On August 4, 2022 BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported its financial results for the second quarter ended June 30, 2022, and provided an update on the Company’s operations (Press release, BridgeBio, AUG 4, 2022, View Source [SID1234617564]).
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"Focused execution is our top priority, and we are delivering with positive proof-of-concept data in three of our key programs so far this year – achondroplasia, ADH1 and LGMD2i. At the same time, we’ve reported positive data for five additional early-to-mid-stage pipeline programs designed to target a range of genetic diseases with high unmet need. Our productive pipeline is bolstered by new value-creating partnerships, which we believe allow us to keep our attention fixed on driving forward the strongest science for patients," said Neil Kumar, Ph.D., founder and CEO of BridgeBio.
BridgeBio’s Key Programs
Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia and hypochondroplasia
Positive interim results from Phase 2 trial of infigratinib demonstrated a mean increase in annualized height velocity (AHV) of 1.52 cm/year among all children 5 years of age and older enrolled in Cohort 4 (dose: 0.128 mg/kg once daily) (p=0.02, n=11), the highest dose level evaluated to date based on longest available follow-up at time of data cut
The responder rate was 64% (7 of 11 children) in children 5 years and older enrolled in Cohort 4 (dose: 0.128 mg/kg once daily), with response defined as ≥25% increase in AHV from baseline
For the avoidance of doubt, the 1.52 cm/year AHV was calculated based on all participants 5 years and older in Cohort 4 and not just the responders
Given infigratinib’s profile to date, and after discussions with regulators, BridgeBio has added a 5th cohort to the trial and has begun dosing children in Cohort 5 (dose: 0.25 mg/kg once daily), with an expected readout of full data at a medical conference in the first half of 2023
Infigratinib was well-tolerated with no serious adverse events (SAE), no treatment-related ocular adverse events (AE) and no discontinuations due to AEs including in Cohort 5 (dose: 0.25 mg/kg once daily) participants dosed to date, with a median duration of follow-up of 48.1 weeks across all participants in the study; only a limited number of AEs were assessed as related to study drug and all were Grade 1, the lowest level
There were no dose or exposure-dependent serum phosphorus elevations; a single case of mild hyperphosphatemia (Grade 1, <10% above upper limit of normal) led to a dose reduction in a participant in Cohort 3 (dose: 0.064 mg/kg once daily), the only dose adjustment made to date in the study, and the participant continues at the lower dose without issue
As predicted based on preclinical data, BridgeBio began to see efficacy in Cohort 4; also consistent with preclinical data, the Company expects to see efficacy increase further in Cohort 5 as a result of the higher dose
Baseline AHV for Cohort 4 was 4.01 cm/year, which aligns with expectations for natural history, and responder rates were consistent irrespective of baseline AHV
Infigratinib is the only known oral product candidate currently under clinical investigation for achondroplasia, with issued patents and filed patent applications expected to provide market protection as late as 2041
With more than 55,000 cases estimated in the United States (US) and Europe, achondroplasia is the most common form of genetic short stature and one of the most common genetic conditions
BridgeBio expects to evaluate development of infigratinib in other FGFR-driven skeletal dysplasias, which affect more than 50,000 people in the US and Europe, building on the positive interim Phase 2 data in achondroplasia as well as preclinical data in hypochondroplasia presented at the Endocrine Society’s 2022 annual meeting earlier this year
The Company expects to initiate its pivotal Phase 3 trial in the first half of 2023
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1)
The Company intends to initiate a Phase 3 pivotal study of encaleret in patients with ADH1 by the end of 2022 and expects to release topline data by year-end 2023
Positive data from BridgeBio’s Phase 2b study of encaleret in ADH1 were shared in an oral presentation at the Endocrine Society’s 2022 annual meeting
The Phase 2b study demonstrated that treatment with encaleret resulted in rapid and sustained restoration of normal mineral homeostasis by day 5 of therapy which sustained at 24 weeks, and encaleret was well-tolerated without any reported SAEs
If approved, encaleret could be the first therapy indicated for the treatment of ADH1, a condition caused by gain-of-function variants of the CASR gene estimated to be carried by 12,000 individuals in the US alone
Issued patents and filed patent applications are expected to provide market protection for encaleret in ADH1 into 2041
BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2i (LGMD2i)
BridgeBio engaged with regulatory health bodies to align on a Phase 3 trial design and intends to initiate a Phase 3 clinical trial in the first half of 2023
Positive Phase 2 data were shared in a poster presentation at the Muscular Dystrophy Association (MDA) 2022 Annual Meeting in March and in an oral presentation at the International Congress on Neuromuscular Diseases (ICNMD) in July
If proven to be successful, BBP-418 could be the first approved therapy for patients with LGMD2i
Initial Phase 2 results indicate the potential for BBP-418 to increase glycosylation of alpha-dystroglycan (αDG), which is directly linked to the underlying disease mechanism, and to drive consistent improvements of muscle function in patients through the reduction of creatine kinase, a key marker of muscle breakdown
90- and 180-day data show improvements on walk tests from baseline, which BridgeBio believes suggests a potential impact on clinical function and on the rate of disease progression
Acoramidis (AG10) – Transthyretin (TTR) stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM)
Topline data from the Month 30 primary endpoint, a hierarchical composite including all-cause mortality and cardiovascular hospitalizations, of the ongoing Phase 3 ATTRibute-CM trial of acoramidis in ATTR-CM are expected in mid-2023
In an oral presentation at the American College of Cardiology (ACC) Annual Scientific Session & Expo, BridgeBio shared updates on its data from its ongoing Phase 2 open-label extension (OLE) study of acoramidis in patients with ATTR-CM, which demonstrated that acoramidis continued to be well-tolerated and to potently stabilize TTR
NT-proBNP, a biomarker of cardiac failure and independent predictor of mortality in ATTR-CM patients, was stable or improving throughout the study and serum TTR levels were sustainably increased from baseline at Month 30
BBP-631 – AAV5 gene therapy candidate for congenital adrenal hyperplasia (CAH)
Initial Phase 1/2 data readout is anticipated by year-end 2022
With more than 75,000 patients estimated in the US and EU, CAH is one of the most prevalent genetic diseases potentially addressable with adeno-associated virus (AAV) gene therapy
The disease is caused by deleterious mutations in the gene encoding an enzyme called 21-hydroxylase, leading to a lack of endogenous cortisol production
BBP-631 is designed to provide a functional copy of the 21-hydroxylase-encoding gene (CYP21A2) and potentially address many aspects of the disease course
If successful, BridgeBio’s investigational gene therapy would be the first therapy for CAH to restore the body’s hormone and steroid balance by enabling people with CAH to make their own cortisol and aldosterone
RAS cancer portfolio
BridgeBio has selected a next-generation KRAS G12C dual inhibitor development candidate and plans to be in the clinic in mid-2023. The Company’s development candidate is the first-known small molecule that directly binds and inhibits KRAS G12C in both its active (GTP bound) and inactive (GDP bound) conformations. BridgeBio believes this will lead to differentiated activity in cancer patients with KRAS G12C driven disease as all other clinical stage direct KRAS G12C inhibitors do not inhibit the active oncogenic form of the protein (GTP-bound KRAS G12C)
BridgeBio is also pursuing PI3Ka:RAS breakers, small molecules that block RAS driven PI3Ka activation – a novel approach with the potential to inhibit oncogenic PI3Ka signaling without adverse effects on glucose metabolism
RAS is one of the most well-known oncogenic drivers with approximately 30% of all cancers being driven by RAS mutations, including large proportions of lung, colorectal and pancreatic tumors
Recent Corporate Updates
Exclusive license agreement of up to $905 million with Bristol Myers Squibb to develop and commercialize BBP-398, a potentially best-in-class SHP2 inhibitor, in oncology: Under the terms of the agreement, BridgeBio received an upfront payment of $90 million from Bristol Myers Squibb and is eligible to receive up to $815 million in development, regulatory and sales milestone payments, and tiered royalties in the low- to mid-teens. BridgeBio will retain the option to acquire higher royalties in the US in connection with funding a portion of development costs upon the initiation of registrational studies. Based on the terms of the agreement, BridgeBio continues to lead its ongoing Phase 1 monotherapy and combination therapy trials. Bristol Myers Squibb will lead and fund all other development and commercial activities.
Sale of PRV for $110 million: Entered into a definitive agreement with an undisclosed purchaser to sell its PRV for $110 million. The Company received the voucher in February 2021 through the U.S. Food and Drug Administration (FDA) approval of NULIBRY (fosdenopterin) for injection as the first therapy to reduce the risk of mortality in patients with MoCD Type A.
Two-year extension for principal payment on senior debt: Executed an amendment to the Company’s existing senior secured credit facility. Amendment extended the interest-only period by two years and principal repayment to November 17, 2026. BridgeBio retains access to up to $100 million in delayed debt draws through year-end 2022, subject to certain conditions. The amendment was approved unanimously by existing lenders in the syndicate without adjusting pricing and without imposing financial covenants.
Positive Phase 1 data and Phase 2/3 trial design for GO inhibitor for patients with primary hyperoxaluria type 1 (PH1) and recurrent kidney stone formers: Positive data in a feature oral presentation at the European Society for Pediatric Nephrology (ESPN 2022) showed that BBP-711 led to near complete inhibition of glycolate oxidase throughout the dosing period and greater than 10-fold increases in plasma glycolate, suggesting it has the potential to be both a best-in-class therapy and the first oral therapy for PH1 and recurrent kidney stone formations. Overproduction of oxalate in hyperoxaluria, including PH1 and recurrent kidney stone formation with elevated oxalate, can lead to kidney stone formation, nephrocalcinosis and renal impairment. PH1 affects an estimated 5,000 patients in the US and EU, while recurrent stone formers are much more common, affecting an estimated 1.5 million individuals in the US and EU. Based on the tolerability and potency of the oral therapy, BridgeBio has met with regulators and intends to initiate a Phase 2/3 pivotal study by the end of 2022. At the end of 2022, BridgeBio also intends to launch a Phase 2 study of BBP-711 in adult recurrent kidney stone formers.
Positive early data for investigational AAV9 gene therapy in Canavan disease: Promising pharmacodynamic data from the first two participants dosed in the Phase 1/2 clinical trial of BBP-812 for the treatment of Canavan disease. Results showed unprecedented decreases in N-acetylaspartate (NAA) in the brain and urine, suggesting the therapy is producing functional ASPA enzyme. Affecting approximately 1,000 children in the US and EU, Canavan disease is an ultra-rare, disabling and fatal disease with no approved therapy.
Positive data in healthy volunteers to support BBP-671 for pantothenate kinase-associated neurodegeneration (PKAN) and organic acidemias: Positive interim Phase 1 data from healthy volunteers was shared in a scientific poster session in support of the development of BBP-671 for PKAN and organic acidemias at the Pan American Parkinson and Movement Disorders (PAS) Congress. Results showed that BBP-671 was detected in healthy volunteer plasma and cerebrospinal fluid, suggesting that BBP-671 is entering the brain, a location critical to target neurological complications of PKAN and organic acidemias at their source. BBP-671 also increased whole blood acetyl-coenzyme-A (CoA) levels in healthy volunteers, a signal supporting proof of mechanism of the therapy. These data represent, to the best of the Company’s knowledge, the first time acetyl-CoA has been directly increased by a pharmacological intervention in humans. Based on these data, BridgeBio intends to move forward with the second part of the Phase 1 clinical study in patients with propionic acidemia and methylmalonic acidemia in the second half of 2022 and plans to initiate a pivotal Phase 2/3 study in PKAN in 2023.
Positive data from PTR-01 in patients with recessive dystrophic epidermolysis bullosa (RDEB): Shared updates on positive Phase 2 data in a poster at the Society for Investigative Dermatology (SID) Annual Meeting 2022. Treatment with PTR-01 led to rapid, consistent, and durable wound healing as observed in reduction of wound surface area and clinician-reported assessments. All patients that completed the study reported a decrease in pain over the course of treatment with PTR-01.
Positive preliminary data in patients with venous, lymphatic and mixed venolymphatic malformations (VM, LM and VLM): Positive Phase 1b data for VM, LM and VLM was shared in a virtual presentation at the International Society for the Study of Vascular Anomalies (ISSVA). Data showed that the investigational drug was well-tolerated and showed a reduction of pS6 in lesions from baseline to day 28.
Positive opinion from CHMP for NULIBRY (fosdenopterin): The CHMP of the European Medicines Agency (EMA) issued a positive opinion recommending approval of NULIBRY in the EU for the treatment of patients with MoCD Type A. Opinion is based on the efficacy and safety data collected to date compared to data from a natural history study. Under an accelerated assessment pathway, a decision by the European Commission (EC), which authorizes marketing approval in the EU, is expected later this year. If approved by the EC, NULIBRY would be the first and only approved therapy in the EU to treat patients with MoCD type A, an ultra-rare, life-threatening genetic disorder that often progresses rapidly in infants with a median overall survival age of about four years. NULIBRY was BridgeBio’s first FDA-approved therapeutic. Sentynl Therapeutics, Inc. acquired global rights to NULIBRY in March 2022.
Academic research collaborations: Initiated an academic partnership with Baylor School of Medicine, and a founding affiliation with Bakar Labs, the incubator at UC Berkeley’s Bakar BioEnginuity Hub.
Second Quarter 2022 Financial Results:
Cash, Cash Equivalents and Marketable Securities
Cash, cash equivalents and marketable securities, excluding restricted cash, totaled $688.6 million as of June 30, 2022, compared to $787.5 million as of December 31, 2021. The net decrease of $98.9 million is primarily attributable to net cash used in operating activities of $191.1 million. The net cash used in operating activities was partially offset by a $90.0 million in upfront payment received under the License, Development and Commercialization Agreement between the Company, its affiliate, Navire Pharma, Inc., and Bristol Myers Squibb (the "Navire-BMS License Agreement"). During the six months ended June 30, 2022, the Company also received upfront payments of $110.0 million from the sale of its priority review voucher and $10.0 million upon closing of an asset purchase agreement between its affiliate, Origin Biosciences, Inc., and Sentynl Therapeutics, Inc. The Company also made a $20.5 million mandatory prepayment of a portion of its term loan obligations under its Amended Loan and Security Agreement in connection with the upfront payment received from BMS.
Cash, cash equivalents and marketable securities, excluding restricted cash, increased by $55.1 million when compared to the balance as of March 31, 2022 of $633.5 million. Net cash used in operating activities, which was partially offset by a $90.0 million in upfront payment received from BMS, was $30.5 million for the three months ended June 30, 2022. Net cash used in operating activities was $160.6 million for the three months ended March 31, 2022.
Operating Costs and Expenses
Operating costs and expenses for the three and six months ended June 30, 2022 were $153.9 million and $329.3 million, respectively, as compared to $148.0 million and $316.0 million for the same periods in the prior year. The overall increase in operating costs and expenses for the three and six months ended June 30, 2022 compared to the comparative periods was due mainly to costs incurred related to the restructuring initiative that was started in the first quarter of 2022. Restructuring, impairment and related charges for the three and six months ended June 30, 2022 of $8.4 million and $31.1 million, respectively, were primarily comprised of impairments and write-offs of long-lived assets, severance and employee-related expenses, and exit costs. The Company continues to evaluate restructuring alternatives to drive operational changes in business processes, efficiencies, and cost savings.
"We expect that operating expenses and cash burn will continue to decline meaningfully in the third and fourth quarters as restructuring charges decline and anticipated additional business development activity allows us to further decrease from this baseline. Cash on hand provides us with runway into 2024," said Brian Stephenson, Ph.D., CFA, BridgeBio’s Chief Financial Officer.
The Company’s research and development and other expenses have not been significantly impacted by the global COVID-19 pandemic for the periods presented. While BridgeBio experienced some delays in certain of its clinical enrollment and trial commencement activities, it continues to adapt with alternative site, telehealth and home visits, and at-home drug delivery, as well as mitigation strategies with its contract manufacturing organizations. The longer-term impact, if any, of COVID-19 on BridgeBio’s operating costs and expenses is currently unknown.