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Join us as we explore the history and evolution of the orphan drug revolution with James Geraghty, a health care executive. Discover how the pharmaceutical industry of the 1970s, driven by a pursuit of predictable profitability, led to the neglect of rare diseases and the rise of the orphan drug revolution. Get an inside look at how the intersection of science, medicine, and entrepreneurship has improved the lives of thousands of patients through innovative therapies.

James Geraghty is a health care executive.

He shares his story and discusses his book, Inside The Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology.

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Transcript

Kevin Pho: Hi, and welcome to the show. Rate and review at KevinMD.com/rate. Subscribe at KevinMD.com/podcast. Today on the show, we have Jim Geraghty. He’s a health care executive. He’s the author of the book Inside the Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology. Jim, welcome to the show.

James Geraghty: Thank you, Kevin. It’s a pleasure to be here.

Kevin Pho: So we’ll talk about your book in a little bit, but first off, just briefly share your story and journey to where you are today.

James Geraghty: Sure, thank you. I started in the orphan drug world actually 40 years ago, just about the same time the Orphan Drug Act was passed and helped trigger the orphan drug revolution. I started working as a consultant to a company hoping to develop safer therapies for hemophilia, around the time of the tainted blood scandal, when HIV had devastated the hemophilia community, and I was inspired by the power of what effective therapies could do.

Kevin Pho: Wonderful. So before getting to your book, let’s get everyone on the same page. What is an orphan drug?

James Geraghty: An orphan drug is a drug for an orphan disease. An orphan disease would colloquially just be called a rare disease. It’s technically defined in the Orphan Drug Act as a disease in the United States that afflicts fewer than 200,000 people, which is less than one-half of 1 percent of the population. There are similar definitions in other countries.

Kevin Pho: All right. And what are some examples of orphan drugs, so my clinician audience would get a sense of what we’re talking about?

James Geraghty: You know, there’s a small number of genetic diseases that are well known. They are orphan, but they’re widely enough known that most people know them, and most of your physicians know them well. Those include diseases like hemophilia; muscular dystrophy, the various forms of muscular dystrophy, Duchenne and others; cystic fibrosis, the most prevalent monogenic disease in Caucasian populations; and sickle cell disease, the most prevalent monogenic disease in African American populations.

But there are 7,000 identified monogenic diseases, and one of the reasons it’s a pleasure to have a chance to talk with your audience is that most physicians, when they go through medical school, never hear about most of them, right? They’re kind of an alphabet soup of metachromatic leukodystrophy and adrenoleukodystrophy and so many others that people don’t know, or they’re named after obscure 19th-century European discoverers, like Gaucher disease, Fabry disease, Pompe disease, and many even rarer than those.

Kevin Pho: All right. And you wrote about this in your book, of course, Inside the Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology. So tell us some of the major issues that face orphan drugs today. Why is it that you needed to write a book about this? What are the major challenges that this industry faces?

James Geraghty: Collectively, these 7,000 diseases are estimated to afflict almost 30 million Americans, almost 10 percent of the American population. But most of them go undiagnosed for many years, because physicians are not aware of them and don’t recognize the symptoms. Patients are regularly misdiagnosed for many years and mistreated. And the true tragedy, Kevin, is that many, if not most, of these diseases have an onset at birth or in infancy, and they are rapidly progressive. If identified and treated at birth or soon afterwards, with the therapies that are available today, patients can live normal, healthy lives. But if left untreated for even a few years, they progress irreversibly, both physically and neurologically, in ways that are tragically irreparable.

So the more we know about early diagnosis, and newborn screening is a major priority, the more we’re able to develop and bring these therapies to people. And then the second issue, which we’ll come back to in a moment, I’m sure, is the challenge of developing new therapies, which is really what’s on the future horizon.

Kevin Pho: Sure. So before moving on, just to illustrate the point, tell us a story or a case study that would really bring the point you just made to life.

James Geraghty: There are a lot of examples. Today, there’s metachromatic leukodystrophy, or MLD. There’s a therapy for that disease called Libmeldy that’s approved in Europe. It was approved by the European Medicines Agency, now I would say two, maybe two-plus years ago, and it’s still not approved by the FDA, because the regulatory bars are so high and so complex.

And sadly, there are children being born with metachromatic leukodystrophy in the United States today who, first of all, are not diagnosed, because we don’t have newborn screening available in the states in which they live, and secondly, do not have access to the therapy that’s available in Europe. Those children, if treated at birth, could be playing soccer as children. Untreated at birth, they’ll be wheelchair-bound and incapacitated for life.

Kevin Pho: And just give us a sense of the bar that the FDA sets. Contrast that to Europe. What are the major differences, with that bar being so high?

James Geraghty: Yeah, they’re very complex matters. The bar is high, appropriately high, in both jurisdictions, as it should be. The issue is that we need regulatory flexibility that recognizes the case of these orphan, or, as we often call them, ultra-orphan diseases, these very rare diseases. It concerns some of the standards around what’s called, in the regulatory world, CMC: chemistry, manufacturing, and controls, the manufacturing side of drugs. There are traditional requirements around things like process validation and lot comparability, which, when you’re only treating a handful of patients, are extremely difficult to demonstrate.

And so what we need is much more flexible use of what’s called accelerated approval, where drugs are approved for these chronic, devastating diseases with very safe therapies, and then, over a period of years post-approval, we can confirm that all the things we thought we saw are validated, or the drugs can be withdrawn. In some cases, senior officials at the FDA speak out very strongly in favor of the use of this process. But when you get into the bowels of the organization, the bureaucracy, a kind of conservatism sets in, and the flexibility that the leaders of the agency are calling for doesn’t get applied.

Kevin Pho: Who are the companies that, in general, create these orphan drugs?

James Geraghty: In general, they’re created by biotech companies. Many people are aware of big pharma companies. I’m sure your listeners are aware that the genetic engineering revolution created biotechnology, with Genentech the first company to really become a celebrated leader. Genzyme Corporation, the company I had the privilege to work for for over 20 years, is widely considered the founder of the orphan drug revolution. Henri Termeer, the longtime president and CEO, is often seen in that light, and I tell that story at length in my book.

But Genzyme has now been acquired by a French company, Sanofi, and today there’s been an explosion of new companies. Some of them are well-known mid-sized biotech companies, from Vertex and Biogen to Alnylam and BioMarin, but there are hundreds of small biotech companies, many in Boston or in the Bay Area of San Francisco, that are working on many new therapies for many new diseases with new platforms like RNA, gene editing, and gene therapy, the genetic therapies that will be the wave of the future.

Kevin Pho: So can you comment on the economics of orphan drugs? I can only imagine, by definition, these drugs aren’t prescribed very frequently, if at all, just because, of course, these are for rare and ultra-rare conditions. So what are the economic incentives for these biotech companies to create and expand the role of orphan drugs?

James Geraghty: That’s an important topic, and I address it at length in the book: the incentives, the affordability, and the sustainability. Probably the key provision of the Orphan Drug Act was providing a period of extended market exclusivity for these drugs, which, by the time they come to market, by the time they’re approved, are often nearing the end of their patent life. And so the Orphan Drug Act provides a period of seven years of market exclusivity to allow companies and investors to recoup the cost of their investments. That’s been central to the flowering of orphan drugs.

But today, there’s a lot of pressure. People listen and hear all the time about campaigns on Capitol Hill to cap drug prices or lower drug costs. What’s important for people to understand is that what matters to patients and families are the out-of-pocket costs incurred through their insurance policies, their co-pays, and their deductibles. No patient pays, or should pay, the list price of an orphan drug. And so insurance companies often try to kind of confuse patients by making them think that the price of the drug is the problem, whereas it’s the insurance costs that are the problem.

Today, because these drugs are so rare, because these diseases are so rare, they have not driven up the overall cost of health care or even drug spending. But if the incentives are further reduced, well, today we are in a climate of a kind of freeze on investment, because people are so concerned about the lack of adequate reimbursement, and that continues today. Companies are going bankrupt, programs are being terminated, and we’re at risk of losing the momentum that’s been generated.

Kevin Pho: All right. So in your book, Inside the Orphan Drug Revolution, what are some of the high points that you want readers to come away with?

James Geraghty: Well, I think there are a couple. The reasons I wrote the book: Number one is to celebrate and tell the stories of people I’ve been inspired by for 40 years. I’m not a physician or a scientist, but I’ve had the privilege of working with some of what I think are truly the best and brightest minds of our time, who are incredibly passionate and dedicated, and of working with patients and patient advocates to create miracles. I tell the story of miracles and of these different therapies that have been developed against all odds, and their stories deserve to be known.

And secondly, for the reason we were just talking about: These orphan diseases can strike any family. Sometimes people think genetic diseases, quote, “run in families,” and if you don’t have one in your family, you don’t need to worry about it. But as you know, they can strike any family. If people want to be sure that their children, their grandchildren, their nieces, and their nephews have access to these therapies, it’s important to maintain the patient advocacy that got the Orphan Drug Act passed in the first place and that is needed to sustain appropriate support for these therapies.

Kevin Pho: So tell us about the future, in terms of what you think the road map is for these sometimes smaller biotechnology companies, for orphan drugs, and for their impact on the larger pharmaceutical industry as a whole.

James Geraghty: Well, to your last point, it’s had a big impact on the pharmaceutical industry, because much of the innovation has come from these biotech companies and these rare diseases, and so they have transformed the industry. But the future is challenged, because increasingly, the diseases that are untreated are these ultra-orphan diseases. The economic incentives are very challenging. The economics of one-time therapies are very challenging. Gene therapy offers the promise of a one-time administration with a lifetime of benefit, but if you look at the way reimbursement systems work today, companies will receive far less reimbursement over the life of a patient for a one-time administration than they would for today’s standard of chronic IV administration every two weeks or every four weeks. And so we need to address that; we need to provide incentives for these one-time therapies.

I think the bottom line, the way I would answer your question in one way, is that the future is very bright with regard to emerging new scientific technologies and our ability to find ways to treat these diseases. It’s much cloudier with regard to finding the financial incentives to support investment to allow those developments to proceed.

Kevin Pho: How are these drugs tested? Typically, drugs are tested double-blind and placebo-controlled, but for rare and ultra-rare diseases, sometimes that’s difficult to do. So in general, how are these drugs tested to make sure that they are indeed effective?

James Geraghty: Yeah, sometimes they are done in those double-blind, randomized, placebo-controlled trials, but sometimes, in truly ultra-orphan populations, it’s not feasible. And so a typical alternative would be what’s called a natural history study, and these have to be done very carefully. A company identifies untreated patients with the disease and, over a period of many years, typically with the support of academic physicians and of the patient community, puts together a very clear analysis of the path of the disease left untreated. Then, by identifying very similar, comparable patients to treat, it compares their results with the natural history cohort and is able to demonstrate a clear benefit based on that comparison.

Kevin Pho: And just to give us a sense of the economics in general: To develop an orphan drug, how much would it cost a biotech company to bring it to market?

James Geraghty: Well, it costs hundreds of millions of dollars to develop individual drugs, because of the cost of research, development, manufacturing, clinical trials, and supporting the infrastructure along the way. What’s even more important for people to understand, and again, I discuss this in the book, as others have, is that the risk of these programs is so high. We sometimes say 90 percent of all drugs fail. If you go back to the early stages of discovery, I think you could say 98 percent of all programs fail. Fifty percent of all programs that get into very expensive phase 3 clinical trials fail.

And so, for the programs that are successful, if we want research to be continued, if we want further investment in research and new therapies, the drugs that are successful need to cover not only the cost of developing that drug but also the cost of all the failures that are incurred along the way.

Kevin Pho: We’re talking to Jim Geraghty. He’s a health care executive, and he’s the author of the book Inside the Orphan Drug Revolution: The Promise of Patient-Centered Biotechnology. Jim, tell us some of the take-home messages that you want to leave with the KevinMD audience.

James Geraghty: Well, Kevin, first of all, I appreciate this time. I think many of your listeners are probably hearing more and more about these diseases and this movement. It’s becoming much better known. And I think, for all of them, there are active patient communities worth engaging with. These patient communities are inspiring. I’ve been inspired by them. They are the ones on the forefront of energizing new research, new clinical trials, and movements like newborn screening and early diagnosis. I encourage those of your listeners who are in the medical community to engage with those groups. I think they’ll be inspired by them, and hopefully they can find some way to contribute to the continuing improvement of therapy for them.

Kevin Pho: Jim, thank you so much for sharing your time and insight, and thanks again for being on the show.

James Geraghty: Thank you, Kevin. It’s my pleasure.