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Conversation between Omar Kamlin, Senior Medical Director at Orphalan SA and Prof Pramod Mistry, MBBS, PhD, MA, MD, Director of Yale Lysosomal Disease Center and Gaucher Disease Treatment Center at Yale University to celebrate World Rare Disease Day on February 28th, 2022

Biography: Professor Pramod Mistry, Yale School of Medicine, USA

Professor Pramod Mistry has dedicated most of his distinguished career to rare liver disease and is the Chair of the advisory board of Orphalan’s Wilson Disease Registry. He has more than 25 years’ experience as lead in the Gaucher Disease Registry.

Omar Kamlin (OK): Welcome Professor Mistry and thank you for taking part in this Q&A to celebrate Rare Disease Day 2022.

Professor Pramod Mistry (PM): Thank you for inviting me to do this blog in recognition of Rare Disease Day 2022. This is a very important global celebration of a neglected population of individuals who suffer from rare diseases. As you know, more than 40 million individuals globally suffer from rare diseases.

OK: How did you become involved with rare diseases?

PM: I trained at the Royal Free School of Medicine, and although I was fascinated by diseases affecting the liver as an undergraduate, it was during my informative PhD studies at St. Thomas, London where I was investigating the role of the LDL receptor in cholesterol metabolism, that I became interested in the rare but devastating condition of familial homozygous hypercholesterolaemia; a disease affecting children and at that time, associated with a life expectancy of teenage years. It was the lack of therapies, unstructured service provision, limiting patients’ access to expert physicians that affected me very deeply. I recognised a need and was determined to use my career to try and address these unmet needs of patients with rare diseases. A lot of these inborn errors of metabolism affecting the liver can impact children and their families. Liver disease across the ages has been my passion since graduating from medical school. This gives me a unique window into the lives of patients irrespective of age; in my clinic today, I will see a patient aged one month with their parents followed by an independent patient in their 70’s!

I feel very lucky to be involved in supporting the paediatric patient transition to adulthood and to help them take control of their disease and this is one of the most fulfilling roles for me personally.

OK: From your PhD studies, you describe how you were attracted by the pathophysiology and molecular biology of diseases and clinical manifestations to drive the research agenda to identify mechanisms that may lead to therapeutic solutions, and this appears to be true today; would you agree?

PM: You are exactly right in how I approach this. I would call this reverse translation. My priority is always to be the best physician for my patients and to empower them to reach the best outcomes for their condition. I want to be clear that everything begins and ends with the patient. At the same time, I am very firmly grounded in reverse translation. In that, I mean going from the patient (frequently they ask critical questions which raises clinical conundrums), which I then take back to the laboratory. In the current era of biomedical research – we are very fortunate to have technologies such as single cell resolution transcriptomics, biomarker discovery and genetic phenotype-genotype correlations. A lot of this information and data can be fed back to patients to improve their management. For example, getting the right genotype for the disease allows us to screen for the defect in first degree relatives and provide important prognostic advice. If we take Wilson’s disease (WD) for example, the identification of an important biomarker for neurodegeneration such as a neurofilament light chain for example, would be potentially transformative for management of patients in clinic; earlier identification of those at risk with pre-emptive targeted therapies and/or adjustment of existing therapies. These technologies did not exist when I was studying for my PhD, but I always envisioned that we would have access to it one day, and for this, and many other reasons, I feel my career has only just started!

I am excited about how modern biomedical science can transform patients’ lives. We have just validated the neurofilament light chain in a different rare disease that I am very much involved with, Gaucher Disease (GD). These findings are transformative for those affected and it is extremely illuminating to match biology with disease pathology and symptomatology.

OK: I like the term reverse translation but in your academic-clinician researcher role, I would suggest bidirectional translation as more appropriate?

PM: I totally agree; this is in fact what we do all the time; taking research ideas from the clinic, testing them and then implementing them in practice with an open mind that further bench work can refine feedback from the clinical setting. To give you an example of GD, during the phase 2 and 3 trials of the oral substrate inhibitor were in progress, our laboratory group’s work on the mouse model and lipidomics identified a novel biomarker – a highly sensitive marker of disease severity and progression and most importantly response to therapy. So, when we discovered this, it gave an incredible impetus to the clinical trial approval of the drug and real-world evidence to find the correct indication for this novel therapy (i.e.. targeted or personalised medicine). For all the inborn errors in that I include GD and WD, biomarkers are extremely important and Orphalan’s key findings of a potentially novel biomarker with NCC (non-ceruloplasmin bound copper) resonates so much with me as I see this is a parallel finding. The CHELATE trial used the NCC as a biomarker for an endpoint in a clinical trial, as we did with the GD trial, and this is so important when you have such a heterogenous disease phenotype. Identifying a biomarker that can predict disease progression is of the utmost priority in all diseases.

OK: How would you define a biomarker?

PM: From a clinician’s perspective, a biomarker would be one that you would look at the variable with a pre-defined endpoint. It would need to be something that is consistently elevated when compared to controls and then apply comparative performance analysis (such as receiver operator curves or ROC) to test clinical significance. Secondly it would need to correlate with disease severity and thirdly a response to treatment is seen. This may be seen as a narrow viewpoint. For regulatory authorities the approval of a biomarker is set at a higher bar; there is another major factor to be addressed; the biomarker must be predictive of clinical events or natural history. The US FDA has a central premise on how to approve drugs and this incorporates how the patient feels, functions and survives. For a rare heterogeneous rare disease such WD, it is impossible to collate this information from

individual centres. This is why we need patient registries, especially global registries like the international Wilson Disease (iWD) patient registry that Orphalan is establishing. International experts sharing contemporary and longitudinal data from their patients can contribute to that final approval step for any biomarker (to actually show any predictable clinical events based on biomarker analysis). This is one of the most important gaps in rare diseases in my opinion, the lack of good quality registries.

A global registry provides the opportunity to provide data on a heterogenous population from patients of different racial backgrounds and ages. This is my personal viewpoint after 30 years’ experience with the international GD patient registry.

OK: Why have you dedicated your career to rare inherited metabolic diseases of the liver, most notably Gaucher disease? Can you help us understand this through an informative patient of yours?

PM: What drew me to GD, was that there was so much interesting biology centred around the liver. The attraction to the disease was the patients. I can vividly remember the first GD patient I took care of; a highly successful businessman who was in bone marrow failure and reliant on multiple transfusions and just around that time enzyme replacement therapy was approved in the US. We tried but failed to provide access to this patient through the NHS (the health authorities rejected the application because of cost). Fortunately, this gentleman could afford to self-fund this therapy and we saw an amazing transformation after six months and more so after a year; he was able to stop all the transfusions, his blood counts normalised, his mobility improved and he no longer needed a wheelchair and he was able to head back to the office to run his business. I saw the full impact of “what is possible” with this one patient and over the years I have been fortunate to see this replicated in over a thousand patients throughout the world.

OK: Presumably, this therapy is now standard of care?

PM: Yes it is, but again through the reverse translation process, we now have an even better treatment which is oral. This is the substrate inhibitor and has offered incremental value to patients affected by GD.

OK: Has life expectancy improved over the course of your career for patients with GD?

PM: Yes, it has. These patients died early but it does depend on the type of GD. For example, type 3 GD was regarded as fatal with death in very early childhood but now, with treatment, we can expect life expectancy to adulthood with the affected individuals expected to complete schooling, get a job, get married and have children. For a subset who have neurological disease, we are currently performing phase 2 clinical trials to assess brain penetrance of the substrate inhibitor. It also prolongs life in adults who make have tumours or skeletal problems as complications. It is now well established that life expectancy has improved and it’s not unusual for me to see patients in their 70’s; in fact, my oldest patient turns 86 this year. None of this would be possible without treatments.

OK: It must be very humbling to have witnessed this in your career and for your personal contributions to have advanced life expectancy in GD.

PM: Yes of course and these are the drivers for what I do. To build hope for patients and a healthcare system that these patients who have been neglected for so long, can access.

OK: These are indeed fantastic achievements for patients with GD where improved longevity is recognised. As we mark Rare Disease Day in 2022, there are still unmet needs and challenges to overcome for this community. What would you see as the biggest challenge for patients attending your clinic?

PM: I see the biggest challenge is the paucity of evidence generation for rare diseases. The preferred therapeutic options put to patients by physicians is based on very weak science and data. I think whatever rare disease you look at, even in highly developed nations, patients are simply told to have treatments based on weak data. That is a very major gap. Just to draw an analogy on a very common disease, Hepatitis C, it is like these patients being told their insurance companies will only fund interferon and ribavirin therapy. For this condition, that drug combination is now obsolete. In Hepatitis C, there are shorter treatment alternatives that guarantee 100% cure. The numbers of affected patients make it easier to advocate for change but in rare disease where physician experience is limited, changing therapies without evidence is even more challenging. Nevertheless, like-minded clinicians working with industry, supporting registries, working with patient support organisations are important pillars from which to establish therapeutic transformation in this patient population.

OK: There are hurdles for patients and physicians to overcome in order to attract funding and to prioritise the research agenda to acquire new scientific insights for a disease. Can you share with us some positive experiences on how you have overcome these obstacles?

PM: There is a high level of awareness now thanks to the rare disease office at the National Institute of Health (NIH). We need to do more and better for families affected by rare diseases. There are several innovative treatments that have been funded by NIH for example in the treatment of porphyria but not Wilson Disease thus far. There are examples of how registries (e.g. porphyria consortium) can enhance these advances. The consortium and NIH joined forces and complied a natural history registry which was an important stimulus in the successful design and implementation and subsequent approval of an RNAi therapy for porphyria. This consortium has a patient advocate to provide a patient voice in all discussions and decisions. Another path is philanthropy and independent fund raising. The very first patient with GD I took care of, was very generous in funding my research. The most important emerging area is having registries with industry support as registries are very expensive undertakings and cannot be done by individual clinics without support. The value proposition is not there to obtain and continue funding from government authorities as we have witnessed with the EuroWilson project.

OK: Is the patient voice being heard with regards to the aims and priorities of the research agenda? How can we empower patients to be part of the study design process?

PM: This is a very important question that I have been reflecting much upon recently. I became a member of the medical advisory board for the PFIC (Progressive Familial Intrahepatic Cholestasis) Association which is run by a patient organisation. It seems to me that rare disease advocacy groups are traditionally dictated to by physicians without discourse. This is totally different from how I communicate with my lysosomal disease groups. Communication needs to be bidirectional; patients are highly informed and knowledgeable about their condition. So, it is the role of the physician to present the data and provide guidance on interpretation and we all need to democratise medicine so that the patient voice can be heard throughout the research agenda and treatment recommendation discussions. We need to develop partnerships and give patients their voice back.

OK: One of the issues with WD patients is the importance of compliance and adherence. Physicians need to engage with their patients in a way that they can understand to highlight the importance of this issue as no matter how good the treatment, if it’s not being taken and taken appropriately then it will be ineffective! This is an important aspect of a physician-patient relationship too, would you agree?

PM: Yes, 100%. Physicians have to take responsibility to explain the disease, the biology, the therapy, how it works… then the patient is hooked, and you are able to build a trustful relationship and the patient is more likely to comply with the treatments prescribed. I can give you an example of patient I recently saw who travelled from North Carolina to see me in Connecticut. He is a teenager who has Central Hickman catheter for repeated intravenous infusions who was feeling acutely embarrassed by it; he did not want to undress in front of his peers and whenever his friends called at his house, he was hooked up to an infusion and unable to share with their activities. All of this had made him profoundly depressed. When I saw this young man with his mother, I took the time to describe his options and I could see how withdrawn he was. I was able to provide alternative solutions for them and although he didn’t engage much, I received an email from his mother a few days later, on how grateful he was to have made this visit and how by implementing some of my suggestions he would be able to overcome some of the issues that had been causing him much anxiety. So what I am trying to say is that it is how you talk and how you empower the patients; explain the value of taking the medicine and talk about their bright future if they do and also advising them that there are means by which we can tell that they are not! This develops healthy doctor patient relationships.

Another example I can share with you is of a young lady with WD who I started on trientine but she was non-compliant and did not come to clinic for eighteen months (she had gone to college, graduated, started two jobs) and unfortunately her disease progressed and she presented with evolving liver failure. Now we were able to avoid transplantation and she is back on trientine and I can assure you she will comply with her treatment after my consultation with her. What disappointed me with this story is that if we had an extra layer of protection from a patient registry where we can identify non-attendance at clinic and make contact with the patient, this complication might have been avoided.

OK: That’s a benefit of patient registries that I have until now not appreciated so thank you! I was going to discuss your experience with registries. By reflecting on your experience spanning more than 20 years with the GD registry, what benefits do you foresee that the international Wilson Disease (iWD) patient registry will bring for patients?

PM: I think the iWD is much overdue. I am very pleased to see that it is taking off with Orphalan bringing together physicians from all continents to contribute and advise on the charter, goals and objectives. It has surprised me that this type of registry has not been established before, with publications on WD dominated by single centre experience. This provides a very narrow perspective on the disease ignoring the effect of race and access to different therapies. Now WD is a global disease and it’s not uncommon for me to receive an enquiry on management from a physician in India. iWD will propel data generation and encourage physician-led epidemiological studies and harness patient participation too because there always will be questions from patients that individual centres cannot answer. A registry will establish relations between physicians from different centres, providing a platform to engage and share cases and consult with each other. I am fortunate to work alongside an expert in WD, Prof. Michael Schilsky who was the Principal Investigator of the CHELATE Trial. With the patient whom I described earlier who didn’t attend for 18 months and presented with florid haemolytic anaemia and liver failure, I was able to discuss the case with him and even though he had not seen this presentation himself before, collaborations through an international registry may have identified such a presentation before. The final point on how the registry may make a difference is the provision of long-term data – including long term adverse outcomes. There is no clear data from over 50 years of chelation therapy with d-Penicillamine to highlight the harmful effects especially on skin from this agent, but from my own clinical experience, I have witnessed several devastating dermopathies because of this treatment. I can tell you from my own patients, that having this complication is worse than having the disease itself. We need a solid foundation of data to detect and report adverse events of this nature and it doesn’t exist today. A registry would allow us to capture this in a very meaningful way.

OK: That’s a very powerful statement on the benefits of patient registries to end on. Thank you for your time to put together this blog. One final question….. At Orphalan, a small company of 75 staff spread across Europe and the US, we are going to acknowledge World Rare Disease 2022 on Monday 28th 2022 by pausing and convening virtually for an afternoon tea to raise our cups and mugs in recognition of patients with rare disease and reaffirm our commitment to do our utmost to make a difference to their lives. How will you mark the occasion?

PM: For my part, we had an earlier celebration for Rare Disease Day at Yale on Friday 25th February, developing the roadmap in recognition of the diamond jubilee of the liver centre at Yale. I was asked to talk about rare diseases affecting the liver and I dedicated my lecture to the rare disease community.

A link to the event is here: