Brad H. Rovin, MD, professor of medicine and pathology and director of the Division of Nephrology at The Ohio State University Wexner Medical Center, talks about new medicines that could help fight against lupus nephritis.
For our viewers who have never heard of lupus nephritis, can you describe what it is and what’s happening in a patient’s body.
ROVIN: So, lupus nephritis occurs in patients with systemic lupus erythematosus or SLE, and this is a disease called an autoimmune disease in which the body produces autoantibodies which attack proteins and cells and tissues of your own body. So, in lupus nephritis, these antibodies tend to accumulate in the kidney and in patients who do develop lupus nephritis and that’s not everyone. It’s about overall about thirty-nine to forty percent of patients will eventually develop lupus nephritis, and when they accumulate in the kidney, they set off an inflammatory program that actually results in damage to the filtering units of the kidney and we call that lupus nephritis.
When you have that damaged filter, what essentially is that?
ROVIN: So, what it means clinically is the filtering units are called glomeruli, and the glomeruli are very smart filters. So, they allow the body to get rid of waste products and they retain cells and things we need like proteins that we want to retain in the blood, and so when you have damage or inflammation to the glomeruli one of a couple of the signs clinically are that you find, for example, red blood cells or white blood cells in the urine. Normally you may see one or two cells, but not a lot. You also, in almost every lupus patient, find a significant amount of protein in the urine if they develop lupus nephritis and that’s what we look for whenever we examine patients with systemic lupus.
How common is it and do we know what causes it?
ROVIN: Well, again, it’s really common in patients with lupus. When you think about almost 40 percent will develop it. That’s very different across races and ethnicities. People who are Hispanic or of African origin tend to develop it more often than people who are white. Also, the disease tends to be more severe. What causes lupus nephritis is a million dollar question. So, we know sort of the pathogenesis. It’s you know, the antibodies accumulate in the kidney. They set off various inflammatory mechanisms. They recruit red blood cells to the kidney, so we know how the kidney gets damaged, why people in particular are predisposed sometimes to get lupus nephritis and other people not to. We don’t really know that. There’s been a lot of genetic studies looking at predisposition, genetic predisposition. So, my feeling is that people who have lupus have a genetic component to their disease. The disease is then triggered probably by an environmental event, an infection, something, you know, to do with their environment. I use the word environment pretty loosely, the hormonal environment, because lupus is much more common in women than men, about nine to one, but then to try and figure out within the lupus population, we found some genes that are associated with predisposition to nephritis, but we’re really not sure at this point. So, that is an open question for investigation.
What kind of data do you get in laymen’s terms is this causing this to the system, to the kidneys? Eventually do patients with condition need transplants?
ROVIN: So, what we try to emphasize with our patients with lupus is that they check get checked yearly at the minimum for any evidence of kidney involvement. The quicker you can get to the patient and treat them, the more effective the medications are to decrease the inflammation, turn off the inflammatory systems and allow the kidney to recover. Now, if the damage is very severe, so this is inflammatory damage and goes on for a long period of time, you actually can get sufficient chronic damage to the kidney. So, scarring that the patient could require at some point in the future, kidney replacement with dialysis or transplantation. We try to prevent that, of course.
So as medication, the first line of defense can you tell me is it a pretty effective medication that we got to this point or not for everybody?
ROVIN: Yeah, so the medications we have are effective for many people. We try to strive for what we call a complete kidney response or a complete renal response. The current medications achieve that in maybe after a year, maybe up to 40 percent of patients and then another percentage respond partially. We really want to increase that number of complete responses because that’s really been shown to preserve kidney function over the long term over many, many years. The medications we have now, as I said, are effective in a lot of people. They are not without side effects, sort of the basic regimen that we use, our large doses of steroids called prednisone is what we use commonly. These are not anabolic steroids like you would use for bodybuilding, not appropriately, but people do. These are steroids and they have a lot of side effects. They’re anti-inflammatory, they’re very good medications, but they’re fraught with side effects, both acutely and then over the long term and especially have side effects in terms of weight gain, skin problems and then long-term damage to the bones. Then we also use what we call immunosuppressive drugs, which are either cytotoxic agent like cyclophosphamide, which has been borrowed from the cancer realm, or something we call an anti-metabolite, which is microfauna late Morphettville, which is really what we’ve been using for years and years in the organ transplant field. Those drugs are general immunosuppressive and tend to inhibit many aspects of the immune system, leaving the patient really susceptible to infection as one of the main side effects. Then each drug has its own series of individual side effects. So, the treatment of lupus basically is to use fairly strong therapies that are effective but are associated with lots and lots of potential side effects.
Can you tell me about the clinical trials? What have you and your colleagues done in terms of a new potential therapy?
ROVIN: So we’ve been participating in lupus nephritis, clinical trials for a number of years. I’m really happy to say that in this past couple of years, we’ve finally had trials that have actually been successful. We’ve prior to this had a lot of very interesting trials that have really not showed a difference between adding the novel agent on or adding a placebo on, which was disappointing. I think in the learning process really helped us because it really helped us rethink how we design clinical trials and how we implement them and bring them to the patients. That really bore fruit. I like to think of these past this past year really as a renaissance in lupus nephritis trials because we’ve had three trials positive. Of the three drugs, two of those were in phase three trials, which then went to the FDA and were approved, one in the latter part of 2020 and one just last month in 2021 well, two months, so January of 2021. So, the trials, the initial trials, because lupus nephritis is, a disease that can be very aggressive and can move very quickly. The trials cannot be simply be a new drug versus nothing. We always have to have a background therapy, and so the trials have been designed to add new therapies that sort of target just one aspect of the immune system and add those on to sort of the standard of care to see if they provide a boost to the number of patients that we can get to go into complete renal response. The new drugs that we’ve now trialed, have been approved, and have actually targeted either the bissel system B cells or one of the immune cells. They’re responsible ultimately as they progressed through maturity to make antibodies. Of course, in lupus, they make these auto antibodies and then T cells and T cells are another cell type of the immune system that is important in helping these cells make antibodies, as well as providing inflammatory cytokines and also direct tissue damage. So, each of those two cell types have been targeted in different clinical trials for lupus nephritis and have actually now shown effectiveness.
Can you tell me just very quickly about each of the drugs which systems it targets, the T cells? And of course, just for clarification, these drugs are not taken together. These are too separate, separate trials that you have?
ROVIN: These are separate trials. Right now, the drugs that have been approved, we know how they were given in the trials. The fact that they’re approved actually may allow us to experiment a little bit and see if we can develop regimens that are less toxic than what we’ve had in the past. So let me start with the two drugs that are approved. One of the drugs that’s approved is vocal sporran. Vocal sporran is called a calcineurin inhibitor. This is a type of drug that, again, we’ve been using for many, many years in the kidney transplantation field, solid organ transplantation. It this particular one is a newer calcineurin inhibitor. It targets the T cell. By doing that, we added that onto a background of steroids, but much less in this particular trial than what we would usually use, and then also combine that with Michael Finile, but again, in a sort of lower dose than one might usually use. That trial showed about a 20 percent improvement in the patients, the frequency of patients responding after one year. The second drug that was approved is called Balomamab. Balaomamb is a drug that does target the B cell system. It inhibits a factor called BLIS. And BLIS is a growth and survival factor for B cells. So, if that is taken out of the picture, then B cells don’t do well. Just to make the point, Baloomamab had been approved for non-kidney systemic lupus several years. It was the first novel biologic therapy approved for lupus in decades. It’s called a monoclonal antibody. So, it’s a designed antibody. It’s humanized and it inhibits this B cell factor that’s necessary for survival. Adding that to background therapies also improved the response rate. That’s an interesting trial because it was done at a two-year end point. These B sell drugs may work a little bit more slowly. The other thing that came out of that trial that we presented last year at some of the meetings was that it seemed to preserve kidney function and it also seemed to inhibit or decrease the rate of flares. So, lupus nephritis is a disease that goes down in activity and then can bump up in activity. It’s very important to limit these episodes of active inflammatory disease because the more times you have active inflammation, you can start to accumulate scar tissue in the kidney and then get into trouble later in life. So those are the two drugs that were approved. Then the third drug had a successful phase two clinical trial and is now in a Phase three clinical trial as we speak. Tthat’s called Obanatuzaman. Obanatuzaman is a drug that directly is toxic to B cells. As I said before, B cells are the precursors to plasma cells. Plasma cells are actually the type of B cell lineage that makes antibodies. So by knocking those cells out, then we hope that we deplete eventually the plasma cells and that we control the sort of starting point of kidney inflammation and other organ inflammation as well.
What’s the benefit of having these two drugs that are approved and maybe a third in the pipeline after years of not having much else that you could have?
ROVIN: So, I think there’s several benefits. One benefit, which is sort of maybe philosophical, but we’ve had so many years of failure that I think people, including maybe pharma, we’re getting discouraged. People started to think that, well, maybe this wasn’t a good place to invest sort of research because it was really hard to get a positive trial. So, I think the fact that three successful trials have now been, you know, realized has really invigorated the field. We now have a whole menu of new drugs that are being tested in lupus that are very exciting. So, I think overall, this benefits the community as a whole because it really has accelerated, if you will, research investment into this. So that’s important. The second thing is it’s been a remarkable finding to me that you can add these drugs onto immunotherapy. The trials show that we do not have an excess of adverse events. That really suggests that there’s some good safety signals from these new drugs. So, what’s the next step? This is my own thoughts. I really am encouraged by this. What I’d like to know do is start thinking about how we can use these new drugs, possibly together, but also to sort of look at the patient and say, ok, if we can find evidence that your disease is overwhelmingly T cell dependent. I’m using this as an example, and it may or may not be real is overwhelmingly T cell dependent. Maybe we want to put you on a T cell drug, overwhelmingly B cell dependent. Maybe we’ll choose a B cell drugs. So, what I’m getting at is can we take the lupus nephritis population? The disease is called lupus nephritis, but it’s very heterogeneous. All the patients showed different variations. Can we then look at your particular disease and find the best regimen for you that not only may induce remission, but induce it in a safer way? So that’s really, I think, the goal or my goal anyway. I think it truly is the goal of many of us who are in the field.
What’s the benefit for patients especially?
ROVIN: So, I think the benefit is going to be realized, one of the trials I told you about really had cut back significantly on the dose of prednisone. I think other trials will follow suit. I think the benefit is that we start to eliminate or decrease medications that have known severe toxicities that that patients really don’t like. If I talk to any one of my lupus patients and I would have said, what would you think about eliminating steroids from your regimen? I think they would be fantastic, right? Because of most of the drugs we use, the steroids really have the most diverse and unhappy side effects right away. Patients just don’t like them, so I think this will help patient’s quality of life if we can eliminate drugs that have a lot of side effects. I think adherence to the regimen will be improved because, you know, if you’re feeling terrible when you take a medication, you may not want to take it. I think that will help us achieve far fewer cases of progression to end stage kidney disease over time if people stick with the regimen. So, I think there’s a lot of potential advantages. Then if we can if we can start to back off on some of these, I call them broad spectrum immunosuppressive drugs, the background therapy that we use now is standard of care and maybe combine some of these drugs with really good safety profiles. Then, of course, we may completely change, you know, how a patient not only responds to therapy, but feels, well, they’re undergoing therapy and allow the patient to get back to really a normal life, which is ultimately our goal.
Tell me a little bit about Diana when she was struggling with it and how you were able to handle that?
ROVIN: So, Diana had a class four lupus nephritis. We had to do a kidney biopsy to detect that which we do on almost all our patients and it was pretty active disease. She was enrolled in the vocal sporran trial and actually did really well. She went into remission and we she was randomized. So, she had either standard of care therapy, but lower dose of steroids or that plus the vocal sporran. We don’t know which because that’s blinded data to the investigator. Then she enrolled in the extension trials. So, then she was given the vocal sporn for another year and she went into complete renal response. She’s been in complete renal response. She was able to really resume a lot of the activities that a young person would be doing, not the least of which is going back to school, and she was pretty ill when she was diagnosed, and it was in the hospital. So, she is clearly a success story and sort of what we hope to achieve in all our patients about.
How many people in the United States have lupus nephritis?
ROVIN: It’s really hard number to pick out. It’s beyond simply a rare disease, you know, by FDA standards. If we think about this sort of globally, probably several hundred thousand people have the disease and it’s very, very prevalent in Asia. For example, China has a very large lupus population and a lot of folks with lupus nephritis. Then there’s some countries we just don’t know about because we don’t have the data.
Is there anything I didn’t ask you, Doctor, that you would want people to know?
ROVIN: I think my message for people with the disease and families with the disease is to talk to your doctor about participating in a clinical trial. I think that, you know, we take all the precautions and the clinical are really engineered to be very safe, but it’s really the only way we’re going to make progress in finding new therapies for this disease. I realize that it’s sort of an altruistic act and clinical trials that are registered with the FDA. You don’t know if you’re getting the active drug or the placebo, but you’re going to get something to treat the disease. You’re not going to be left alone. Then a lot of trials have open label extensions, which means you can get the medication after you finish the trial. I think that too many people think about this is sort of a Frankenstein experiment that we’re doing on human beings. These trials are really well thought out. Prior to any bringing any drug to trial, it undergoes extensive safety testing. So, we make this as safe as possible. Things can happen, of course, but if we don’t have the participation of the lupus patients and their families, it makes it very difficult to advance the field.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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