On February 26, 2024 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company, reported its continued global expansion, rapid global and U.S. revenue growth, and innovative R&D strategy with the presentation of results from the fourth quarter and full year 2023 and business highlights (Press release, BeiGene, FEB 26, 2024, View Source [SID1234640439]).

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"BeiGene made great progress in the fourth quarter and full year 2023 toward our goal to become an impactful next-generation oncology innovator. We have solidified our leadership in hematology with the continued success of BRUKINSA’s global launch, led by U.S. and Europe," said John V. Oyler, Chairman, Co-Founder and CEO at BeiGene. "Our cost advantaged research and development and manufacturing have enabled us to build one of the largest and most exciting oncology pipelines in the industry. We look forward to a transformative year for BeiGene as we continue to deliver on operational excellence propelled by outstanding growth in revenue across new and existing geographies."

Key Business and Pipeline Highlights

•Product revenues for the quarter, $630.5 million, and full year, $2.2 billion, increased 86% and 75% from prior-year totals;
•Disciplined management of operating expense growth drove operating loss decreases of 18% and 33% on a GAAP basis and 28% and 47% on an adjusted basis for the quarter and full year;
•Solidified BRUKINSA’s position as a BTK inhibitor of choice with U.S. Food and Drug Administration (FDA) approval of a label update to include superior progression-free survival (PFS) results at a median follow up of 29.6 months from the Phase 3 ALPINE trial comparing BRUKINSA against IMBRUVICA (ibrutinib) in previously treated patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL);
•Expanded global label for BRUKINSA with European Commission approval for the treatment of adult patients with R/R follicular lymphoma (FL) who have received at least two prior systematic treatments, making it the first BTK inhibitor ever approved in this indication and the BTK inhibitor with the broadest label in the class;
•Demonstrated leadership in hematology and strength of the Company’s pipeline with 25 abstracts presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December, including:
◦Updated results from the ALPINE trial demonstrating sustained PFS superiority at a median follow up of 39 months for BRUKINSA against IMBRUVICA for the treatment of adult patients with R/R CLL;
◦Phase 1/2 trial data for sonrotoclax demonstrating safety and tolerability in combination with BRUKINSA with deep and durable responses in treatment-naïve CLL; promising single-agent activity in patients with R/R marginal zone lymphoma; and promising efficacy and safety in combination with dexamethasone in multiple myeloma (MM) with t(11,14); and
◦First-in-human data for BTK CDAC BGB-16673 demonstrating notable clinical responses and a tolerable safety profile in heavily pretreated patients with B-cell malignancies, including those with BTKi-resistant disease.
•Expanded the global impact of anti-PD-1 antibody TEVIMBRA (tislelizumab) with a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval as a treatment for non-small cell lung cancer (NSCLC) across three indications, EMA acceptance of submission for the treatment of adult patients with first-line esophageal squamous cell carcinoma (ESCC), and regulatory reviews ongoing in 10 markets, including the U.S. and Europe; and

•Advanced innovative R&D strategy by entering five New Molecular Entities (NMEs) into the clinic in 2023, including potential best-in-class CDK4 inhibitor BGB-43395.

Fourth Quarter and Full Year 2023 Financial Highlights

Revenue for the fourth quarter and full year 2023 was $634.4 million and $2.5 billion, respectively, compared to $380.1 million and $1.4 billion in the prior-year periods. The increase in total revenue in the quarter compared to the prior year is primarily attributable to product sales growth in the Company’s major markets. For the fourth quarter and full year 2023, the U.S. was the largest market the Company derived revenue from, with revenue of $313.2 million and $1.1 billion, respectively, compared to $155.4 million and $502.6 million in the prior-year periods. The Company expects this trend to continue in 2024 as U.S. sales of BRUKINSA continue to grow.
Three Months Ended December 31, Twelve Months Ended December 31,
(in thousands, except per share amounts) 2023 2022 2023 2022
Net product revenues $ 630,526 $ 339,022 $ 2,189,852 $ 1,254,612
Net revenue from collaborations $ 3,883 $ 41,073 $ 268,927 $ 161,309
Total Revenue $ 634,409 $ 380,095 $ 2,458,779 $ 1,415,921
GAAP loss from operations $ (383,795) $ (468,622) $ (1,207,736) $ (1,789,665)
Adjusted loss from operations* $ (267,224) $ (372,480) $ (752,473) $ (1,420,225)

* For an explanation of our use of non-GAAP financial measures refer to the "Use of Non-GAAP Financial Measures" section later in this press release and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measures, see the table at the end of this press release.

Product Revenue totaled $630.5 million and $2.2 billion for the fourth quarter and full year 2023, respectively, compared to $339.0 million and $1.3 billion in the prior-year periods, and include:
•Global sales of BRUKINSA of $413.0 million and $1.3 billion for the fourth quarter and full year 2023, respectively, compared to $176.1 million and $564.7 million in the prior-year periods;
•Sales of tislelizumab of $128.0 million and $536.6 million for the fourth quarter and full year 2023, respectively, compared to $102.2 million and $422.9 million in the prior-year periods;
•Sales of Amgen in-licensed products of $51.1 million and $188.3 million for the fourth quarter and full year 2023, respectively, compared to $27.7 million and $114.6 million in the prior-year periods.
Gross Margin as a percentage of global product sales for the fourth quarter and full year 2023 was 83.2% and 82.7%, respectively, compared to 78.3% and 77.2% in the prior-year periods. The gross margin percentage increased in both the quarter-over-quarter and year-over-year period due to a proportionally higher product sales mix of global BRUKINSA compared to other products in our portfolio and compared to lower margin in-licensed products, as well as lower costs per unit for both BRUKINSA and tislelizumab.

Operating Expenses
The following table summarizes operating expenses for the fourth quarter 2023 and 2022, respectively:
GAAP Non-GAAP
(in thousands, except percentages) Q4 2023 Q4 2022 % Change Q4 2023 Q4 2022 % Change
Research and development $ 493,987 $ 446,023 11 % $ 437,383 $ 404,186 8 %
Selling, general and administrative $ 416,547 $ 328,984 27 % $ 361,435 $ 275,648 31 %
Amortization(1)
$ 1,838 $ 188 878 % $ — $ — NM
Total operating expenses $ 912,372 $ 775,195 18 % $ 798,818 $ 679,834 18 %

The following table summarizes operating expenses for the full year 2023 and 2022, respectively:
GAAP Non-GAAP
(in thousands, except percentages) FY 2023 FY 2022 % Change FY 2023 FY 2022 % Change
Research and development $ 1,778,594 $ 1,640,508 8 % $ 1,558,960 $ 1,474,919 6 %
Selling, general and administrative $ 1,504,501 $ 1,277,852 18 % $ 1,284,689 $ 1,077,977 19 %
Amortization(1)
$ 3,500 $ 751 366 % $ — $ — NM
Total operating expenses $ 3,286,595 $ 2,919,111 13 % $ 2,843,649 $ 2,552,896 11 %

(1)Relates to BMS product distribution rights intangible asset that was fully amortized as of December 31, 2023, when the rights reverted back to BMS under the terms of the Settlement Agreement.

Research and Development (R&D) Expenses increased for the fourth quarter and full year 2023 compared to the prior-year periods on both a GAAP and adjusted basis primarily due to investing in new platforms/modalities to advance preclinical programs into the clinic and early clinical programs into late stage. Upfront fees related to in-process R&D for in-licensed assets totaled $31.8 million and $46.8 million in the fourth quarter and full year 2023, respectively, compared to $48.7 million and $68.7 million in the prior-year periods.

Selling, General and Administrative (SG&A) Expenses increased for the fourth quarter and full year 2023 compared to the prior-year periods on both a GAAP and adjusted basis due to continued investment in the global commercial launch of BRUKINSA primarily in the U.S. and Europe.

Net Loss
GAAP net loss improved for the fourth quarter and full year 2023, as compared to the prior-year periods, primarily attributable to reduced operating losses and the non-operating gain of $362.9 million related to the BMS arbitration settlement for full year 2023.
For the fourth quarter of 2023, net loss per share was $0.27 per share and $3.53 per ADS, compared to $0.33 per share and $4.29 per ADS in the prior-year period. Net loss for full year 2023 was $0.65 per share and $8.45 per ADS, compared to $1.49 per share and $19.43 per ADS in the prior-year period.
Cash, Cash Equivalents, and Restricted Cash
Year Ended December 31,
2023 2022
(in thousands)
Cash, cash equivalents and restricted cash at beginning of period $ 3,875,037 $ 4,382,887
Net cash used in operating activities (1,157,453) (1,496,619)
Net cash provided by investing activities 60,004 1,077,123
Net cash provided by (used in) financing activities 416,478 (18,971)
Net effect of foreign exchange rate changes (8,082) (69,383)
Net decrease in cash, cash equivalents and restricted cash (689,053) (507,850)
Cash, cash equivalents and restricted cash at end of period $ 3,185,984 $ 3,875,037

Cash Used in Operations in fourth quarter and full year 2023, was $221.6 million and $1.2 billion, respectively, compared to $318.2 million and $1.5 billion in the prior-year periods, driven by improved operating leverage.
For further details on BeiGene’s 2023 Financial Statements, please see BeiGene’s Annual Report on Form 10-K for the year of 2023 filed with the U.S. Securities and Exchange Commission.

Regulatory Progress and Development Programs
Key Highlights
•Solidified BRUKINSA as a BTK inhibitor of choice with PFS superiority label update from the FDA, approvals in R/R FL in Europe and Canada
•Expanded TEVIMBRA global reach with pending regulatory submissions in 10 markets, including the U.S. and Europe
•Enrolled first patients in a Phase 3 global trial of sonrotoclax in first-line CLL and expansion cohorts with registration potential for BTK CDAC

Category Asset Recent Milestones
Regulatory Approvals BRUKINSA
•Received FDA approved label update to include superior PFS results in adult patients with R/R CLL/SLL based on results from the Phase 3 ALPINE trial
•Received approval from European Commission and authorization from Health Canada for the treatment of adult patients with R/R FL in combination with obinutuzumab who have received at least two prior lines of systemic therapy
•Received regulatory approval in four additional markets for R/R and treatment-naïve (TN) CLL
TEVIMBRA
•Received China National Medicinal Products Administration (NMPA) approval as first-line treatment in patients with unresectable hepatocellular carcinoma
•Received approval from the UK Medicines and Healthcare Regulatory Agency (MHRA) as second-line treatment in patients with advanced ESCC
Regulatory Submissions Tislelizumab
•Received a positive opinion from the CHMP of the EMA recommending approval as a treatment for NSCLC across three indications
•Received NMPA acceptance of a supplemental Biologics License Application (sBLA) submission for the treatment of previously untreated extensive stage small cell lung cancer (ES-SCLC) in combination with chemotherapy
•Received NMPA acceptance of a sBLA submission for treatment plus platinum-based chemotherapy followed by adjuvant treatment of adult patients with resectable Stage II or IIIA NSCLC
•Received EMA acceptance of submission for the treatment of adult patients with first-line ESCC

Clinical Activities BRUKINSA
•Announced positive follow-up data from the Phase 3 ALPINE study in R/R CLL/SLL versus IMBRUVICA at ASH (Free ASH Whitepaper) showing sustained PFS benefit and persistently lower rates of cardiovascular events
Tislelizumab
•Enrolled first patient in a Phase 1 clinical trial evaluating subcutaneous injection in the first-line treatment of patients with advanced or metastatic NSCLC
Sonrotoclax (BGB-11417)
•FDA granted orphan designations for multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM), acute myeloid leukemia (AML), and mantle cell lymphoma (MCL)
•Enrolled first patient in a global pivotal trial in combination with BRUKINSA in first-line CLL
•Presented data at ASH (Free ASH Whitepaper) demonstrating:
◦Sonrotoclax is safe and tolerable in combination with BRUKINSA with deep and durable responses in TN CLL
◦Encouraging data with potential to be first BCL2i approved in MM with t(11,14)
◦Promising single-agent activity in patients with R/R MZL

BTK CDAC
(BGB-16673)
•Presented data at ASH (Free ASH Whitepaper) from ongoing first-in-human study demonstrating notable clinical responses and a tolerable safety profile in heavily pretreated patients with B-cell malignancies, including those with BTKi-resistant disease
•Enrolled first patients in R/R MCL expansion cohort with potential for registration
•Fast Track and Orphan Drug designations received from FDA for R/R MCL

Anti-LAG3
(LBL-0071)
•In partnership with Leads Biolabs, first subject enrolled in a Phase 2 study as first-line treatment in patients with inoperable locally advanced or metastatic ESCC in combination with tislelizumab and chemotherapy
Early development
•Fully enrolled the first two cohorts in Phase 1 clinical trials for NME BGB-43395 (CDK4 inhibitor)

Anticipated Upcoming Milestones
Key Highlights

•Secure FDA approval for BRUKINSA in combination with obinutuzumab in R/R FL, making it the BTK inhibitor with the broadest label in the class
•Receive FDA approval for tislelizumab in first- and second-line ESCC, demonstrating global expansion of innovative solid tumor portfolio
Category Asset Anticipated Milestones
Anticipated Regulatory Approvals BRUKINSA
•Receive FDA approval in combination with obinutuzumab for the treatment of adult patients with R/R FL who have received at least two prior lines of systemic therapy in March 2024 and NMPA approval in June 2024
Tislelizumab
•Receive FDA approval for the treatment of second line ESCC in first half of 2024
•Receive FDA approval for the treatment of first-line unresectable, recurrent, locally advanced, or metastatic ESCC with a target PDUFA in July 2024
•Receive EMA approval for the treatment of first line metastatic NSCLC in combination with chemotherapy and second line metastatic NSCLC as monotherapy in the first half of 2024
•Receive NMPA approval for the treatment of previously untreated ES-SCLC in combination with chemotherapy in the third quarter of 2024
•Receive NMPA approval for the first-line treatment of inoperable, locally advanced, or metastatic gastric or gastroesophageal junction (G/GEJ) carcinoma in the second quarter of 2024

Anticipated Regulatory Submissions BRUKINSA
•Submit an sNDA for a new tablet formulation with the EMA and Health Canada in the first of half of 2024 and the FDA in the second half of 2024
Tislelizumab
•Submit a marketing application with the Japan PMDA for the treatment of first- and second-line ESCC in the first half of 2024
•Submit an sBLA with the EMA for the first-line treatment of inoperable, locally advanced, or metastatic G/GEJ carcinoma in the first quarter of 2024

Zanidatamab2
•In partnership with Jazz Pharmaceuticals and Zymeworks, submit a BLA with the NMPA for treatment of HER2-amplified inoperable and advanced or metastatic biliary tract cancer in the second half of 2024
Anticipated Clinical Activities Sonrotoclax
•Complete enrollment in a global Phase 2 trial in R/R MCL with potential for registration in the second quarter of 2024
Ociperlimab
(Anti-TIGIT)
•Complete enrollment in the Phase 3 AdvanTIG-302 trial in first-line NSCLC in the first quarter of 2024 

Tarlatamab3
(DLL3 x CD3 bispecific T-cell engager)

•In partnership with Amgen, begin China enrollment in a global Phase 3 trial in limited-stage small cell lung cancer in the second half of 2024
Early development
•Initiate first-in-human trials for at least 10 NMEs in 2024, including pan-KRAS inhibitor, MTA cooperative PRMT5 inhibitor, EGFR degrader, CDK2 inhibitor, ADCs, and bispecific immune cell engagers
•In partnership with Amgen3, enroll first patient in China in a Phase 1 study in metastatic castration-resistant prostate cancer for xaluritamig (AMG 509, STEAP1 x CD3 XmAb T-cell engager molecule4) in the first half of 2024

1 Leads Biolabs collaboration; BeiGene has commercial rights excluding China
2 Jazz/Zymeworks collaboration; BeiGene has commercial rights in APAC (excluding Japan), Australia, New Zealand
3 Amgen collaboration; BeiGene will have commercial rights in China and tiered mid-single digit royalties on net sales outside of China
4 XmAb is a registered trademark of Xencor, Inc.

Manufacturing Operations
•Neared completion of $800 million U.S. flagship biologics manufacturing and clinical R&D facility at the Princeton West Innovation Campus in Hopewell, New Jersey, which is expected to be operational in July 2024; the property has more than 1 million square feet of total developable real estate allowing for future expansion;

•Completed construction on new small molecule manufacturing campus in Suzhou, China. Phase 1 of construction added more than 559,000 square feet and expanded production capacity to 1 billion solid dosage form units annually; and

•Completed construction of a 250,000-square-foot ADC production facility and additional 170,000-square-foot biologics clinical production capabilities at our state-of-the-art biologics facility in Guangzhou, China, which brings the total capacity to 65,000 liters.

Corporate Developments
•Acquired an exclusive global license to a differentiated CDK2 inhibitor from Ensem Therapeutics, Inc., complementing the Company’s early development pipeline in breast cancer and other solid tumors.

Financial Summary
Select Condensed Consolidated Balance Sheet Data (U.S. GAAP)
(Amounts in thousands of U.S. Dollars)
As of
December 31, December 31,
2023 2022
(audited)
Assets:
Cash, cash equivalents, restricted cash and short-term investments $ 3,188,584 $ 4,540,288
Accounts receivable, net 358,027 173,168
Inventories, net 416,122 282,346
Property, plant and equipment, net 1,324,154 845,946
Total assets $ 5,805,275 $ 6,379,290
Liabilities and equity:
Accounts payable $ 315,111 $ 294,781
Accrued expenses and other payables 693,731 467,352
Deferred revenue 300 255,887
R&D cost share liability 238,666 293,960
Debt 885,984 538,117
Total liabilities 2,267,948 1,995,935
Total equity $ 3,537,327 $ 4,383,355

Condensed Consolidated Statements of Operations (U.S. GAAP)
(Amounts in thousands of U.S. dollars, except for shares, American Depositary Shares (ADSs), per share and per ADS data)
Three Months Ended
December 31, Twelve Months Ended
December 31,
2023 2022 2023 2022
(unaudited) (audited)
Revenue
Product revenue, net $ 630,526 $ 339,022 $ 2,189,852 $ 1,254,612
Collaboration revenue 3,883 41,073 268,927 161,309
Total revenues 634,409 380,095 2,458,779 1,415,921
Cost of sales – products 105,832 73,522 379,920 286,475
Gross profit 528,577 306,573 2,078,859 1,129,446
Operating expenses
Research and development 493,987 446,023 1,778,594 1,640,508
Selling, general and administrative 416,547 328,984 1,504,501 1,277,852
Amortization of intangible assets 1,838 188 3,500 751
Total operating expenses 912,372 775,195 3,286,595 2,919,111
Loss from operations (383,795) (468,622) (1,207,736) (1,789,665)
Interest income , net 16,274 18,219 74,009 52,480
Other income (expense), net 16,749 19,438 307,891 (223,852)
Loss before income taxes (350,772) (430,965) (825,836) (1,961,037)
Income tax expense 16,781 14,370 55,872 42,778
Net loss (367,553) (445,335) (881,708) (2,003,815)
Net loss per share $ (0.27) $ (0.33) $ (0.65) $ (1.49)
Weighted-average shares outstanding—basic and diluted 1,353,005,058 1,348,916,108 1,357,034,547 1,340,729,572
Net loss per American Depositary Share ("ADS") $ (3.53) $ (4.29) $ (8.45) $ (19.43)
Weighted-average ADSs outstanding—basic and diluted 104,077,312 103,762,778 104,387,273 103,133,044

On February 22, 2024 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 fourth quarter and full year ended December 31, 2023, and provided an update on the Company’s operations (Press release, BridgeBio, FEB 24, 2024, View Source [SID1234640418]).

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"Our focus this year is executing on the launch of acoramidis for patients with ATTR cardiomyopathy," said Neil Kumar, Ph.D., founder and CEO of BridgeBio. "At the same time, we are also focused on fully enrolling three ongoing Phase 3 clinical trials by the end of 2024. Finally, we hope that reading out potentially exciting data from our Phase 1/2 trial in congenital adrenal hyperplasia later this year will let us take the next step in serving that patient community."

BridgeBio’s key programs:

•
Acoramidis (AG10) – Transthyretin (TTR) stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM):
o
The Company filed an NDA for acoramidis for the treatment of ATTR-CM with the US FDA; the NDA was accepted for review with a PDUFA date of November 29, 2024. The Company has also filed a Marketing Authorization Application for acoramidis with the EMA, which has been accepted for review.
o
The regulatory filings were based on data from the Phase 3 ATTRibute-CM study, which met its primary endpoint (Win Ratio of 1.8) with a highly statistically significant p-value (p<0.0001). Additional results from ATTRibute-CM include:
▪
An 81% survival rate on acoramidis, which approaches the survival rate in the age-matched U.S. database (~85%), and a 0.29 mean annual CVH rate on acoramidis, which approaches the annual hospitalization rate observed in the broader U.S. Medicare population (~0.26);
▪
Improvements from baseline observed for a large proportion of participants treated with acoramidis on laboratory and functional measures including n-terminal prohormone of brain natriuiretic peptide (NT-proBNP) and 6-minute walk distance;
▪
Rapid clinical benefit on the composite endpoint of ACM and CVH in participants treated with acoramidis, demonstrated by placebo and acoramidis time-to-first event Kaplan-Meier curves for a composite of ACM and CVH that separated at Month 3 and continued to diverge steadily through Month 30 as presented at the American Heart Association Scientific Sessions in November 2023; and
▪
Acoramidis was well-tolerated with no safety signals of potential clinical concern identified.
o
The Company also shared positive results of an open-label, single-arm Phase 3 study conducted in Japan by licensing partner Alexion, AstraZeneca Rare Disease, including that no mortality was reported over the 30 month acoramidis treatment period.
o
Additional detailed results of ATTRibute-CM are planned for presentation at 2024 medical meetings.
•
Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia and hypochondroplasia:
o
In December 2023, the Company announced the dosing of the first child in PROPEL 3, its global Phase 3 registrational study of infigratinib in achondroplasia.
o
In February 2024, the Company announced a partnership with Kyowa Kirin wherein the Company grants Kyowa Kirin an exclusive license to develop and commercialize infigratinib for achondroplasia, hypochondroplasia, and other skeletal dysplasias in Japan; in exchange, the Company will receive an upfront payment of $100 million as well as royalties up to the high-twenties percent on sales of infigratinib in Japan, with the potential for additional milestone-based payments.
2

o
The Company is committed to exploring the potential of infigratinib on the wider medical and functional impacts of achondroplasia, hypochondroplasia and other skeletal dysplasias, and anticipates initiating its clinical program for hypochondroplasia in 2024.
•
BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9):
o
FORTIFY, the global Phase 3 registrational trial of BBP-418, continues to enroll in the U.S. with clinical trial sites planned for Europe and Australia. Full enrollment of the interim analysis population is expected in 2024. The Company believes there is potential to pursue Accelerated Approval for BBP-418 based on recent interactions with the FDA on the use of glycosylated αDG levels as a surrogate endpoint.

•
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1):
o
CALIBRATE, the Phase 3 clinical trial of encaleret, continues to enroll; the Company anticipates sharing topline data from CALIBRATE in 2025.

Recent Corporate Updates:

•
Secured up to $1.25 billion of capital from Blue Owl and CPP Investments: The raise includes $500 million in cash from Blue Owl and CPP Investments available upon FDA approval of acoramidis in exchange for a 5% royalty on future global net sales of acoramidis, as well as a $450 million credit facility from Blue Owl that refinanced existing senior secured credit, extending maturity from 2026 to 2029 subject to certain conditions.

Fourth Quarter and Full Year 2023 Financial Results:

Cash, Cash Equivalents, Marketable Securities and Short-term Restricted Cash

Cash, cash equivalents and short-term restricted cash, totaled $392.6 million as of December 31, 2023, compared to cash, cash equivalents, marketable securities and short-term restricted cash of $466.2 million as of December 31, 2022. The net decrease of $73.6 million in cash, cash equivalents, marketable securities and short-term restricted cash was primarily attributable to net cash used in operating activities of $527.7 million and $6.9 million in repurchase of shares to satisfy tax withholdings, primarily offset by net proceeds received of $449.8 million from various equity financings, $6.0 million from stock option exercises, and $3.4 million from common stock issuances under our employee stock purchase plan during the year ended December 31, 2023.

Revenue

Revenue for the three months and year ended December 31, 2023 were $1.7 million and $9.3 million, respectively, as compared to $1.9 million and $77.6 million for the same periods in the prior year, respectively. The net decreases of $0.2 million and $68.3 million for the three months and year ended December 31, 2023, respectively, compared to the same periods in the prior year, were primarily due to license revenue recognized in 2022 upon the transfer of the license in accordance with the Navire-BMS License Agreement which was entered into in May 2022.

3

Operating Costs and Expenses

Operating costs and expenses for the three months and year ended December 31, 2023 were $179.2 million and $616.7 million, respectively, compared to $131.1 million and $589.9 million, for the same periods in the prior year, respectively.

The overall increase of $48.1 million in operating costs and expenses for the three months ended December 31, 2023, compared to the same period in the prior year, was primarily due to an increase of $39.3 million in research and development and other expenses (R&D) to advance the Company’s pipeline of development programs, an increase of $15.7 million in selling, general and administrative (SG&A) expenses to support commercialization readiness efforts, offset by a decrease of $6.9 million in restructuring, impairment and related charges given that the majority of the restructuring initiatives occurred in the prior year.

The overall increase of $26.8 million in operating costs and expenses for the year ended December 31, 2023 , compared to the same period in the prior year, was primarily due to an increase of $55.2 million in R&D expenses to advance the Company’s pipeline of development programs, an increase of $7.4 million in SG&A expenses to support commercialization readiness efforts, offset by a decrease of $35.8 million in restructuring, impairment and related charges given that the majority of the restructuring initiatives occurred in the prior year.

Restructuring, impairment and related charges for the three months and year ended December 31, 2023, amounted to $0.8 million and $7.9 million, respectively. These charges primarily consisted of winding down, exit costs, and severance and employee-related costs. Restructuring, impairment and related charges for the same periods in the prior year were $7.7 million and $43.8 million, respectively. These charges primarily consisted of impairments and write-offs of long-lived assets, severance and employee-related costs, and exit and other related costs.

Stock-based compensation expenses included in operating costs and expenses for the three months ended December 31, 2023 were $37.1 million, of which $22.5 million is included in R&D expenses, and $14.6 million is included in SG&A expenses. Stock-based compensation expenses included in operating costs and expenses for the same period in the prior year were $22.6 million, of which $8.9 million is included in R&D expenses, and $13.6 million is included in SG&A expenses.

Stock-based compensation expenses included in operating costs and expenses for the year ended December 31, 2023 were $115.0 million, of which $61.6 million is included in R&D expenses, and $53.4 million is included in SG&A expenses. Stock-based compensation expenses included in operating costs and expenses for the same period in the prior year were $93.8 million, of which $38.0 million is included in R&D expenses, $54.7 million is included in SG&A expenses, and $1.2 million is included in restructuring, impairment and related charges.

"Coming off of our recent royalty financing, we find ourselves well capitalized to launch acoramidis this year alongside strong new partners who share our confidence in acoramidis’ potential in the ATTR-CM market," said Brian Stephenson, Ph.D., CFA, Chief Financial Officer of BridgeBio. "We are excited for this launch, as well as for the continued advancement of our late stage pipeline, which we hope will allow us to serve patients with genetic diseases both directly with the advancement of those medicines towards the market as well as by diversifying our top line revenue and enabling reinvestment into the R&D and business development opportunities that will allow us to be sustainable in the long term."

4

BRIDGEBIO PHARMA, INC.

Condensed Consolidated Statements of Operations

(in thousands, except shares and per share amounts)

Three Months Ended December 31,

Year Ended December 31,

2023

2022

2023

2022

(Unaudited)

(Unaudited)

(1)

Revenue

$

1,745

$

1,870

$

9,303

$

77,648

Operating costs and expenses:

Research, development and other expenses

130,824

91,549

458,157

402,896

Selling, general and administrative

47,583

31,862

150,590

143,189

Restructuring, impairment and related charges

754

7,691

7,926

43,765

Total operating costs and expenses

179,161

131,102

616,673

589,850

Loss from operations

(177,416

)

(129,232

)

(607,370

)

(512,202

)

Other income (expense), net:

Interest income

5,578

4,092

18,038

7,542

Interest expense

(20,268

)

(19,990

)

(81,289

)

(80,438

)

Gain from sale of priority review voucher, net

—

—

—

107,946

Other income (expense), net

21,778

4,560

17,370

(7,500

)

Total other income (expense), net

7,088

(11,338

)

(45,881

)

27,550

Net loss

(170,328

)

(140,570

)

(653,251

)

(484,652

)

Net loss attributable to redeemable convertible
noncontrolling interests and noncontrolling interests

2,180

2,979

10,049

3,469

Net loss attributable to common stockholders
of BridgeBio

$

(168,148

)

$

(137,591

)

$

(643,202

)

$

(481,183

)

Net loss per share, basic and diluted

$

(0.96

)

$

(0.92

)

$

(3.95

)

$

(3.26

)

Weighted-average shares used in computing net
loss per share, basic and diluted

174,462,332

149,344,380

162,791,511

147,473,076

Three Months Ended December 31,

Year Ended December 31,

Stock-based Compensation

2023

2022

2023

2022

(Unaudited)

(Unaudited)

(1)

Research, development and others

$

22,495

$

8,941

$

61,647

$

37,987

Selling, general and administrative

14,638

13,643

53,369

54,669

Restructuring, impairment and related charges

—

—

—

1,172

Total stock-based compensation

$

37,133

$

22,584

$

115,016

$

93,828

(1)

The condensed consolidated financial statements as of and for the year ended December 31, 2022 are derived from the audited consolidated financial statements as of that date.

5

BRIDGEBIO PHARMA, INC.

Condensed Consolidated Balance Sheets

(In thousands)

December 31,

December 31,

2023

2022

(Unaudited)

(1)

Assets

Cash, cash equivalents and marketable securities

$

375,935

$

428,269

Investment in equity securities

58,949

43,653

Receivable from licensing and collaboration agreements

1,751

17,079

Short-term restricted cash

16,653

37,930

Prepaid expenses and other current assets

24,305

21,922

Property and equipment, net

11,816

14,569

Operating lease right-of-use assets

8,027

10,678

Intangible assets, net

26,319

28,712

Other assets

22,625

20,224

Total assets

$

546,380

$

623,036

Liabilities, Redeemable Convertible Noncontrolling Interests and Stockholders’ Deficit

Accounts payable

$

10,655

$

11,558

Accrued and other liabilities

129,061

106,195

Operating lease liabilities

13,109

15,949

2029 Notes, net

736,905

734,988

2027 Notes, net

543,379

541,634

Term loan, net

446,445

430,993

Other long-term liabilities

9,361

26,643

Redeemable convertible noncontrolling interests

478

(1,589

)

Total BridgeBio stockholders’ deficit

(1,354,257

)

(1,254,617

)

Noncontrolling interests

11,244

11,282

Total liabilities, redeemable convertible noncontrolling interests and stockholders’ deficit

$

546,380

$

623,036

(1)

The condensed consolidated financial statements as of and for the year ended December 31, 2022 are derived from the audited consolidated financial statements as of that date.

6

BRIDGEBIO PHARMA, INC.

Condensed Consolidated Statements of Cash Flows

(In thousands)

Year Ended December 31,

2023

2022

(Unaudited)

(1)

Operating activities:

Net loss

$

(653,251

)

$

(484,652

)

Adjustments to reconcile net loss to net cash used in operating activities:

Stock-based compensation

108,710

91,559

Depreciation and amortization

6,494

6,771

Noncash lease expense

4,032

5,172

Accrual of payment-in-kind interest on term loan

10,207

13,562

Loss on deconsolidation of PellePharm

1,241

—

(Gain) loss from investment in equity securities, net

(18,314

)

8,222

Fair value of shares issued under a license agreement

—

4,567

Accretion of debt

8,907

8,570

Fair value adjustment of warrants

(984

)

1,571

Loss on sale of certain assets

—

6,261

Impairment of long-lived assets

—

12,720

Gain from sale of priority review voucher, excluding transaction costs

—

(110,000

)

Gain from recognition of receivable from licensing and collaboration agreement

—

(12,500

)

Other noncash adjustments

181

604

Changes in operating assets and liabilities:

Receivable from licensing and collaboration agreements

15,328

15,169

Prepaid expenses and other current assets

(2,702

)

7,671

Other assets

(1,546

)

10,971

Accounts payable

2,780

(349

)

Accrued compensation and benefits

7,802

(2,362

)

Accrued research and development liabilities

(9,855

)

(4,309

)

Operating lease liabilities

(4,829

)

(6,245

)

Deferred revenue

(5,438

)

15,262

Accrued professional and other liabilities

3,517

(7,729

)

Net cash used in operating activities

(527,720

)

(419,494

)

Investing activities:

Purchases of marketable securities

(29,726

)

(137,493

)

Maturities of marketable securities

82,550

479,688

Purchases of investment in equity securities

(107,538

)

(55,562

)

Sales of investment in equity securities

110,556

52,835

Decrease in cash and cash equivalents resulting from deconsolidation of PellePharm

(503

)

—

Payment for intangible asset

—

(1,500

)

Proceeds from sale of priority review voucher

—

110,000

Proceeds from sale of certain assets

—

10,000

Purchases of property and equipment

(1,306

)

(4,821

)

Net cash provided by investing activities

54,033

453,147

Financing activities:

Proceeds from issuance of common stock through Private Placement offering, net

240,796

—

Proceeds from issuance of common stock through Follow-on offering, net

144,049

—

Proceeds from issuance of common stock through ATM offering, net

64,965

4,852

Transactions with noncontrolling interests

(801

)

—

Repayment of term loan

—

(20,486

)

Proceeds from BridgeBio common stock issuances under ESPP

3,398

2,558

Repurchase of RSU shares to satisfy tax withholding

(6,880

)

(1,561

)

Proceeds from stock option exercises, net of repurchases

6,008

666

Other financing activities

—

837

Net cash provided by (used in) financing activities

451,535

(13,134

)

Net increase (decrease) in cash, cash equivalents and restricted cash

(22,152

)

20,519

Cash, cash equivalents and restricted cash at beginning of period

416,884

396,365

Cash, cash equivalents and restricted cash at end of period

$

394,732

$

416,884

7

Year Ended December 31,

2023

2022

(Unaudited)

(1)

Supplemental Disclosure of Cash Flow Information:

Cash paid for interest

$

61,108

$

54,443

Supplemental Disclosures of Noncash Investing and Financing Information:

Unpaid property and equipment

$

100

$

47

Recognized intangible asset recorded in "Other accrued and other long-term liabilities"

$

—

$

11,000

Transfers (to) from noncontrolling interests

$

(10,534

)

$

(3,512

)

Payment-in-kind interest added to principal of term loan

$

—

$

1,763

Reconciliation of Cash, Cash Equivalents and Restricted Cash:

Cash and cash equivalents

$

375,935

$

376,689

Short-term restricted cash

16,653

37,930

Restricted cash — Included in "Other assets"

2,144

2,265

Total cash, cash equivalents and restricted cash at end of periods

$

394,732

$

416,884

(1)

The condensed consolidated financial statements as of and for the year ended December 31, 2022 are derived from the audited consolidated financial statements as of that date.

On February 23, 2024 Oncopeptides, a biotech company focused on difficult-to-treat cancers, reported that the U.S. Food and Drug Administration (FDA) has made a decision regarding the withdrawal of Pepaxto, which Oncopeptides had appealed (Press release, Oncopeptides, FEB 23, 2024, View Source [SID1234646780]).

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In their decision, the FDA concludes that they have determined that the grounds for withdrawing the approval have been met. The full decision is, or will momentarily be, available in the public docket created by the FDA through the following link. Oncopeptides will now thoroughly assess the decision.

Oncopeptides’ focus remains on commercialization in Europe where the company has a full marketing authorization.

On February 23, 2024 TME Pharma N.V. (Euronext Growth Paris: ALTME), a biotechnology company focused on developing novel therapies for treatment of cancer by targeting the tumor microenvironment (TME), reported results of the final exercise of Warrants Y and an update on the outstanding number of ordinary shares, Warrants Y and Warrants Z (Press release, TME Pharma, FEB 23, 2024, View Source [SID1234640428]). The exercise of 8,539,955 Warrants Y has triggered the issuance of 3,415,982 new shares for gross proceeds of €853,995.50. The net proceeds from the exercise extend the company’s cash runway from May 2024 into early July 2024.

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"We are very pleased to announce the results of our latest successful warrant exercise, which reflects strong support demonstrated by a very high participation from our existing shareholders, extending our financial visibility into early July – well past the upcoming regulatory milestones," said Aram Mangasarian, CEO of TME Pharma. "We would like to thank our shareholders for their ongoing support and confidence in our mission. We believe that the recent termination of our convertible debt program and the end of the company’s reliance on convertible bond financing have alleviated pressure on the share price and contributed to the success of this exercise. We are now looking forward to achieving our next targeted clinical and regulatory milestones, notably approval of the Investigational New Drug application for NOX-A12 in glioblastoma and a response to our Fast Track request targeted by quarter’s end, both of which are important milestones in advancing the development of our lead asset to become the best available therapy for aggressive brain cancer patients."

When exercising 5 Warrants Y held, a holder was entitled to subscribe for 2 ABSA Z at an exercise price of €0.25 per ABSA Z, each comprised of one new ordinary ALTME share and one Warrant Z (Bon de souscription d’actions Z). As a result of the exercises that took place during the final exercise period between February 10-16, 2024, 3,415,982 new ordinary shares and 3,415,982 Warrants Z are being issued by TME Pharma and settled today. Warrants Y that were not exercised by February 16, 2024, have become null and void. The following numbers of TME Pharma securities are thus issued and outstanding:

ALTME ordinary shares (ISIN: NL0015000YE1): 27,853,843
Warrants Y (ISIN : NL0015001SS1): 0 (all have either been exercised or expired)
Warrants Z (ISIN: NL0015001SR3): 3,805,728.
As a reminder, in the first exercise period, from January 10-16, 2024, 974,365 Warrants Y were exercised for €97,436.50, resulting in issuance of 389,746 new ordinary shares and 389,746 Warrants Z.

The first Warrant Z exercise period will run from February 26 to March 22, 2024, with settlement on March 29, 2024. For every 4 Warrants Z held, a holder is entitled to subscribe for 5 new shares at €0.20 per share. Warrants Z may be exercised through June 20, 2025. Outstanding 3,805,728 Warrants Z have potential to raise additional €951,432 if exercised in full before the end of the final exercise period on June 20, 2025.

Additional Information
The characteristics, terms and conditions and dilution resulting from the transaction are summarized in the press releases published on November 24 and November 28, 2023 and in the dedicated Rights Issue page on the TME Pharma website.

Dilution
The table below summarizes the dilution from the new ordinary shares issued today, and the maximum additional dilutive potential for an investor who did NOT participate in the transaction should all potential Warrants Z be exercised. Shareholders who participated fully in the transaction, i.e. who purchased the ABSA Y and subsequently exercise both Warrants Y and Z will not be diluted by this transaction.

Description

Shares to be issued

Total shares outstanding

Dilution (cumulative)

Shareholder starting with 1% on February 22, 2024, would then hold

Outstanding shares on February 22, 2024

–

24,437,861

–

1%

Shares Issued on February 23, 2024, from exercise of 8,539,955 Warrants Y

3,415,982

27,853,843

12.26%

0.88%

Exercise of Warrant Z (latest on June 20, 2025)

4,757,160

32,611,003

25.06%

0.75%

On February 23, 2024 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global leader in cell therapy, reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended expansion of the CARVYKTI label to include adult patients with relapsed and refractory multiple myeloma, who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide (Press release, Legend Biotech, FEB 23, 2024, View Source [SID1234640427]). The Type II variation application was submitted to the EMA by Janssen-Cilag International N.V., an affiliate of Janssen Biotech, Inc., Legend Biotech’s collaborator for the development and commercialization of CARVYKTI. The positive opinion from the CHMP will now be reviewed by the European Commission which renders the final decision on approval.

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"The positive CHMP opinion is an important step towards making CARVYKTI available to more patients in Europe who can benefit from this one-time infusion."

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"This milestone demonstrates our commitment to transforming the treatment landscape by bringing CARVYKTI to more patients around the world and in earlier lines of treatment," said Ying Huang, Ph.D., CEO of Legend Biotech. "This positive opinion showcases our fierce drive, in collaboration with Janssen, to deliver innovative treatment options to patients and provide hope for them and their families."

The CHMP recommendation for CARVYKTI is supported by data from the CARTITUDE-4 study (NCT04181827), the first randomized Phase 3 study evaluating the efficacy and safety of CARVYKTI versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in the treatment of patients with relapsed and lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy.1

"The results of the CARTITUDE-4 study demonstrated significant clinical benefit for patients who experience a relapse early in the treatment of their disease," said Jesús San Miguel, M.D., Ph.D., Professor of Medicine-Haematology, Head of Clinical and Senior Consultant at the Cancer Center Clinica Universidad de Navarra Spain.† "The positive CHMP opinion is an important step towards making CARVYKTI available to more patients in Europe who can benefit from this one-time infusion."

CARVYKTI INDICATIONS AND USAGE

CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.

Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred following treatment with CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

CYTOKINE RELEASE SYNDROME (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1-12 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation and hemorrhage, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. One patient with CRS and suspected HLH/MAS developed a fatal retroperitoneal hemorrhage in the setting of thrombocytopenia, coagulopathy and anticoagulation in another ongoing study of CARVYKTI.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

NEUROLOGIC TOXICITIES, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, six male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 6 patients in CARTITUDE-1 was 64 days (range 14-914 days) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulin (IVIG). Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulin and plasma exchange, depending on severity of GBS.

Immune Mediated Myelitis: Grade 3 myelitis has occurred 25 days following treatment in another ongoing study. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral Neuropathy: Seven patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 66 days (range 4-914 days), median duration of peripheral neuropathies was 138 days (range 2-692 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of peripheral neuropathies.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)/MACROPHAGE ACTIVATION SYNDROME (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction.

One patient with Grade 4 HLH/MAS developed fatal intracerebral and gastrointestinal hemorrhage in the setting of coagulopathy and thrombocytopenia 12 days after treatment in another ongoing study. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematological parameters in patients with HLH/MAS and transfuse per institutional guidelines.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

PROLONGED AND RECURRENT CYTOPENIAS: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 19% (18/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Eight and 12 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

INFECTIONS: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 21% (20/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 15%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, 5 patients had Grade 5 infections: lung abscess (n=1), sepsis (n=3) and pneumonia (n=1).

Grade 5 infections reported in other studies include bronchopulmonary aspergillosis, pneumocystis jirovecii pneumonia, and CMV colitis (with HSV-1 hepatitis). Another patient developed mycotic aneurysm due to cerebral aspergillosis and died of subarachnoid hemorrhage.

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

In a randomized controlled study of relapsed or refractory multiple myeloma (CARTITUDE-4), patients treated with ciltacabtagene autoleucel had an increased rate of fatal COVID-19 infections compared to the standard therapy arm. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

HYPOGAMMAGLOBULINEMIA was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

HYPERSENSITIVITY REACTIONS have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

SECONDARY MALIGNANCIES: Patients treated with CARVYKTI may develop secondary malignancies. Myeloid neoplasms (five cases of myelodysplastic syndrome, three cases of acute myeloid leukemia and two cases of myelodysplastic syndrome followed by acute myeloid leukemia) occurred in 10% (10/97) of patients in CARTITUDE-1 study following treatment with CARVYKTI. The median time to onset of myeloid neoplasms was 485 days (range: 162 to 1040 days) after treatment with CARVYKTI. Nine of these 10 patients died following the development of myeloid neoplasms; four of the 10 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information, including Boxed Warning, for CARVYKTI.

ABOUT CARVYKTI (CILTACABTAGENE AUTOLEUCEL; CILTA-CEL)

Ciltacabtagene autoleucel is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. The cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.2

In December 2017, Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen), a Johnson & Johnson company, to develop and commercialize cilta-cel. In February 2022, cilta-cel was approved by the U.S. Food and Drug Administration (FDA) under the brand name CARVYKTI for the treatment of adults with relapsed or refractory multiple myeloma. In May 2022, the European Commission (EC) granted conditional marketing authorization of CARVYKTI for the treatment of adults with relapsed and refractory multiple myeloma. In September 2022, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI. Cilta-cel was granted Breakthrough Therapy Designation in the U.S. in December 2019 and in China in August 2020. In addition, cilta-cel received a PRIority MEdicines (PRIME) designation from the European Commission in April 2019. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, from the European Commission in February 2020, and from the Pharmaceuticals and Medicinal Devices Agency (PMDA) in Japan in June 2020. In March 2022, the European Medicines Agency’s Committee for Orphan Medicinal Products recommended by consensus that the orphan designation for cilta-cel be maintained on the basis of clinical data demonstrating improved and sustained complete response rates following treatment.

ABOUT CARTITUDE-4

CARTITUDE-4 (NCT04181827) is an ongoing, international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy, including a PI and an IMiD. The primary endpoint of the study was progression-free survival.3

ABOUT MULTIPLE MYELOMA

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.4 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.5 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.