BridgeBio Pharma Initiates CALIBRATE, A Pivotal Phase 3 Study of Encaleret in Autosomal Dominant Hypocalcemia Type 1

By: BridgeBio Pharma, Inc. via GlobeNewswire

December 22, 2022 at 07:30 AM EST

- 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, Calif., Dec. 22, 2022 (GLOBE NEWSWIRE) -- 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.

CALIBRATE Design
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.

BridgeBio Pharma, Inc. Forward-Looking Statements
This press release contains forward-looking statements. Statements we make 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,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to expectations, plans and prospects regarding the preclinical and clinical development plans, clinical trial designs, clinical and therapeutic potential, and strategy of our product candidates, including, but not limited to: the potential size of the target patient population with a rare genetic form of hypoparathyroidism caused by pathogenic variants in the CASR gene; the inability of current standard of care therapies to treat ADH1; encaleret continuing to be well-tolerated with no serious adverse events and no adverse events of moderate or severe intensity reported in our ongoing Phase 3 registrational study; tolerability and consistent mineral responses following encaleret administration in all ADH1 trial participants continuing to demonstrate that encaleret may be an efficacious therapy option for ADH1; the timing and success of our interactions with regulatory health authorities, including the FDA, in connection with our Phase 3 study in patients with ADH1; the ability of encaleret to be the first approved therapy option indicated specifically for the treatment of ADH1, if the development program is successful; the continuing close collaboration between world-leading experts in calcium homeostasis at the National Institute of Dental and Craniofacial Research at the National Institutes of Health and BridgeBio; the clinical study designs for our Phase 3 study of encaleret in ADH1; and the timing of these events, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to: the potential size of the target patient population for ADH1 not being as large as anticipated; encaleret not being well-tolerated, with serious adverse events and adverse events of moderate or severe intensity being reported in the Phase 3 study data; encaleret not continuing to demonstrate that it may be an efficacious therapy option for ADH1 based on the Phase 3 data; encaleret not being the first approved therapy option indicated specifically for the treatment of ADH1, if the development program is not successful or if a competing therapy option is approved; the design and success of ongoing and planned clinical trials, future regulatory filings, approvals and/or sales; despite having ongoing and future interactions with the FDA or other regulatory agencies, the FDA or such other regulatory agencies may not agree with our regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; the continuing success of our close collaboration between the National Institute of Dental and Craniofacial Research at the National Institutes of Health; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those risks set forth in the Risk Factors section of our most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the U.S. Securities and Exchange Commission (SEC) and our other SEC filings. Moreover, BridgeBio operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of BridgeBio’s management as of the date of this release and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.