Print BCTV: Profiles: Orphan Drug Act -- Sickle-cell therapies; Profiles in Innovation: rare disease, Rep. Waxman

Profiles: Orphan Drug Act

Transcript of BioCentury This Week TV Episode 179




Dr. Kim Smith-Whitley, Chief Medical Officer, Sickle Cell Disease Association of America

Mattie Robinson, William E. Proudford Sickle Cell Fund

Rachel King, CEO, GlycoMimetics


Abbey S. Meyers, President Emeritus, National Organization for Rare Disorders

Ms. Leanna Mullen, Gaucher's Patient

Emil Kakkis, President and CEO, Ultragenyx Pharmaceuticals Inc.

Frank Sasinowski, Director, Hyman Phelps & McNamara, P.C.




UCLA-Harbor Medical Center

American Society of Hematology

Tourette's Syndrome Association, Inc.

National Gaucher Foundation

Ryan Foundation for Orphan Disease Research

National MPS Society

International Conference on Harmonisation


Dr. Marion Finkel, former director, Office of Orphan Products Development, FDA

Janet Woodcock, director, Center for Drug Evaluation and Research, FDA


John K. Jenkins, M.D. Director, Office of New Drugs, Center for Drug Evaluation and Research


Dr. Robert Temple, Deputy Center Director for Clinical Science and Acting Deputy Director, Office of Drug Evaluation and Research, FDA


Congressman Henry A. Waxman (D-CA)

Senator Orrin G. Hatch (R-UT)

Ronald W. Reagan, 40th President of the United States

Senator Samuel Dale Brownback (R-KS)

Senator Sherrod Brown (D-OH)


Naglazyme galsulfase, BioMarin Pharmaceutical Inc.

Kuvan sapropterin, BioMarin Pharmaceutical Inc.

Aldurazyme laronidase, Genzyme Corp.

Cerezyme imiglucerase, Genzyme Corp.

United Therapeutics Corp.

Flolan epoprostenol, GlaxoSmithKline plc

Suboxone buprenorphine/naloxone, Reckitt Benckiser Pharmaceuticals Inc. Subutex buprenoriphrine, Reckitt Benckiser Group plc

Remodulin treprostinil, United Therapeutics Corp.


National Institutes of Health

Food & Drug Administration


Jack Klugman, Actor

Maurice Klugman, Television Producer

Quincy, M.E. (TV Series 1976-1983)



Steve Usdin, Senior Editor




STEVE USDIN: Sickle-cell patients told FDA what it's like to live with the disease and their hopes for new treatments. Today, they'll tell us. And in today's Profiles in Innovation, how one law unleashed treatments for hundreds of rare diseases around the world. I'm Steve Usdin. Welcome to BioCentury This Week.


NARRATOR: Connecting patients, scientists, innovators, and policymakers to the future of medicine. BioCentury This Week.


STEVE USDIN: Medicine and society have left sickle-cell disease patients behind. The blood disorder was identified in 1910, and the pattern of inheritance was described in the 1940s. There still isn't a cure. Sickle-cell patients struggle with pain and life-threatening complications, and patients are stigmatized by society and even by the medical profession.


This month, sickle-cell patients told FDA what they need to improve their lives. Today, we'll hear from a patient who spoke at FDA's meeting, Mattie Robinson of the William E. Proudford Sickle-Cell Fund, from a leading sickle-cell researcher and clinician, Dr. Kim Smith-Whitley, and from Rachel King, CEO of a biotech that's developing a sickle-cell therapy.


Joining us today are Mattie Robinson of the William E. Proudford Sickle-Cell Fund and Dr. Kim Smith-Whitley, Chief Medical Officer of the Sickle-Cell Disease Organization. Mattie, to start with, can you give us an idea -- what's it like to live with sickle-cell disease on an average day, and what's it like on the worst day?


MATTIE ROBINSON: For myself on an average day, I struggle with fatigue, so it's very important to eat a balanced diet and get plenty of rest. Also, on the worst day, I experience acute pain and even more severe fatigue, so I end up having to go to the hospital, and it really disrupts my life for several hours while I'm getting treated and getting back on track.


STEVE USDIN: And what are the kind of treatments that patients use? Mattie said she goes the hospital. What are the kind of treatments patients can get when they're in the hospital with a kind of crisis for the disease? How does that look like, and what are the things that they can do for the disease in their average lives?


DR. KIM SMITH-WHITLEY: Unfortunately, most of the care that we have for individuals living with sickle-cell disease is supportive care. So if they're having pain, they have medications that we can use to lessen the pain, but that pain episode itself will go through its natural course. It would be better if we had treatments that were more focused on treating the underlying mechanisms behind sickle-cell disease so that that treatment itself could then impact and shorten the duration of the episode. We have supportive care. We have transfusion therapy. We have other medications that are sickle-cell focused, but there are very few.


STEVE USDIN: So you've described you've got this constant pain and fatigue that you've got to deal with, but there are also long-term effects of the disease, aren't there?


MATTIE ROBINSON: Right. Long-term, people struggle with cumulative organ damage due to ischemic injuries that occur during these acute crises, and for people who have chronic pain during lower profusion rates in those areas. Also, people develop wounds in their extremities. I don't deal with that complication itself, but it's widely known. I did, however, have to have a joint replacement due to lack of blood flow to my femoral head. So some complications you can treat and bounce back from. Other complications develop and then you have to learn how to live with that on top of everything else.


STEVE USDIN: So both of you attended the meeting that FDA had recently where they asked patients to talk about their experience with the disease. What were your takeaways from that meeting?


MATTIE ROBINSON: I thought the meeting brought awareness to the different genotypes under the umbrella of sickle-cell disease. People stood up and talked about their symptoms as carriers with one wild-type hemoglobin allele and sickle-cell allele, so that was important, I thought.


DR. KIM SMITH-WHITLEY: I think the other thing that was really important was the wide variety of experiences in individuals living with sickle-cell disease, whereas fatigue, sleep disorders, and other patterns emerged, as well as the pain, strokes, the lung complications, the bony complications. You really began to see that individuals living with sickle-cell disease experience things daily, not just within that hospital in-patient experience, but also on a daily basis. And I think it brought those symptoms forward.


STEVE USDIN: One of the other things I know that you've talked about, both of you, is stigmatization that people with sickle-cell feel. Can you talk about that a little bit?


MATTIE ROBINSON: Stigmatization with regards to sickle-cell -- I've experienced it from many different sources, either from family members who found it difficult to relate -- it's not like I can say, oh, it's hard for me to breathe, or something like that. It's difficult to relate to someone saying their bones feel like glass. Also in the workplace and in school settings, it's difficult for people to understand needing to compensate for unexpected trips to the hospital or unexpected bouts with fatigue that you just have no choice but to deal with.


DR. KIM SMITH-WHITLEY: In the medical community, sickle-cell disease is a fairly rare disorder, with 80,000 to 100,000 individuals in the U.S. living with sickle-cell disease. And when you have a disorder that's associated with acute pain, and you need to come to the emergency department, where often, there are not many practitioners experienced in the care of sickle-cell patients, then often, that pain may be misinterpreted as seeking drugs or other substances. And so unfortunately, that's really stigmatized individuals living with sickle-cell disease and made them isolated.


STEVE USDIN: Let's talk about that more and what it's like to live with sickle-cell disease in just a moment. First, a snapshot of the disease.


NARRATOR: You're watching BioCentury This Week.




STEVE USDIN: We're speaking with a sickle-cell advocate Mattie Robinson and sickle-cell specialist Kim Smith-Whitley. We were talking about stigmatization there a moment ago. I would imagine that also probably prevents people from even going to the hospital to get treatment if they're going to be treated like they're a drug seeker.


KIM SMITH-WHITLEY: And that was one of the things that really came forward in the FDA meeting this past week, is really that it's an isolating disease, because you don't want to come to the emergency department, you don't want to involve people in your community, because you're afraid that you'll be considered not a worker, not a good student. You're often absent when others are present.


And so it becomes very difficult. So yeah, I think that stigmatization spreads into all different environments.


STEVE USDIN: And what about screening for the disease? How thoroughly do people get screened in the United States and then get the follow-up treatment that should have?


MATTIE ROBINSON: There's a lot of variation in screening between the states in the U.S., because there are national recommendations and guidelines. But it's up to individual states to implement their own policies. And even states that do have screening programs, the follow up is also similarly individually controlled. So for instance, Maryland has a screening program and very good success with following up with babies who are identified to have sickle-cell disease, whereas the state of Florida doesn't have a very good success rate at all.


KIM SMITH-WHITLEY: And screening doesn't capture all, because we also have a very wonderful population of individuals who come into the U.S., who may not be appropriately diagnosed with sickle-cell disease in their home countries, and then come here and are often missed. So I think it's important to include screening into older age groups as well.


STEVE USDIN: One of the things that's interesting there also is that people think of sickle cell as an African-American disease, and of course, it's more prominent in African Americans. But it's not just African Americans, is it?


KIM SMITH-WHITLEY: You're correct. People of Greek and Italian ancestry can have sickle-cell trait and disease. Often in central India, anywhere in the Diaspora and in the Afro Caribbean, you can see sickle cell emerge.


STEVE USDIN: So you mentioned sickle-cell trait and sickle-cell disease. It's very complicated. Very quickly, can you describe what sickle-cell trait, as opposed to sickle-cell disease?


KIM SMITH-WHITLEY: Sickle-cell disease often occurs when you have two genes that are hemoglobin variants, one from each parent. You get a sickle gene from one and a sickle gene from another or another hemoglobin variant. With sickle-cell trait, you have a normal hemoglobin variant and a sickle hemoglobin variant.


And there's a misconception that sickle-cell trait is an asymptomatic condition. But it's not always an asymptomatic condition. Those individuals can have complications.


STEVE USDIN: And that also then I guess spills over into the screening question again, because people need to be screened for that. To wrap up, one of the things that the FDA asked was, what would patients want other than just a cure for the whole disease? What was your response to that?


MATTIE ROBINSON: Well, my response is, I want a therapy that will address very specifically the tissue damage and ischemia associated with an acute crisis, because when I am in that state, I worry about the damage being done to my body. And in some cases, it's irreparable damage.


In other cases, I feel like I heal all the way.


STEVE USDIN: So patients come into the hospital, they have this crisis. And you can help them get over it with supportive care. But they're suffering some kind of progressive damage. Is that the idea?


KIM SMITH-WHITLEY: That's correct. There's already a process that started with this vaso-occulusion and the ischemia that really needs to be halted in an innovative way. And therapies directed toward that could theoretically shorten the duration of these episodes.


STEVE USDIN: Great, thanks. That's all the time we have today. In a moment, we'll hear from the CEO of a company that's developing a new therapy for sickle-cell anemia.






STEVE USDIN: To talk about the realities of developing treatments for sickle cell, I'm joined by Rachel King, CEO of GlycoMimetics. Rachel, FDA is having a meeting, and they're gathering input from patients about their experience with sickle cell and what they're looking for in therapies. How does the patient experience factor into your job of developing a drug that can be a therapy for sickle cell?


RACHEL KING: First, I want to say it's wonderful that the FDA has recognized the unmet need in sickle cell by convening this meeting. I think it's very exciting and important. From the standpoint of a company, we look at the patient perspective from a number of angles. One is looking at the endpoints that would be relevant to the patient's experience of the disease.


These are very consistent with what the clinicians also identify as being important. The other is from the aspect of recruitment and trying to look at how we might design the study and how we might run the logistics of a study to facilitate patient enrollment in the clinical trial.


STEVE USDIN: And you've got top-line results from a Phase II trial that have been announced. What have you got?


RACHEL KING: Well, we just presented those results actually last month at the ASH meeting -- the American Society for Hematology. And we were very pleased with the reception that we got. It was chosen as one of the presentations selected for what they call best of ASH. So we were very gratified by that and by the reception in the hematology community in general.


We looked at several things in that study. We were looking at the effect on the duration of crisis, we were looking at whether we could get patients of IV narcotics faster. And we were looking at whether they used less narcotics when they were on our drug. And we got some very encouraging results on all of those endpoints.


STEVE USDIN: Can you explain the first? What do you mean by the duration of crisis? What is a crisis? What kind of results did you get?


RACHEL KING: Sure. In fact, that's a great point. We need to think a little bit about what we were trying to treat. The specific indication is called vaso-occlusive crisis. And vaso-occlusive crisis occurs when a red blood cell becomes sickled, and it no longer can traffic smoothly through the small blood vessel. So the sickled cells pile up and clump with other red blood cells and form these small occlusions that are spread out throughout the body of the patient so that the person experiences exceedingly painful events.


These are debilitatingly painful crises. And currently, they can only be treated with narcotic pain relief and supportive care. In the United States, patients come into the hospital, they're hospitalized, on average, for about six days. And during that time, they get the pain relief and the supportive care through the conclusion through the natural resolution of the crisis.


So what we were trying to do was to look at whether we could reduce the duration of the crisis or the intensity of the crisis or reduce the need for narcotics. And in fact, on all of the endpoints that we studied and in all of the sub-groups that we looked at, we did see important improvements on those endpoints.


STEVE USDIN: Taking it one at a time on that the duration of the crisis, on average, how much did you decrease it?


RACHEL KING: We decreased it by two-to-three days, depending on the statistical method that you use. I should say we did not achieve statistical significance in the primary endpoint. But there was a lot of variability in the patient population. And we believe that with a larger study, we will be able to see significance. But now, we need to test it in Phase III and see if we do, in fact, see improvements along the endpoint that we've identified.


STEVE USDIN: And that was two or three days out of --


RACHEL KING: About six days.


STEVE USDIN: And the second endpoint, reducing the amount of narcotics that had to be used -- there was a big number there, wasn't there?


RACHEL KING: We saw an 83% reduction in the use of narcotics. And that was statistically significant. And that was a very exciting result. In many cases, these patients were on patient-controlled analgesics. So they were controlling the pain relief themselves.


And in this placebo controlled blinded study, they used significantly less narcotics when they were receiving our drug.


STEVE USDIN: And then the third thing -- how long they're in the hospital?


RACHEL KING: Yes, and there, again, we saw a two to three-day reduction in the length of hospital stay. And again, we hope that that continues to hold up when we look at the drug in Phase III.


STEVE USDIN: So that gets to another point, I think, which is, today into the current environment, it's not enough to develop a drug that helps people. You also have to be able to show some kind of economic advantage of it in order to get reimbursed for it. And that's where the reduction of hospital stay comes in.


RACHEL KING: Exactly, that's right. So in this case, I think there's a very nice alignment between the endpoints that we believe are going to be important to the patients, important to the clinicians, and important to the payers.


RACHEL KING: Rachel, GlycoMimetics is studying GMI 1070 in patients who are already in the hospital. Is there some reason to believe that the drug might actually be able to help people prevent them from having to go to the hospital in the first place?


RACHEL KING: That's a really interesting and very good question. And that's possible. We don't know yet. But that is something that we are considering studying going forward. We went into the acute setting -- that is to say, patients in the hospital -- because we thought it made sense in the early development to test it first for patients who are experiencing a crisis and being hospitalized for it. But it's possible that it could be tested in the emergency room setting or perhaps even an outpatient setting in the future to see if it could prevent hospitalization.


STEVE USDIN: I want to take a step back. Sickle cell is a disease that science has known about for over 100 years. It's probably the first or one of the first genetically-caused diseases to be identified. Why has it taken more than 100 years to start to have therapies that might actually affect the course of the disease?


RACHEL KING: Well, I think like a lot of biology, it's more complicated than perhaps it may seem initially. And so the complexity of the disease is one factor. The thing that's interesting and what's interesting about our compound is that sickle-cell disease classically is thought of it and it is a hemoglobinopathy. That is, it's a disease of the hemoglobin in the red blood cells.


What's been recognized more recently, and what our product, we think, affects is the inflammatory component of sickle-cell disease, particularly the inflammatory component during a crisis. So our drug actually does not affect the hemoglobin of sickle cell. We believe that it will affect the inflammatory aspects that are important in the crisis.


And that's why we're studying it in sickle-cell crisis.


STEVE USDIN: So you're not treating, actually, the hallmark feature of sickle-cell anemia, which is that red blood cells that get deformed into that sickle shape. You're treating the outcome of that.


RACHEL KING: That's correct. We do not affect the sickling. We do not affect the hemoglobin of the sickled red-blood cells. What we think we might affect is the inflammatory aspect of the disease, particularly the inflammatory component of the vaso-occlusive crisis. We do know that the drug acts as a selectant antagonist.


That is, it binds to this family of adhesion molecules called the selectants. And those are involved in the cell adhesion to the lining of the blood vessel. And they're also involved in activation of some inflammatory pathways and some pathways associated with thrombosis. So we hope that in sickle-cell patients, the drug will work by affecting those pathways in such a way as to reduce the effects of the sickle-cell crisis.


STEVE USDIN: Thank you, Rachel. We've been hearing about sickle cell, a rare disease. Next, in this month's Profiles in Innovation, we'll learn how a mother teamed up with a celebrity to pass a law that's created hope for millions of patients with rare diseases.


NARRATOR: Now in its 22nd year, visit for the most in-depth biotech news and analysis. And visit for exclusive free content.




STEVE USDIN: Medical innovation isn't always about drugs and technology, and scientists and physicians aren't the only innovators who transform lives. Today, we'll learn how a law, the Orphan Drug Act, unleashed a flood of new treatments, how a mom forged an extraordinary partnership with a member of Congress and a TV star to get the Orphan Drug Act passed, and we'll meet some of the many people who've dedicated their lives to helping people with rare diseases and some of those who have benefited from the Orphan Drug Act.


The story started in 1980, when a mom was unable to import a drug that had been helping her son cope with a devastating, rare condition, Tourette's syndrome. She called another mom, Abbey Meyers, whose son also had the neurological condition.


ABBEY MEYERS: The mother called me and said, what should I do? And I said, call your congressman. By the way, who is your congressman? And she said, Henry Waxman. And Henry Waxman is one of the most powerful people in Congress on issues that have to do with health. And so she called her congressman. He said, I think this subject is important enough to hold a hearing.


STEVE USDIN: Meyers, who later founded the National Organization for Rare Disorders, testified along with a physician and a patient.


ABBEY MEYERS: The following day in the Los Angeles Times, there was a small article printed about this young man who was sitting next to me and his problems of getting the drug. And then a couple of days later -- I was working at the Tourette's Syndrome Association at that time -- and somebody said, there's a man on the phone, and he says his name is Maurice Klugman and he's the brother of Jack Klugman. And he was a producer of the Quincy show, and he said, I think that my brother should make a show about this topic.


STEVE USDIN: The Klugmans broadcast a show about Tourette's and orphan drugs. A year later, Waxman held another hearing, and Jack Klugman testified. The publicity propelled the act through the House, but Senator Orrin Hatch refused to allow a Senate vote.


ABBEY MEYERS: Klugman decided he would do another show about a senator holding up the Orphan Drug Bill, and he said, what I want to do in this one is have a march on Washington. And so that second show actually got the law passed.


STEVE USDIN: President Reagan signed the Orphan Drug Act into law on January 4, 1983. It granted manufacturers a seven-year monopoly on drugs for rare conditions and tax breaks for testing them. Patients and families expected a flood of new treatments, but at first, they were disappointed. Frank Sasinowski helped implement the law at FDA.


FRANK SASINOWSKI: FDA anticipated that this was such a novel, important piece of legislation there would be an overwhelming response from industry. Unfortunately, that didn't happen.


STEVE USDIN: There were two major problems with the law.


FRANK SASINOWSKI: One was, it said that in order to be designated as an orphan drug, you had to prove that you were not patentable. Second, it said that you also, during the seven-year period of market exclusivity, that you couldn't recoup more than your cost of research and development.


STEVE USDIN: FDA and Congress collaborated to fix the Orphan Drug Act economic incentives, and biotech companies started making drugs that transformed lives. One of the first was Genzyme, which makes Cerezyme for Gaucher's disease. Without treatment, Gaucher's patients like Leanna Mullen would suffer from agonizing symptoms.


LEANNA MULLEN: I started having symptoms when I was about three or four years old. I'd wake up with almost a morning sickness problem, where I'd be vomiting and wouldn't be able to even get my day started. Finally, it was my stomach that was causing problems, and I was going to an OB/GYN in addition to numerous other doctors who weren't quite figuring out what my problem was. And in the end, they ended up realizing I had an enlarged spleen and liver, which ended up leading to a bone-marrow biopsy. And then they confirmed it was Gaucher's disease. So I was able to get the Cerezyme in intravenous treatment. So I was very fortunate to start intravenous right away, every two weeks. And since then, I've been doing pretty well.


STEVE USDIN: Cerezyme, like many orphan drugs, is extraordinarily expensive.


LEANNA MULLEN: There was a period of time where my parents insurance was no longer going to be able to cover the treatment. Well, the National Gaucher's Foundation has put together a care program so they're able to help subsidize the cost, because it can be as much as $50,000 a treatment without the insurance.


STEVE USDIN: Orphan drug advocates say the potential for profits is essential to incentivize drug development.


ABBEY MEYERS: The law is so effective because it was an economic problem, and we found an economic solution to solve the problem.


STEVE USDIN: Emil Kakkis led the development of three drugs for ultra-rare conditions, first as a researcher at UCLA Harbor Medical Center and then as Chief Medical Officer of Biomarin, a California biotech. Now, he's CEO of Ultragenyx, which last month raised $139 million in an IPO to develop orphan drugs.


DR. EMIL KAKKIS: The Orphan Drug Act was really instrumental in allowing those therapies to go forward. None of them had patents when we started this program, so in order to get people to think about investing in a rare-disease treatment, there has to be some belief that there is going to be a return for them in the end.


STEVE USDIN: Patient advocates have driven the development of orphan drugs, a path that now has been followed by the European Union and Japan.


DR. EMIL KAKKIS: The patients and the patient organizations can play a really important role in this process, particularly in the beginning. In the beginning, they can galvanize interest, help the researcher, the guy that's struggling in the lab and doesn't have any money and can't get anywhere with this disease that no one cares about and no one can pronounce. And gives him the shot and says, look, we really care about what you're doing.


FRANK SASINOWSKI: There are 7,000 rare diseases. Before the Orphan Drug Act became law, there were fewer than 10 therapies approved for any rare disease. Since 1983, now there are almost 400 therapies that have been approved. That's what the Orphan Drug Act has meant.


STEVE USDIN: You can see extended interviews from this month's profile, as well as previous profiles, at Have a thought about today's show? Remember, you can tweet about it using the hashtag BioCenturyTV. I'm Steve Usdin. I'll see you next week.




EMIL KAKKIS: I've been working in rare disease for 22 years. And I've worked on three drug approvals to date -- Aldurazyme for MPS1, Naglazyme for MPS6, and Kuvan for PKU. They're all three metabolic genetic disorders. Well, with MPS1, there's probably less than 1,000 on therapy today. And for MPS6, similarly, well less than 1,000 on therapy.


For PKU, the number is a little bit more. There's maybe 13,000, in the US, maybe a few thousand only on therapy. So these are all ultra-rare disorders. Well, for diseases like MPS1 or MPS6, these are devastating diseases that lead to death usually by teenage years in these patients. And it's not an easy death.


It's slow, progressive decline and often many admissions of the hospital and the ICU and crises for the family. So it is definitely a horrific disorder that you would not want to experience. For PKU, it's a little less devastating. But if you have high blood Phe levels that injures your brain, and your brain leads to a mental retardation and other problems.


So these kids also can have trouble if they're not controlled. That means they have trouble at school. They can't concentrate. They have trouble going to school.


And so it's an important one, maybe not as devastating as MPS disease, but PKU is pretty bad too. Orphan Drug Act was really instrumental in allowing those therapies to go forward. None of them had patents when we started those programs. So in order to get people to think about investing in a rare disease treatment, there has to be some belief that there is going to be a return for them in the end.


That's just the nature of the business. And in order to get millions and millions dollars to develop, you need to be able to have an ability to get it back at some point. So the Orphan Drug Act was essential in the initiation of those programs. Among all the provisions of the Orphan Drug Act, exclusivity is probably the most key and important one. In exclusivity, the difficulty is that you want to be able to know that without a patent and some compound that you can actually continue to go out and sell the product in a protected way.


That's what exclusivity is about, and that's why it's so important. But if you look at the other provisions, they're important, like the tax provision, et cetera. But I would say the top and most important piece is the exclusivity. The exclusivity of the Orphan Drug Act is really an essential step. And a step is essential in the beginning.


When you're in the room and you have a bunch of investors in front of you and you say to them, I want to take this disease XYZ, and I'm going to save these patients. And they say, well, why is that going to work? And what's the business case for that? You've got to be able to say, look, we have orphan drug protection.


If we get this product approved, we'll get seven years of protection in US, 10 years in Europe. And that will make it clear that we have a period of time where we can recover this that we're not going to lose the business right off the bat. And most of the time in rare diseases, everything is public domain. There's no patents, there's nothing done.


It's that immature as a business proposal. And you've got to have something to say, this is going to work, because, people don't want to invest anything in things that are not going somewhere. And it's just the nature of it. A lot of these people, some of the money comes from mutual funds or other things. A lot of people invested in these things. It's not just very wealthy people.


And when you invest your own money, you want some returns. It's the way the world works. And so you've got to be able to make that case. The Orphan Drug Act actually gives you the opportunity to say, look, it may be really small, but these patients are really sick. This is going to work.


And there's a case that this is going to last at least long enough to be able to get your money back and make something from it. The tax incentives really allow the business to make sense in the long run, because if you don't have the tax incentives, than a lot of the invested money takes forever to come back. And I think the challenge is, remember that it takes many years to develop a drug.


And then you launch it, and then you slowly build the revenue. All that time you have this money that you've put out and are trying to recover. The tax incentive just allows that return to come in a little center in the process, which makes the business case work better. And the better the business case, then the more of those really rare diseases can get treated. Without a good business case, it's hard to make the argument to why you're going to invest and get these things done.


And that's what I've learned. As a physician, I'm interested in getting the treatments developed. And the only way to make it work is to make sure that it makes good business sense to do so.


Well, Aldurazyme, I started the work in 1991. The companies didn't start investing until 1997. So six years or work before the companies even started. At that time, from '97, it took until 2003. So it took about five or six years to get developed.


We had to do two studies. It took a fair amount of time and international effort and more then $100 million spent. And yet with over $100 million spent, there's probably 200 patients or so on therapy in the US, or something like that. So that's a lot of money to spend for just a few patients.


Well, with Aldurazyme, the patient foundation played a really key role, because before the company stepped forward, the patient groups had stepped forward. Both the Ryan Foundation initially, the National MPS Society. The foundations kind of stepped forward to give you that early seed capital kind of money that keeps things going and moves it forward to the next level and prepares you so that if you can get a more significant investment from investors or from a company, in this case, you're ready to go, you're able to move the thing to the next level and take it to patients.


Well, the patients and the patient organizations can play a really important role in this process, particularly in the beginning. In the beginning, they can galvanize interest, help the researcher, the guy that's struggling in the lab and doesn't have any money, can't get anywhere with this disease, and no one cares about and no one can pronounce and gives him the shot, and says, look, we really care about what you're doing, we're going to help you.


And they realize they're not alone. And not only that, they have responsibility too. They've got someone they got to work for. And that gets it going. That rejuvenates what may be something was going to die and gets it going and builds it up and maybe gets a little bit more work. And then a company notices finally, because patients have been talking, and the company says, this is pretty interesting.


And maybe the patients find out, hey, it's not just a few hundred. Maybe it's a few thousand patients. Maybe there's more of us.


And by organizing themselves, they help create that sense that this is a disease worth working on and gets the information and gets a company to say, we should be working on this. The Orphan Drug Act was initiated the US in the '80s, but it's now present in Europe as well as in Japan.


And in three territories, certainly it's been extremely important in broadening the protection, which together, make the business case, because it's not just US. These commercial cases for these products are made worldwide. And by having the three major territories covered, that definitely helps.




EMIL KAKKIS: I think, first of all, I agree with you that orphan drugs cost a lot, sometimes shockingly expensive. And it's unfortunate. But the reality is, we're trying to treat a very small number of patients and spend a lot of money to get there. But what's more important than the price is access.


And it's really important than to assure that we put in place programs that allow patients to have access regardless of ability to pay. And what most companies do, for example, is set up a nonprofit that they provide a grant to. And that nonprofit can help support patients, pay for co-pays, pay for insurance. Or if they can't get free drug, and patient support programs are an essential part of being in the orphan drug business. It's the only way to make this work.


And so cost is terrible, but unfortunately, it's the reality of what you have to do when you're working with very small patient populations. There's definitely some difference in the cost of development for a very small disease and a large disease. But on a cost-per-patient, it's probably higher for a small population. In other words, even if you don't spend the total amount of dollars is less, the amount of money you spend for the number of patients around is that.


So as I said, we spend more than $100 million on 200 patients in MPS1. And there's no big pharma in the world that would spend that kind of money in that ratio for blood pressure or something. So yes, the cost of these programs are less. But on a per-patient basis, probably they're a lot more.


Well, I think access is an extremely important part of drugs and rare disease space and that companies who have very expensive drugs have to be thinking about how to make sure that patients get treated. I think that's just a necessary part of this symbiosis between companies and the healthcare system and the patients. So in doing that, what companies normally do is set up and organize foundation.


So it's an organized program that patients get access to. So it is organized. The question is whether the government needs to be involved in that, or not. I don't think so. I think that these organizations work quite well.


And they set standards for what it takes to get access. And the hope is that you don't end up with anyone falling through the cracks. But that's the goal of what companies do. The only place where it comes into public policy is that in the recent changes in healthcare system, there are some questions about the support policies that companies are providing and whether they're appropriate or not.


And if they were taken away, it would create a great stress on families who are really dependent on these things because of how expensive their drugs are. No one can really afford these drugs. Even very wealthy people cannot really afford these drugs.


And so these systems and programs are there to help people make it happen. I think it's essential to doing the right thing, because we want these drugs developed. They end up being expensive. Can we not figure out how, in the end of the day, we're doing the right thing for these patients? That's what matters.


And that's what I think these programs need to be in place.




EMIL KAKKIS: I think the major parts of the Orphan Drug Act, which is orphan drug designation, orphan drug exclusivity, the FDA has done as well as they could have kind of imagined. They have gotten hundreds of drugs developed and many more actually into development. So that's good. They've done well in that regard.


The hard part is, how do you regulate the actual development of rare disease drugs? There's a view that we certainly want these drugs to be as effective and safe as other drugs. But at the same time, what does that mean? That is, how much data is required? How hard is it to get that data? And how do we deal with the fact that rare diseases are just very different from common diseases?


And these are challenges that the FDA struggles with, that companies struggle with, and Congress struggles with, as we try to find the balance between getting safe and effective drugs and versus making it possible to actually get them developed. Finding that balance is really important, and that's certainly one of the things we work on. I think the Orphan Drug Act works just as it is, and I think it should be maintained as it is.


I don't think there's anything that needs to be open there. I do think there's more we can do in addition to the Orphan Drug Act rather than opening the Orphan Drug Act. I think there's, for example, improvement in access to accelerated approval pathway, which is what my foundation has been working on. How do we improve our ability to take good science and translate that into a policy that makes sense so that we can get some very rare diseases treatments developed?


I think there's a lot more we could do there. And we've been working with the FDA closely in workshops and other settings to find those answers and help move forward. There's probably also improvements and incentives out there. I think if you think about how many patented drugs are out there that won't be developed for rare diseases because they have a big market indication, well, there's a reason for that. Companies don't want to risk their big market drug by doing rare-disease studies.


There's no incentive for them to take that drug and apply it to more patients. We think at the foundation, that makes sense. If we had some incentives in place so that companies with patented drugs would have an incentive to develop the rare disease indications when there's no financial benefit, we think that would help. We've been talking about maybe for example, an exclusivity period, just like for a pediatric exclusivity, that would enhance the probability that a company with a patented drug would want to look at orphan indications.


We think that could have a major impact on accelerating investment in orphan indications for common drugs. And the best benefit of that is the fact those drugs have been priced based on a large market so that they would be inexpensive drugs for orphan indications. We think that's also a plus.


There's a lot of good evidence that common drugs can be repurposed to be effective drugs for rare diseases. And there's been some very good examples of that. The problem is, you have to try it out. You have to study it. And right now, what's happening is, a doctor's trying it off-label. And they're randomly doing it. They're not studying the dose.


They're not looking at safety and efficacy in an accurate way. And therefore, it's a lot of case reports and not a very thorough and rigorous approach. But if we incented companies who had patented drugs to invest in some orphan indications by making it sensible for them to do so, we think then you'd get good dosing data done so that you know what the right doses, you understand the safety profile really well, and you understand what the efficacy really is.


And I think then we are making real progress at doing good therapy and exposing patients to things are going to help them and not hurt them. One of the other areas that we think that Congress or the FDA could work on relates to rationalizing safety testing. There has been a move to standardize it across the board. But unfortunately, the risks of different drugs and their exposures, who's getting them, is different.


Therefore, the risks proposed are different. And we think in many cases, there is irrational use of a lot of safety testing that is not likely to provide any benefit or simply waste money. It may feel somewhat safer you may think. But you're actually spending a lot of money that might be used to develop another therapy for other disease that's untreated.


We think there should be some thought about how to rationalize safety testing that relates to the risk really at hand and not necessarily apply one size fits all safety testing for every program. We think that's one of the reasons why there has been some difference in the initiation of clinical trials in Europe versus US. And there's been a number of rare disease programs initiating in UK or in Europe because of differences in the threshold for safety testing required.


And some of that I think, safety testing is very important. For some of it may not be necessary. And there's a more flexible way to apply the ICH guidelines that is going on in Europe and not necessarily in the US. And we think that's caused a lot of trouble for some families, where the study is going on in Europe and they can't get access, even though the company may be based here in the US.


We think there's some thought that we could put toward a rational solution to rationalizing safety testing. That's one area that the foundation is looking at and we're doing a workshop on. Well, I first agree with you that while we've had great success with the Orphan Drug Act, we are talking about 5% of the diseases have a treatment. And at the rate of whatever 20 a year, 10 a year, five a year, depending on the number, it's going to take hundreds of years to get there.


So that's definitely not the plan. And so the question is, what could you do? And your question you asked is, how can we make this go faster? We think we need to apply our science more efficiently and figure out how to lower the threshold for getting drugs in development.


And one of the key areas we think is the accelerated approval pathway, an ability to get investment using a biomarker type endpoint in the disease that may be very hard to study otherwise. We think that the application of the accelerated approval pathway in a way that was applied for cancer or for HIV could have a similar dramatic effect. For example, in HIV, in '92, there was one drug out there.


The accelerated approval pathway came into existence at that time when the FDA came out with those regulations. Within the next 16 years, there were 29 HIV drugs. Four of them were multi-drug combinations. You can't do a drug combination nor that many drugs with six different novel mechansive action.


And the reason that happened is, many little start-ups came up with new ideas. They got the money, because they could do a small study, get the marker, and show this was going to be viable. And that turned the whole thing around, and that's how we took was thought to be a total tragedy for the nation, when in the early '90s, when people thought we were all going to end up with HIV, and turned it into a manageable, terrible, but manageable disease today.


We think that same thing, that same kind of explosion could happen in the rare-disease community, if you made the process work better on accelerated approval that you could get hundreds of diseases more in development and actually get them through and use the good science we have and apply it in a way that makes sense.


That's correct. There are no validated surrogate markers of rare diseases. But that's what's the whole accelerated approval pathway is about. The whole pathway was about having a marker that is reasonably likely to predict clinical benefit, not most definitely assuredly predicts clinical benefit -- reasonably likely based on all the science we had. And that's what they've been doing in HIV in the early days, when it was CD4 counts or viral load.


Those were the best science we had said that would help. That meant that sometimes you may be wrong. But the disease was bad enough, severe enough, untreated that we had to make this step forward. We think the same thing does exist in the rare disease. The thing that's better is that many of the rare diseases have a pure and single genetic cause -- many of them.


So we understand their pathophysiology better than for lot of the common diseases, where surrogates are used today, like heart disease and cholesterol. So what we'd like to see is a better application of the scientific principles that underpin good surrogates or good biomarkers and allow an ability to take a disease that doesn't have enough data to get validated and put it into play and say, look, for this terrible disease, where you have a marker that's directly in the line of the biology, that should be reasonable.


Let's get that going. Let's take that step out. Let's start the process. And then let's keep working on it, because the first step is not enough. You need to keep working on it. But we got to make the first step, and I think if we start making those steps, you'll see a whole bunch of diseases being applied, a whole bunch of learning, and the evolution of medicine for those diseases beginning, because you can't start treating a disease unless you take the first step and put the first drug and move forward on it. We think that's what better access to accelerated approval would do for the rare disease world.




FRANK SASINOWSKI: Well, the first thing the FDA did is, they took the person who was the head of the Bureau of Drugs, which was the equivalent of today's Center for Drugs, Dr. Marion Finkel, and they elevated her to a brand new post in the commissioner's office, the head of the Office of Orphan Products. FDA anticipated that this was such a novel, important piece of legislation, there would be an overwhelming response from industry.


Unfortunately, that didn't happen. It surprised FDA. So the FDA commissioner turned to me, a very young attorney at that time, and asked me to investigate it to figure it out. So I looked at the legislation and saw there were two pieces of it that looked to be potential stumbling blocks. One was, it said that in order to be designated as an orphan drug, you had to prove that you were not patentable. Second, it said that you also, during the seven-year period of market exclusivity, that you couldn't recoup more than your cost of research and development -- again, another challenge.


So I worked with FDA economist under Russ [? Scorato ?], and worked with the NIH patent counsel to attack both those issues. I then came back with a report to Dr. Marion Finkel. I walked into her office, told her what I found, that these were the impediments and here's some solutions. She picks up the rotary phone that was on her desk at the time, dials a number -- she didn't tell me who she was dialing -- she says, Hank, have a problem, and then hands the phone to me-- she was calling Henry Waxman, the father of the bill -- and hands the phone to me and says, Frank, explain to Congressman Waxman what you just told me.


And that led then to the 1984 and the 1985 amendments to the Orphan Drug Act. The 1984 amendments created a 200,000-person threshold, so that to be declared an orphan, it had to be for a condition that affected fewer than 200,000 persons in the United States. With respect to patentability, the 1985 amendments simply deleted that requirement. After that then, FDA, our implementation of the law, took off.


When I said that the law, the original law, had an impediment in it, that it required that a company couldn't recoup more than its research and development costs in the seven-year period of exclusivity, exclusive marketing, what I meant was that that provision was essentially made moot by the 1984 amendments, which instead of having that as a requirement to get orphan drug designation, you simply had to show instead that the therapy was intended for fewer than 200,000 persons in the United States. Now, that provision remained in the law. It was not struck.


And the FDA implementing regulations, which I drafted, we retained that provision. And it was many, many, many years later that it was first used. It was used for a drug Suboxone and Subutex, in order to get those designated as orphans. We knew that there are more than 200,000 persons in the United States who had opiate addictions. But nevertheless, because of the limitations on who could prescribe therapies for those who had an opiate addiction, it was estimated that they could not recoup their cost of R&D.


So it was useful to not strike that provision. It then has served some utility -- very limited. But nevertheless, unlike the patentability provision, which was completely struck out of the law in the 1985 amendments, the 1984 amendments just added an alternative additional pathway for getting to orphan drug designation.


The FDA was faced with a conundrum. How does it now deal with an influx of therapies for which the quantity of clinical data is going to be much thinner than that they were used to for other therapies for common diseases, like type 2 diabetes or hypertension? And in fact, over the decades, whenever an orphan drug therapy would come before an FDA public advisory committee, at some point in the deliberations, the chairman or a panel member of that committee would turn to the senior FDA official and say, what do you want us to do with this?


And the FDA would say, well, the original Orphan Drug Act did not change the legal standards for how much safety and efficacy you need to show, full stop. Now, I have to say then, I was elected to the board of an organization called the National Organization for Rare Disorders, in 2000. And as part of that patient advocacy organization, I personally went to Senator Brownback and Senator Brown, who were then the chair and the ranking minority member of the Senate committee responsible for appropriations for the FDA.


And I said to them, on behalf of NORD and behalf of patients, shouldn't we have FDA hold a formal hearing so that FDA could announce what kind of policies it should have in regulating orphan drugs? So there wasn't this confusion as to how much data was necessary. At the same time, we suggested that the FDA start an office of rare diseases inside the Center for Drugs so that patients and sponsors had someplace to turn to within the FDA Center for Drugs.


That led to the June, 2010 FDA's public hearing on orphan drugs, its first ever public hearing, 27 years after enactment of the law. And at that public hearing, a two-day public hearing, NORD was asked to be the first speaker. And I was asked, on behalf of NORD, to be that speaker. At that time, I asked FDA to come up with a formal policy to explain how much data is necessary to deal with a rare disease.


And at a minimum, I asked the FDA, given how heterogeneous all orphan drugs are, everyone would be different. I asked the FDA, at a minimum, to simply catalog what they've done over the years, because that would certainly advance our understanding of how much data would be necessary. After the hearing, FDA senior drug officials came up to me, said, Frank, that's a great idea, cataloging that. We don't have the resources.


Why don't you do it, Frank? And so this is how I spent my summer vacation. I assembled 37 boxes of medical and statistical reviews, did an analysis of the 135 orphan drugs that have been approved, except for cancer, and came out with a report in October, 2011. To show you how important that report is, just last week, I was at a meeting with rare disease patient advocates and rare disease medical experts, and Dr. Woodcock, Dr. Jenkins, and Dr. Temple, perhaps the three most important people at FDA on drug approvals.


And when the experts and the patients pressed the FDA in this meeting for how much flexibility would the FDA afford these kind of therapies, twice, two different occasions, Dr. Temple said, just read Frank's report. So I think we now have at least some mark so that everyone -- the investment community, drug sponsors, the patient advocates -- we know we have some place where we can turn to.


In 2002, there was an FDA approval for a drug for pulmonary hypertension, a United Therapeutics treprostinil product. At the time, there was only one product approved for pulmonary hypertension -- Flolan -- that has a half life in seconds so that if the pump ever failed, the battery ran out or you bumped against the line and that person's life might be ended tragically, it was a terrible way to go about living your life. So the company, United Therapeutics, then did two trials. And both trials came out with a p value that just missed the mark that FDA ordinarily required, which is to have a statistical p value of less than 0.05.


Both of them were about 0.06. So here's a case in which if these were therapies for a prevalent disease, the FDA would have said you have two failed trials. We don't have the wherewithal to provide you with access to patients. We need more evidence.


In that case, the FDA looked at it in a novel way. It said, let's look at whether or not patients were also becoming breathless, because the test was a six-minute walk test. And if we combine looking at how much further they walked on drug with how much less breathless they were, then the p value became convincing. And the FDA approved it under a provision called Accelerated Approval or subpart H, where they had to do a confirmatory trial later on which they did, and overwhelmingly showed the clinical benefit.


Yesterday, I was flying back from San Francisco. And I saw two people there. And it turns out they had short stature. I approached them. They had achondroplasia.


I asked them about their condition. And I told them and I'm helping a company with a drug for achondroplasia. There are 7,000 rare diseases. Before the Orphan Drug Act became law, there were fewer than 10 therapies approved for any rare disease. Since 1983 now, there are almost 400 therapies that have been approved. That's what the Orphan Drug Act has meant.