RARE Daily

In Push for Treatment, a Patient Organization Becomes a Trial Sponsor

November 16, 2023

Pazopanib, a targeted therapy marketed as Votrient, is used to treat certain cancers. The drug has shown promise as a potential treatment for the rare genetic blood vessel disorder hereditary hemorrhagic telangiectasia (HHT), but when a change in ownership of the drug took place, efforts to develop the drug for HHT ended. That led the patient advocacy organization Cure HHT to step in and sponsor a phase 2/3 trial on its own. We spoke to Marianne Clancy, executive director and senior director of strategic partnerships for Cure HHT about the organization’s decision to sponsor a clinical trial, why it felt it was necessary to do, and what other patient organizations can learn from its experience.

Daniel Levine: Marianne, thanks for joining us.

Marianne Clancy: Oh, thank you so much for having me, Danny. I’m really appreciative to be here.

Daniel Levine: We’re going to talk about HHT, the Cure HHT Foundation, and its sponsorship of a clinical trial for an experimental therapy to treat the condition. Let’s start with HHT. For listeners not familiar with it, what is it?

Marianne Clancy: HHT is short for hereditary hemorrhagic telangiectasia. Quite a mouthful. That’s why we call it HHT. And it is a genetic disease affecting the blood vessels in several organs in the body. And when these blood vessels—they’re malformed in the brain, the lung, and the liver—those are large vessels that create arteriovenous malformations or direct connections. And those AV malformations in the brain and the lung can rupture suddenly without warning, causing stroke and sudden death, disability. When they are in the liver, it leads to heart failure as well as pulmonary hypertension. The vessels that are smaller are in the nose and the gastrointestinal tract, and they cause chronic bleeding. Over a lifetime, 50 percent of the population is anemic and iron deficient, and in about 15 to 20 percent of the population, patients are transfusion dependent. It affects about one in 5,000 people, we think 1.6 million people globally. So, I think it’s one of the more common rare diseases, and it’s also the second most common cause of inherited bleeding, two times more common than hemophilia, but most people have never heard of it.

Daniel Levine: Does this disease progress in any expected way or do people just discover they have it after a crisis?

Marianne Clancy: That’s a very good question. Many people discover they have this disease when there’s an event, a crisis, and people think that the most common manifestation—90 percent of patients have nosebleeds—many patients, and many people in our community think that this is just normal. This is what we have in our family. And then there oftentimes is a catastrophic event and no one’s really putting the pieces together because most of these malformations are internal and they’re invisible. So the only outward sign are nosebleeds. And in fact, we have quite an odyssey of diagnosis because it’s multi-organ. Many patients in our community see many different specialists for different problems. And as such, if we’re not really taking an accurate family history and know about this disease, the odyssey of diagnosis from your first nosebleed to a diagnosis is 27 years. Totally unacceptable.

Daniel Levine: Given that, how are people generally diagnosed?

Marianne Clancy: So, we have something called the carousel criteria, and there are four areas that are critical. One are recurrent and spontaneous nosebleeds. And as I said, that can affect anywhere from 90 to 95 percent of people, although there are families and some patients that don’t have nosebleeds. And what complicates this, too, is that it’s genetic, it’s autosomal dominant, and so people in the same family may not have the same manifestations, and these nosebleeds can be mild or severe. Also, number two are the presence of multiple, what are called telangiectasia. And these are small red spots that when you press on them, they turn white and that occurs on the skin of the hands, the lips, the face, inside the mouth and nose. And then number three would be these arteriovenous malformations or telangiectasia in one or more internal organs. And fourth is family history, a first degree relative. So if you have two or three of these characteristics, that is your diagnosis. We also have genetic testing for genes that were discovered in 1994. And so, we do have genetic testing for three genes in HHT.

Daniel Levine: And what treatment options exist today?

Marianne Clancy: So, the history of the treatment has been primarily interventional in the brain. If you have an AVM in the brain, they can be treated by what’s called embolization, which is taking a catheter with coils or glue or some embolic material to seal off that artery to prevent the bleeding. The other, depending on the size of the AVM in the brain or the location, you could either have embolization—something called stereotactic radiation, which shrinks the AVM, or brain surgery through a craniotomy. In the lung, it’s primarily embolization. However, many of the AVMs in the lung are multiple. So these procedures are done throughout life. In the nose there’s been laser, bipolar cautery, and something called sclerotherapy, although in the last 10 years or so, we’ve had really great success with using therapeutics—actually cancer drugs at lower dose. The same thing in the gastrointestinal tract. In the liver, it’s a bit more complicated. Therapeutics are showing promise but some patients move on to liver transplant, which is certainly a big undertaking.

Daniel Levine: And if there is a lack of interest in pursuing potential therapies, is that a function of understanding the underlying biology, the economics of the disease, or does it have to do with the fact that it’s difficult to identify a patient population?

Marianne Clancy: Really great question. HHT was first described in 1896, believe it or not. And we still don’t have an approved treatment. It really has been under the radar. And I think most people have thought, “Well, people get nosebleeds. They might be anemic. Just take some iron supplements. It’s not a big deal.” And I will tell you that the tide has really changed because a lot of these treatments are interventional. And we know through science that when you have these interventional treatments, you are really creating injury to the vessel. And even though you think you’re treating the vessel by, say with laser in the nose, that’s temporary, that lasts for six months and then you get twice as many telangiectasia than you had in the first place. So I would say it was a lack of awareness. And the big breakthrough came, I believe, when by happenstance a few patients were undergoing treatment for cancer and were getting Avastin, and suddenly their nose bleed stopped, anemia changed, the quality of life went up and they were successful. So that has been used off label. So I would say in the last five years there’s been a lot of interest, but this disease has been under the radar for a long time.

Daniel Levine: Cure HHT is a patient advocacy organization. We’ve seen many organizations fund research, but HHT is unusual in that it’s moved directly into the clinical trials realm, sponsoring a phase 2/3 study for a potential treatment for HHT-related bleeding. This is an approved drug that’s now off-label. Before we talk about it, I’d like to take a step back though and talk about Cure HHT’S evolution and how it got to this point. What’s been the research landscape into HHT and how has the organization use seed grants to engage young investigators to work on studying the condition?

Marianne Clancy: Thanks for asking. Cure HHT was started in 1991. I also have HHT. I was diagnosed, believe it or not, in 1994, and have my own challenges. I lost a sister when she was just 14. That was 1959. We didn’t know why. Now I know my brother had part of his lung out when he was 17. I lost my mother at 21. And so I was diagnosed in 1994 and asked to join the board. And early on we were a very young organization kind of building, making connections, supporting each other, really helping patients and families that were learning that they had this disease and referring for treatment. We had three centers of excellence in 1996. Now we are up to 32 in North America and about 22 globally. And we started out small as every organization does. And back then our genes were patented. I became executive director in 2001. I was the first employee that was hired part-time and certainly working as we all do in rare disease advocacy, working 60, 70 hours a week and really feeling, having such meaning in this organization. So we started fundraising because we wanted to get those patents released and get genetic testing, and we were successful. So, we started providing seed grants, small seed grants, $50,000, [to] some of our young investigators, $30,000. And we continue to do that to this day. And that has resulted in—we’ve invested about $3 million in seed grants that have been leveraged to over $55 million in federal funding. It’s really been amazing, and we’ve grown our research community, our science, our clinicians. So we really felt that no one was going to come to our rescue. We needed to build our research portfolio and look at what questions needed to be answered and provide the initial seed funding to answer those questions.

Daniel Levine: As you sought to do it, did the organization construct a formal research agenda and how did it prioritize what needed to be done?

Marianne Clancy: In the early days, we have a scientific medical advisory board, and we attended our scientific conferences. We sponsored them primarily, and we worked really closely with our scientific community. And then as we grew as an organization, I’d say the real turning point is that we were awarded the “Rare as One” grant in the first 30 organizations with the Chan Zuckerberg Initiative. And that allowed us to really become a patient focused, organized international research network where we were able then to bring all three of our audiences together—our clinicians, our basic scientists, translational, and patients. And we surveyed all three audiences. And what we did was develop work streams and we came together and each one of these work streams provided priorities, what were important, where were the gaps, and we were able then to create a research roadmap. Last July, I was able to create a therapeutic arm specifically to focus on executing against this research roadmap, providing the tools that we didn’t have, like a bio tissue or biorepository, registries, both for patients in our centers of excellence and also for our organization that would be patient-centered. So we just continued to grow. Our community of families have been incredibly generous. They have suffered through multi-generations of this disease in seeing so much suffering that really people step up and want to end this.

Daniel Levine: You have a background in healthcare administration, but what did the organization do to build expertise to pursue research? How did you think about expertise needed in-house and through advisory boards, or what steps did it take?

Marianne Clancy: In 1992, we had an initial scientific and medical advisory board. And then as we grew and we started to fund research, we looked around and said, okay, this is expertise we don’t have. So we attended different meetings. We invited speakers at our scientific conferences. We had a scientific conference. Our first one was in 1996. We’re an international organization. There were 60 scientists and physicians. The one we had in Portugal last year [there] were 300. And we did that I think primarily because we are incredibly collaborative with our scientists in-house. We’ve invited speakers where we knew that we lacked the expertise to our scientific conferences, to our patient conferences. We have funded international consensus guidelines for screening and treatment, and we slowly built that network. We also provide travel grants for young people, young scientists and young physicians and fellows and students who don’t have the funds to come to these meetings to present posters or abstracts. And that has really grown the community and grown the pipeline. And really our centers of excellence have also grown. And so there are young fellows that then have moved on to continue to work in this area. So it’s been a whole combination of things through the years.

Daniel Levine: Pazopanib is used to treat kidney cancer. It’s been marketed under the brand name, Votrient. What is pazopanib?

Marianne Clancy: So pazopanib is, as you said, a drug that has been approved to treat kidney cancer. So, in HHT at the vascular level, you have something called too much VEGF, which is what you have in cancer. Cancer is really growth of blood vessels really growing out of control. So Pazopanib belongs to a class of drugs called tyrosine kinase inhibitors. It’s also a VEGF blockade. And so, this drug, we were able to have a phase 1 trial, when it was owned by GlaxoSmithKline, funded. One of our board members worked at Glaxo, has HHT in the family, and saw this drug and said, “I wonder if this would work.” And so, they funded this phase 1. We had planned for 30 patients. And after the seventh patient and again, it was low dose, this was 50 milligrams, so it one fifth of the cancer dose, and it was amazing. After the seventh patient was recruited and completed, the whole portfolio, the oncology portfolio, was sold to another company and we appealed and pleaded, please continue the study. And they did not. I personally went and talked to the patients that were involved in this study and they got their life back. They weren’t transfusion dependent, they weren’t going in for iron infusions. Every month, their quality of life increased. Many people go on disability because they’re homebound. When you are transfusion dependent, you have zero energy. You are really suffering tremendously. And this drug did really help reduce bleeding substantially in these patients, and in some patients reversed heart failure.

Daniel Levine: How did Cure HHT get involved in the development of it for the disease?

Marianne Clancy: So, we are pretty relentless, and we looked at this landscape, looked at this drug, and we knew at the time we were trying to talk with different companies to invest in us and it wasn’t happening. So, we went to the board and made the pitch that this drug was going to be going off patent and that we would invest in the biosimilar, the generic. And so for the last six years, we invested a hundred thousand dollars every year, and we couldn’t have done any of this without the board’s confidence feeling that we need to do something and get some therapeutics for our patients. This has been going on much too long. And so we were able to recruit the expertise from outside of our organization. We had our physicians serve as principal investigators. We funded the early part of the PK studies and worked with the FDA. They provided a breakthrough designation. And so we get every step of the way. We were excited, we were motivated, but we didn’t know what we didn’t know, and we certainly didn’t have millions of dollars to fund a double-blind placebo controlled clinical trial. So, we applied for two grants, one to the Department of Defense Congressional Medical Research Program, and then again to the FDA, and this was all pre-Covid, and we got the grants. So now we had to build out an organization and how we were going to do this. So we have all the outside contractors. We interviewed CROs, drug manufacturers, but again, not an easy undertaking. There were things that we learned along the way, a lot that we didn’t know, costs that increased, but we now have just launched this trial. We have 12 sites planned, there may be more, 60 patients, and we hope to take this all the way through to registration.

Daniel Levine: You mentioned you’re using a dose that’s one fifth the dose that would be used in kidney cancer.

Daniel Levine: One of the implications of that, I suspect, is that you need a pill that’s not commercially available, something that’s a smaller dose. What have you had to do to address that?

Marianne Clancy: So, we contracted with a company where we get the drug formulation and we partnered with Thermo Fisher Pantheon, and they are the drug manufacturer and they are manufacturing it in 25 milligrams. So we are looking at 25, 50 milligrams. One of our researchers has put a grant in for a dose escalation study to see if in some patients that might be more severe, we have to go for a higher dose, maybe a hundred, 150, even 200 till they’re bleeding gets under control and then can reduce that. So it definitely is a labor of love. We are really fortunate to have our lead person, our board member, has done all this pro bono for a decade and he has pharma experience and we have had another board member who worked for a law firm, and so they’re helping us with all the contracts. So, we are manufacturing and we are really sponsoring, not only sponsoring, but creating a whole drug that we hope to probably partner with a biotech or company as we move forward, provided that the clinical trial, everything, goes well, we have minimal side effects, and can take this all the way through.

Daniel Levine: You talk about having access to people with expertise in pharma, you have people expertise in law, but I suspect you needed to tap some regulatory expertise as well. How did you go about doing that?

Marianne Clancy: Right. We’re in the midst of doing that, actually. Exactly right, because that was a big area that we didn’t have. And so again, you never know who’s in your community. And so it’s really important because if you talk to people within your community and they have colleagues or they know people, you can really talk to people who see what you’re doing and really want to help you and understand your cause. And so we have had to do that. And we do rely on outside consultants to help us. We have a clinical trial manager. We’ve also used outside strategic consultants. I mean, there were all kinds of people that have really helped us. And I would say it’s really through connections and colleagues of people within our community.

Daniel Levine: I imagine if you are successful, this will require that someone make a low dose version of this drug. Have you had those conversations yet with potential partners on the other side?

Marianne Clancy: We are beginning to. We have not. Our focus has been really to get the project launched and now we are recruiting and enrolling patients, and that will be the next step. We’re not going to be manufacturing the drug at Cure HHT, so we will seek partnerships, but we have a big stake in this. I mean, we’ve been working on this for a decade and we did it because no one else was stepping up, and we decided to take our own future into our hands and help our patients and help our families who really deserve this in our community. They deserve treatment that isn’t interventional, where we could have drugs and not surgeries, and felt that we needed to be bold and relentless and strategic. And it’s been partnerships. We couldn’t do this alone. It’s been partnerships and really having a board that believed in what we were doing.

Daniel Levine: We’ve seen this migration from patient advocacy organizations funding basic research to getting involved in funding clinical trials, either through venture philanthropy or grants. This is something beyond that, a very hands-on approach to getting involved in drug development without a pharmaceutical partner. What lessons have you learned from this that you would share with other patient advocacy organizations looking to advance therapies for their conditions?

Marianne Clancy: I would say several things. One is really collaborate with your physicians and with scientists. Talk to as many people as possible. Be bold. You’re going to make mistakes, and you learn from those mistakes and you can’t dwell on them. You have to pick up and move forward. Trust me, all along the way, for example, we had estimates of the manufacturer of the drug, which were pre Covid. Well after Covid, that price doubled. So what are we going to do? So we continue to move forward, and I would say that we have a seat at the table where there is mutual respect. And as an advocacy organization, don’t ever forget that we have the patient perspective. We are living this every day, and those of us that are in leadership are really the voice of our community. We really represent our families out there who are really deserving. I would say also, you have to think strategically as well as you’re going to work a lot of long hours and you roll up your sleeves and you get the expertise in that you need. And sometimes you have to have very serious conversations, even with those people who are your partners, to basically state that, “Hey, this is what our budget is. It’s not an ending budget. We’re not a pharma company. These are patient donations, and we’ve worked really hard to get these grants and advocate, take charge to make change.” You really have to do that.

Daniel Levine: Marianne Clancy, executive director and senior director of strategic partnerships for Cure HHT. Marianne, thanks so much for your time today.

Marianne Clancy: Thank you so much for having me. I really enjoyed it, and I love your podcasts. They really bring a lot to the rare disease community.

This transcript has been edited for clarity and readability.


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