Kyle Wood, MD

How can we help educate other providers? Similarly, how can we educate patients about the disease?

: I think the provider should be knowledgeable about the disease process. Some of it is just talking about it, like we’re doing here today, but also getting the information out there. There are plenty of groups that are looking at this. For example, the Oxalosis & Hyperoxaluria Foundation, does a lot of these clinical trials. You can have patient testimonies, which families can access. There are community-based points of access to educate patients and providers of disease awareness. That’s an education process—talking to providers and presenting the data. With anything in medicine, when we have a treatment, we often become more knowledgeable and educated about it because we actually have a tool in our toolbox to treat these patients. Again, with enteric hyperoxaluria [EH], there isn’t a drug currently approved to treat it. We manage EH through dietary means and medical means. If we do eventually have a drug that is approved for this condition, we’ll become more knowledgeable on it.

What are the implications from this data and what do we have to look forward to?

: I think, obviously, it’s a great study. There’s never been a group to bring 115 enteric hyperoxaluria patients through a medication study like this. However, with the data, I think we are taking a step back. The enthusiasm’s tempered right now because there was a reduction in their primary end point, which was urinary oxalate excretion. I think, as a community, we’re still wondering whether that will translate into a clinical benefit. Currently, we’re waiting on this next study. The implications are that we know these things work. The studies have shown that the primary end point is statistically significant so we know, with oxalate degrading enzymes, we can reduce urinary oxalate excretion. I think the next step is trying to understand whether that reduction translates into clinical benefit. Once that can be shown, there’s going to be a lot of enthusiasm about it and the implication will be significant. The other issue is that this medication relies heavily on patient compliance because the patient needs 3 to 5 doses per day. As we move forward, hopefully, there’ll be development opportunities where patients don’t need as many dosages, and compliance would be easier. The future of drug development is bright. I think this clinical trial demonstrates that working through these mechanisms can reduce urinary oxalate excretion. There’s still a lot to be seen.

What are the unmet needs for the treatment and management of this disease?

: We still have many unmet needs—drugs and other management strategies—to manage these patients. I think there are unmet needs. We need more research on this population. As we talked about, there are multiple causes. We still don’t have a great understanding regarding the number of people who have enteric hyperoxaluria. We still don’t understand whether we’ve classified as idiopathic or secondary hyperoxaluria, which could be a component of enteric hyperoxaluria. We don’t have a real grasp of the population. We can learn more about the pathophysiology of the disease. We could do a lot of research on phenotyping our enteric hyperoxaluria population and understanding who would most likely benefit from certain drug treatments and options. I don’t think we’ve done enough with intensive medicine and dietary management of this population so we can see how much a patient could truly benefit in regards to oxalate. A lot needs to be done on the research front. There’s a lot that needs to be done on the drug development front, although it looks promising. We need to educate both the providers, as well as the patients, and build a community where patients, families, and providers can gather information. Providers have to learn how to treat these individuals and have resources available to them.

What are your final thoughts on the future management of enteric hyperoxaluria?

: I think we’re at a great point where there’s a lot more interest in it. There’s drug development and more research focused on this disease state. I think it’s a bright future. I think we’re seeing a lot of positives and recognizing a lot of the limitations as well. This population is a large population. It’s a patient population that suffers from recurrent kidney stone disease. The more we look at EH as a chronic disease instead of an episodic event, I think we’re going to do more and more for this patient population and benefit them significantly.

Absolutely. Thank you so much Dr. Wood. Thank you to our viewing audience. We hope you’ve found this 

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Dr. Kyle Wood discusses optimal avenues to increase patient and provider education on enteric hyperoxaluria and provides closing thoughts on the future management of enteric hyperoxaluria.

Unmet Needs for the Treatment of Enteric Hyperoxaluria

You mentioned 1 of the concerns is trying to address the underlying condition. What are some of the ongoing trials for the treatment of enteric hyperoxaluria [EH]?

: The leading trial is the URIROX-1 trial, which is a phase 3 study being performed by Allena Pharmaceuticals. It is an enzyme that breaks down oxalate. It’s an oxalate degrading enzyme. The data that we have is from the first phase 3 trial. They’re in a second phase 3 trial now, but their first phase 3 trial was looking at 115 individuals with enteric hyperoxaluria and kidney stone disease. They observed them for 4 weeks of treatment: Having baseline data, treating them with their enzyme, and then looking at urinary oxalate excretion as their primary end point. Their primary end point was reduction in urinary oxalate excretion, and they saw a reduction, or an absolute reduction, of 12.9%. So both the placebo arm and the drug arm had an effect. Again, when you look at the absolute reduction it was close to 13%. One of the problems with this drug is that it has to be dosed 3 to 5 times a day. It’s given with meals so you’re breaking down the oxalate load that comes with diet. If they’re having 3 meals or snacking, you might have to take upwards of 3 to 5 doses per day. It’s heavily reliant on patient compliance. Their secondary end points were looking at say, greater than 20% reduction, and urinary oxalate excretion from baseline. They didn’t see a difference between the treatment arm and the placebo arm. The 

 value was .06, which is a slight concern because we don’t know how much oxalate needs to be reduced in order to see a clinical benefit, or a reduction in kidney stone events. A lot of us believe that you would need to see a reduction greater than 20% in urinary oxalate excretion to see a clinical benefit. With the phase 3 trial data, there’s still some concerns about whether the data, although significant, will translate into a clinically significant benefit. They are currently pursuing their other phase 3 trial, which will have significantly more individuals over a longer time frame. We’ll have some more conclusive data about the benefits of that. The other ongoing trials are looking at other oxalate degrading enzymes. For example, Oxidien Pharmaceuticals is looking at an oxalate degrading enzyme and has published some data from early studies that show a benefit. Other companies are looking at bacteria that have been modified to degrade oxalates. This bacterium has been engineered and modified to degrade oxalate. There are 2 types of synthetic bacteria that can be used. You either colonize the gut with it—that would be like, for example, Synlogic Theraputics where you colonize the gut—or you give the bacteria and when it’s transiently present within the gut, you have to keep redosing it. That would be like the no volumes clinical trial. There are multiple ongoing trials looking at degrading enzymes, as well as trials with bacterial modifications that degrade oxalate. I think the future is bright. Hopefully we’ll see some benefit from those trials.

Kyle Wood, MD, reviews data and clinical implications for the use of reloxaliase in enteric hyperoxaluria as seen in the phase 3 URIROX-1 trial and shares insight on additional ongoing trials.

Phase 3 URIROX-1 Trial for Enteric Hyperoxaluria

What are some concerns with the current treatment options available?

: The current concern is that some of our patients have profound enteric hyperoxaluria, so their oxalate levels can be extremely high. Despite our best management strategies with dietary management and supplementation, we still have issues reducing their oxalate. As we know, it is hard for patients to continuously manage their diets and various aspects. Following a dietary protocol, taking medications regularly, and all these interventions may not reduce oxalate perfectly. Those are the problems because there isn’t a perfect way to reduce oxalate levels and it requires a lot of commitment on both the physician’s side and the patient’s side.

For patients who have recurring or complex kidney stones, are the providers treating them able to identify a enteric hyperoxaluria diagnosis?

: The best thing to do for all urology providers is to follow the AUA [American Urological Association] guidelines. If the patient has complex kidney stones or is a recurrent kidney stone former, we should be offering a metabolic workup, which would be a 24-hour urine test. In that 24-hour urine test, oxalate should be measured. That would help us identify the patients that have enteric hyperoxaluria because we would have an oxalate value and a history that would point to an enteric cause. That’s the best way to identify and manage these patients. As I had mentioned, I think, as a community and as urologists, we have not done enough work in working-up our patients and determining whether they have enteric hyperoxaluria or other causes of kidney stone disease.

When it comes to pain management, where are the patients obtaining pain medications for their kidney stones?

: Pain management’s an interesting aspect. We’ve had an opioid crisis within the United States, and kidney stone formers aren’t immune, so they’ve been prescribed opioids over the course of many decades for their kidney stone events. Unfortunately, that has probably become an expectation when patients are having a kidney stone event. There’s plenty of data showing that opioids may not be needed and kidney stones can be managed with nonopioid medications. Opioids, during a patient’s initial kidney stone event, are oftentimes prescribed in the emergency department setting or the primary care setting. Data at our institution, the University of Alabama in Birmingham, Alabama, that we’ve looked at shows that for the most part, urologists aren’t the biggest prescribers for patients. They’re getting medication through the primary care setting as well as their pain physician, so a lot of patients under our pain contracts seek pain doctors for their opioids. Again, we as urologists perform surgeries on these patients and manage their kidney stone events, and we will be dealing with their pain medications, so we just need to be cognizant that kidney stones can be managed in other ways other than opioid treatments.

An expert in endourology discusses concerns with currently available treatment options for enteric hyperoxaluria and comments on detecting the disease for patients with recurring stones.

Challenges with available treatment options for enteric hyperoxaluria

 It can be. When you look at the big picture, you can say, “Well, the majority of patients with enteric hyperoxaluria have had bariatric surgery.” So if we look at a global prevention strategy, or a national prevention strategy, it would address the obesity epidemic and other factors outside the surgical means. It would be dietary recommendations and weight loss clinics. In addition, if a patient is choosing to have a bariatric surgery, you can try to do another type of surgery, different from the malabsorptive surgeries—although they’ve been shown to be the most beneficial for patients with weight loss. You can consider gastric bands, which is a restrictive procedure. There are obviously treatment options and management strategies that can prevent enteric hyperoxaluria once we identify these patients. With Crohn disease, if you treat the active disease form, you may prevent the patient from having the malabsorptive state. There are various ways to treat the conditions that they have and understanding the population. This avoids malabsorption by gastric bypass if that’s a concern. These patients are often managed with bariatric surgery for obvious reasons—for health benefits—and this is the sequel of those procedures. But there are ways to prevent enteric hyperoxaluria.

You mentioned therapies. What are some treatment options for this disease?

 I break it down into 4 categories. That’s the way I like to view it. The first 1 is dietary management. Obviously, if you persuade them to take a lower-oxalate diet, which is hard to do, they’ll understand oxalate content in the things they’re eating, which is obviously less oxalate burden to the gut and, therefore, less absorption. The other thing is because of a fat malabsorptive state. If you focus on low-fat foods so that the patient has less fat malabsorption, that can be beneficial. You can talk to them about a high-calcium diet. In the pathophysiological processes, the calcium is being saponified, so if you get them to have a higher-calcium diet—giving them calcium supplements or calcium in their diet—you can bind to more of the oxalate and reduce the oxalate load to the kidneys. As with all kidney stone formers, increased fluids—if you persuade them to drink more fluids—will dilute their urine and make kidney stone formation less likely. That’s the dietary approach that I usually take. The second category is looking at oxalate binders.

I alluded to it, but the use of calcium supplements—giving patients prescription calcium—to increase the amount of calcium that can bind to oxalate will lower oxalate in the urine. Magnesium can be used the same way. The third category we think about is bile acid sequestrants [resins]. This is a malabsorptive process of fat and bile acids. If you use cholestyramine [Questran], or other medications to reduce the bile acids, you may reduce the saponification to calcium, and thus reduce the oxalate load that’s getting absorbed.

The fourth category is for newer ideas that are coming out in clinical trials, which are the oxalate-degrading enzymes or bacteria. We’ve known about Oxalobacter formigenes for quite some time. It’s a normal, gram-negative bacteria that may colonize in the gut and degrade oxalates. The newer novel therapies, currently in phase studies, are looking at degrading oxalate by using enzymes or modifying bacteria. None of those have been approved by the FDA, but those are things we can think about for treating our patients.

Kyle Wood, MD, reviews current therapies and strategies for the management of enteric hyperoxaluria.

Kyle Wood, MD

Articles

Unmet Needs for the Treatment of Enteric Hyperoxaluria

Phase 3 URIROX-1 Trial for Enteric Hyperoxaluria

Challenges with available treatment options for enteric hyperoxaluria

Treatment Options for Enteric Hyperoxaluria