Transcript
Announcer:
You’re listening to GLC on ReachMD. This activity, titled ‘Rewriting the Calcium Code in ADH1,’ is provided by Global Learning Collaborative.
Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements, as well as the learning objectives.
Dr. Michael Levine:
Hello, and welcome. This is CE with GLC. I'm Dr. Michael Levine.
Dr. Aliya Khan:
Hi, everybody, and I'm Dr. Aliya Khan with a sore throat.
Dr. Michael Levine:
ADH1 is a rare genetic disorder caused by activating variants in the calcium-sensing receptor and results in hypocalcemia, suppressed parathyroid hormone secretion, and often significant hypercalciuria.
Historically, management has focused on symptom control using calcium supplementation and active vitamin D. Often, this leads to ongoing concerns around hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive declines in renal function. In addition, conventional therapy may improve serum calcium levels but does not address the underlying pathophysiology of the disease, thereby creating challenges in balancing symptom control with long-term safety.
Today, Aliya and I will discuss how emerging data, particularly findings presented at ENDO 2026 and the CALIBRATE clinical trial, may reshape how we diagnose, monitor, and manage ADH1.
Dr. Aliya Khan:
Michael, you and I have been investigators in the CALIBRATE trial, and this is a very important step forward for the autosomal dominant hypocalcemia type 1 community.
So we know that calcium binds and activates the calcium-sensing receptor. And in patients with ADH1, there are gain-of-function variants of the calcium-sensing receptor so that there will be a decrease in the PTH synthesis and secretion at lower levels of serum calcium.
So what happens in ADH1 is we will have a shift in the calcium-sensing receptor, and this will result in a decrease in PTH synthesis and secretion, resulting in decreases in serum calcium and hypercalciuria at lower levels of serum calcium.
And when the receptor is super sensitive, calcium is decreasing PTH synthesis and secretion at lower levels of calcium. And because the receptor is super sensitive, we have further rises in urine calcium higher than we would have expected, even for patients with hypoparathyroidism.
So encaleret is a negative allosteric modulator of the calcium-sensing receptor. It can normalize the sensitivity of the receptor to calcium.
So the CALIBRATE study was a multinational, open-label, phase 3 clinical trial looking at the safety and the effectiveness of encaleret. And encaleret was compared to conventional therapy with calcium and active vitamin D in 67 patients with a genetically confirmed molecular diagnosis of autosomal dominant hypocalcemia type 1.
After a 4-week period of optimization of conventional therapy, patients were randomized 2:1 to encaleret. And patients who received encaleret discontinued conventional therapy and, over the next 20 weeks, the dose of twice-daily encaleret was titrated to achieve a normal serum and urine calcium [levels], and the next phase was a 4-week maintenance phase.
So, Michael, would you like to share with us the key findings from the CALIBRATE study, and what this means for patients?
Dr. Michael Levine:
Certainly. The primary outcome of CALIBRATE was a within-group comparison of patients on encaleret who achieved a target serum calcium level between 8.3 and 10.7 mg/dL and a urine calcium of <250 mg per day in women and <300 mg per day in men, and this was at 24 weeks compared to week 4.
At week 24, 75.6% of patients on encaleret met these primary endpoints of a normal serum calcium and normal urine calcium, compared to only 4.4% of the same patients when they were taking standard of care at week 4. By contrast, only 19% of patients who continued conventional therapy met the primary endpoint at week 24.
In the encaleret treatment group, over 91% of patients had a normal PTH level. Moreover, nearly 89% achieved a normal serum calcium level, and 80% achieved normal urine calcium levels. The mean serum calcium level increased by day 3 of encaleret treatment, and the mean urine calcium levels decreased by week 3. Serum phosphate levels were in the normal range for over 90% of encaleret-treated patients, compared to only 52.4% of patients who received the continuing standard of care.
Importantly, encaleret was well tolerated, with no discontinuations. There were very few serious adverse events, or AEs, reported, and the frequency of AEs was similar between patients who received encaleret and those who received standard of care.
I think these results are important because they demonstrate the power of precision medicine using a drug that targets the overactive calcium-sensing receptor, which is the underlying primary defect in ADH1.
Perhaps even more important than normalizing serum calcium levels, encaleret reduced urinary calcium excretion. This is transformative, in my opinion, as the calcium-sensing receptor defect in patients with ADH1 leads to hypercalciuria and renal complications. And here encaleret was demonstrated to normalize urinary calcium excretion, even as it increased the serum calcium level.
It's important to monitor urinary calcium excretion in all patients with any form of hypoparathyroidism due to the increased risk of hypercalciuria with conventional therapy. The normalization of urinary calcium excretion in ADH1 patients receiving encaleret brings the potential of reducing or preventing long-term renal complications, such as nephrolithiasis and impaired renal function.
Further, I think these results provide a compelling rationale for performing genetic screening for ADH1 in all patients who have nonsurgical hypoparathyroidism in order to identify patients who will be candidates for encaleret therapy.
Dr. Aliya Khan:
Thank you so much, Michael. I think it's really important for us to recognize that when we evaluate patients with hypoparathyroidism, hypocalcemia, we need to find out why they have hypoparathyroidism. If we confirm that they have autosomal dominant hypocalcemia, then we need to be able to consider the fact that real precision targeted therapy is going to be available for such patients in the very near future. These results are very positive and very encouraging.
And we need to discuss, also, about management of hypoparathyroidism and in patients with ADH1 in children. Would you like to discuss about the CALIBRATE Pediatric Study?
Dr. Michael Levine:
It's fantastic. As a pediatric endocrinologist, I'm very encouraged and excited about CALIBRATE-PEDS. This is a phase 2/3 single-arm, open-label, multicenter study—clinical trial—evaluating the safety, efficacy, and pharmacokinetics of encaleret in children who have autosomal dominant hypocalcemia type 1.
This study aims to determine whether encaleret can safely normalize serum calcium levels while minimizing urinary calcium excretion in pediatric patients.
The primary endpoint will be a composite measure of serum calcium that's corrected for albumin within age-specific target ranges, and urine calcium below defined thresholds for children.
There'll also be some secondary endpoints. Safety and tolerability will be assessed. Overall mineral homeostasis will be evaluated. There'll be renal ultrasound studies, bone density, and, of course, patient-reported outcomes.
I think this is a highly significant step forward in the management of ADH1 and, in fact, hypoparathyroidism in children. CALIBRATE-PEDS is the first pediatric study of encaleret, building on the success of adult trials that we've just discussed that demonstrated sustained normalization of PTH, calcium, phosphorus, magnesium, and urinary calcium in adults without serious adverse effects.
So this brings us to a question I have for Dr. Khan. As we look beyond CALIBRATE, how do you see the therapeutic landscape for ADH1 evolving over the next several years?
I'm Dr. Michael Levine, and here with me today is Dr. Aliya Khan. We're discussing emerging data in ADH1, including findings from the CALIBRATE trial and key updates presented at ENDO 2026 that may help reshape clinical management and improve patient outcomes.
Dr. Aliya Khan:
Thank you, Dr. Levine. And right now, the biggest problem that we have in patients who have ADH1 is to improve the serum calcium without further deteriorating the renal function and without compromising renal safety. And with ADH1, we see patients, we see young people in their 20s who have stage 3 chronic kidney disease, and so it is absolutely critical that we identify these patients, confirm their underlying diagnosis, do family evaluation, and identify patients who may not have previously been confirmed with the diagnosis, and then provide them with effective and safe therapy.
And we need to recognize that the field of hypoparathyroidism is evolving, and we are developing new therapies for hypoparathyroidism. But when we can give targeted treatment to patients who have a molecular diagnosis of ADH1, it is absolutely critical that we confirm the diagnosis and then carefully treat these patients, because if we give them excessive calcium and active vitamin D, we will further deteriorate their renal function and impair their long-term prognosis and the quality of life.
So I feel that we have very positive data. We're excited to share this result with our medical community colleagues, and we want to further emphasize the importance of evaluating patients with hypoparathyroidism, confirming the diagnosis, assess for comorbidity, assess renal function and renal status, and then treat patients according to the guidelines so that we do not compromise renal function further.
Dr. Michael Levine:
Fantastic points, Dr. Khan. Thank you very much for pointing out all of those important points. I would amplify a couple of the points you made. I think what you've described is the importance of a multidisciplinary approach to coordinate care among endocrinology, nephrology, genetics, and, in some cases, even pediatrics.
I think I was also excited to hear you talk about the genetic approach as well as the importance of screening even asymptomatic first-degree relatives because many of these patients may not have symptoms of hypocalcemia but still could have ADH1 with low serum calcium levels and increased urinary calcium levels. So I think it's important for us to be aware that when you identify a patient within a family, this is an autosomal dominant genetic disorder, we should begin to screen other first-degree relatives.
So let's bring this back to day-to-day clinical care. Dr. Khan, how should clinicians begin integrating these newer data into clinical practice today?
Dr. Aliya Khan:
Well, I think that we need to encourage our colleagues to evaluate patients, look at the serum calcium, look at serum phosphate, and also look at the urine calcium. There are so many clinicians who still do not measure phosphate and urine calcium in patients with hypoparathyroidism. And we need to ensure that our colleagues are completing an assessment, evaluating cognitive function, and ensuring that we evaluate respiratory and cardiac complications of hypoparathyroidism, assess renal function, do a renal ultrasound, evaluate for the presence of nephrocalcinosis and occult nephrolithiasis. And once we've completed the assessment, then begin therapy with appropriate calcium and active vitamin D.
Currently, encaleret is still investigational and is not available for clinical use, but we hope that this will change in the near future. So, right now, patients do not have access to this molecule, but we need to treat patients with calcium and active vitamin D and monitor the urine calcium closely, because if we treat a serum calcium and elevate it, that urine calcium will start to rise. And if it rises further, that will impair chronic kidney function. It will increase the risk of nephrocalcinosis and nephrolithiasis, and we do not want to further impair renal function and compromise our patient's well-being with ADH1.
These are very important parameters to monitor, and we need to monitor the field, and as we see the results of CALIBRATE progress, we're hoping to see that this molecule will be available for clinical use in the near future.
Dr. Michael Levine:
This has been great. Before we wrap up, Dr. Khan, can you provide us with one takeaway for this activity?
Dr. Aliya Khan:
And, Dr. Levine, my recommendation would be investigate patients with hypoparathyroidism. Eighty percent will be postsurgical, but the remaining 20%, we need to find out. Most commonly, it's autoimmune or genetic, but there are many other causes for hypoparathyroidism. Always check serum magnesium and evaluate our patients and know what we're dealing with. That would be my key pearl, [which] is underlying cause for the hypoparathyroidism.
Dr. Michael Levine:
And I, again, would amplify what you've just said, and perhaps wax a little philosophical, and note that although genetics are not destiny for the vast majority of common diseases, in the rare disease space, such as hypoparathyroidism, we see that genetics can play a role and a critical role in selecting an optimized therapeutic pathway.
Well, that's all the time we have today. And I want to thank our audience for joining us, and to thank you, Dr. Khan, for sharing your insights and expertise. It was great speaking with you today.
Dr. Aliya Khan:
Thank you, Dr. Levine. It was my pleasure.
Announcer:
You have been listening to GLC on ReachMD. This activity is provided by Global Learning Collaborative.
To receive your free CE credit or to download this activity, visit ReachMD.com/CME. Thank you for listening.
In support of improving patient care, Global Learning Collaborative (GLC) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. 
Global Learning Collaborative (GLC) has been authorized by the American Academy of Physician Associates (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 0.25 AAPA Category 1 CME credit(s). Approval is valid until 07/31/26. PAs should claim only the credit commensurate with the extent of their participation in the activity. 
Global Learning Collaborative (GLC) designates this activity for a maximum of 0.25 contact hour(s)/0.025 CEUs of pharmacy continuing education credit. 
