this made the biggest dif­fer­ence?

David Fa­j­gen­baum:

I think thing that made the biggest dif­fer­ence was es­tab­lish­ing a di­ag­nos­tic cri­te­ria. It prob­a­bly doesn’t seem that ex­cit­ing, right, it’s not like new drugs or new tech­nolo­gies. But ac­tu­al­ly, if you don’t have a check­list to di­ag­nose a dis­ease, it’s re­al­ly hard to di­ag­nose that dis­ease.

Be­fore this di­ag­nos­tic cri­te­ria, Castle­man dis­ease was first de­scribed by Ben­jamin Castle­man back in 1954. And it’s been di­ag­nosed in thou­sands of peo­ple over the last 70 years. How­ev­er, for the first 65 years, there was no check­list. It was on­ly di­ag­nosed if you hap­pened to come across a pathol­o­gist who knew what to look for, maybe they read a pa­per de­scrib­ing Castle­man dis­ease, or they read about it in a text­book, or they learned about it in res­i­den­cy. And that is just not the way things should be done. Right? Like you shouldn’t just have to ran­dom­ly run in­to the right pathol­o­gist who sees the right lymph node at the right time.

So, we spent a lot of ef­fort get­ting those ex­perts to­geth­er, go­ing through da­ta from over 200 pa­tients to es­tab­lish this di­ag­nos­tic cri­te­ria. And so now pa­tients ac­tu­al­ly get di­ag­nosed based on a cri­te­ria.

Michelle Long­mire:

As you look for­ward, what are you the most ex­cit­ed about for the new treat­ment of Castle­man dis­ease?

David Fa­j­gen­baum:

This is a rare dis­ease, I men­tioned that ear­li­er, but we’ve been able to con­nect a re­al­ly large com­mu­ni­ty of Castle­man dis­ease pa­tients. And we’re ac­tu­al­ly get­ting ready to launch a re­al­ly big ini­tia­tive to get blood sam­ples from these pa­tients so we can per­form ge­net­ic se­quenc­ing on a num­ber of pa­tients and hope to re­al­ly get to the un­der­ly­ing bi­ol­o­gy. What caus­es the im­mune sys­tem to just get out of con­trol and start at­tack­ing vi­tal or­gans? We don’t know. I’m re­al­ly ex­cit­ed about this idea that we fi­nal­ly have the kind of the net­work in place to get dozens and even hun­dreds of sam­ples to be able to do re­al­ly im­por­tant pro­fil­ing. We’ve built the com­mu­ni­ty. I’m now ex­cit­ed to start lever­ag­ing that net­work the sam­ples and the da­ta to be able to treat pa­tients bet­ter.

I think out­side of Castle­man dis­ease, I’m most op­ti­mistic about drug re­pur­pos­ing. I know I’ve said it a num­ber of times, but the con­cept that for all these dis­eases out there that don’t have a so­lu­tion, that maybe there’s a drug that could be help­ful for them. That gives me a tremen­dous amount of hope.

Michelle Long­mire:

Some­thing that I think is re­mark­able is that when we look at the HIV cri­sis, AZT was al­so shown shelf drug. It was some­thing that was on the shelf and was re­pur­posed for the treat­ment of AIDS, and it was a game chang­er for that in­di­ca­tion. What are things that we can do in the com­mu­ni­ty to re­al­ly dri­ve our re­pur­pos­ing for­ward faster?

David Fa­j­gen­baum:

I think num­ber one is try­ing to crack this code around in­cen­tiviz­ing drug re­pur­pos­ing. How can you make it so that there tru­ly is a fi­nan­cial in­cen­tive? I spent quite a bit of time a few years ago ad­vo­cat­ing for a bill called the Open Act that would make it so that drug com­pa­nies that have a drug ap­proved for a com­mon dis­ease, if they could get an ap­proval for a rare dis­ease, they’d get six ex­tra months of mar­ket ex­clu­siv­i­ty. That would be a huge in­cen­tive, and we think that it al­so would lead to com­pa­nies ac­tu­al­ly do­ing the ef­fort to see if their drug would work in the rare dis­ease space. It got re­al­ly close. It was part of the 21st Cen­tu­ry Cures Act. It was lit­er­al­ly a day away from be­ing signed be­fore it got pulled out of leg­is­la­tion a cou­ple of years ago, and it’s just been sit­ting on the Sen­ate floor.

And of course, as you guys know in the cur­rent po­lit­i­cal cli­mate, there’s no ap­petite for any­thing that could be even thought of as pro-phar­ma. And this is not pro-phar­ma. This is pro-pa­tients. Yes, it’s an in­cen­tive for phar­ma, but un­for­tu­nate­ly the po­lit­i­cal en­vi­ron­ment isn’t con­ducive.

Thalido­mide is a great ex­am­ple of a drug that was de­vel­oped for morn­ing sick­ness, and ob­vi­ous­ly has a ter­ri­ble his­to­ry of caus­ing birth de­fects, but now it’s this life­sav­ing drug in mul­ti­ple myelo­ma. And so, re­mem­ber­ing that there are these cas­es out there and think­ing about how we im­prove the sys­tem so that we can lever­age them.

Michelle Long­mire:

Yeah. Ac­tu­al­ly, I’ve had pa­tients that I’ve treat­ed with lu­pus, who had se­vere lu­pus, alope­cia, and ex­treme­ly ad­vanced dis­ease. And Thalido­mide was the on­ly treat­ment.

David Fa­j­gen­baum:

Re­al­ly?

Michelle Long­mire:

Yeah.

David Fa­j­gen­baum:

I didn’t know that.

Michelle Long­mire:

So how can we re­al­ly bet­ter en­able physi­cians to pro­vide those in­sights around re­pur­pos­ing?

David Fa­j­gen­baum:

You’re hit­ting such an im­por­tant point, and that’s track­ing when things do get used. I think that, with­in dis­ease states, cap­tur­ing off-la­bel drug use is crit­i­cal be­cause, to your point, even if there’s not a com­pa­ny be­hind Thalido­mide in lu­pus, if doc­tors out­side of Stan­ford that aren’t just the pre­mier med­ical cen­ters learn about this, they can get ac­cess to this drug, and it can con­tin­ue to be used off-la­bel.

And then I think it’s al­so im­por­tant to fig­ure out when drugs are be­ing used off-la­bel and there is a sig­nal in the re­al world that it’s work­ing. How can you do a clin­i­cal tri­al that is cheap enough and re­source ef­fi­cient enough to where you can ac­tu­al­ly ef­fi­cient­ly and ef­fec­tive­ly and rig­or­ous­ly eval­u­ate how well this works out­side of the re­al world set­ting so that we’re not just re­ly­ing on re­al world da­ta?

I think that us­ing the same tech­nolo­gies that help us un­der­stand dis­ease bi­ol­o­gy across dis­ease, we need to use those same tech­nolo­gies to un­der­stand bi­ol­o­gy with­in dis­ease. So, cut­ting these dis­eases up based on, of course ge­nom­ic, pro­teomics pro­fil­ing, but al­so even based on re­sponse to this ther­a­py or that ther­a­py.

With Castle­man dis­ease, we’ve been able to sub­type it a few dif­fer­ent ways, pro­teom­i­cal­ly and al­so histopatho­log­i­cal­ly, but at the end of the day, what we re­al­ly care is: Do you re­spond to first line ther­a­py or not? Do you re­spond to sec­ond line ther­a­py or not? Be­cause that’s the on­ly rea­son we do all this pro­teomics or any­thing, is about help­ing these pa­tients. As a field we’ve been shift­ing to­wards get­ting away from call­ing it plas­ma­cyt­ic rich or call­ing it based on our pro­teomics sub­type, but ac­tu­al­ly say­ing it’s sil­tux­imab re­spon­der, sil­tux­imab non­re­spon­der, sirolimus re­spon­der, sirolimus non­re­spon­der. Be­cause that’s all we re­al­ly care about at the end of the day, we want to get it to where there are no more non-re­spon­ders, where there is a re­spon­der for every­thing.

Michelle Long­mire:

Let me open it up to the au­di­ence.

Au­di­ence Mem­ber:

My ques­tion is around in­no­va­tion. We’re with JP Mor­gan, and re­al­ly, your sto­ry is the epit­o­me of break­through, or a se­ries of break­throughs, that led to maybe an ad­vance. What ad­vice do you have for folks around in­no­va­tion?

David Fa­j­gen­baum:

That’s a great ques­tion. There’s kind of two thoughts with in­no­va­tion. I think one is that in­no­va­tion oc­curs when you’re re­al­ly cre­ative, and you’re not re­strict­ed.

And then there’s an­oth­er school of thought: In­no­va­tion oc­curs when you’re re­al­ly sys­tem­at­ic. You start out with a lot of op­tions, and then you start whit­tling them down, you test them out, you whit­tle it down, test it out, very much a sys­tem­at­ic ap­proach to in­no­va­tion.

I’ve def­i­nite­ly tak­en this ap­proach. I think that’s prob­a­bly a per­son­al­i­ty thing, but I think that when you’re in a sit­u­a­tion where there’s 1500 al­ready FDA ap­proved drugs, there are lit­er­al­ly tens of thou­sands of dif­fer­ent kinds of ex­per­i­ments you can do to try to fig­ure out what drug could work for you. I think you have to ap­ply some sort of sys­tem­at­ic ap­proach to try­ing to get from noth­ing to some­thing. You can just too eas­i­ly get lost. I mean, there lit­er­al­ly are an in­fi­nite num­ber of as­says or part­ners that you could work with, so I think that my ap­proach to in­no­va­tion has al­ways been: Let’s get every­one who has any idea at the ta­ble. They might have a bad idea, and that’s okay. If any­one has an idea, then we want to get it.

So, get as many good and bad ideas as you can, and then get a re­al­ly, re­al­ly ded­i­cat­ed group of peo­ple who are very smart to start sift­ing through those ideas, pri­or­i­tiz­ing them, and check­ing one an­oth­er. Al­ways re­ly­ing on da­ta, and then sift­ing down un­til you get to what you think is your best shot.

Au­di­ence Mem­ber:

There’s 7000 cas­es of rare dis­eases. The ma­jor­i­ty of them are ac­tu­al­ly sub­types. Castle­man’s is one of them, and it’sre­ferred to at the very end. The prob­lem with hav­ing sub­types de­fined in terms of how they re­spond to treat­ment is de­pen­dent on hav­ing the treat­ments. Okay?

David Fa­j­gen­baum:

Yeah.

Au­di­ence Mem­ber:

I don’t un­der­stand the bi­ol­o­gy of what these sub­types ac­tu­al­ly rep­re­sent. I think, ob­vi­ous­ly, prag­mat­i­cal­ly, you want to as­so­ciate both ends of that, and not just one end of that. And you re­al­ly need to look at, in al­most all these dis­eases, how the com­plex dis­or­ders have to be di­ag­nosed and strat­i­fied be­cause the first ques­tion would be: if the treat­ment that was suc­cess­ful for you ac­tu­al­ly fluc­tu­at­ed in oth­er sub­types of Castle­man’s, if they ex­ist? So that’s one ques­tion.

The oth­er side of it is you pre­fer to bring to­geth­er a pan­el of ex­perts to come up with di­ag­nos­tic cri­te­ria. Well, I as­sume you prob­a­bly use a Del­phi method.

David Fa­j­gen­baum:

We did.

Au­di­ence Mem­ber:

Okay, and the Del­phi method is a con­sen­sus, and the prob­lem with the con­sen­sus is you may range from 10 per­cent con­fi­dence to 90 per­cent con­fi­dence, so… It’s ob­vi­ous­ly a process that’s been used quite a bit. It’s a guide­line. And then the next ques­tion is: what kind of clear­ance do you have from the physi­cians in ac­tu­al­ly defin­ing those guide­lines?

David Fa­j­gen­baum:

Good ques­tion. We use Del­phi be­cause, for the rea­sons you said, it’s been used be­fore. I think Del­phi works if you have good da­ta to make your de­ci­sions based off of. We spent about two years get­ting to­geth­er da­ta from 288 pa­tients, and so… you’re right, Del­phi doesn’t work if it’s just opin­ions. It works, I think pret­ty well, if you’ve got a lot of da­ta, and this is rel­a­tive. In Castle­man’s, 288 pa­tients is a lot of da­ta. And so, I think that helped us to al­ways be fo­cused on the da­ta, and then build­ing con­sen­sus around the da­ta.

And the sec­ond ques­tion about how well peo­ple uti­lize it? I think bet­ter than you would think, main­ly be­cause most peo­ple di­ag­nos­ing Castle­man Dis­ease are not peo­ple who are go­ing to treat Castle­man Dis­ease. They’re ICU doc­tors. They’re in­ternists who are work­ing in the hos­pi­tal. They’re PCPs. These are peo­ple who… They’re thrilled when they have a check­list to be able to say, “You know, I re­al­ly think I’ve found a so­lu­tion for my pa­tient,” ver­sus the hema­tol­o­gist on­col­o­gist who maybe will want to think, maybe it could be this even though the check­list says that. And then they don’t stick to it.

Au­di­ence Mem­ber:

We work with a lot of dis­eases, have to deal with those con­sen­sus­es. Even the NIH will tell you that in rare dis­eases, less than 30 per­cent are due to ge­net­ic caus­es, and so they’re much more com­plex than we would like them to be, but again be­cause of the need to as­sign di­ag­nos­tic cri­te­ria, or some­times a DSM-5 code, we’re sort of re­strict­ed how we can de­scribe them. I think chal­lenges the abil­i­ty to bring back old drugs be­cause we’re look­ing at ap­ply­ing it to a het­ero­ge­neous pop­u­la­tion.

David Fa­j­gen­baum:

These are great points. See, I think that maybe you need to do both, and so you need to uti­lize all these brand new tools to pro­file them in every way pos­si­ble, but then you need to al­so cap­ture when drugs are used off-la­bel to un­der­stand, to your point, how they con­nect. How does the pro­fil­ing con­nect to the re­sponse to ther­a­py? I wish there was an easy an­swer.

Au­di­ence Mem­ber:

Have you thought about how to get in­ter­est from the ven­ture com­mu­ni­ty or phar­ma in ac­tu­al­ly in­vest­ing dol­lars in re­search in phar­ma­ceu­ti­cal com­pa­nies?

David Fa­j­gen­baum:

So, in our case, we have gone to part­ners that have been po­ten­tial­ly good ven­dors and tried to es­tab­lish part­ner­ships, and some­times it’s worked re­al­ly well, where it re­al­ly has aligned with busi­ness in­ter­ests, but it doesn’t al­ways align. We have had a great part­ner­ship with Janssen Phar­ma­ceu­ti­cals to do this large serum pro­teomics pro­fil­ing. They pro­vid­ed a bunch of sam­ples. They were just ter­rif­ic part­ners through­out the whole project, and I re­al­ly don’t think it was based on a busi­ness case.

We were look­ing for path­ways, oth­er drugs that could be used in pa­tients who don’t re­spond to sil­tux­imab, so there’s al­most clear­ly no busi­ness case what­so­ev­er if you own sil­tux­imab. But they made the case in­ter­nal­ly, be­cause they were just a bunch of re­al­ly great peo­ple who want­ed to see progress for Castle­man Dis­ease. I think we should all look to cre­ate those kinds of part­ner­ships, and we can re­al­ly make progress.

Au­di­ence Mem­ber:

His­tor­i­cal­ly, if you think about how drugs even de­vel­oped… Hun­dreds of pa­tients en­rolled in these sprawl­ing clin­i­cal tri­als that could last 10 years that were ex­treme­ly cap­i­tal in­ten­sive, not par­tic­u­lar­ly re­course ef­fi­cient. So, I’m cu­ri­ous about what’s de­vel­oped in re­cent years as a new mod­el for drug adop­tion, es­pe­cial­ly in rare dis­ease and ul­tra-rare dis­ease. Even a one and two type ul­tra, ul­tra-rare dis­ease where they might on­ly have two or three known pa­tients across the world.

David Fa­j­gen­baum:

I think that what I’ve been pleased to see what I would de­scribe as the FDA’s be­ing adap­tive. I think that they’ve been adap­tive in ways that, as a pa­tient, have been pos­i­tive.

For Sil­tux­imab, the drug that’s ap­proved for Castle­man Dis­ease, when the tri­al was done around 2009, 2010, it was in­cred­i­bly strin­gent, the re­quire­ments that the FDA put in, and the bar to get that drug ap­proved. The bar was in­cred­i­bly high, and so I think that that’s been a good trend, is will­ing­ness to shift.

I think that from the biotech side of things, I’m just so thrilled to see there’s so much in­ter­est in rare dis­ease. We call them or­phan dis­eases. We’ve al­ways called them or­phan be­cause they were rare and ne­glect­ed. For­tu­nate­ly, a lot of them are on­ly now rare, they’re no longer ne­glect­ed. So, let’s change the name back to rare. Let’s get rid of call­ing them or­phan be­cause maybe we can get to a point where they’re no longer ne­glect­ed.

Au­di­ence Mem­ber:

What can we re­al­ly do in clin­i­cal drug de­vel­op­ment to change the game? I think we re­al­ly need a world where we can con­nect pa­tients to op­por­tu­ni­ties or give them bet­ter treat­ments di­rect­ly, tak­ing that op­por­tu­ni­ty and hope di­rect­ly to pa­tients. Screen­ing and en­roll­ment are the large com­po­nent of time in a tri­al, so clin­i­cal drug de­vel­op­ment would be trans­formed if you knew, as a con­sumer, your op­por­tu­ni­ties for re­search. It’s such a sim­ple thing, but when we re­ly on that point of care be­tween a pa­tient and physi­cian, and physi­cian is go­ing to meet 30 oth­er pa­tients that day. I think we re­al­ly need to re­move that as a bar­ri­er and put that op­por­tu­ni­ty di­rect­ly with pa­tients.

David Fa­j­gen­baum:

I to­tal­ly agree. I mean, I think what we have done with the reg­istry di­rect on­line con­sent… We were talk­ing about that ear­li­er on. Go­ing di­rect­ly to the pa­tient, be­ing able to con­sent them on­line. IRB is be­ing more flex­i­ble. I’m al­so a huge pro­po­nent of re­al-world ev­i­dence and fig­ur­ing out ways that we can try to har­ness da­ta that’s al­ready be­ing au­to­mat­i­cal­ly gen­er­at­ed. Ob­vi­ous­ly, it can’t re­place clin­i­cal tri­al da­ta, but I think that there are ways that it can sup­ple­ment and sup­port it.

Michelle Long­mire:

Hope isn’t about cast­ing a wish out in­to the uni­verse, but it’s about tak­ing ac­tion, it’s about mak­ing some­thing ma­te­ri­al­ize. So, you’ve made in­cred­i­ble progress with Castle­man dis­ease. How can every­one in this room be a part of that progress?

David Fa­j­gen­baum:

One is by help­ing to spread the word about what we’re do­ing with Castle­man Dis­ease. We call our ap­proach to re­search we’ve spear­head­ed for Castle­man’s the col­lab­o­ra­tive net­work ap­proach. We hope that this ap­proach can be used for many, many oth­er rare dis­eases.

Ob­vi­ous­ly, you can do­nate to­wards the CDC. And the third is help­ing to raise aware­ness about the sto­ry, Chas­ing My Cure. What’s been so cool since the book came out a few months ago, we have more pa­tients en­rolling in­to our stud­ies. There are pa­tients get­ting di­ag­nosed more quick­ly be­cause their doc­tor saw some­thing on the news about Chas­ing My Cure.

I learned so much about life and liv­ing from near­ly dy­ing five times. I got it on pa­per, and I want to get it out to the world, and so I hope you guys will help to share some of these mes­sages as well, and help to spread the word about Chas­ing My Cure as well.

You can do­nate to the Castle­man Dis­ease Col­lab­o­ra­tive Net­work here.
Fol­low this link to David Fa­j­gen­baum’s au­to­bi­o­graph­i­cal book, Chas­ing My Cure.
For more in­for­ma­tion on Med­able, click here.