New Insights on Genetic Variants Linked to ADH1 from BridgeBio

Understanding the Genetic Landscape of ADH1
Recent research has shed light on the genetic variants associated with the calcium-sensing receptor gene (CASR) linked to autosomal dominant hypocalcemia type 1 (ADH1). With analysis covering over 100 unique CASR variants, it has been estimated that the average frequency of gain-of-function CASR variants is around 3.7 per 100,000 individuals. This statistic closely mirrors earlier findings that estimated a frequency of 3.9 per 100,000, signifying a stable and significant presence of these genetic variants.
The Alarmingly Low Diagnosis Rate
An astonishing finding from the research is that only about 20% of individuals carrying these genetic variants have received a formal diagnosis. This underdiagnosis reflects a severe gap in recognizing and managing ADH1, which could help improve patient outcomes dramatically. The low rate of diagnosis raises concerns about the adequacy of healthcare awareness surrounding genetic conditions and highlights a need for concerted efforts to provide better care for affected individuals.
New Discoveries in Genetic Variants Associated with ADH1
The analysis also unveiled nine previously unrecognized gain-of-function CASR variants. These variants contribute to a symptom burden that aligns with the clinical manifestations traditionally seen in ADH1 patients. Such discoveries are crucial as they enhance our understanding of calcium metabolism disturbances and can lead to better therapeutic strategies.
Gene Regulation and Calcium Homeostasis
This research indicates a clear allelic series, suggesting that CASR plays a pivotal role in regulating calcium homeostasis in not just ADH1 but potentially in other complex calcium metabolism disorders such as chronic hypoparathyroidism. Proper regulation is essential since calcium levels are closely tied to numerous physiological functions in the body.
Dr. Mannstadt's Insights on ADH1
Dr. Michael Mannstadt from Massachusetts General Hospital and Harvard Medical School emphasized the pressing need for more awareness about ADH1. He stated that ADH1, a recognized genetic form of the rare endocrine disorder hypoparathyroidism, is caused by activating variants in the CASR. It presents with symptoms including hypocalcemia—an imbalance that can lead to critical health issues like seizures and irregular heartbeats. Dr. Mannstadt highlighted that the study reinforces the necessity for genetic testing in diagnosing hypoparathyroidism properly.
Community Advocacy and Awareness
Furthermore, Patty Keating, Executive Director of the HypoPARAthyroidism Association, noted how ADH1 often goes unnoticed. This oversight can take a toll on patients’ quality of life, mainly due to the mismanagement of symptoms. Keating advocates for heightened awareness regarding genetic testing to facilitate timely and accurate diagnosis, ultimately leading to improved care and management of this condition.
The Future with Encaleret: A New Hope for ADH1 Patients
Building on the current research, BridgeBio is conducting CALIBRATE, a pivotal Phase 3 clinical trial of encaleret, which is designed specifically to treat ADH1. This study is fully enrolled with 71 participants, marking it as a significant step in clinical research focused on ADH1 treatment. With the largest prospective interventional study in this field, topline results are expected to be announced in the second half of the following year. If successful, encaleret will be a groundbreaking approved therapy for ADH1 patients.
Beyond ADH1: Research Aspirations
In addition to ADH1, BridgeBio intends to launch a registrational study of encaleret targeting chronic hypoparathyroidism, taking yet another step toward addressing calcium-related disorders. The initiative for this study to begin in 2026 exemplifies their commitment to innovating and providing therapeutic options for those affected.
About ADH1 and BridgeBio
ADH1 is induced by gain-of-function variants of the CASR gene, which serves as a calcium sensor. This receptor is essential for maintaining the extracellular calcium concentration in the body by functioning prominently in the parathyroid glands and kidneys. The ramifications of these genetic variants can lead to dangerously low blood calcium levels and consequently severe neuromuscular symptoms.
Studies propose that there are around 25,000 individuals carrying pathogenic gain-of-function variants of the CASR gene in the U.S. and EU. These figures stem from analyses across various genetic datasets, confirming the conditions caused by these genetic variations and reflecting the importance of diagnosing these disorders accurately.
An Investigational Approach to Patient Care
Encaleret, an oral small molecule currently under investigation for ADH1, is designed to antagonize the calcium-sensing receptor to mitigate symptoms from the source. Recognized by the U.S. FDA as a Fast Track Designation project, it has also gained Orphan Drug Designation in numerous regions, including the U.S. and EU, highlighting its potential to transform patient care.
BridgeBio Pharma is on a mission to develop and distribute transformative medicines for genetic diseases. Since its founding in 2015, BridgeBio has committed to pushing the boundaries of genetic medicine, enhancing the lives of patients grappling with various health challenges. For individuals and communities impacted by genetic disorders, this research and its implications mark hopeful progress.
Frequently Asked Questions
What is ADH1?
ADH1 stands for autosomal dominant hypocalcemia type 1, a genetic disorder linked to variants in the CASR gene leading to low calcium levels in the blood.
What are the symptoms of ADH1?
Common symptoms of ADH1 can include seizures, muscle cramps, irregular heart rhythms, and breathing difficulties due to hypocalcemia.
Why is genetic testing important for patients?
Genetic testing helps identify patients with ADH1, enabling timely diagnosis and management to improve their quality of life significantly.
What is encaleret?
Encaleret is an investigational drug being studied for treating ADH1 by antagonizing the calcium-sensing receptor to address the underlying cause of the condition.
How many people are estimated to carry CASR variants in the U.S. and EU?
Studies estimate that around 25,000 people carry gain-of-function variants of the CASR gene in both the U.S. and EU.
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