– The CALIBRATE Phase 3 study design incorporates feedback from global regulatory agencies and will compare the effects of encaleret to standard of care on blood and urinary calcium concentrations over a 24 week treatment period in patients with autosomal dominant hypocalcemia type 1 (ADH1)

– The primary composite endpoint evaluates the proportion of participants with ADH1 achieving blood and urinary calcium within widely accepted normal ranges

– In an ongoing single arm, open-label, Phase 2 safety and efficacy study of patients with ADH1, 69% of participating patients achieved concurrent values of both blood calcium and 24hr urinary calcium excretion in the reference range. None of these individuals had attained this dual therapeutic goal while on standard of care

– If approved, encaleret would be the first therapy specifically indicated for ADH1

– Population genetics analyses estimate that there are approximately 25,000 carriers of gain-of-function variants of the calcium sensing receptor (CaSR), the underlying cause of ADH1, in the United States (US) and European Union (EU)

– Current standard of care (oral supplements of calcium and/or vitamin D) inadequately addresses both the short- and long-term clinical manifestations related to hypocalcemia and hypercalciuria

PALO ALTO, CA, USA I December 22, 2022 I BridgeBio Pharma, Inc. (Nasdaq: BBIO) (“BridgeBio” or the “Company”), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today announced the initiation of its multicenter, international, pivotal Phase 3 randomized trial of encaleret in patients with autosomal dominant hypocalcemia type 1 (ADH1) (CALIBRATE). The design of the CALIBRATE study incorporates feedback from global regulatory authorities and patients, with a primary composite endpoint of blood and urine calcium concentrations within normal ranges in participants treated with encaleret compared to standard of care (SoC). SoC for ADH1 consists of extra-dietary supplementation with calcium and/or active vitamin D analogs. While SoC may address acute symptoms related to hypocalcemia, it may exacerbate high urine calcium levels, which can cause renal complications1. Secondary endpoints will evaluate other measures of mineral homeostasis, quality of life, and kidney function.

“We are excited to have reached this important milestone in the development of encaleret,” said Mary Scott Roberts, executive director of clinical development at BridgeBio and clinical lead of the encaleret program. “The pivotal CALIBRATE study will evaluate the potential for encaleret to provide a meaningful benefit to patients and families living with ADH1. If successful, this study could lead to an approval of encaleret for the treatment of ADH1, a disease with significant unmet medical need and no interventions specifically indicated for its treatment.”

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 US and EU. This estimate is based on analyses of independent general population genetic datasets, including Geisinger Health System, UK Biobank, gnomAD, and TopMed.2,3

The CALIBRATE study advances the clinical development of encaleret following positive data from an ongoing Phase 2b trial in 13 participants with ADH1. In the Phase 2b study encaleret was generally well-tolerated, with no observed safety signals of potential clinical concern, and restored normal mineral homeostasis. Mean values of blood calcium, urinary calcium, and blood PTH came within the normal range by day 5 of encaleret treatment and were sustained for 24 weeks. At week 24 of outpatient treatment, 92% of participants receiving encaleret achieved normal blood calcium levels in the absence of SoC, and 77% of participants had achieved normal 24-hr urinary calcium excretion. Results of this study were presented at the Endocrine Society (ENDO) Annual Conference in June 2022. The long-term extension of the Phase 2b study is ongoing.

The Phase 3 multicenter, international, randomized, open-label, two-arm, three-period clinical study will assess the efficacy and safety of encaleret for 24 weeks. The trial will enroll approximately 45 participants 16 years of age or older with biochemical evidence of hyperparathyroidism (low PTH, low blood calcium, high urinary calcium) and genetic confirmation of ADH1. Following a SoC maintenance period, participants will be randomized 2:1 to the encaleret treatment arm or the SoC treatment arm and will undergo a 20-week titration period. Finally, encaleret or SoC doses will be maintained during a 4-week maintenance period where doses will only be adjusted to address potential safety concerns, including hypocalcemia or hypercalcemia. The primary composite endpoint will compare the effect of encaleret to SoC on the ability to concurrently achieve blood and urine calcium within widely accepted normal ranges.

About Encaleret
Encaleret is an investigational, orally administered small molecule that selectively antagonizes the calcium sensing receptor (CaSR), targeting ADH1 at its source. The current standard of care for patients with ADH1 includes oral calcium and/or active vitamin D supplements that are typically administered to manage signs and symptoms associated with hypocalcemia. Encaleret has received Fast Track Designation by the U.S. Food and Drug Administration (FDA) and Orphan Drug status in the United States and the European Union.

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.

About BridgeBio Pharma, Inc.
BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers. 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 and Twitter.

SOURCE: BridgeBio Pharma