On May 28, 2021 BridgeBio Pharma, Inc. (Nasdaq: BBIO), through its affiliate QED Therapeutics, Inc., and Helsinn Group reported that the US Food and Drug Administration (FDA) has approved TRUSELTIQ (infigratinib) under the accelerated approval program for the treatment of patients with previously-treated locally advanced or metastatic cholangiocarcinoma (CCA) harboring an FGFR2 fusion or rearrangement (Press release, BridgeBio, MAY 28, 2021, View Source [SID1234583264]). TRUSELTIQ is an orally administered, ATP-competitive, tyrosine kinase inhibitor of FGFR. In the pivotal trial of patients with advanced, unresectable CCA, an aggressive malignancy with poor prognosis, TRUSELTIQ led to cases of tumor shrinkage. CCA is known to affect approximately 20,000 people in the United States and European Union each year and has a median five-year survival rate of only 9%.1

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"This is an important milestone for patients diagnosed with FGFR2-fusion-driven cholangiocarcinoma who have recurred after first-line therapy and are in need of targeted options for further treatment," said Susan Moran, M.D., M.S.C.E., Chief Medical Officer for QED. "Based on the efficacy seen to date, our team believes infigratinib possesses promise for a range of FGFR-driven conditions, including other cancers. We will continue to evaluate its safety and efficacy in these areas of unmet need."

The approval of TRUSELTIQ is based on a Phase 2 clinical study in which 108 patients who had undergone at least one prior treatment for advanced CCA received 125 mg of TRUSELTIQ daily for 21 days of 28-day cycles. Of these patients, 107 (99%) had Stage IV CCA. All patients had received at least 1 prior line of systemic therapy. The study’s primary endpoint demonstrated a confirmed objective response rate (ORR) of 23% (95% CI 16-32%). The study also showed a median duration of response (DOR) of 5.0 months (95% CI 3.7–9.3 months). Common adverse reactions and laboratory abnormalities (of >30%) were increased creatinine, increased phosphate, decreased phosphate, nail toxicity, stomatitis, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, dry eye, fatigue, increased lipase, decreased lymphocytes, increased calcium, decreased sodium, alopecia, increased triglycerides, increased aspartate aminotransferase, decreased platelets, increased urate, palmar-plantar erythrodysesthesia syndrome, arthralgia, and dysgeusia. Please see below for additional important safety information for TRUSELTIQ.

The above data were presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium by the lead investigator, Milind Javle, M.D., Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center.

"While targeted treatments have extended survival for many types of cancer, people diagnosed with cholangiocarcinoma have previously been presented with extremely limited treatment options coupled with low statistical survival data," said Dr. Javle. "In this study, TRUSELTIQ showed promise as a targeted treatment option for patients with FGFR2-fusion-driven cholangiocarcinoma with a well-tolerated safety profile in line with previous observations in this patient population."

"The approval of TRUSELTIQ provides a new and exciting treatment option for patients with CCA harboring an FGFR2 fusion," said Stacie Lindsey, Chief Executive Officer of the Cholangiocarcinoma Foundation. "We appreciate the fact that there is a robust patient support program, ForgingBridges, to help patients access care and support them throughout their treatment journey."

Additional marketing applications for infigratinib are currently under review in Australia and Canada under Project Orbis, an initiative of the FDA’s Oncology Center of Excellence that allows for concurrent submission and review of oncology drugs among participating international regulatory agencies.

BridgeBio and Helsinn Group’s affiliate, Helsinn Therapeutics (U.S.), Inc., will be jointly responsible for commercialization activities in the U.S. and will share U.S. profits and losses on an equal basis. Helsinn Group will have exclusive commercialization rights on infigratinib outside of the U.S., excluding China, Hong Kong and Macau. BridgeBio will be eligible for tiered royalties as a percentage of adjusted net sales, and payments totaling up to approximately $2.45 billion USD in the aggregate. Helsinn Group will fund the majority of ongoing and future research and development related to infigratinib in oncology. BridgeBio and Helsinn Group entered into a global collaboration and licensing agreement in March 2021. BridgeBio previously entered a strategic collaboration with LianBio for development and commercialization of infigratinib in oncology indications in China, Hong Kong and Macau.

Paul Rittman, Chief Executive Officer of Helsinn Therapeutics, said, "Today’s FDA approval of TRUSELTIQ for patients with previously-treated locally advanced or metastatic CCA harboring an FGFR2 fusion or rearrangement provides a new therapy option for patients with a very low rate of survival. This new therapy has the potential to make a life changing impact on patients with few treatment options, and Helsinn Therapeutics looks forward to working with BridgeBio to make it widely accessible to health care providers and patients in the US."

ForgingBridges | TRUSELTIQ is a comprehensive patient support program designed specifically to provide education, access and affordability resources for patients during their TRUSELTIQ journey. For more information, visit: TRUSELTIQ.com/forgingbridges-overview.

Visit TRUSELTIQ.com for more information, including full Prescribing Information.

About TRUSELTIQ (infigratinib)
TRUSELTIQ (infigratinib) is an orally administered, ATP-competitive, tyrosine kinase inhibitor of FGFR, approved for the treatment of individuals with FGFR2 fusion-driven cholangiocarcinoma (bile duct cancer). TRUSELTIQ targets the fibroblast growth factor receptor (FGFR) protein, blocking downstream activity. In clinical studies, TRUSELTIQ demonstrated a clinically meaningful rate of tumor shrinkage (overall response rate) and duration of response. Visit TRUSELTIQ.com for more information. Infigratinib is not FDA approved for any other indication in the U.S. and is not approved for use by any other health authority. It is currently being evaluated in clinical studies for first-line cholangiocarcinoma and urothelial carcinoma (bladder cancer). For more information, visit QEDTx.com.

About Cholangiocarcinoma (CCA)
Cholangiocarcinoma, a cancer of the bile ducts of the liver, is a serious and often fatal disease which affects approximately 20,000 people in the United States and European Union each year. FGFR2 genetic aberrations are present in approximately 15% to 20% of people who have this disease. Currently, the five-year survival rate is only 9%.1 Advanced, unresectable CCA is a rare, aggressive malignancy with a poor prognosis.

Clinical Studies1
The efficacy of TRUSELTIQ was based on a single-arm Phase 2 study which included 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement. Ninety-nine percent of patients had metastatic (Stage IV) disease at the time of study entry.

These 108 adult patients with advanced/metastatic CCA received infigratinib 125 mg orally for 21 days of each 28-day cycle until unacceptable toxicity or disease progression. All patients received prophylaxis with the oral phosphate binder sevelamer. TRUSELTIQ achieved a 23% objective response rate (ORR) and a median duration of response (DOR) of 5.0 months.

U.S. Indication for TRUSELTIQ
TRUSELTIQ is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

Accelerated approval was granted based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

U.S. Important Safety Information for TRUSELTIQ
Warnings and precautions

Ocular toxicity: Retinal pigment epithelial detachment (RPED), which may cause blurred vision, occurred in 11% of 351 patients treated with TRUSELTIQ, including patients with asymptomatic RPED, with a median onset of 26 days. Perform comprehensive ophthalmological exam including optical coherence tomography prior to initiating, at 1 month, at 3 months, and then every 3 months during treatment with TRUSELTIQ. Urgently evaluate patients for onset of visual symptoms and follow up every 3 weeks until resolved or TRUSELTIQ is discontinued. Withhold TRUSELTIQ as recommended. Dry eye occurred in 29% of 351 patients; treat with ocular demulcents as needed
Hyperphosphatemia and soft tissue mineralization: Hyperphosphatemia, which can lead to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis, vascular calcification, and myocardial calcification, occurred in 82% of 351 patients treated with TRUSELTIQ, with a median time to onset of 8 days (range 1-349); 83% of 351 patients treated with TRUSELTIQ received phosphate binders. Monitor for hyperphosphatemia throughout treatment. Initiate phosphate-lowering therapy for serum phosphate >5.5 mg/dL; withhold TRUSELTIQ and initiate phosphate-lowering therapy for serum phosphate >7.5 mg/dL; withhold, reduce the dose, or permanently discontinue TRUSELTIQ based on duration and severity of hyperphosphatemia
Embryo-fetal toxicity: TRUSELTIQ can cause fetal harm. Advise pregnant women of the potential risk to the fetus; advise females of reproductive potential and men who are partnered with women of reproductive potential to use effective contraception during treatment with TRUSELTIQ and for 1 month after the final dose
Adverse reactions

Most common adverse reactions (incidence ≥20%, all grades): nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting
Most common laboratory abnormalities (incidence ≥20%, all grades): increased creatinine, increased phosphate, decreased phosphate, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased lipase, increased calcium, decreased lymphocytes, decreased sodium, increased triglycerides, increased aspartate aminotransferase (AST), increased urate, decreased platelets, decreased leukocytes, decreased albumin, increased bilirubin, and decreased potassium
Drug interactions

CYP3A inhibitors: Avoid use with strong and moderate CYP3A inhibitors
CYP3A inducers: Avoid use with strong and moderate CYP3A inducers
Gastric acid–reducing agents: Avoid coadministration with proton pump inhibitors, histamine-2 receptor antagonists (H2RA), and locally acting antacids. If coadministration of H2RA or locally acting antacids cannot be avoided, separate TRUSELTIQ administration
H2RA: Take TRUSELTIQ 2 hours before or 10 hours after
Locally-acting antacid: Take TRUSELTIQ 2 hours before or 2 hours after
Dosage and administration

Prior to initiating TRUSELTIQ: Confirm FGFR2 fusion or rearrangement; perform comprehensive ophthalmic exam including OCT; confirm negative pregnancy test in females of reproductive potential
Starting dose: Take TRUSELTIQ orally once daily on Days 1-21 of 28-day cycles; continue treatment until disease progression or unacceptable toxicity. Take TRUSELTIQ on an empty stomach with a glass of water at least 1 hour before or 2 hours after food
No renal or hepatic impairment
125 mg (one 100 mg capsule and one 25 mg capsule)
Mild and moderate renal impairment (creatinine clearance 30-89 mL/min)
100 mg (one 100 mg capsule)
Mild hepatic impairment (total bilirubin >upper limit of normal [ULN] to 1.5 x ULN or AST > ULN)
100 mg (one 100 mg capsule)
Moderate hepatic impairment (total bilirubin >1.5 to 3 x ULN with any AST)
75 mg (three 25 mg capsules)
Dose modification: Consult the TRUSELTIQ full Prescribing Information for dose modifications and monitoring recommendations for RPED, hyperphosphatemia, and other Grades 3-4 adverse reactions