Dario C. Altieri, MD
March 2, 2009. Just published in the Journal of Clinical Investigation.1 And we even got the cover. Twists and turns of heat shock protein-90 (Hsp90), the chaperone, the evolutionary capacitor. Great name and important cancer target. People smiled when I talked about this at the Hsp90 conference. No, no, really there is a lot of it in the mitochondria and only in the mitochondria of tumor cells.
And, I don’t know why, but Hsp90 drugs don’t touch it: somehow, they don’t get to the mitochondria.
So, I made my own. Took an old Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, and attached it to triphenylphosphonium, a carrier that basically gets anything into the mitochondria. No, of course, I didn’t do the synthesis in my laboratory. What do I know about medicinal chemistry? Outsourced it. Like sneakers and sweaters.
And after 3 months, there it was: an Hsp90 inhibitor that only goes to the mitochondria, causes aggregation of a lot of proteins, and kills tumor cells in minutes. Makes sense, right? Mitochondria must control protein folding, especially in cancer, and they do it with chaperones. Inhibit the process, and tumor cells can’t cope. Normal cells don’t seem to mind. So, there is strong preclinical activity, and against a lot of different tumor types. Better than any other Hsp90 inhibitor. Good safety. Totally different mechanism of action. And even a cool name: gamitrinib.
From Drug Discovery to Development
Tired of curing mice. What if this were to work in people? Ideas are made in academia; drugs are made in companies. Okay, fine, then I’ll launch a startup, spinout, whatever they are called. The (former) doctor-turned scientist now turns entrepreneur, and then captain of industry. Problem is, I am not like that. More like an (aged) boy scout.
The inner soapbox says it belongs to the American taxpayers; they funded it; it’s theirs. Excellent start. What else? If doctors and scientists become businessmen (or businesswomen), who will take care of humanity and discover new things? Perfect for a campaign ad. Sold. Bring it to the patients solely from academia: no pharma, no biotech, no investors, no nothing. Soapbox meme for the day: Yes, we can. It’s going to cost. So? I’ll write a grant; that’s what I do for a living anyway. And the fact that I know zero about drug discovery? Or drug development?
“Ideas are made in academia; drugs are made in companies.”— Dario C. Altieri, MD
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Laboratory-Clinical Transition Award from the Department of Defense. Great title. Three years of funding. Perfect for me. Pass-through money, nothing for the laboratory, but it pays the bills of outsourcing. First things first. Synthesize Good Laboratory Practice (GLP) gamitrinib. Already getting a pretty good hang of the acronyms. Hey, we made this drug lots of times before and it has never taken this long. It’s almost a year and counting. The Department of Defense is on my case because I am already behind. What’s going on? Yes, I understand we don’t make anything in this country anymore. New import permits that need to clear the Indian government? The what? This is just a chemical, not an international incident. Yes, I get it; nothing I can do about it.
My new job is mailman. And telephone operator. Finally shipped the GLP drug for the toxicology. Two animal species, says the U.S. Food and Drug Administration (FDA). Rats and dogs sound good to me. Should I feel sorry for the dogs? Rats not so much. But what if gamitrinib poisons the mitochondria in the brains? Or hearts? Wait, you said it’s just perfect? Animals are doing great, all of them. And no toxicity at all, like giving them…water.
Wow, that’s some news. Feeling quite pleased with myself. See? I said it all along: mitochondria are wired differently in cancer. That’s why the drug is safe for normal tissues. Maybe I should write a review article about that. Serious boost of the citation index. I am sorry, what? Yes, of course I know the drug is purple. Okay, you filtered it before giving it to the animals and instead of purple it turned white? And you did that to all the animals. For the entire time. Oh, what do I think it means? I think it means you filtered out the drug, and we have been giving animals…water. Yes, I get it. I need a new formulation. And start over. Note to self: find a new contract research organization that doesn’t give water to the animals.
‘Everybody Is an Entrepreneur’
Formulation experts. Big pharma expats who now have their own contract research organization. Everybody is an entrepreneur here. Is this drug oral? Nope. Is it soluble in water? Not at all. So, it’s an intravenous (IV) infusion? Yes, that’s what it is. Sorry, then it’s not a drug. It’s not? And what about things like, you know, paclitaxel or doxorubicin? Aren’t they also insoluble and given IV? Last time I checked, we used them for half a century and saved millions. Oh, now we think differently? I see, fail fast: that’s how we think now. And mine, whatever it is if it is not a drug, it has already failed. Nobody likes to take risks. Soapbox meme for the day: If nobody takes risks, how do we make progress, exactly? So, maybe I am in good company: Paclitaxel and doxorubicin would also fail fast today.
It’s doable. Nobody likes it, but it’s doable. Sterile-filter the emulsion components and then bring the particle size below 200 nm. Nice. How do I do that? With a microfluidizer. And why nobody likes it? Oh, because the microfluidizer is a dirty machine, and where you make Good Manufacturing Practice is called a clean room. Impeccable logic. But a place in California may do it. For a fee, of course. Oh, and you have to buy the machine. Buy what? Or lease it, whatever. People may not like it, but the whole thing works like a charm. Except, of course, when the microfluidizer stops for no reason in the middle of the run. Media fill looks good. Drug is stable for months in the new formulation. Release testing coming together nicely.
I am running out of money. Burned through not just one but two Department of Defense grants and all my research kitty. Nothing saved for the swim back: talk about risk-taking. At least the repeat toxicology is paid for and looks good. The drug, the real thing this time, is safe. They even did electrocardiograms on the dogs. Thank goodness I didn’t have to read them, but they are normal: no QTc liability. Can’t drop the ball now, but I really need money.
Here is how you do it: silence the inner soapbox and enchant the big pharma suits who are coming over. Use the right words. It’s not early stage anymore. Asset totally de-risked. Sure, it’s ready for prime time. It works. I am a natural. Maybe I should have done this before. A lot of nodding around the table. The suits must be in awe with the great pharmacokinetics, long half-life, and fabulous safety. A hand goes up. I am sorry? Sales data? Sales of what? What is the unit price? No, no, no, we are not there yet. I haven’t even filed an investigational new drug (IND) application.
The Bumpy Road to a Clinical Trial
Something different now. Analysts who advise big-time investors. They don’t wear suits. Sweaters for sure. Maybe black T-shirts à la Steve Jobs. They like new things and totally live by risks. Sounds like my crowd. And, don’t forget, they can get tons of money from people who already have tons of money and want to make even more money. My crowd? Voices out of a polyphone. Yes, it is Hsp90. Yeah, the chaperone. Sure, I know, it has been around for a long time, but this is a completely new story; nobody ever tested a cancer drug that goes to a subcellular organelle: that’s really where the action is. Yes, Hsp90. And mitochondria, they used to be bacteria two and a half billion years ago, but they turned out to be important in cancer. I know that, too, Hsp90 drugs didn’t fare well in the clinic. Lot of toxicity, basically no efficacy. Yes, very unfortunate. But this one has a completely different mechan…. Sure, I would like to hear that perspective. I am sorry, did you say, Wall Street doesn’t believe in this target?
Triaged the first time but funded on the resubmission. Could have been worse. This one is a grant from the National Cancer Institute. And a nice award from the Gateway Foundation is coming, too. Enough to pay for the clinical trial. Single site, standard phase I. Accelerated dose escalation. Up to 35 patients with advanced cancer. All comers. Drug vials ready to go. And a fantastic clinical investigator to run the trial. You really don’t want me in the clinic.
“So, maybe I am in good company: Paclitaxel and doxorubicin would also fail fast today.”— Dario C. Altieri, MD
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The only thing missing is IND approval. Right, there is that. No, not a commercial IND, investigator-initiated IND, thank you very much. The FDA people are the nicest in the world. Super-helpful, don’t believe otherwise. Or maybe they just feel sorry for the clueless applicant. Thirty days to respond to the questions. Totally getting a promotion to a higher rank of telephone operator. And publisher of FDA modules. And certifier of United States Pharmacopeia (USP) <85> recommendations. And fixer of chemistry, manufacturing, and controls deficiencies. Oh, and let’s not forget the specs for polytetrafluoroethylene filters. Then, the examiner mutters two words at the end of a phone call. Good luck. Then, nothing. No more questions, e-mails, or phone calls. Right on the 30-day mark. Were you expecting this? It’s a letter; it says study may proceed.
Close but Not Quite There Yet
What would the day look like? The first patient to be dosed. Maybe I should go to the clinic: it’s in town, not far from where I am. I don’t think I can pass muster as one of those confidence-inspiring docs in pharma ads. But I do well as chief executive officer. The cufflinks look good, and so do the shoes. I can impress the family. My Italian accent can pass as straight from South Philly, so I have that also going for me. And I can more than hold my own if I need to talk about Philadelphia Eagles football and worries with Jalen Hurts’ arm for next season.
I used to be good with my patients. Or at least I convinced myself of that. Yes, this is an experimental drug straight out of our backyard, right here in Philadelphia. No, I don’t know if it will work, but I sure hope it will. And thank you, thank you so much for being part of the trial. What if I make these people even sicker than they are? I took an oath a long time ago. Anyway, I know the literature on phase I studies; chances are it just won’t do anything, so nobody gets hurt, and I am finally done with it. I never thought this moment would arrive.
There is none of that. January 10, 2022. It’s just a late-night e-mail on the anniversary of my mom passing from lung cancer. Hey, the first patient did great at the starting dose of gamitrinib. No problem whatsoever. The next patient will now get twice the dose. I hope we get that started this month. Happy New Year. And that was that. A total of 12 years, 10 months, and 9 days from that Journal of Clinical Investigation paper.1
DISCLOSURE: Supported by National Institutes of Health (NIH) grants R35 CA220446, P01 CA140043, and R01 CA225913 (to Dr. Altieri and Dr. Anthony J. Olszanski). Dr. Altieri is a named inventor on the Patent #2,699,794 Title: Mitochondria-Targeted Anti-Tumor Agents; issue date: July 19, 2016 (institutional).
ACKNOWLEDGMENT: Dr. Altieri thanks Drs. Umar Hayat of PharmaAdvisors and Gary Elliott of Galenic Strategies for superb advice in all aspects of gamitrinib drug development; Drs. Jonathan Van Dyke and Fritz Wayne at Covance (now Labcorp Drug Development) for directing GLP studies of gamitrinib in Sprague-Dawley rats and beagle dogs, respectively; Drs. Chuong Pham, Deping Chen, Taylor McArthur, and Catherine Clifton at Alliance Pharma for absorption, distribution, metabolism, and excretion studies of gamitrinib; Dr. Heidi Schlager at Albany Molecular Research International (AMRI now Curia) as program manager for chemical synthesis of GLP and GMP gamitrinib drug substance; Dr. Saiful Islam at Latitude Pharmaceuticals for gamitrinib formulation development; and Dr. Anthony J. Olszanski, Director, Phase I Developmental Therapeutics Program, Fox Chase Cancer Center, for the clinical development of gamitrinib.
At the time this article was published in the Journal of Clinical Oncology, Dr. Altieri was President and Chief Executive Officer of The Wistar Institute, Philadelphia.
REFERENCE
1. Kang BH, Plescia J, Song HY, et al: Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J Clin Invest 119:454-464, 2009.
Originally published in the Journal of Clinical Oncology 40:1838-1840, 2022. © American Society of Clinical Oncology. All rights reserved.
