Novel Human Genetics Evidence Confirms Estimates of Genetic Prevalence, Underdiagnosis, and Potentially Greater Symptom Burden of Gain-of-Function CASR Variants Associated with ADH1
BridgeBio Pharma (Nasdaq: BBIO) has published a significant genetic analysis study in the American Journal of Human Genetics, examining over 100 unique variants associated with autosomal dominant hypocalcemia type 1 (ADH1). The research revealed that approximately 25,000 people in the US and EU carry ADH1-causing variants, with a frequency of ~3.7 per 100,000 individuals.
The study highlighted that only 20% of individuals with ADH1-linked genetic variants have been properly diagnosed, indicating a substantial gap in disease recognition. Additionally, researchers identified nine novel gain-of-function CASR variants. The company's Phase 3 CALIBRATE trial for encaleret, potentially the first approved therapy for ADH1, is fully enrolled with 71 participants, with topline results expected in H2 2025.
BridgeBio Pharma (Nasdaq: BBIO) ha pubblicato uno studio genetico importante sull'American Journal of Human Genetics, analizzando oltre 100 varianti uniche associate all'ipocalcemia autosomica dominante di tipo 1 (ADH1). La ricerca ha rivelato che circa 25.000 persone negli Stati Uniti e nell'UE sono portatrici di varianti che causano ADH1, con una frequenza di circa 3,7 ogni 100.000 individui.
Lo studio ha evidenziato che solo il 20% delle persone con varianti genetiche legate ad ADH1 è stato correttamente diagnosticato, indicando una significativa carenza nel riconoscimento della malattia. Inoltre, i ricercatori hanno identificato nove nuove varianti CASR con guadagno di funzione. Il trial di fase 3 CALIBRATE dell'azienda per l'encaleret, potenzialmente la prima terapia approvata per ADH1, è completamente arruolato con 71 partecipanti, con risultati principali attesi nella seconda metà del 2025.
BridgeBio Pharma (Nasdaq: BBIO) ha publicado un estudio genético significativo en el American Journal of Human Genetics, examinando más de 100 variantes únicas asociadas con la hipocalcemia autosómica dominante tipo 1 (ADH1). La investigación reveló que aproximadamente 25,000 personas en EE. UU. y la UE portan variantes causantes de ADH1, con una frecuencia de alrededor de 3.7 por cada 100,000 individuos.
El estudio destacó que solo el 20% de las personas con variantes genéticas vinculadas a ADH1 han sido diagnosticadas correctamente, indicando una brecha considerable en el reconocimiento de la enfermedad. Además, los investigadores identificaron nueve nuevas variantes CASR con ganancia de función. El ensayo de fase 3 CALIBRATE de la compañía para encaleret, posiblemente la primera terapia aprobada para ADH1, está completamente inscrito con 71 participantes, y se esperan resultados principales en la segunda mitad de 2025.
BridgeBio Pharma (나스닥: BBIO)는 American Journal of Human Genetics에 자가우성 저칼슘혈증 1형(ADH1)과 관련된 100가지 이상의 고유 변이를 분석한 중요한 유전 연구를 발표했습니다. 연구 결과 미국과 유럽연합에서 약 25,000명이 ADH1 원인 변이를 보유하고 있다는 사실이 밝혀졌으며, 인구 10만 명당 약 3.7명의 빈도를 보였습니다.
연구는 ADH1 관련 유전 변이를 가진 사람 중 단 20%만이 제대로 진단받았다는 점을 강조하며, 질병 인식에 큰 격차가 있음을 나타냈습니다. 또한 연구진은 아홉 가지 새로운 기능획득형 CASR 변이를 확인했습니다. 회사의 3상 CALIBRATE 시험은 ADH1에 대한 최초 승인 가능 치료제인 엔칼레렛을 대상으로 71명의 참가자로 완전 등록되었으며, 주요 결과는 2025년 하반기에 발표될 예정입니다.
BridgeBio Pharma (Nasdaq : BBIO) a publié une étude génétique importante dans l'American Journal of Human Genetics, analysant plus de 100 variantes uniques associées à l'hypocalcémie autosomique dominante de type 1 (ADH1). La recherche a révélé que environ 25 000 personnes aux États-Unis et dans l'UE portent des variantes causant l'ADH1, avec une fréquence d'environ 3,7 pour 100 000 individus.
L'étude a souligné que seulement 20 % des personnes porteuses de variantes génétiques liées à l'ADH1 ont été correctement diagnostiquées, ce qui indique un important déficit dans la reconnaissance de la maladie. De plus, les chercheurs ont identifié neuf nouvelles variantes CASR à gain de fonction. L'essai de phase 3 CALIBRATE de la société pour l'encaleret, potentiellement la première thérapie approuvée pour l'ADH1, est entièrement recruté avec 71 participants, et les résultats principaux sont attendus au second semestre 2025.
BridgeBio Pharma (Nasdaq: BBIO) hat eine bedeutende genetische Analyse im American Journal of Human Genetics veröffentlicht, in der über 100 einzigartige Varianten untersucht wurden, die mit der autosomal dominanten Hypokalzämie Typ 1 (ADH1) in Verbindung stehen. Die Studie zeigte, dass etwa 25.000 Menschen in den USA und der EU ADH1-verursachende Varianten tragen, mit einer Häufigkeit von etwa 3,7 pro 100.000 Personen.
Die Untersuchung hob hervor, dass nur 20 % der Personen mit ADH1-assoziierten genetischen Varianten korrekt diagnostiziert wurden, was auf eine erhebliche Lücke in der Krankheitsdiagnose hinweist. Zudem identifizierten die Forscher neun neuartige Gain-of-Function-CASR-Varianten. Die Phase-3-Studie CALIBRATE des Unternehmens für Encaleret, möglicherweise die erste zugelassene Therapie für ADH1, ist mit 71 Teilnehmern vollständig eingeschrieben, und die wichtigsten Ergebnisse werden für die zweite Hälfte des Jahres 2025 erwartet.
- Discovery of nine novel gain-of-function CASR variants expands understanding of ADH1
- Phase 3 CALIBRATE trial for encaleret is fully enrolled with 71 participants
- Potential to be first approved therapy for ADH1 if trial successful
- Plans to expand encaleret development into chronic hypoparathyroidism in 2026
- Only 20% of individuals with ADH1-linked genetic variants are properly diagnosed
- Significant gap in disease recognition and care needs to be addressed
Insights
BridgeBio's study confirms ADH1 genetic prevalence, reveals 80% underdiagnosis rate, and advances Phase 3 trial for first potential treatment.
BridgeBio's publication in the American Journal of Human Genetics represents a significant advancement in understanding autosomal dominant hypocalcemia type 1 (ADH1). By analyzing data from over 700,000 individuals across four biobanks, the study confirms the genetic prevalence of ADH1 at approximately
The most striking finding is the
The discovery of nine novel gain-of-function CASR variants expands our understanding of the genetic landscape of ADH1 and provides new diagnostic targets. Furthermore, the identification of an allelic series connecting CASR regulation to both ADH1 and more complex disorders like chronic hypoparathyroidism suggests broader applications for CASR-targeted therapeutics.
BridgeBio's fully enrolled Phase 3 CALIBRATE trial for encaleret, with 71 participants, represents the largest interventional study ever conducted for ADH1. With topline results expected in H2 2025, this trial could lead to the first approved therapy specifically for ADH1. The company's plans to extend investigation to chronic hypoparathyroidism in 2026 demonstrates a strategic expansion of their calcium metabolism disorder pipeline based on these genetic insights.
- By examining over 100 unique variants associated with the CASR gene causative of ADH1, the average frequency of gain-of-function CASR variants was ~3.7 per 100,000, closely aligned to previously published estimates1 (3.9 per 100,000), which equates to approximately 25,000 carriers of ADH1-causing variants in the US and EU
- Only ~
- Nine novel gain-of-function CASR variants were identified, which were associated with a symptom burden consistent with the known clinical presentation of ADH1
- The findings show an allelic series, indicating that CASR regulates calcium homeostasis in ADH1 and more complex disorders of calcium metabolism, such as chronic hypoparathyroidism
PALO ALTO, Calif., July 23, 2025 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) (“BridgeBio” or the “Company”), a new type of biopharmaceutical company focused on genetic diseases, published an analysis of genetic and health data from more than 700,000 individuals in the American Journal of Human Genetics, confirming prior estimates of the genetic prevalence of autosomal dominant hypocalcemia type 1 (ADH1) and underscoring opportunities to elevate diagnostic suspicion.
“ADH1 is a common genetic form of the rare endocrine disorder hypoparathyroidism. ADH1 is caused by activating variants in the calcium-sensing receptor gene (CASR) and presents as hypocalcemia that can cause serious symptoms like seizures, irregular heart rhythms, muscle cramps, and breathing problems. This study confirms estimates of the genetic prevalence of ADH1 across four biobanks and reveals that many affected individuals remain undiagnosed. The study illuminates a critical gap in recognizing and diagnosing ADH1 and providing appropriate care. Beyond expanding the number of genetic variants linked to ADH1, this work reinforces the vital role of genetic testing in uncovering the underlying cause of hypoparathyroidism,” said Dr. Michael Mannstadt of Massachusetts General Hospital and Harvard Medical School.
“ADH1 is a genetic condition that is often misdiagnosed or overlooked, taking a toll on an individual's quality of life due to mismanaged symptoms. These findings show that ADH1 is more prevalent and underdiagnosed than we thought and it is important to raise awareness around genetic testing to identify the root cause of a condition to help manage symptoms and improve quality of life. This is a step towards closing the gap in care by potentially providing a diagnosis earlier and more easily, addressing a constant concern of the community,” said Patty Keating, Executive Director of HypoPARAthyroidism Association, a non-profit patient association supporting and advocating for people impacted by hypoparathyroidism.
CALIBRATE, BridgeBio’s Phase 3 clinical trial of encaleret for ADH1, a condition caused by activating variants of the CASR, is fully enrolled with 71 participants. The registrational study is the largest prospective interventional study ever to be conducted in ADH1. The Company expects to report topline results in the second half of 2025. If successful, encaleret would be the first approved therapy for individuals living with ADH1. The Company also intends to initiate a registrational study of encaleret in chronic hypoparathyroidism, another condition linked with the newly found CASR allelic series, in 2026.
About Autosomal Dominant Hypocalcemia Type 1 (ADH1)
ADH1 is caused by gain-of-function variants of the CASR gene encoding the CaSR. The calcium-sensing receptor regulates the extracellular calcium concentration in the body primarily through its activity in the parathyroid glands and the kidney. Due to increased sensitivity of the variant CaSR to extracellular calcium, patients with ADH1 have low blood calcium (hypocalcemia), inappropriately low parathyroid hormone levels, and excess excretion of calcium in the urine (hypercalciuria). Hypocalcemia can cause neuromuscular symptoms, which can include severe muscle cramping and seizures, while hypercalciuria can lead to kidney calcifications and impaired kidney function.
Studies estimate that there are 25,000 carriers of gain-of-function variants of the calcium-sensing receptor (CaSR) gene, the underlying cause of ADH1, in the U.S. and EU. This estimate is based on analyses of independent general population genetic datasets, including Geisinger Health System, UK Biobank, gnomAD, All of Us, TopMed, and Mass General Brigham Biobank.1,2
About Encaleret
Encaleret is an investigational, orally administered small molecule under investigation to treat ADH1, that is designed to selectively antagonizes the calcium sensing receptor (CaSR), targeting ADH1 at its source. Encaleret has received Fast Track Designation by the U.S. FDA and Orphan Drug Designation in the U.S., European Union, and Japan.
About BridgeBio Pharma, Inc.
BridgeBio Pharma, Inc. (BridgeBio) is a new type of biopharmaceutical company founded to discover, create, test, and deliver transformative medicines to treat patients who suffer from genetic diseases. BridgeBio’s pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn, Twitter, Facebook, and YouTube.
BridgeBio Forward-Looking Statements
This press release contains forward-looking statements. Statements in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), which are usually identified by the use of words such as “anticipates,” “believes,” “continues,” “could,” “estimates,” “expects,” “hopes,” “intends,” “may,” “plans,” “projects,” “potential,” “seeks,” “should,” “will,” and variations of such words or similar expressions. BridgeBio intends these forward-looking statements to be covered by the safe harbor provisions of the Securities Act and the Exchange Act. These forward-looking statements include, but are not limited to, statements regarding BridgeBio’s expectations for topline results from the Phase 3 CALIBRATE study of encaleret for ADH1, the potential for encaleret to become the first approved therapy for ADH1, and the planned initiation of a registrational study in chronic hypoparathyroidism in 2026. These statements reflect BridgeBio’s current views about its plans, intentions, expectations, and strategies, which are based on information currently available and assumptions it has made. Although BridgeBio believes that its plans, intentions, expectations, and strategies as reflected in or suggested by these forward-looking statements are reasonable, it can give no assurance that they will be attained or achieved. Actual results may differ materially from those described in these statements due to a number of risks, uncertainties, and assumptions, including, but not limited to: the risk that topline results may be delayed or not yield positive outcomes; the risk that regulatory authorities may require additional data or studies; and the risk that encaleret may not be approved or commercialized. These risks also include impacts from global health emergencies, such as delays in regulatory reviews and disruptions to the global economy, as well as the effects of macroeconomic and geopolitical events, including hostilities in Ukraine and the Middle East, rising inflation, and fluctuating interest rates. Additional risks are described in the Risk Factors section of BridgeBio’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q, and other filings with the U.S. Securities and Exchange Commission. Moreover, BridgeBio operates in a competitive and rapidly evolving environment in which new risks may emerge from time to time. Except as required by applicable law, BridgeBio assumes no obligation to publicly update any forward-looking statements, whether as a result of new information, future events, or otherwise.
References
- Dershem et al., Am. J. Hum. Genet., 2020.
- Chang et al., Am. J. Hum. Genet., 2025.
BridgeBio Media Contact:
Bubba Murarka, Executive Vice President, Corporate Development
contact@bridgebio.com
(650)-789-8220
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Chinmay Shukla, Senior Vice President, Strategic Finance
ir@bridgebio.com
FAQ
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