Hypercalciuria

AstraZeneca is splashing out $800 million upfront to bolster its rare disease pipeline with the purchase of Amolyt Pharma and its Phase III asset for chronic hypoparathyroidism.Marc Dunoyer, chief executive of AstraZeneca’s rare-disease unit Alexion, noted that patients with chronic hypoparathyroidism “face a significant need for an alternative to current supportive therapies,” with Amolyt’s eneboparatide holding “the potential to lessen the often debilitating impact of low parathyroid hormone and avoid the risks of high-dose calcium supplementation.”Eneboparatide – also known as AZP-3601 – is a PTH receptor 1 agonist that in Phase II studies has shown the ability to achieve normalisation of serum calcium levels, as well as the potential to eliminate dependence on daily calcium and vitamin D supplementation. AstraZeneca noted that in adults with chronic hypoparathyroidism and hypercalciuria, eneboparatide normalised calcium in urine, while it also preserved bone mineral density.According to Amolyt’s website, its pipeline also includes AZP-3813 for acromegaly - with initial Phase I results expected later this year - and the preclinical candidate AZP-40XX for primary hyperparathyroidism and humoral hypercalcemia of malignancy.Along with the upfront payment, Amolyt shareholders are eligible to receive an additional $250 million payable upon achievement of a specified regulatory milestone. The acquisition is expected to close by the end of the third quarter.

- Submitted New Drug Application (NDA) to US Food and Drug Administration (FDA) for acoramidis for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) based on positive results of Phase 3 ATTRibute-CM trial, which were published in the New England Journal of Medicine; NDA has been accepted for review with a PDUFA date of November 29, 2024; Marketing Authorization Application (MAA) for acoramidis has also been accepted by the European Medicines Agency (EMA) - Presented additional data from ATTRibute-CM at the American Heart Association Scientific Sessions, demonstrating separation at Month 3 of the placebo and acoramidis time-to-first-event Kaplan-Meier curves for a composite of all-cause mortality (ACM) and cardiovascular-related hospitalization (CVH); separation was sustained through Month 30 and represents the most rapid clinical benefit on the composite endpoint of ACM and CVH in ATTR-CM patients to the Company’s knowledge - Shared positive results of single-arm Phase 3 study of acoramidis in Japanese ATTR-CM patients, including no mortality reported over the 30 month acoramidis treatment period - PROPEL 3, the Company's Phase 3 study of infigratinib for achondroplasia continues to enroll with full enrollment expected in 2024; the Company has also announced a partnership granting Kyowa Kirin exclusive license on infigratinib for skeletal dysplasias in Japan in exchange for an upfront payment of $100 million, royalties up to the high twenties percent, and additional milestone-based payments - FORTIFY, the Company's Phase 3 study BBP-418 for limb-girdle muscular dystrophy type 2I (LMGD2I), continues to enroll, with full enrollment of interim analysis population expected in 2024 - CALIBRATE, the Company's Phase 3 study of encaleret for autosomal dominant hypocalcemia type 1 (ADH1) continues to enroll, with full enrollment expected in 2024 and topline data expected in 2025 - Secured up to $1.25 billion of capital from Blue Owl and CPP investments, including $500 million in cash in exchange for a 5% royalty on future global net sales of acoramidis and a $450 million credit facility from Blue Owl that refinanced existing senior secured credit, extending maturity from 2026 to 2029 subject to certain conditions - Ended the quarter with $393 million in cash, cash equivalents, and short-term restricted cash, and $59 million of investments in equity securities PALO ALTO, Calif., Feb. 22, 2024 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today reported its financial results for the fourth quarter and full year ended December 31, 2023, and provided an update on the Company’s operations. “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): 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.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; andAcoramidis was well-tolerated with no safety signals of potential clinical concern identified. 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.Additional detailed results of ATTRibute-CM are planned for presentation at 2024 medical meetings. Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia and hypochondroplasia: 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.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.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): 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): 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. 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.” 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. 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. 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 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. About BridgeBio Pharma, Inc.BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test, and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers. BridgeBio’s pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn and Twitter. BridgeBio Pharma, Inc. Forward-Looking Statements This press release contains forward-looking statements. Statements in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as “anticipates,” “believes,” “continues,” “estimates,” “expects,” “hopes,” “intends,” “may,” “plans,” “projects,” “remains,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act. These forward-looking statements, including statements relating to the clinical and therapeutic, market potential of our programs and product candidates, including the statements in Dr. Kumar’s and Dr. Stephenson's quotes regarding the potential commercial launch of acoramidis (if approved), continued advancement in our pipeline, including enrollments in clinical trials and anticipated readout, and other benefits resulting from recent financing; the statements related to the FDA's planned actions regarding our NDA for acoramidis for the treatment of ATTR-CM; the potential outcomes of regulatory reviews by the FDA and the EMA; the timing and success of our clinical development programs, including the progress of our clinical development program for acoramidis for patients with ATTR-CM, and our plan for, and the expected timing of, presenting additional detailed results of ATTRibute-CM study at medical meetings; the potential success of our partnership granting Kyowa Kirin an exclusive license on infigratinib for skeletal dysplasias in Japan and the potential payments we may receive under the license; the continuation of PROPEL 3, our Phase 3 study of infigratinib for achondroplasia and the expected timing for full enrollment in the study; our commitment to exploring the potential of infigratinib and the expectation and timing of the initiation of our clinical program for hypochondroplasia; the continuation and progress of FORTIFY, the Phase 3 trial of BBP-418 for LGMD2I, including the ongoing enrollment in the United States, the expectation to enroll in clinical trial sites planned in Europe and Australia, the expectation and timing of full enrollment of the interim analysis population, and the potential to pursue Accelerated Approval for BBP-418 based on recent interactions with the FDA; the continued enrollment in CALIBRATE, the Phase 3 clinical trial of encaleret, and the expectation and timing of full enrollment and sharing topline data from CALIBRATE; the Company’s financial performance, capitalization status, strategy, business plans and goals reflect our current views about our plans, intentions, expectations and strategies, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations and strategies as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, initial and ongoing data from our preclinical studies and clinical trials not being indicative of final data, the potential size of the target patient populations our product candidates are designed to treat not being as large as anticipated, the design and success of ongoing and planned clinical trials, future regulatory filings, approvals and/or sales, despite having ongoing and future interactions with the FDA or other regulatory agencies to discuss potential paths to registration for our product candidates, the FDA or such other regulatory agencies not agreeing with our regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted, the continuing success of our collaborations, the Company’s ability to obtain additional funding, including through less dilutive sources of capital than equity financings, potential volatility in our share price, uncertainty regarding any impacts due to global health emergencies such as COVID-19, including delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy, the impacts of current macroeconomic and geopolitical events, including changing conditions from hostilities in Ukraine and in Israel and the Gaza Strip, increasing rates of inflation and rising interest rates, on business operations and expectations, as well as those risks set forth in the Risk Factors section of our most recent Annual Report on Form 10-K and our other filings with the U.S. Securities and Exchange Commission. Moreover, we operate in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of our management as of the date of this press release, and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. BridgeBio Contact: Vikram Bali contact@bridgebio.com (650)-789-8220

- Presentations Highlight Potential Benefits of Therapies Incorporating J-Brain Cargo®, JCR’s Proprietary, Blood-Brain Barrier-Penetrating Technology - HYOGO, Japan--(BUSINESS WIRE)-- JCR Pharmaceuticals Co., Ltd. (TSE 4552; Chairman and President: Shin Ashida; “JCR”) today announced the presentation of several datasets demonstrating the potential benefits of its investigational therapies for lysosomal storage disorders (LSDs). In a series of oral and poster presentations at the 20th Annual WORLDSymposium™ in San Diego, Calif., JCR highlighted several programs that rely on J-Brain Cargo®, a proprietary technology developed by JCR, to deliver medicines across the blood-brain barrier (BBB). “Lysosomal storage disorders present a lifelong burden for patients because of the somatic, and most importantly, the progressive neurological signs and symptoms associated with these devastating and life-threatening diseases for which there are inadequate treatment options or no approved therapies available. JCR is dedicated to address the unmet medical needs for this community,” said Shin Ashida, President and CEO of JCR Pharmaceuticals. “The clinical data presented at the WORLDSymposium™ demonstrate the safety and efficacy of JR-141 in individuals with MPS II and the potential of our proprietary J-Brain Cargo® technology across multiple lysosomal storage disorders. In addition, we’re excited to present preclinical data focused on retinal function and bone abnormalities.” There are three JR-141 presentations, including one presentation focused on the long-term safety and efficacy and behavioral effects of JR-141 (pabinafusp alfa) for mucopolysaccharidosis type II (MPS II, or Hunter syndrome). JR-141 is a recombinant iduronate-2-sulfatase (I2S) enzyme replacement therapy (ERT) that was approved in March 2021 by the Ministry of Health, Labour and Welfare (MHLW) in Japan, where it is marketed as IZCARGO® for the treatment of patients with MPS II. The second JR-141 presentation details the global phase III clinical trial study. Finally, the third JR-141 presentation is pre-clinical and highlights the recovery of retinal function in mice with MPS II. “We are pleased to be able to offer IZCARGO® to patients with MPS II in Japan,” said Yoshikatsu Eto, M.D., Ph.D., Institute of Neurological Disorders, Advanced Clinical Research Center, Kanagawa, Japan. “As we continue gathering new data from the Japanese and Brazilian long-term efficacy study and from the ongoing phase III global JR-141 clinical study, currently in recruitment, we look forward to providing updates as appropriate. These data sets will make it more certain that JR-141 can treat not only the somatic symptoms of MPS II, but also the neurocognitive symptoms of this devastating and life-threatening disease.” In addition to the three JR-141 presentations, the WORLDSymposium™ 2024 scientific program featured presentations focusing on: 52-week interim data from the JR-171 phase I/II clinical trial (Hurler syndrome, Hurler-Scheie syndrome or Scheie syndrome); pre-clinical data on an ERT with JR-171 preventing bone deformities in a mouse model of MPS I; JR-441 global clinical trial study design (Sanfilippo syndrome type A). JR-141 MPS II Datasets The following poster presentation provides additional evidence and context for the use of JR-141 in the treatment of MPS II: Integrated long-term efficacy and safety data on enzyme replacement therapy with pabinafusp alfa for neuronopathic mucopolysaccharidosis II (MPS-II): updated clinical data from Japan and Brazil (Abstract 81) Presenter: Yoshikatsu Eto, M.D., Ph.D. (Institute of Neurological Disorders, Advanced Clinical Research Center, Kanagawa, Japan) This abstract analyzes the long-term efficacy and safety data on pabinafusp alfa for the treatment of individuals with MPS II. This study analyzed 104 patients over 260 weeks. In terms of safety, the data include four pabinafusp alfa-related serious adverse events (consciousness disturbance, hypotension, pyrexia and facial palour) in one individual, but all four were managed and resolved. Infusion-associated reactions were noted to gradually decrease in frequency as the length of exposure to pabinafusp alfa increased. The Kyoto Scale of Psychological Development, Bayley Scale for Infant Development, Kaufman Assessment Battery for Children, and Vineland Adaptive Behavioral Scale were used to evaluate the efficacy of pabinafusp alfa against neurocognitive impairment. A developmental quotient (DQ) of >70 was identified as the best predictor of treatment response in achieving age-equivalent neurodevelopment. Another predictor was age at initiation of treatment, with initiation before 36 months of age associated with the most favorable response in subjects with severe MPS II. Analysis of adaptive behavior showed a trend to overall improvement in most individuals with the attenuated subtype, and some improvement in those with the severe subtype and a DQ of >70, while changes, as expected, were limited in those with a DQ of <70. Notable sustained efficacy was seen in terms of liver and spleen volumes, joint range of motion, and left ventricular mass index. These outcomes of ERT with pabinafusp alfa for more than five years provide good evidence of its safety as well as peripheral efficacy, with preliminary data of central efficacy particularly in certain patients with attenuated form of the disease. Post-marketing studies will last for a total of 10 years and provide long-term evidence of pabinafusp alfa’s safety and efficacy. The following poster presentation provides an overview of the global phase III clinical trial study design for JR-141 in the treatment of MPS II: A global phase III study of pabinafusp alfa (JR-141) for neuronopathic mucopolysaccharidosis type II: updated study design (Abstract 154) Presenter: Toshiaki Ikeda (JCR Pharmaceuticals) This abstract provides an overview of the ongoing global phase III clinical trial of pabinafusp alfa (JR-141) for neuronopathic MPS II. The trial began in February 2022 and spans 10 countries as of now. The study consists of two cohorts with a total of 80 patients with MPS II. Cohort A includes individuals with the severe (neuronopathic) subtype aged 30 to 71 months, who are randomized into a treatment arm given a weekly administration of JR-141 at 2.0 mg/kg, and a control arm receiving ERT idursulfase; the total study duration is 24 months, and the purpose is to demonstrate that the efficacy of JR-141 in patients with neuronopathic MPS II is superior to that of conventional ERT. Cohort B consists of attenuated patients aged 6 years and older, randomized into two arms in the same manner as above; the study duration is 12 months, and the purpose is to evaluate the efficacy of JR-141 in patients with somatic symptoms in comparison with that of idursulfase. Primary efficacy endpoints are assessed on the basis of HS levels in the CSF and neurocognitive test (BSID-III) results. Key secondary outcome measures include liver and spleen volumes and further neurological outcomes. The study thus designed is expected to establish the efficacy of JR-141 against both the central nervous system (CNS) and peripheral/somatic symptoms. Details of other outcome measures and study design components will be presented at the symposium. The following poster presentation showcases preclinical data on retinal function for the use of JR-141 in the treatment of MPS II: Recovery of retinal function in MPS II mice by treatment with pabinafusp alfa (Abstract 155) Presenter: Atsushi Imakiire (JCR Pharmaceuticals) This abstract explains how pabinafusp alfa addresses one of the difficult-to-treat complications of MPS II: Retinal disorders in individuals with MPS II are known to be resistant to conventional intravenous ERT due to the presence of the blood-retinal barrier (BRB), which interferes with drug transport into the eye. The retinal function assessed by electroretinography (ERG) was found to worsen with age in a murine model of MPS II (hTfR knock-in/Ids knock-out mice). The presented study demonstrates that pabinafusp alfa crosses the BRB and reaches the retina in MPS II mice. Repeated intravenous dose of pabinafusp alfa started at an early age decreased HS deposition in the retina, optic nerve, and visual cortex and preserved or improved ERG response in MPS II mice. Retinal degeneration was also ameliorated by pabinafusp alfa. Recombinant non-fused I2S did not enter the retina and minimally affected the retinal disease. These results substantiate the postulate that pabinafusp alfa penetrates the BRB and exerts beneficial effects on retinal dysfunction in MPS II. JR-171 MPS I Datasets The following poster presentation focuses on the use of JR-171 in the treatment MPS I: Efficacy and safety data (52-week) from a phase 1/2 trial and extension study of JR-171 (lepunafusp alfa) used in enzyme replacement therapy for patients with MPS I (Abstract 113) Presenter: Roberto Giugliani, M.D., Ph.D. (Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil) This abstract reports the 52-week safety and efficacy data from the first-in-human, open-label, multicenter phase I/II trial and an extension study of JR-171 used to treat 14 individuals with MPS I. The 14 individuals had a broad spectrum of disease severity. 12 of them had received treatment with laronidase prior to enrollment, one was treated with laronidase after hematopoietic stem cell transplantation, and the other individual was treatment-naïve. The most common adverse drug reactions were infusion-associated reactions, all manageable without requiring discontinuation of the test drug. Ability to target the neuronopathy was evaluated by measuring HS levels in the CSF from baseline through weeks 13, 26, and 52, all of which were significantly reduced in all subjects. Also, in several individuals with the severe subtype whose treatment started early, neurocognitive data suggested some stabilization of neurodevelopmental decline in comparison with the natural history data. Liver and spleen volumes were stabilized in most of the patients. Other somatic signs and symptoms, including urine and serum HS/DS concentrations, were well-controlled in the subjects switched from laronidase, while they decreased significantly and then remained stable in the naïve patients. These data provide further evidence that JR-171 is delivered across the BBB to address the CNS manifestations of MPS I as well as the somatic/peripheral symptoms while maintaining an appropriate safety profile. A pivotal phase III clinical trial is planned to establish the efficacy and safety of the drug. The following poster presentation highlights preclinical data on bone deformities for the use of JR-171 in the treatment of MPS I: Enzyme replacement therapy with a blood-brain barrier-penetrating antibody-fused a-L-iduronidase prevents bone deformities in a mouse model of mucopolysaccharidosis I (Abstract 229) Presenter: Hiroki Morioka (JCR Pharmaceuticals) This abstract reports on the effect of JR-171 on the CNS and bone abnormalities in hTfR knock-in/Idua knock-out mice, an animal model of MPS I. JR-171 was intravenously administered to the mice once a week at 2.0 and 4.0 mg/kg for 24 weeks. The long-term intravenous treatment with JR-171 markedly reduced HS and DS concentrations and improved histopathological changes in the peripheral and CNS tissues. In addition, using micro-computed tomography, MPS I mice were found to have skeletal abnormalities such as increased bone mass and density. The treatment with JR-171 prevented or improved the skeletal abnormalities observed in MPS I mice. These results suggest the potential efficacy of JR-171 against neurodegeneration and neurological impairments, and demonstrate the beneficial effects on bone deformities characteristic of MPS I. The following late-breaking abstract discloses patient experiences upon treatment with JR-171: The impact of lepunafusp alfa (JR 171) on the disease burden in MPS I: Patient reported outcomes (Abstract LB-39) Presenter: Ana Maria Martins (Reference Center in Inborn Errors of Metabolism, Federal University of Sao Paulo, Brazil) This late-breaking abstract presents data on patient reported outcomes of individuals treated in an ongoing phase I/II study with lepunafusp alfa, a fusion protein consisting of a transferrin-receptor binding domain and α-L-iduronidase, the enzyme missing or malfunctioning in MPS I. JR-441 MPS IIIA Dataset The following poster presentation showcases the company’s pipeline of innovative, BBB-penetrating ERT products for the treatment of MPS IIIA: A phase I/II clinical trial of JR-441 for treatment of Sanfilippo syndrome type A (MPS IIIA) (Abstract 234): Presenter: Nicole Muschol, M.D. (University Medical Center Hamburg-Eppendorf, International Center for Lysosomal Disorders (ICLD), Hamburg, Germany) This abstract reports the Phase I/II clinical trial study design of JR-441 as a first-in-human, open-label, single-center trial to evaluate the optimal dose, safety/tolerability, pharmacokinetics and exploratory efficacy in individuals with MPS IIIA aged ≥1 year to ≤18 years. This study consists of a treatment period (52-week), a drug holiday period (6-week), and an extension period (202-week). After confirming the tolerability in the first 6 individuals with MPS IIIA in a dose escalating manner, a total of 12 individuals are then treated with JR-441 for approximately 5 years. During the drug holiday period, potential rebound effects due to withholding JR-441 are evaluated. Following dose escalation, all individuals are randomized to 2 treatment doses until an optimal dose is determined, which is applied thereafter to all of the enrolled subjects. A broad range of assessments are performed including substrate levels in the CSF, blood and urine, MRI of the brain, liver and spleen, neurodevelopmental function tests, adaptive behavior tests, quality-of-life questionnaires, and life-habit-related questionnaires regarding sleeping, eating and stool to identify and validate suitable endpoints to inform the design of a future global registrational trial. About Pabinafusp Alfa (JR-141) Pabinafusp alfa is a recombinant fusion protein of an antibody against the human transferrin receptor and idursulfase, the enzyme missing or malfunctioning in subjects with Hunter syndrome. It utilizes J-Brain Cargo®, JCR’s proprietary blood-brain barrier (BBB)-penetrating technology, to cross the BBB via transferrin receptor-mediated transcytosis. Uptake into cells is mediated through the mannose-6-phosphate receptor or the transferrin receptor. This novel mechanism of action is expected to make IZCARGO® effective against the CNS symptoms of Hunter syndrome. In pre-clinical studies, JCR has confirmed both high-affinity binding of pabinafusp alfa to transferrin receptors and passage across the BBB into neuronal cells. In addition, JCR has confirmed enzyme uptake in various brain tissues. The company has also confirmed a reduction of substrate accumulation in the CNS and peripheral organs in an animal model of Hunter syndrome.1,2 In several clinical trials with pabinafusp alfa, JCR obtained evidence of reducing heparan sulfate (HS) concentrations in the CSF, a biomarker that is believed to reflect substrate reduction in the brain and changes in CNS function. These results were consistent with those obtained in pre-clinical studies. Clinical studies have also demonstrated positive effects of pabinafusp alfa on CNS symptoms.3,4,5,6 Pabinafusp alfa was approved by the Ministry of Health, Labour and Welfare in Japan and marketed since May 2021 under the brand name “IZCARGO® I.V. Infusion 10mg.” In September 2021, JCR and Takeda announced a collaboration and license agreement to commercialize JR-141. Under the agreement, Takeda will exclusively commercialize JR-141 outside of the United States, including Canada, Europe, and other regions (excluding Japan and certain other Asia-Pacific countries). Takeda also received an option for an exclusive license to commercialize JR-141 in the U.S. upon completion of the phase III program. Important Safety Information INDICATION: IZCARGO® is indicated for the treatment of mucopolysaccharidosis type II (MPS II), which is also known as Hunter syndrome. IZCARGO® is approved in Japan only. CONTRAINDICATION: IZCARGO® is contraindicated in patients with a history of anaphylactic shock to any of its components. WARNINGS AND PRECAUTIONS: Warnings Since serious anaphylaxis and shock may occur with the use of IZCARGO®, adequate emergency measures should be made ready for application before initiation of administration, and the patient should be closely monitored during and after the administration. If a serious infusion associated reaction (IAR) occurs, administration of IZCARGO® should be discontinued, and appropriate actions should be taken. When IZCARGO® is administered to patients with severe respiratory failure or acute respiratory disease, an IAR may lead to acute exacerbation of symptoms. The patient’s condition should be closely monitored, and appropriate actions should be taken as needed. Precautions for Use IZCARGO® is a protein medicinal product and may cause anaphylactic shock, for which close monitoring is required. If any signs of anaphylaxis are noted, discontinue the infusion, and take appropriate actions. Considering the onset of such symptoms, emergency measures should be made ready for application. IZCARGO® may cause IARs such as headache, chills, syncope, fatigue, dizziness, pyrexia, rash, erythema, urticaria, or other symptoms. If an IAR occurs, reduce the rate or temporarily discontinue the infusion, and initiate appropriate drug treatment (e.g., corticosteroids, antihistamines, antipyretic analgesics, anti-inflammatory drugs) or emergency procedures (e.g., oxygen administration, securing of airway, adrenaline administration). Premedication with antihistamines, corticosteroids, etc. should be considered for the subsequent infusion of IZCARGO®. ADVERSE REACTIONS: The most commonly reported adverse reactions were pyrexia and urticaria. About the J-Brain Cargo® Platform Technology JCR Pharmaceuticals has developed a proprietary BBB-penetrating technology J-Brain Cargo®, to bring biotherapeutics into the CNS. The first drug developed based on this technology and approved in Japan for the treatment of MPS II (mucopolysaccharidosis type II) is IZGARGO® (INN: pabinafusp alfa). Based on the same platform technology, JR-171 (INN:lepunafusp alfa) and JR-441 are advancing into global clinical stage. JCR intends to start clinical trials on four additional programs from its LSD pipeline by FY2028. About Mucopolysaccharidosis II (Hunter Syndrome) Mucopolysaccharidosis II (Hunter syndrome) is an X-linked recessive LSD caused by a deficiency of iduronate-2-sulfatase, an enzyme that breaks down complex carbohydrates called glycosaminoglycans (GAGs, also known as mucopolysaccharides) in the body. Hunter syndrome, which affects an estimated 7,800 individuals worldwide (according to JCR research), gives rise to a wide range of somatic and neurological symptoms. The current standard of care for Hunter syndrome is ERT. CNS symptoms related MPS II have been unmet medical needs so far. About Mucopolysaccharidosis I (Hurler, Hurler-Scheie, Scheie syndrome) MPS I is an autosomal recessive lysosomal storage disorders (“LSD”) caused by a deficiency of α-L-iduronidase, an enzyme that breaks down glycosaminoglycans (mucopolysaccharides) in the body. The current worldwide prevalence of MPS I is estimated to be approximately 3,000 (according to JCR internal research). MPS I gives rise to a wide range of somatic and neurological symptoms. A major limitation of current ERT is that it does not address CNS symptoms because of the enzyme’s inability cross the BBB. MPS I is the only LSD in which hematopoietic stem cell transplantation (“HSCT”) is part of the standard of case for the severe form of the disease. Significant unmet medical need persists in all forms of MPS I. About Sanfilippo Syndrome (MPS III) Sanfilippo syndrome is an autosomal recessive disease caused by a deficiency of the enzymes that metabolize mucopolysaccharides within the body. The disease is classified into four subtypes (A, B, C, and D) according to the respective deficient enzymes. Symptoms include accumulation of heparan sulfate in tissues throughout the body. Notably, the rapidly progressive form of the disease frequently affects neurologic development, which peaks around two or three years of age, before subsequently deteriorating, resulting in a complete loss of speech by the age of seven or eight. Progression further gives rise to symptoms such as sleep disorders, hepatosplenomegaly, seizures, and neurobehavioral abnormalities. About JCR Pharmaceuticals Co., Ltd. JCR Pharmaceuticals Co., Ltd. (TSE 4552) is a global specialty pharmaceuticals company that is redefining expectations and expanding possibilities for people with rare and genetic diseases worldwide. We continue to build upon our 49-year legacy in Japan while expanding our global footprint into the US, Europe, and Latin America. We improve patients’ lives by applying our scientific expertise and unique technologies to research, develop, and deliver next-generation therapies. Our approved products in Japan include therapies for the treatment of growth disorder, Fabry disease, MPS II (Hunter syndrome), acute graft-versus host disease, and renal anemia. Our investigational products in development worldwide are aimed at treating rare diseases including MPS I (Hurler, Hurler-Scheie and Scheie syndrome), Hunter syndrome, Pompe disease, and more. JCR strives to expand the possibilities for patients while accelerating medical advancement at a global level. Our core values – reliability, confidence, and persistence – benefit all our stakeholders, including employees, partners, and patients. Together we soar. For more information, please visit . Cautionary Statement Regarding Forward-Looking Statements This document contains forward-looking statements that are subject to known and unknown risks and uncertainties, many of which are outside our control. Forward-looking statements often contain words such as “believe,” “estimate,” “anticipate,” “intend,” “plan,” “will,” “would,” “target” and similar references to future periods. All forward-looking statements regarding our plans, outlook, strategy and future business, financial performance and financial condition are based on judgments derived from the information available to us at this time. Factors or events that could cause our actual results to be materially different from those expressed in our forward-looking statements include, but are not limited to, a deterioration of economic conditions, a change in the legal or governmental system, a delay in launching a new product, impact on competitors’ pricing and product strategies, a decline in marketing capabilities relating to our products, manufacturing difficulties or delays, an infringement of our intellectual property rights, an adverse court decision in a significant lawsuit and regulatory actions. This document involves information on pharmaceutical products (including those under development). However, it is not intended for advertising or providing medical advice. Furthermore, it is intended to provide information on our company and businesses and not to solicit investment in securities we issue. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the factors that could cause actual results to differ materially, even if new information becomes available in the future. References 1: Sonoda, et al. A blood-brain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Mol. Ther. 2018; 26(5):1366-1374. 2: Morimoto, et al. Clearance of heparin sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Mol. Ther. 2021; 29(5): 1853-1861. 3: Okuyama, et al. Iduronate-2-sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial. Mol Ther. 2020; 27(2): 456-464. 4: Okuyama, et al. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol Ther. 2021; 29(2): 671-679. 5: Giugliani, et al. Iduronate-2-sulfatase fused with anti-human transferrin receptor antibody, pabinafusp alfa, for treatment of neuronopathic and non-neuronopathic mucopolysaccharidosis II: Report of a phase 2 trial in Brazil. Mol Ther. 2021; 29(7): 2378-2386. 6: Giugliani, et al. Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic　Mucopolysaccharidosis II; an Integrated Analysis of Preclinical and Clinical Data. Int. J. Mol. Sci. 2021, Volume 22, Issue 20, 10938.