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Alagille Syndrome
Video

Global Alagille Alliance (GALA): Advancing Science and Understanding of Alagille Syndrome

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Rare Disease 360® is the Official Media Partner and Official Publication of The Alagille Syndrome Alliance (Alagille.org).

 

Binita Kamath, MD:

Hi, my name’s Binita Kamath. I’m one of the pediatric hepatologists liver specialists at the Hospital for Sick Children in Toronto. I trained in the UK and then at the Children’s Hospital of Philadelphia and have been in Toronto for the last 15 years. And my interests are cholestatic liver disease and specifically Alagille syndrome.

Shannon Vandriel:

Hello, my name is Shannon Vandriel. I work with Dr. Binita Kamath at the Hospital for Sick Children in Toronto, Ontario. I am the program manager of the Inherited Liver Disease Research Program. So we focus on genetic causes of liver disease in children, and our research portfolio is primarily Alagille syndrome.

Question:

What is the primary goal of the GALA Study and how does it differ from traditional patient registries in rare disease research?

Shannon Vandriel:

Our goal of the GALA Study was to truly get a global perspective on Alagille syndrome. And so a lot of the older studies were primarily from North America or small groups in Europe. And so by initiating the GALA study, we’ve been able to get a truly global perspective of what Alagille syndrome is.

I think one of the things that makes the GALA database so unique in comparison to a traditional patient registry is we’ve been able to collaborate with investigators all around the world. So to date, we have more than a hundred investigators involved from 38 countries around the world, which is truly incredible for rare disease. So in a traditional patient registry, patients are able to input their own data. In contrast, the GALA Study is a research database. And so that means before a center can start contributing data to the GALA database, they have to first get all the necessary approvals at their center. That typically involves a research ethics board approval, as well as a data transfer agreement to send that data to sick kids. And then once they get all the necessary approvals, they can start inputting the data.

Research databases also are more powerful in that we’re able to clean the data. So once an investigator has submitted their data from their patients, we at the GALA Data Coordinating Center go in and review their entries. So we look for completeness, missing data points, we look for outliers. We ensure that there’s no mistakes within the data just so that we can really stand behind the data that we’ve collected.

Question:

ALGS is considered a rare disease. Can you explain why rare diseases like ALGS are often understudied, and how does the GALA study address these challenges?

Binita Kamath, MD:

Sure, I think I can take that. I mean, one of the biggest limitations or the restrictions that you have for studying a rare disease is funding. All research requires money, requires money for personnel, for time, for effort, for resources, and available research grants and funding are limited. And so that really is why rare disease research… Unless there are specific pots of money allocated for rare disease or a specific rare disease, it can be hard if you’re competing for research pots that are also being allocated to cancer or diabetes research, which affect many more people.

However, of course we strongly believe, Shannon and myself, that rare disease research is very important. And I think the key way in which we have circumvented this problem is by partnering with industry and pharmaceutical companies who, two of which in this space gave us unrestricted educational grants with which to start the GALA Study. If we had gone to a federal body or a foundation to say we wanted to set up a clinical research database, it would’ve been highly unlikely for us to have received funding. But by partnering with industry who don’t have any control over the study, but were able to give us unrestricted funds to initiate the study, we were really able to get going and be quite successful.

Question:

Could you elaborate on the significance of creating an international database of clinical, genetic, and laboratory data for children and young adults with ALGS? How will this database benefit the medical community and patients with ALGS?

Binita Kamath, MD:

Shannon, do you want to take that?

Shannon Vandriel:

Yeah, of course. So the significance of the GALA Study is we’re truly accelerating progress. As I’ve alluded to earlier, a lot of studies in Alagille syndrome were primarily coming out of North America and they were from high-volume tertiary referral centers. And so the GALA Study, we’ve been able to collect data from all countries around the world. And so again, we’re really getting that global perspective and then we’re truly accelerating progress. Just within a few years, we’ve been able to ascertain more than 1,700 patients, which is truly incredible. And we can start answering really clinically meaningful questions and also questions that are really important to families.

Furthermore, Alagille syndrome is a very heterogeneous disorder. No two patients are alike. Even within a family of patients who might harbor the same genetic variant, they actually manifest clinically quite different. And so through this database, we’re going to be able to not only look at Alagille syndrome from more of a comprehensive perspective, but we’re also going to be able to do sub-analysis looking at different phenotypes, so patients who might present with more of a cardiac phenotype or more of a renal phenotype. Whereas today, predominantly the literature has focused on children with cholestatic liver disease, which is the most prominent symptom to date.

Question:

What led to the initiation of the GALA study? Were there any specific research gaps or unmet needs in the ALGS field that prompted this global initiative?

Binita Kamath, MD:

I think it was just the same notion that the data that were coming out were either limited to high volume quaternary or tertiary level centers, or it was coming out of single centers. So either a group of small centers who were all of a particular type in North America or a single center and thereby not really representing the world. So that would’ve been the major gap. And then what initiated it actually was a request from industry that we do this knowing that new drugs were going to come to the market, that a large natural history studies would be needed to help understand the disease better.

Question:

Can you provide some insights into the research scope of the GALA Study? Which aspects of ALGS will be the primary focus, and how will this contribute to better treatment outcomes and management?

Binita Kamath, MD:

Hey Shannon, you know the study inside out, I’ll let you take that.

Shannon Vandriel:

Kind of building on my previous response, one of the taglines for the GALA Study is looking beyond the liver. So when we set out, when we initiated the GALA Study, we not only wanted to look at liver disease, which is to date, most burdensome aspect of Alagille syndrome, but we also wanted to look at the cardiac patients, the renal patients, the vascular patients. And by having a study with so many patients on such a large global scale, we’re going to be able to collect information on patients who have more unique or rare features. I think this will also lead to more holistic management of patients and hopefully improve long-term outcomes as we better understand the disease and treatment options.

Question:

The GALA study involves collaboration with multiple clinicians from various countries. How does this diverse collaboration enhance the study’s potential and impact on ALGS research?

Binita Kamath, MD:

Yeah, I think this is sort of what we just said before. It’s just representing different geographies, different ethnicities, but I think also what you’re doing is you’re looking at different size centers. So rather than everything just coming from a particular type of a high-volume ivory center hospital, you’re also looking at some of the smaller practices. And I think that encapsulates what real world Alagille syndrome looks like.

Question:

How do you ensure patient anonymity and data integrity in the GALA database while collecting information from multiple approved and verified sites?

Shannon Vandriel:

So we do this. The GALA Study is a research database. And so from as soon as an investigator reaches out to us to participate or we reach out to them to see if they’d like to collaborate with us, we always ensure that we’ve obtained all the necessary institutional approvals before they’re onboarded and granted access to the database. So that’s typically a research ethics board approval from the primary institution as well as a data transfer agreement to ensure lawful transfer of data.

The GALA database is a secure database, it’s password protected on multiple servers and only authorized individuals are allowed access to that data. Patients are also assigned a unique study identifier that we at the GALA Data Coordinating Center do not have access to. And so every patient has that identifier, so we’re not able to actually link them back. And through all of these steps, we’re able to protect the data that we’ve collected.

And then of course, we also have… The advantage of being a research database is being able to go back to source documentation. So once a site has completed all their data entry, we then clean it. And so we’ll collaborate with the investigator to, again, to ensure completeness, missing data points, looking for outliers or information that doesn’t look quite right. And thankfully investigators are so great at ensuring that we get those queries rectified so that we really have a strong robust database.

Question:

Could you share some information about the support and sponsorship that GALA Study has received? How does this financial support contribute to the study’s success and its ability to address the needs of ALGS patients effectively?

Binita Kamath, MD:

We received unrestricted educational grants from two pharmaceutical companies, so that was the main source of funding. We also received really important startup funding from the Alagille Syndrome Alliance. So a big shout-out to them for really getting us off the ground. So this was not done through grants to the government as is sometimes done for research funding. I think it’s really important to understand this was money that was given to us by industry and by families, essentially, to get the studies going. And I’ll be very clear, this research would not have happened without those types of sources of funding.

Shannon Vandriel:

Expanding on what Dr. Kamath said, we have been so lucky to partnership with the Alagille Syndrome Alliance, particularly Roberta and Cher. When the study was first initiated, Roberta and Cher reviewed all the study documents, so our study protocol and our case report forms, and they played an integral role in ensuring that the patient voice was brought to the forefront of our research. To this day, we still continue to collaborate with the Alagille Syndrome Alliance. We’ve just had a wonderful partnership with them, and they are constantly sharing what matters to patients and their families, what do they want to know? And so they help guide us in our future research pursuits and have been providing impact along the way over the last five years.

Question:

The GALA Study aims to focus on non-liver features of ALGS as well. Why is it essential to include these aspects in the research, and what unique challenges and needs do individuals with ALGS face beyond liver manifestations?

Binita Kamath, MD:

Yeah, it’s a multi-system disorder that affects the face, heart, skeleton, kidneys, vasculature. And so it’s crucial that you don’t just focus on the liver disease. The legacy was that Daniel Alagille was a pediatric hepatologist. He first described this disorder. And so that’s why the care is often led by pediatric hepatologists. But in fact, we are all very aware that it’s a multi-system disorder and we want to not just take care of one organ, we want to take care of our whole patient. And that’s why it’s crucial that you cannot understand one piece of a patient in isolation. You want to understand the whole patient and for that matter, the whole family as well. So I think this is very much what we believe in holistic care, and that’s why it’s crucial to understand the other organ systems as well.

Question:

How will the GALA Study findings pave the way for future research projects related to ALGS? What are the potential long-term benefits for the ALGS community and medical practitioners?

Shannon Vandriel:

So through some of the long-term benefits of the GALA studies, I think Alagille syndrome has merely been studied from a pediatric perspective and through the GALA database, we’re seeing that children reach adulthood not only and move on to adult care. And so we’re hoping to have a better understanding of Alagille syndrome throughout life, not just in pediatrics. We recently did some adult management guidelines in collaboration with one of our fellows to help adult clinicians treat Alagille syndrome patients and also diagnosed those who might’ve presented later on in life.

I think with the GALA Study though, it is, we are kind of at the tip of the iceberg and there’s still so much more to come and that we don’t know. We published our first paper last year, which predominantly focused on the liver side of Alagille syndrome, but we have lots of collaborations underway to understand more of the multi-system involvement of the disease, which I think will be really integral to some of our subspecialty partners and ensuring that patients really have that holistic care.

One collaboration that we’re doing is we’re working with Dr. Jeff Feinstein at Stanford University and doing a really deep dive into the cardiac phenotype of Alagille syndrome. This is something that we’ve been wanting to for a long time, and we’re at a place where we finally have enough data to be able to do a really comprehensive look. We’re also looking at working with one of our colleagues in Belgium, Kun, to develop an Alagille syndrome specific growth curve, which is really exciting and something that patients and families have wanted for a long time. However, we finally have the data to do that, so we have more than 20,000 follow-up visits with growth parameters. And so we’re going to be able to develop a really robust growth curve and able to track patients, which before, a lot of Alagille syndrome patients just intrinsically were on the smaller side. And so having their own disease specific growth curve I think is really going to be amazing for families as well as clinicians.

Question:

Can you discuss the multi-year effort and the expected timeline for the completion of the GALA Study? What are some of the milestones achieved thus far and what lies ahead in terms of data collection and analysis?

Shannon Vandriel:

For sure. So the GALA Study’s been going on for several years now, and we’re truly kind of just at the beginning. We have lots and lots of goals and ambitions for this study and what we can do. As you shared earlier, our first big manuscript was published last year, and that was on just over 400 patients who presented with neonatal cholestasis and had more of a liver disease phenotype. But now we want to continue looking into that as well as also other organ systems. We have a genetics manuscript underway to understand patients who present with the NOTCH2 variant, which is a little bit different than we see with patients with a JAG1 variant. We have our collaboration with Stanford for cardiac disease, growth with our collaboration in Belgium.

So we have lots and lots of work to do, and I think as we continue to answer some of our questions, there’s going to be new questions and we’ll hopefully continue to expand the database and enroll new investigators and continue to grow the database to be able to answer clinically meaningful questions for patients and families.

Question:

For doctors currently treating patients with ALGS, how do you envision the GALA Study findings translating into improved patient care and better management strategies in the future?

Binita Kamath, MD:

Sure. I mean, I think the first thing is with our… And this is an evolving question. With our first dataset, we’ve really understood more about the liver disease than we did before. We’ve got more realistic information about how many patients will require a liver transplant if they have liver disease. We’ve now been able to identify ways to predict who will need a liver transplant. I think that’s really crucial. And we know much more about the pattern of disease that kids will have with Alagille syndrome. But just as Shannon alluded to, there are so many unanswered questions and we’ve got other analyses that are ongoing.

We’ve got an analysis going on right now to look at the genetics that’s coming down shortly. We have another analysis to look at another parameter that hasn’t been well-studied in Alagille syndrome, which is serum bile acid levels, which is very crucial to understand since the new drugs that we have target serum bile acids, and we have an ongoing analysis to look at serum bile acid levels in Alagille syndrome. These are just two examples of things that are coming down the pipeline, but just as Shannon said, the more we study, the more questions we get, and that’s what we’ll continue to keep doing, trying to answer those questions.

Question:

Do you have any final thoughts to share with our audience?

Shannon Vandriel:

Just in closing, we just really wanted to reiterate our collaborators in this study and the power of collaboration in rare disease research to be able to have a cohort of 1,700 patients is truly remarkable. And we’re so proud of where we’ve come and where we’re hopefully going to go. And so this study would not have been possible with the many, many, many over a hundred investigators who are involved and have contributed data. For many of them, they do not have research teams to support the data entry. So it’s them taking time out of their very busy and demanding clinical schedule and entering the data into our database. There’s more than 300 baseline data fields and it is something that is very timely. And so these individuals have done this, and so without them, we would not have been able to get to where we are. And so I just really want to reiterate how proud and how thankful we are for all our collaborators for working with us.

 

Rare Disease 360® is the Official Media Partner and Official Publication of The Alagille Syndrome Alliance (Alagille.org).

 

 

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