Episode Transcript:

Dr. Maddux: Kidney diseases are being reclassified as we uncover more precise mechanisms for kidney injury and the predisposing characteristics of individuals with these disorders. APOL-1 mediated kidney disease is a kidney disorder associated with certain APL-1 genetic mutations often found in people of Western and Central African descent. The disease can lead to glomerular injury or scarring of the blood filtering units and permanent damage to the kidney. Patients have abnormal amounts of protein in their urine and develop progressive kidney failure. Today's guest, Dr. Reshma Kewalramani, is CEO of Vertex Pharmaceuticals. She will discuss with me research into the underlying cause of APOL-1 mediated kidney disease and potential approaches to treating this disorder.

Welcome, Reshma.

Dr. Kewalramani: Frank. Thank you so much. It’s a pleasure to be here.

Dr. Maddux: Let’s start by talking about APL1-mediated kidney disease that many of us thought was really in this basket of focal segmental glomerular sclerosis for many years. Tell us about that.

Dr. Kewalramani: Frank, we’ve known each other for almost 20 years, and I became a nephrologist in the early 2000s. And certainly, when I was practicing nephrology, when we saw a person who had hypertensive kidney disease, some protein in their urine, we would call it hypertensive kidney disease. If it was a kidney disease that was more aggressive for which we decided to do a biopsy, we would look at the finding under a microscope and sometimes call what we see FSGS, which is ultimately a histological diagnosis. And when you think about those two diseases in particular, and you think about black patients, we have all seen in our clinics who have progressed on to dialysis or have had aggressive kidney disease. We often thought of it as perhaps this is happening because of social determinants of health, and I think there's an absolute component of that.

But it turns out, exactly as you said, for people of especially Western African descent, recent African descent over the last ten years, we have discovered that there is a gene APOL1 and if you have two alleles two APOL1 alleles, you are at significant risk, significantly predisposed to having kidney disease. Historically, we may have called it FSGS because we did a biopsy on you and we happen to have tissue that we could look at under the microscope, or we called you hypertensive kidney disease because we saw you. You had hypertension, you had some kidney disease, a little protein in your urine. But it actually turns out that the unifying diagnosis in many people of recent African descent is having two APOL1 alleles.

If you think about non-diabetic kidney disease, about 70% of black people who have what we used to call FSGS, actually have APOL1 mediated FSGS. If you look at people of recent African descent who have what we would call hypertensive kidney disease, 40% of those patients actually have two APOL1 alleles. This is a recent discovery, and you're so right about talking through the reclassification of disease. This is a very recent understanding, a very recent understanding, that this is a genetically mediated kidney disease. And so a lot of what we are doing right now is trying to understand this better, bring potential therapies forward, have people be diagnosed and raise the awareness of this particular condition.

Dr. Maddux: I've always worried that so many of our negative clinical trials in nephrology have been driven by the fact that we use this observational pathologic classification of kidney disease, as opposed to really understanding the mechanisms of injury and the disease. There's some overlap of those mechanisms. And so, we've been treating very heterogeneous populations with a homogenous intervention. This is one of the greatest potential opportunities to begin to realize we've got to become much more precise in how we look at kidney disease.

Dr. Kewalramani: You have hit on a really important set of, I would say, three points in that observation. One is, we have had in renal medicine, a reliance on observational research for far too long. Second, we really haven't kept pace with diagnosing based on precision medicine, certainly not treating based on precision medicine. That's to say the genetic underpinnings of disease we have fallen behind.

And the third point, and you and I have talked about this before, we simply need to do more clinical trials, real randomized clinical trials to understand cause and effect, not simply associations. I do think this discovery that was made right here in Boston by Martin Pollack and his group at the B.I. Deaconess has that potential. This is potentially APOL1-mediated kidney disease is what I mean. APOL1-mediated kidney disease is potentially the first disease that we diagnose precisely using a genetic test, and that we might be able to treat with a medicine that's targeted at that exact cause. What we've done historically: take all comers and treat them with one treatment and then we are surprised that the treatment may not have worked or the magnitude of the treatment effect is lower than we would have thought.

But what we were studying was a wide array of disease that we tried to make into maybe something like chronic kidney disease. I am really enthused about this now. We have to go through the clinical trials. We have to come out the other end, but I'm enthusiastic about the idea that we're diagnosis based on genetic understanding and that we are targeting treatments to that specific disease.

Dr. Maddux: I think that's great. Tell us a little bit more about the AMKD trial and the way you're sort of approaching trying to find the right patients for this particular intervention.

Dr. Kewalramani: I'm a nephrologist by training, but when I came to Vertex in 2017, I ended up doing quite a bit of work on cystic fibrosis. That's what Vertex has historically been known for. What we're doing in our APOL1-mediated kidney disease program takes a lot of the learnings from cystic fibrosis and are applying it here.

For example, the prevalence is approximately the same. There's about 83,000 people with cystic fibrosis. There's about 100,000 people with APOL1-mediated kidney disease in Europe and the US. Cystic fibrosis is a genetically defined disease. APOL1-mediated kidney disease is a genetically defined, genetically influenced kidney disease. The way we were successful in CF was being very, very deliberate about going after the underlying cause of disease, not upstream, not downstream. The underlying cause of disease. That's exactly what we are aiming to do here with APOL1-mediated kidney disease. So, what we've done to date, we have done a phase two study. In that study, we studied about a dozen or so patients with APOL1-mediated FSGS. So, the more severe kind of disease biopsy proven FSGS. And we saw 47.6% reduction in proteinuria. Pretty amazing.

Dr. Maddux: Really amazing.

Dr. Kewalramani: What we've done in this is something I take great pride in is we've designed a phase two three adaptive study in which we are studying approximately 466 patients with two APOL1 alleles. Proteinuria of more than 0.7 grams and reduced renal function, with a goal of doing an interim analysis after one year of treatment to see if we have impacted EGFR and the study will continue for a total of two years of treatment to the final endpoint.

And the reason I take so much pride in this study is going back to the point you have made about observational research and associations. We've done a lot of observational studies. We've always talked about doing more clinical trials in renal medicine, more innovative clinical trials, and I see this as the trifecta of clinical trials. It's adaptive. It is a trial that selects individuals based on underlying genetic, precise diagnosis, and it has the opportunity for an interim analysis where after one year of treatment, if it works, there's an opportunity to move that forward. So, I'm very pleased with the trial and I'm very pleased with the fact that we are up and running now.

Dr. Maddux: Rare diseases in general are sometimes quite difficult to recruit. How do you go about taking a field like nephrology in which, unlike oncology, where just about every oncologist is looking for every single trial that's in whatever case is in front of them, and patient presents to them. But nephrology doesn’t have that culture and that history. How do we change that? How do we get the number of patients you’re going to need to have here in a reasonable period of time?

Dr. Kewalramani: What a great question. I don’t think it’s any one singular silver bullet. But if I think about our trainees, we need more trainees coming out of internal medicine who go into nephrology, period. But we need more trainees who go into nephrology who have the desire to have research basic science or clinical as part of their practice. I think that is far more common in oncology, far more common in cardiovascular disease.

I do think it starts with our trainees. One thing I've learned from working in CF is the clinical trial infrastructure in the cystic fibrosis arena is fairly significant and actually quite impressive and that is through training. It is through support and it is through education of not only the physicians but the patients. Everybody's geared towards wanting innovation and wanting to be part of the clinical trial enterprise. I think we could do better on that front as well. And maybe the last thing is around having more automated, electronic, easier ways for our physicians and nurses to be able to look for patients who would qualify for clinical trials. I think there are many other things we can do, but I think these are the three prime things that we could do in order to accelerate clinical trials in nephrology.

But I have to say, I don't see it as an all negative or glass half empty situation. In just the past five years, I've seen more clinical trials in renal medicine than I'd ever seen before. More randomized clinical trials, more emphasis on sorting out IGA nephropathy or C3 nephropathy or AMKD. In our case, where I do think people are becoming more precise in the diagnosis so that we have a better chance of successful clinical trials. And I see simply more, simply more than I've ever seen before.

Dr. Maddux: Certainly, since the executive order in 2019 and the activities that have recognized that end-stage kidney disease, CKD, transplant, don't really live in different buildings. They're actually one disease state and one area of care that needs to be improved. It seems like there has been more investment and interest in companies like yours in the renal space. Do you anticipate there are other areas in the renal space that might follow the APOL1 story?

Dr. Kewalramani: Yeah, another really great question. I do think so. I think that at least if I speak for Vertex alone, there are a number of other kidney diseases where we are gaining better and better understanding as to the genetic underpinnings of the disease. For Vertex, we have a very strict way in which we do R&D and in brief the way we decide on what diseases we can work on based on what has not worked in the industry, are the following:

We only work on diseases where we understand causal human biology. We only work on diseases where we have validated targets, usually genetic, but pharmacologic is just fine. We only work on diseases where we have biomarkers that translate from the bench to the bedside. In the instance of cystic fibrosis, it's chloride transport that translates to sweat chloride. In the case of AMKD, it's proteinuria and we study proteinuria and GFR in the clinic.

The last two are that we only study diseases that have an efficient development and regulatory pathway, and we only work on diseases in specialty markets. That's because, in that way, we can keep a very small SGNA expense and spend the vast majority of our budget on R&D, on research. Exactly right. So, there are a couple of other diseases that fit these criteria.

I think the one that people are probably most familiar with is, are diseases like polycystic kidney disease. But there are others now that we're causal human biology is being understood where the targets are being understood and that follow our criteria. And so, I do see us becoming more involved in diseases, including in the kidney that follow these criteria.

Dr. Maddux: So very much a precision approach. Start to finish.

Dr. Kewalramani: Very much so.

Dr. Maddux: One last question before we finish up. There's so much interest in recognition today that our patient populations are not homogenous in many different ways. And the impact of disparities of health access, disparities and understanding of care, the fact that we tend to include and exclude and miss populations of patients in some RCTs.

How is it that we actually can broaden the base of recognition that health equity even extends into the development of innovations like these? This is one example that you've had that sort of highlights it, but there's probably a lot of others out there that we need to think about.

Dr. Kewalramani: It's such an interesting question, especially from my vantage point at Vertex, and I say that because cystic fibrosis, which is what the company is very well known for, is not only a genetic disease, but it has this founder effect. It's not exclusively, but largely a disease of northern western Europeans and where they migrated.

It's a disease in Europe, the Americas, Australia. And then you compare and contrast it to something like AMKD, it's a disease of Western African descent. It turns out that if you have one APOL1 allele, it's actually protective against African sleeping sickness. So, there's a real basis for why it is found more in Western Africa.

And the people who have this are black people and people who are descendants of Western Africa. So, there's is some amount of disease for example, in South America, especially in Brazil. When you look at these two as examples, and then I can also tell you about our example in sickle cell disease and beta thalassemia where we have a program using gene editing that is also a disease of almost exclusively black people for sickle cell and Asians, middle Eastern people for beta thalassemia.

These are important characteristics to know about, and it's important to look at what has worked and what has not worked. The gene for cystic fibrosis was discovered in 1989. The gene for sickle cell disease was 1956. However, the first treatment targeting the underlying cause of cystic fibrosis was 2012. The first treatment targeting the underlying cause of some of these diseases are far later than that. Right. So, you do really have to ask yourself, why is that? I think some of it is indeed investment in the diseases. I think another is recognition and scientific clinical effort behind these diseases. On the clinical trials front, when you have diseases that affect across ethnicities, across races, we don't do a good enough job of making it accessible to all people, and I think that you see this more in sickle cell disease. You see it more in an AMKD disease because it affects exclusively the smaller population. But if you look at diseases like heart disease, you look at cancer, you look at diseases that affect all people of all ethnicities and races. We just simply don't do a good enough job of having a clinical trial infrastructure that's welcoming to all. And we have to change that.

Dr. Maddux: Certainly, in nephrology, I think that'll be something we've got to emphasize because we know our patient populations come from many different ethnic groups and certainly even beyond ethnicity, different socio-demographic factors. So the social determinants of what actually leads to some of the disease or is a factor in the disease beyond what you might be predisposed to is going to be vitally important.

Dr. Kewalramani: Very much so. You know, Frank, as we've looked at the AMKD population and as we are working with patients and thinking about our clinical trials, three things come to mind for me. The first is patients who have a genetic underpinning. It's difficult to say: why don't I just genotype you? Why don't I just test you? You have to take time to explain to the patient what this means.

And one repercussion of that is when you're working in disease like APOL1-mediated kidney disease, you have to realize it's going to take more time. The second learning that I've had is that the lead physician, whether it's primary care or in the case of AMKD, their nephrologists, that relationship is critically important. It's not a clinical trial infrastructure where you have a clinical trial list over here and their primary physician over there.

It's very related to the trust that the patient has with their primary physician. I think that's really important. And the last one is we have to be better about bringing clinical trials to where the patients are. The pandemic has made enormous strides in that direction far more than we were able to make in the last five years or ten years.

We and others are doing much more to make it easier for the patients so they don't have to come to hospital. They don't have to come in for every visit. But we are going to them with VNA or the ability to do certain visits by teleconference or to be able to send samples in. I think that helps all patients. I think it helps patients who are a little bit more apprehensive about coming into the clinic or just simply live far away. And people who have rare diseases, they are rare, so they don't always live right where their center is. I think the way we do our clinical trials going forward is going to have to have a component of remote clinical trial considerations.

Dr. Maddux: Thank you so much for being here today. Thanks for talking with me about this, and I have appreciated our 20 year professional relationship and watching you progress from the time we first met when you were at Amgen to now your role at Vertex. This is an important trial and I hope that we can broaden the conversation about what we need to do to have more of these precise therapies. So, thank you. Reshma.

Dr. Kewalramani: Frank, it's so good to see you. It's so good to be in renal medicine, and I'm looking forward to our entire field doing more for our patients.

Dr. Maddux: Great. Thanks so much.

Dr. Kewalramani: Thank you.