I Want a New Drug – Transcript

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RICH MANGANO
Add it all up, it ends up being somewhere between 15 and maybe 20 years to get the drug towards the end.

MAURICE
Welcome to Drexel’s 10,000 Hours podcast. Our goal is to mine the stories behind our region’s innovators, inventors, and thought creator. We’ll be talking to experts in subjects from fashion to neuroscience to find out where their passion for work and inspiration for ideas comes from. I’m your host, Maurice Baynard.
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MAURICE
Rich Mangano is director of the Clinical Research Programs at Drexel University’s College of Medicine. He’s spent years working on drug discovery and development in the pharmaceutical industry for both large and small companies. Incidentally, he’s also an avid New York sports fan.

MAURICE
OK, so tell me about where you grew up and some of your best memories about growing up in that part of the country.

RICH
OK. First few years my life, lived in the Bronx. And I guess by the time I was about two and a half, my parents moved, oh, five miles north into the suburbs in Mount Vernon– just played street sports, stickball–

MAURICE
Oh.

RICH
–football.

MAURICE
What was your favorite sport growing up?

RICH
Favorite sport to watch and play was baseball.

MAURICE
And did you play baseball in high school?

RICH
No. I played– it’s going to be ironic now– hockey in high school on a club team. We didn’t have a high school hockey team.

MAURICE
Right. Who did you root for as a kid?

RICH
Oh, growing up in New York, it was the Rangers, the Knicks, the Yankees, and the Jets.

MAURICE
Did you have a particular player that was sort of your idol?

RICH
Well, on the Yankees, as a kid, I mean, I’m giving away my age, the era of Roger Maris, Mickey Mantle, Yogi Berra.

MAURICE
Right.

RICH
Back in football, Joe Namath was coming on board with the Jets. And I guess that’s when I sort of went counterculture from everybody’s obsession with the National Football League.

MAURICE
Was there something that you really liked about Joe Namath? He was sort of controversial at the time.

RICH
Yeah, he was everything I wasn’t. So, yes.

MAURICE
Oh, that’s amazing. Right.

RICH
I liked his brashness, and he was good.

MAURICE
So that’s interesting. So early in life, you are this big New York sort of sports fan. You try out a variety of things. Were there anything else that you were good at? Or did you have hobbies that you really liked to do? Was there any foreshadowing of what you would eventually do professionally?

RICH
Like, I was always interested in science in school. So academically, I think that was the foreshadowing for my career.

MAURICE
So where did you go to college?

RICH
It was Iona College in New Rochelle, New York.

MAURICE
So when you got there, did you automatically know what you wanted to do? I know you majored in chemistry in college. Correct?

RICH
Yes.

MAURICE
Was that your first choice, your only choice? And where did that love come from?

RICH
Well, it was a lazy decision on my part. There regis–

MAURICE
How so? How so?

RICH
I’m registering at the beginning of the first semester in freshman year. And I’m asked the question, do I have any idea what I would like to major in? And the lazy part of me thought, well, science. I was always good at it and didn’t have to study that much. So it’s a no-brainer. Science is going to be my major. And then the follow-up question was, well, it would help to know in your freshman year whether it’s physics, biology, or chemistry, which then forced me to think, you know, where am I going to get the better grades? And that was chemistry. So literally, that’s the thought that went into my picking chemistry as a major.

MAURICE
So I’m really interested in how a person decides, I’m going to go from majoring in something in college, and instead of going into the workforce and finding my way in the world, I’m going to stay and do even more schooling. So what decisions went on with you that you decided that you were going to go ahead and get an advanced degree?

RICH
It was the end of my junior, year looking for work for the summer. I sent out a number of applications to pharmaceutical companies, other companies that had chemistry involved. And I ended up with a summer job with General Foods at their Technical Center in Tarrytown, New York, and spent an entire summer working on decaffeinating Maxwell House coffee. And what I realized as an undergraduate was that all the scientists with the bachelor’s degrees were the folks at the bench with the messy lab coats doing the work. The people actually planning the programs and the studies all had advanced degrees, and that was my awakening that, as much as I wanted to get out and earn some money–

MAURICE
Right. Absolutely.

RICH
–I might be better off going to graduate school for an advanced degree.

MAURICE
Where did you go?

RICH
Fordham University in the Bronx in New York.

MAURICE
So you go. You decide you’re going to work on a PhD. What was your thesis?

RICH
My PhD was in biochemistry of central nervous system. I was arrogant enough as a graduate to think that everything you needed to know about the other organs were already known.

MAURICE
Right. There was the nervous system and all that other stuff that it controls.

RICH
To paraphrase Captain Kirk, the brain was the final frontier.

MAURICE
That’s fantastic.

RICH
So I was working on understanding mechanisms of neurodegeneration.

MAURICE
So is it possible to walk us through your resume and highlighting the companies that you worked for and the positions that you had there?

RICH
OK, well, as I said, I spent the first five years at Hoffmann-La Roche in discovery research. So after five years there, I had a call from a friend who was working at Lederle Labs, just north of the New Jersey border. And they were looking to set up a biochemical pharmacology group within their department. Most of it was leaning heavily towards the behavioral end. And I ended up accepting that position. And I guess five years into that, we had a number of drugs that we identified that survived toxicology studies, were going into clinical development, but they didn’t have a clinical development group for neuroscience. So that opened an opportunity for me to shift. And I took the opportunity to switch it clinical and then spent about the next 25 years in clinical. Lederle then merged with Wyeth Research, which brought my wife and I down to this area in Philadelphia. I left Wyeth after about 20-plus years between Lederle and Wyeth. I wanted to work for a much smaller company, which was Adolor [INAUDIBLE] next and with a focus on pain medications, hopefully nonopioid. We saw the writing on the wall when I was there in 2006.

MAURICE
So that’s really interesting when you say you saw the writing on the wall. People within the industry understood that there were some upsides to opioids when it– with regard to controlling pain, but then the downsides were considerable.

RICH
Well, the biggest upside is that there is no analgesic out there as potent opioids. The downside is that it’s a very addictive drug.

MAURICE
It’s very addictive.

RICH
And if you have chronic pain and take them chronically, you can see how that can develop into–

MAURICE
Like a full-blown addiction.

RICH
–an addiction. So the hunt was always on. There are a number of opioid receptor, subtypes, alpha, delta, mu. Could some of those other subtypes have the analgesic effect without the effect of the addiction? But it’s a tough field. Nobody’s gotten there yet.

MAURICE
Do you, with your understanding of the field, do you think it’s only a matter of time before we’re able to develop something with all the benefits of pain relief with none of the addictive properties?

RICH
Yeah, I think more effort or more time going into the tougher problems. It was extremely easy to synthesize another opioid or to change a formulation from something that– morphine is short acting because it’s metabolized quickly. So the next step was something longer acting. And now you can see where this was starting to go downhill. And it’s better in terms of analgesia. But, you know? I feel like there’s a larger question about drug discovery and its relationship to the public in general here that the sort of the evolution of opioids has to teach us. And that is, so nothing’s perfect, and all drugs have side effects. And as a– both as a society and as a government that oversees how these things are developed and then allowed to be released, we all have to make decisions. How much downside, how many people can be affected in a negative way before we go, enough is enough, or that’s too much?

MAURICE
Do you think we’re more knowledgeable today than we were at the beginning of the development of opioids about how we should think about that?

RICH
In the case of opioids specifically, yes. In the broader context of all drugs across all classes, I don’t think so. I think our educational system could do a lot better educating people in this, in the science and in the meaning of drug development. I think pharmaceutical companies could do a lot better educating the public. And there’s a role for the government in that as well. A lot of people think once a drug is approved by the FDA, it’s safe. But FDA’s approval simply says that the potential benefits outweigh the potential risks if it’s used to treat this specific indication like the studies were conducted. And that’s where people have to understand what drug development is. That approval could be based on treating as few as 3,000, 5,000 patients. Well, if there is a serious adverse event that’s rare and only occurs in 1 out of every 10,000 or 20,000 patients, you may never see it in the development process. So you have to have an understanding of what the limitations are of the data that go into the drug approval. And you see it now with the outbreak of measles.

MAURICE
Measles, right.

RICH
That– and, unfortunately, social media is acting as an amplifier.

MAURICE
It doesn’t help.

RICH
And there’s more misinformation–

MAURICE
Right.

RICH
–being put out than there is correct information to be amplified for it. And that leads to big problems.

MAURICE
So it’s very funny, but it seems that we live in a society that is of two minds when it comes to drugs. We live in a world where we have an antibi– an overuse of antibiotics put up in everything. Everybody wants to get them. If you get a runny nose, do you just call your doctor up and ask them for an antibiotic? Clearly, we believe in how efficacious they are. But on the other end of the spectrum, we’re really, really skeptical about getting vaccines. How they’re developed, we don’t understand it. It seemed– this is one of those examples where a little bit of knowledge seems to work against us. We know that there might be some live, attenuated viruses in there somewhere. And that makes us feel like that can’t be a good thing. In that case, the industry doesn’t know what it’s doing and doesn’t know. So like how do we– is there some– is there a middle ground that we can reach? And how do we get that?

RICH
Well, it is. And I think, and, again, it comes down to education. You brought up antibiotics. And the reason I think a lot of people believe in those and turn to those is you get the infection, and then you’re treated with the antibiotic to eliminate the infection, where a vaccine, you’re healthy. You’re being given something to prevent getting it–

MAURICE
Right.

RICH
–disease.

MAURICE
Right.

RICH
And there’s another problem too because there are a number of folks out there who are of the opinion that, well, if everybody else is getting vaccinated, I don’t have to expose my child to a potential risk, as small and as rare as that risk may be, because the rest of the herd is protected.

MAURICE
Is already protected.

RICH
And my child won’t be. Well, you can see when enough people adopt that attitude where it goes. And we’re a much more connected world now than we were four decades ago where you hop on a plane, and you could fly between London and the United States or anywhere around the world. And there are examples now of somebody stepping off a plane who, at least when he decided or learned that he had measles, went back and told the CDC. He told them the flight, and they had the manifest for that flight. So now they’re contacting all those people.

MAURICE
Right.

RICH
And unfortunately, if one of those people come down with the measles, then you have to try to see where they were.

MAURICE
So even though walking into any, like, CVS or Walgreens, it seems like we have tons, thousands of drugs. I don’t think people have a sense of how difficult it is to get a drug from the discovery phase to it actually being on a shelf somewhere. Could you kind of explain what that process looks like, both in its steps but also in its timeline?

RICH
Sure. I mean, the process begins with some understanding of a biological basis of the disorder to the extent that that information exists. For a lot of disorders, neurological disorders, for instance, where certain brain cells are degenerating for cancers where there’s a lot known about the biology, immunology of the tumor, you can identify a target, hypothesize that that’s a target, design a molecule to either enhance activity or inhibit activity. You can test those in vitro. You could test those in vivo and, from there, take it into the studies that you need to supply enough safety data to then take it into humans. In other areas, psychiatry for instance, unfortunately, a lot isn’t known about the neurobiology of depression and anxiety. And I’m speaking as if they’re two distinct disorders where, in effect, they’re a spectrum. So not everybody’s depression or anxiety may have the same biological underpinning. But in that field, which is where I spent most of my career, you can mimic what you hope are certain symptoms of anxiety or depression in a rodent, and treat them with the drug, and see if it ameliorates that behavior. And that gives you enough impetus to take it into the preclinical safety studies to then file an investigational new drug application with the FDA or its equivalent outside the United States and then do all the clinical testing.
You talked about timelines. From your first discovery studies, we could be spending four, five, to six years there alone. The preclinical safety studies can take another year to two years. And then your clinical program could take another five or six years. So add it all up, it ends up being somewhere between 15 and maybe 20 years to get the drug towards the end.

MAURICE
Are there some low-hanging fruits? Are there some diseases out there that maybe you have worked on and you’ve read a lot about that you think, that’s right around the corner. We’re about to eliminate that from the human condition.

RICH
Boy, tough question. Because my immediate answer was going to be the immunological approaches to treating cancer. And that, will it eliminate cancer? No. Because what we’re trying to do now is treat it in patients who are already exhibiting it. And I don’t want to make that sound like it’s an easy process because tumors adapt readily to all sorts of biological interventions. Most biological systems do.
I mean, that’s the reason why people become addicted to opioids. You continually stimulate a receptor, the opioid receptor. It’s natural response is to down regulate. Well, that means there are fewer opioid receptors. You give more drug to try to overcome that, and it just escalates.

MAURICE
It’s the dynamic nature–

RICH
Yeah.

MAURICE
–of the system that forces the change–
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RICH
So trying to understand those processes as well can go a long way to helping bacteria generations mutate over weeks and months. That’s where the resistance is showing up. So I think the wise response is to use them judiciously now to prevent that from happening. But is there a way to understand what’s driving that mutation and how to stop that at the same time that you’re destroying the bacteria?

MAURICE
Oh, right. So we hear a lot about big pharma in the news. It’s just kind of a catch phrase. And it sort of has a negative connotation normally when it’s used. Actually, you put the word “big” in front of anything, and it has a negative connotation. Big education has a negative connotation. What is– how do you respond to the general feeling that people seem to have about the pharmaceutical industry?

RICH
Well, I think a lot of the general reaction, the negative reaction in particular, is due to a misunderstanding and not having enough access or not looking for the information that’s needed. We discussed that it is an expensive process to get through. A lot of breakthroughs come from small companies, some of them private, some of them in their initial stages of funding. But it would be extremely difficult for them to carry it all the way through development, manufacturing, and launch. So even in those cases, you may be turning to a big partner to deliver on that for you. So I guess one of the other aspects that big pharma gets criticized for is, quote, “having researchers in their pockets.” And I don’t think it’s necessarily true. Yes, there are instances where one or two people have abused the system and, in particular, more on the marketing end. But opinion leaders are needed. I mean, these are key scientists who have labs, NIH, in academia who are experts in their area. So pharmaceutical companies need and should be taking advantage of that. And there are ways to do it. It creates a problem because of the perception that they’re biased because they’re consulting for you, that when you go to the FDA for approval, and if they have an advisory committee meeting outside of the FDA personnel, all the other advisors are independent researchers. And then they tend not to use the people who were the key opinion leaders for it because of this perception of bias. So I’m not quite sure.

MAURICE
So if you had all the funding in the world, what would you work on? Or what would be your next big project?

RICH
Well, I’m going to play to my background and bias in psychiatric illness. I don’t want to shortchange. I could pick almost any therapeutic area. But having spent most of my professional career working on those– you know, and it depends, I guess, on which side of the bed I’m getting out on in the morning. Sometimes I think great strides have been made. And other times, I think, are you kidding me? This is as far as we’ve come in that time?

MAURICE
So when you think about one thing that you’re really surprised that we haven’t made any more progress than we have, what do you think about?

RICH
I think that we need to spend more on some fundamental research to understand the biology, neurobiology in the case of psychiatry, that I picked out for it. Again, not all depression is equal. Not all anxiety is equal. Not all schizophrenia is equal. We need to know what the differences are. Is it genetically predetermined? Is it predetermining a susceptibility to it? And if that’s the case, what triggers it? And then I’d spend some of that unlimited funding and all the money in the world on the treatment– and that of all the illnesses that’s out there, the most underserved is psychiatric, which is disappointing.

MAURICE
So with regard to drug development, what dictates what we fund and what we don’t fund?

RICH
What just jumped in my mind is, you know, nothing succeeds like success. And unfortunately, I think, in psychopharmacology, drugs for treating psychiatric disorders, there’s a high failure rate. The measures by which these drugs get approved are behavioral measures. It’s an interview with a psychiatrist. You have depression rating scales, anxiety rating scales. And the structure of a clinical study is different than medical practice. So if I had a three-month depression study running, the patients in that study are seeing the physicians at the very beginning, at the end of week one, week two, week four, week eight, week 12. No one being treated for psychiatry– for depression sees a psychiatrist that often. This tends to lead to a higher placebo response. The higher placebo response, you don’t show a difference between treatment, and the drug isn’t approved. So I think the failure rates there have historically been pretty high. And it doesn’t take a big economist to realize, if I’m a pharmaceutical executive, where can I put that money that has a payout equal to that or bigger with a better success rate? But I can’t blame. It’s limited funding out there. You have shareholders you have to respond to. You have to fund additional studies. Hopefully, you haven’t abandoned a field entirely. You may de-emphasize it, placing more money where you have more success, allowing you to raise more capital to get back into those other areas. And as more becomes known about the causes of those or in those other disorders, you’ll see a shift back. But I think this is what tends to guide it.

MAURICE
Richard, thank you for being on the 10,000 Hours.

RICH
Yeah, thank you for having me.

MAURICE
Drexel’s 10,000 Hour podcast is hosted by me, Maurice Baynard. Our producers are Shaun Fitzpatrick and Nathan Barrick.
Drexel’s 10,000 Hours podcast is powered by Drexel University Online.
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