AUA2021 Program Dives Into Advances in PH1 Research and Therapy

From September 10 to 13, 2021, urologists and nephrologists came together to attend the American Urological Association (AUA) 2021 Annual Meeting (AUA2021), a virtual experience that connected clinicians and experts from around the world. In a program filled with cutting-edge research, a number of abstracts were presented on primary hyperoxaluria type 1 (PH1), the most severe of a group of a rare genetic metabolic disorders characterized by accumulation of oxalate in the kidneys.
 
David S. Goldfarb, MD, clinical director of the Division of Nephrology at NYU Langone Health, provided his perspective on important PH1 research presented at AUA2021.

Which of the abstracts on PHI presented at AUA2021 were most interesting or clinically impactful?

All of them are very important, and they are dramatic. I have personally sent patients with PH1 to the operating room for combined kidney-liver transplantation. People often don’t take kidney stones seriously; this disease is something different.

In some ways PH1 is the most serious kidney disease in that it affects young people. It causes a lot of kidney stones and nephrocalcinosis, which leads to kidney failure. So I think that reducing urinary oxalate and normalizing oxalate excretion in a significant number of people is dramatic. It’s great science and it’s even a little miraculous.
 
Here’s a new technology: molecular biology, brought to the point of being therapeutically important. Beyond lowering urine oxalate, which we’ve known for some time — since lumasiran has already been approved — the next question is: Do reduced oxalate levels have an effect on outcomes that are relevant to these patients? Those outcomes are reduction of kidney stones and reduction of progression of kidney failure. That takes a long time to happen, so these studies haven’t gotten to that point. The signal was positive in the sense of reducing the number of kidney stones and reducing the grade of nephrocalcinosis. They’re not definitive from that point of view.
 
I’ve participated in telephone calls for the Oxalosis & Hyperoxaluria Foundation — a foundation that should be credited for supporting this work — during which people ask, “Can I stop drinking a lot of water?” or “Can I stop taking citrate?” The answer is that we’re not sure yet; it hasn’t been shown at this point.
 
But the hope is that all of these abstracts show that reducing urinary oxalate occurs in a dramatic fashion and should be associated, ultimately, with prevention of clinical outcomes that we care about: kidney stones, nephrocalcinosis, and progression of kidney failure.

One abstract¹ discussed a case of compassionate use of nedosiran injection in a 17-year-old woman with PH1 and end-stage renal disease who was awaiting combined kidney-liver transplantation. According to the authors, nedosiran “transformed” the clinical outcome for this patient. Does this report give you hope for the future about the use of nedosiran injection as a treatment for PH1?

I think that’s exactly what I was saying: I have had the experience of patients under my care going into renal failure and then needing kidney-liver transplantation. That experience is sobering for me.
 
The case report you mention is an interesting study. Here’s the conclusion: The graph at the bottom of the abstract shows a big reduction in urinary oxalate. What happened to this patient was deferral of an offer of combined kidney-liver transplantation in favor of continued treatment. What I don’t understand is: Why didn’t they do kidney transplantation? The patient is in kidney failure; reducing urinary oxalate is good. But just looking at the abstract, you’d say, well, what happened as result of your beautiful reduction in urinary oxalate? Did you now not transplant a kidney? They deferred combined kidney-liver transplantation, but what I’d expect, with the patient on dialysis, is that they would still have to do a kidney transplantation. Perhaps you can avoid liver transplantation because you’ve been able to turn off hepatic production of oxalate. But I think the kidney transplantation is still necessary, and that was what I found a little odd about that abstract. I should ask my friend Marshall Stoller [professor and vice chair of Urology at UCSF Department of Urology and coauthor of the abstract] what happened.

If you find that answer, let us know as it would be interesting to our readers. If you have that question, others probably do, too.

Dr Stoller is my business partner, so I have a conflict of interest here. But at the end of the “Results” section of the abstract, the authors say that the patient had no new nephrolithiasis events. But I have to say: People on dialysis—their kidneys don’t work, they don’t get kidney stones. So, what are you talking about, Marshall?
 
I want to be optimistic, and I want to be supportive of all this; I think it’s a big deal. But this wasn’t the most convincing abstract. What I loved about it was that the accompanying Figure is convincing: You reduced urinary oxalate, but that’s not exactly news. We know that’s going to happen, and this is a beautiful example of that. I think it’s true that you’re going to be able to avoid liver transplantation, but it’s not clear what happened to the patient after that.
 
[Editor’s note: Dr Goldfarb reached out to Dr Stoller for clarification about these results. Dr Stoller replied that the patient deferred kidney-liver transplantation and is awaiting kidney transplantation only. The reduction in plasma oxalate allowed reduction of dialysis from 6 to 3 times a week, which Dr Stoller termed “a big deal.” He agreed that people on dialysis are, presumably, much less likely to develop a kidney stone despite a high plasma level of oxalate.]

Results of a phase 2, open-label extension study² (ClinicalTrials.gov Identifier: NCT03350451) of lumasiran for the treatment of PH1 were described as “encouraging”; kidney stone-related adverse events decreased and improvements in nephrocalcinosis were reported. What aspects of this treatment would you like to see studied in upcoming phase 3 research?

I think these findings are confirmatory. In another cohort of patients they’ve gotten the same results with lumasiran that were expected, which speaks to the efficacy of the drug. I think that the duration of follow-up is a little too short for us to be confident about its effect on kidney stones, but the kidney-stone community would generally expect that lowering urinary oxalate to this degree would be associated with a reduction in kidney stones and nephrocalcinosis.
 
We would consider this a positive result and expect, again, that this is another study that calls for long-term follow-up.

Because PH1 is a rare genetic disorder, there are numerous challenges surrounding recruitment of eligible clinical trial participants. In an AUA2021 abstract,⁴ researchers evaluated the utility of the PEDSnet network [of hospitals, researchers, and patients and their families] in identifying patients with likely primary hyperoxaluria and found that the use of a model might improve recruitment efficiency and effectiveness. As a researcher and clinician, what kind of meaningful changes in PH1 research might be on the horizon with the availability of a large cohort of patients with a rare urologic disease?

I do think that it’s possible that there are patients out there whose disease has not been diagnosed or who are not aware of these breakthroughs. And so, getting the news out and enrolling those patients is important for nephrologists who care for these patients. Many of these patients have had access to these kinds of studies because they’re taken care of in centers where this disorder isn’t so rare. But finding these patients, to develop cohorts, is difficult because it’s a rare disease.

Given the shift in the clinical research community toward decentralized clinical trials, do you think that a condition like PH1 lends itself to the decentralized clinical trial model or does it require more in-person site visits? There are benefits to decentralized clinical trials because you can cast a wider net for participants, but those models might not be appropriate for every condition.

That’s an interesting question. As we have become more “virtual” in healthcare, kidney stones are something that is often amenable to that. You can get patients to do 24-hour urine collection without going to the hospital and without bringing the urine to a laboratory; the patient can ship it by FedEx. Patients can also have imaging studies done wherever they are, that are then sent by email or compact disc to a trial center. We’re always talking about enrolling patients in studies remotely and maintaining their participation in studies remotely as well.

Any last thoughts that you’d like to add?

As someone who has seen PH1 at its worst — causing kidney failure and leading to combined kidney-liver transplantation — I find this work extremely encouraging and positive.