Glycogen Storage Disease Type I

Delivery of Prime Editors with a proprietary, universal liver-targeted LNP was well tolerated, with no safety concerns or detectable off-target edits observed across multiple preclinical studies On track to initiate IND-enabling activities for Wilson’s Disease program in 4Q 2024, with IND and/or CTA filing expected in 1H 2026 CAMBRIDGE, Mass., Oct. 24, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today presented data from multiple studies showcasing the potential of its proprietary, universal lipid nanoparticle (LNP) platform to precisely deliver Prime Editors to correct disease-causing mutations in the liver. The in vivo proof-of-concept data shared at the European Society of Gene and Cell Therapy (ESGCT) 31st Annual Congress demonstrated successful correction of disease-causing mutations in Wilson’s Disease in both mouse and non-human primate (NHP) models. Additionally, the Company highlighted the ability of its universal liver-targeted LNP platform to deliver Prime Editors to correct the underlying mutational cause of Glycogen Storage Disease Type 1b (GSD1b) in humanized mice and NHPs, reinforcing the potential for its modular LNP to support future programs in rare and non-rare liver indications. “Our liver-targeted LNP platform represents a significant step forward in gene editing, providing a novel framework that can be used repeatedly to generate candidates that we believe can safely and precisely correct pathogenic mutations across a range of liver diseases,” said Jeremy Duffield, M.D., Ph.D., Chief Scientific Officer of Prime Medicine. “We believe the modularity of our LNP platform allows us to seamlessly introduce alternative guide RNAs that address different genetic targets, while the shared components of the LNP platform enable increased potency, as well as an improved safety profile and biodistribution compared to other commonly used LNPs in development. The preclinical data from our GSD1b program played a critical role in validating our universal LNP approach, and findings from this work laid the groundwork for our current efforts in Wilson’s Disease, where we believe we can efficiently advance our program into the clinic with the potential to deliver benefit to thousands of patients.” Dr. Duffield continued, “At ESGCT, we will present the first in vivo data from our Wilson’s Disease program. We are very encouraged by these interim results, which show that LNP delivery of our Prime Editors results in efficient editing, well above the threshold anticipated to be necessary to reverse disease manifestations. As we continue to optimize toward our final drug candidate, we expect to share updated data and initiate IND-enabling activities by year end. We remain confident in the potential for our universal LNP to deliver transformative treatments not only for Wilson’s Disease and GSD1b, but also for other rare and non-rare liver indications.” Prime Medicine’s universal LNP contains a GalNAc-targeting ligand (GalNAc-LNP), a validated mechanism for liver-specific delivery of gene editors. In preclinical studies, delivery of Prime Editors using a GalNAc-LNP has demonstrated increased potency and both an improved safety profile and biodistribution when benchmarked against other LNPs that have gone into the clinic. Preclinical studies in GSD1b animal models, including new data presented at ESGCT, demonstrated that delivery of GalNAc-LNP Prime Editors restored glycogen metabolism in a humanized mouse model and achieved up to 85% precise liver cell editing of the L348 mutation in NHPs at a dose that was well tolerated and durable up to 44 weeks, with an excellent safety profile, and no detectable off-target edits or unintended edits at the target site. The Company believes these findings validate Prime Medicine’s LNP platform and support its continued evaluation in other liver-related diseases, including Wilson’s Disease. Wilson’s Disease is a rare and severe disorder caused by excess copper accumulation in the liver and brain that can lead to liver failure and neurocognitive decline, and without liver transplant can be fatal. Research suggests that correcting a Wilson’s Disease mutation in 20-30% of hepatocytes could be potentially curative. To address Wilson’s Disease, Prime Medicine is advancing its GalNAc-LNP Prime Editor program that targets two prevalent mutations in the ATP7B gene – H1069Q and R778L – which combined account for up to 50% of Wilson’s Disease patients. In the data presented today, GalNAc-LNP delivery of Prime Editors targeting the H1069Q mutation in Wilson’s Disease demonstrated up to 80% precise correction of the H1069Q mutation and restoration of ATP7B mRNA to wild-type levels in a humanized mouse model, as well as precise editing of liver cells in NHPs, with up to 51% precise editing with a surrogate H1069Q Prime Editor. In preclinical studies completed to-date, Prime Medicine observed significant reductions in copper accumulation in the livers of humanized mice. In both mouse and NHP studies, no detectable off-target edits or unintended edits at the target site were observed. Prime Medicine is completing the final stages of lead optimization and expects to initiate IND-enabling activities of its Wilson’s Disease program by year-end, with an IND and/or CTA filing expected in the first half of 2026. Details of the presentations are as follows: Presentation Title: LNP delivered Prime Editors restore glycemic control in humanized rodent models of Glycogen Storage Disease Type 1b (GSD1b)Date & Time: October 24, 2024, 5:00 p.m. CEST Poster Title: Prime Editing advancements enable in vivo therapeutic correction of ATP7B p.H1069Q and p.R778L mutations in Wilson’s DiseaseDate & Time: October 24, 2024, 6:00 – 7:30 p.m. CEST About Wilson’s DiseaseWilson’s Disease is a devastating rare disease of the liver, with manifestations throughout the body, that is caused by copper accumulation. Most people are diagnosed between ages five and 35 years. With reported prevalence rates ranging between 1 in 10,000 and 1 in 30,000, Wilson’s Disease is believed to affect upwards of 35,000 to 100,000 patients in the United States and Europe. Normally, excessive copper is excreted through the liver in bile. For patients with Wilson’s Disease, copper is not eliminated correctly and accumulates to toxic levels. While the key site of pathology is the liver, and many patients present with liver disease, patients often show persistent neurological problems including involuntary movements, tremor, and gait disturbance, as well as kidney, hematological or psychiatric problems. Wilson’s Disease is caused by mutations, including H1069Q and R778L, in both genomic copies of the ATP7B gene, which encodes a copper transporter that removes excess copper. Prime Medicine is advancing a liver-directed Prime Editor program that aims to correct mutations in ATP7B to restore copper metabolism. About Prime MedicinePrime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications. Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: hematology, immunology and oncology, liver and lung. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com. © 2024 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the timing, progress, and results of its Wilson’s Disease program, including the timing of the release of updated data, IND-enabling activities, and the opening of an IND and/or CTA application; the potential for its modular universal LNP platform to precisely deliver Prime Editors, correct disease-causing mutations in the liver, and deliver transformative treatments for Wilson’s Disease, GSD1b, and other rare and non-rare liver indications; the modular universal LNP platform’s ability to be used repeatedly to generate candidates that offer an improved safety profile and biodistribution compared to other LNPs in development; the potential for the treatment of Wilson’s Disease with Prime Editors to result in efficient editing well above the threshold anticipated to be necessary to reverse disease manifestations; the safety profile, tolerability, and durability of its universal LNP; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials; the modularity of the Prime Editing platform and the benefits thereof; the potential for Prime Editors to more precisely and effectively achieve genetic modification; the potential for Prime Editors to repair genetic mutations and offer curative genetic therapies for a wide spectrum of diseases; the potential of Prime Editors to reproducibly correct disease-causing genetic mutations across different tissues, organs and cell types; its expectations regarding the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; and the potential of Prime Editing to unlock opportunities across thousands of potential indications. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the authorization, initiation, and conduct of preclinical and IND-enabling studies and other development requirements for potential product candidates, including uncertainties related to opening INDs and obtaining regulatory approvals; risks related to the development and optimization of new technologies, the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; and the effect of unfavorable macroeconomic conditions or market volatility resulting from general economic, industry and market conditions, including rising interest rates, inflation, and adverse developments affecting the financial services industry. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor ContactHannah DeresiewiczPrecision AQ212-362-1200hannah.deresiewicz@precisionaq.com Media ContactDan Budwick, 1ABdan@1ABmedia.com

-- On-track to initiate IND-enabling activities for Wilson’s Disease program in 4Q 2024, with IND or CTA filing expected in 1H 2026 -- CAMBRIDGE, Mass., Oct. 15, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today announced the Company will highlight advances from across its Prime Editing pipeline and platform at the upcoming European Society of Gene and Cell Therapy (ESGCT) 31st Annual Congress, being held October 22-25, 2024 in Rome, and the American Association for the Study of Liver Diseases (AASLD), being held November 15-19, 2024 in San Diego. “At the ESGCT and AASLD meetings, we will present new preclinical data from across our pipeline, including from our efforts in liver disease,” said Jeremy Duffield, M.D., Ph.D., Chief Scientific Officer of Prime Medicine. “We are particularly excited to share in vivo data from our Wilson’s Disease program, as well as from our universal liver-directed lipid nanoparticle (LNP) platform. Together, these data reinforce our strategy of prioritizing Wilson’s Disease – a large, genetically defined condition for which there are no currently approved disease-modifying treatments, and which we believe is uniquely suited to a Prime Editing-based approach – and reinforce the potential for our modular universal LNP to be used broadly across current and future programs. We look forward to advancing our Wilson’s Disease program into IND-enabling studies later this year and, longer term, to potentially leveraging the modularity of our platform to expand into numerous follow-on indications.” Details of the presentations are as follows: European Society of Gene and Cell Therapy 31st Annual Congress (ESGCT); October 22-25, 2024 in Rome Presentation Title: LNP delivered Prime Editors restore glycemic control in humanized rodent models of Glycogen Storage Disease Type 1b (GSD1b)Date & Time: October 24, 2024, 2:00 p.m. CEST Poster Title: Development of PM359, a Prime Edited CD34+ cell drug product for the treatment of p47phox Chronic Granulomatous DiseaseDate & Time: October 24, 2024, 2:00 – 2:30 p.m. CEST Poster Title: An all-Prime Editing one-step approach for non-viral generation of a multiplex-edited allogeneic CAR-T cell productDate & Time: October 24, 2024, 2:00 – 2:30 p.m. CEST Poster Title: Methods for genome-wide detection of single strand breaks induced by gene editors reveals the specificity of SpCas9 nuclease domains and provides comprehensive lists of potential off-targets for Prime EditorsDate & Time: October 24, 2024, 2:00 – 2:30 p.m. CEST Poster Title: Exploring the roles of DNA repair processes across diverse Prime Editing strategies with pooled screens and Knock-Knock PrimeDate & Time: October 24, 2024, 6:00 – 7:30 p.m. CEST Poster Title: Prime Editing advancements enable in vivo therapeutic correction of ATP7B p.H1069Q and p.R778L mutations in Wilson’s DiseaseDate & Time: October 24, 2024, 6:00 – 7:30 p.m. CEST Poster Title: Prime Editors precisely correct pathogenic mutations in RHO and USH2A associated Retinitis Pigmentosa and prevent retinal degenerationDate & Time: October 24, 2024, 6:00 – 7:30 p.m. CEST American Association for the Study of Liver Diseases (AASLD); November 15-19, 2024 in San Diego Presentation Title: LNP delivered Prime Editors restore glycemic control in humanized rodent models of Glycogen Storage Disease Type 1b (GSD1b)Date & Time: Sunday, November 17, 2024, 5:00 – 6:30 p.m. PT Presentation Title: Advances in Prime Editing enable in vivo therapeutic correction of the ATP7B p.H1069Q and p.R778L mutations causing Wilson’s DiseaseDate & Time: Monday, November 18, 2024, 8:00 – 9:30 a.m. PT About Prime Medicine Prime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications. Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: hematology, immunology and oncology, liver and lung. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com. © 2024 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the timing, progress, and results of its Wilson’s Disease program, including the timing of IND-enabling activities and opening an IND and/or CTA application; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials; the modularity of the Prime Editing platform and the benefits thereof; the potential for its modular universal LNP to be used broadly across current and future programs; the potential for Prime Editors to more precisely and effectively achieve genetic modification; the potential for Prime Editors to repair genetic mutations and offer curative genetic therapies for a wide spectrum of diseases; the potential of Prime Editors to reproducibly correct disease-causing genetic mutations across different tissues, organs and cell types; its expectations regarding the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; and the potential of Prime Editing to unlock opportunities across thousands of potential indications. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the authorization, initiation, and conduct of preclinical and IND-enabling studies and other development requirements for potential product candidates, including uncertainties related to opening INDs and obtaining regulatory approvals; risks related to the development and optimization of new technologies, the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; and the effect of unfavorable macroeconomic conditions or market volatility resulting from general economic, industry and market conditions, including rising interest rates, inflation, and adverse developments affecting the financial services industry. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor ContactHannah DeresiewiczPrecision AQ212-362-1200hannah.deresiewicz@precisionaq.com Media ContactDan Budwick, 1ABdan@1ABmedia.com

Second quarter total revenue of $147 million, Crysvita® revenue of $114 million and Dojolvi® revenue of $19 million Increased 2024 expected total revenue guidance to $530 million to $550 million NOVATO, Calif., Aug. 01, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel therapies for serious rare and ultrarare genetic diseases, today reported its financial results for the quarter ended June 30, 2024. “Our strong financial performance in the second quarter was driven by growing revenue across our commercial therapies from increasing global demand, leading us to raise our total revenue guidance for this year,” said Emil D. Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx. “In the quarter, we also reported positive data from our Phase 1/2 study in Angelman syndrome, our Phase 2/3 study in osteogenesis imperfecta, and our Phase 3 study in GSDIa. We are in an excellent position to achieve additional key milestones in the second half of the year including initiating our Phase 3 Angelman study and filing for accelerated approval for UX111 in Sanfilippo syndrome type A.” Second Quarter 2024 Selected Financial Data Tables and Financial Results Revenues (dollars in thousands), (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Crysvita Product sales$40,449 $16,884 $76,690 $38,118 Revenue in Profit-Share Territory 67,045 61,314 107,447 111,220 Royalty revenue in European Territory 6,176 4,816 12,118 9,698 Total Crysvita Revenue 113,670 83,014 196,255 159,036 Dojolvi 19,355 16,491 35,717 30,794 Mepsevii 6,145 8,439 12,756 16,919 Evkeeza 7,856 365 11,131 577 Daiichi Sankyo — — — 1,479 Total revenues$147,026 $108,309 $255,859 $208,805 Total RevenuesUltragenyx reported $147 million in total revenue for the second quarter of 2024, which represents 36% growth compared to the same period in 2023. Second quarter 2024 Crysvita revenue was $114 million, which represents 37% growth compared to the same period in 2023. This includes product sales of $40 million from Latin America and Turkey, which represents 140% growth compared to the same period in 2023. Dojolvi revenue in the second quarter 2024 was $19 million, which represents 17% growth compared to the same period in 2023. Evkeeza revenue in the second quarter 2024 was $8 million, as demand continues to build in the company’s territories outside of the United States. Selected Financial Data (dollars in thousands, except per share amounts), (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Total revenues$147,026 $108,309 $255,859 $208,805 Operating expenses: Cost of sales 21,280 9,914 38,813 22,171 Research and development 161,503 164,949 339,990 330,647 Selling, general and administrative 80,604 81,403 158,764 158,049 Total operating expenses 263,387 256,266 537,567 510,867 Net loss$(131,598) $(159,828) $(302,282) $(323,800)Net loss per share, basic and diluted$(1.52) $(2.25) $(3.54) $(4.58) Operating Expenses Total operating expenses for the second quarter of 2024 were $263 million, including non-cash stock-based compensation of $39 million. In 2024, annual operating expenses are expected to be stable or to decrease as the company continues to manage its costs and focus its investment on advancing multiple Phase 3 programs and executing on commercial product launches. Net Loss For the second quarter of 2024, Ultragenyx reported net loss of $132 million, or $1.52 per share basic and diluted, compared with a net loss for the second quarter of 2023 of $160 million, or $2.25 per share basic and diluted. Net Cash Used in Operations and Cash BalanceFor the three months ended June 30, 2024, net cash used in operations was $77 million and for the six months ended June 30, 2024 it was $268 million. Cash, cash equivalents, and marketable debt securities were $874 million as of June 30, 2024, which includes $381 million of net proceeds from issuance of common stock and pre-funded warrants in connection with an underwritten public offering in June 2024. 2024 Full Year Financial Guidance Total revenue guidance increased to be in the range of $530 million to $550 million (previously $500 million to $530 million)Crysvita revenue expected to be towards the upper end of the range of $375 million to $400 million. This includes all regions where Ultragenyx will recognize revenue: product sales in Latin America and Turkey, royalties in Europe, which have been ongoing, and royalties in North America, which began in April 2023.Dojolvi revenue in the range of $75 million to $80 millionNet Cash Used in Operations less than $400 million Recent Updates and Clinical Milestones UX143 (setrusumab) monoclonal antibody for Osteogenesis Imperfecta (OI): 14-month data resulted in a large, sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of 0.00 (p=0.0014)Positive 14-month results from the Phase 2 portion of the ongoing Phase 2/3 Orbit study demonstrated that, as of the May 24, 2024 data cut-off date, treatment with setrusumab continued to significantly reduce incidence of fractures in patients with OI. Treatment with setrusumab also resulted in ongoing and meaningful improvements in lumbar spine bone mineral density (BMD) at month 12 without evidence of plateau. The median annualized rate of radiologically confirmed fractures across all 24 patients in the 2 years prior to treatment was 0.72. Following a mean treatment duration period of 16 months, the median annualized fracture rate was reduced 67% to 0.00 (p=0.0014; n=24). The reduction in annualized fracture rates was associated with continued, clinically meaningful increases in BMD. Treatment with setrusumab at 12-month demonstrated a mean increase in lumbar spine BMD from baseline of 22% (p<0.0001, n=19) and an improvement of mean baseline lumbar spine BMD Z-score from -1.73 to -0.49 at 12 months. The improvements in BMD and Z-scores were significant and consistent across all OI sub-types studied. As of the data cut-off, there were no treatment-related serious adverse events observed in the study and there were no reported hypersensitivity reactions related to setrusumab. More detailed 14-month data will be presented at a future scientific meeting. GTX-102 antisense oligonucleotide for Angelman syndrome: Successful End-of-Phase 2 (EOP2) meeting with Food and Drug Administration (FDA); on track to initiate Phase 3 by the end of the yearIn July 2024, Ultragenyx completed a successful EOP2 meeting with the FDA supporting the pivotal Phase 3 Aspire study design, which will be a global, randomized, double-blind, sham-controlled trial and will include a 48-week primary efficacy analysis period enrolling approximately 120 patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The primary endpoint will be improvement in cognition assessed by Bayley-4 cognitive raw score. The key secondary endpoint will be the Multi-domain Responder Index (MDRI) across all five domains of cognition, receptive communication, behavior, gross motor function, and sleep. Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function and sleep. Additionally, the company plans to initiate Aurora, an open-label clinical study, to evaluate the safety and efficacy of GTX-102 for the treatment of patients with other Angelman syndrome genotypes and in other age groups. The company has also participated in a PRIME meeting with the European Medicines Agency, receiving acceptance of the overall Phase 3 study design, dosing and evaluations and has met with Japan’s Pharmaceuticals and Medical Devices Agency to inform and discuss its Phase 3 study design. The company expects the pivotal Phase 3 Aspire study to start by the end of 2024 and the Aurora study to start in 2025. UX701 AAV gene therapy for Wilson disease: Last patient in Cohort 3 dosed; expect interim Stage 1 data in the second half of 2024All patients in the three dose-escalation cohorts of Stage 1 have been dosed. During Stage 1, the safety and efficacy of UX701 will be evaluated and a dose will be selected for further evaluation in Stage 2, which is the pivotal, randomized, placebo-controlled stage of the study. Data from Stage 1 are expected in the second half of 2024, which will be followed by dose selection and initiation of Stage 2. UX111 AAV gene therapy for Sanfilippo syndrome type A (MPS IIIA): Agreement reached with FDA that cerebral spinal fluid (CSF) heparan sulfate (HS) can be used as a reasonable surrogate endpoint for accelerated approvalIn June 2024, Ultragenyx announced a successful meeting with the FDA during which the company reached agreement with the FDA that CSF HS is a reasonable surrogate endpoint that could support submission of a biologics license application, or BLA, seeking accelerated approval for UX111. As discussed with the FDA, the BLA filing will be based on the available data including from the ongoing pivotal Transpher A study evaluating the safety and efficacy of UX111 in children with MPS IIIA. The details of a BLA will be finalized with the FDA in a pre-BLA meeting that is expected to happen in the second half of 2024, with the intent to file the application late this year or early next year. DTX401 AAV gene therapy for Glycogen Storage Disease Type Ia (GSDIa): Positive top-line results from Phase 3 Study resulted in a statistically significant reduction in daily cornstarch intake at Week 48 (p<0.0001) with maintenance of glucose control In May 2024, Ultragenyx announced positive topline results from the Phase 3 GlucoGene study for the treatment of patients aged eight years and older. The study achieved its primary endpoint, demonstrating that treatment with DTX401 resulted in a statistically significant and clinically meaningful reduction in daily cornstarch intake compared with placebo at Week 48. The mean percent reduction was 41.3% in the DTX401 group (n=20) compared with 10.3% in the placebo group (n=24) at Week 48 (p<0.0001). Across patients treated with DTX401, the mean reduction in cornstarch continued to decline over the 48-week period. In the treatment group, all patients achieved a reduction in cornstarch, with 68% achieving ≥30% reduction and 37% achieving ≥50% reduction compared to the placebo group, which achieved the same reductions in 13% and 4% of patients, respectively, at Week 48. The study also successfully met key secondary endpoints of reduction in the number of cornstarch doses per day and maintenance of glucose control at Week 48. Full 48 Week data from the Phase 3 study will be presented at a scientific conference later this year. These results will be discussed with regulatory authorities to support a marketing application in 2025. DTX301 AAV gene therapy for Ornithine Transcarbamylase (OTC) Deficiency: Phase 3 study dosing patients; expect enrollment to be completed in the second half of 2024Ultragenyx is randomizing and dosing patients in the ongoing Phase 3 study. The pivotal, 64-week study will include approximately 50 patients, randomized 1:1 to DTX301 or placebo. The primary endpoints are response as measured by removal of ammonia-scavenger medications and protein-restricted diet and change in 24-hour ammonia levels. Enrollment is currently expected to be completed in the second half of 2024. Conference Call and Webcast Information Ultragenyx will host a conference call today, Thursday, August 1, 2024, at 2 p.m. PT/5 p.m. ET to discuss the second quarter 2024 financial results and provide a corporate update. The live and replayed webcast of the call will be available through the company’s website at https://ir.ultragenyx.com/events-presentations. The replay of the call will be available for one year. About Ultragenyx Ultragenyx is a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved medicines and treatment candidates aimed at addressing diseases with high unmet medical need and clear biology, for which there are typically no approved therapies treating the underlying disease. The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency. For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com. Forward-Looking Statements and Use of Digital Media Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, anticipated cost or expense reductions, the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, risks related to serious or undesirable side effects of our product candidates, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, our limited experience in generating revenue from product sales, risks related to product liability lawsuits, our dependence on Kyowa Kirin for the commercial supply of Crysvita, fluctuations in buying or distribution patterns from distributors and specialty pharmacies, the transition back to Kyowa Kirin of our exclusive rights to promote Crysvita in the United States and Canada and unexpected costs, delays, difficulties or adverse impact to revenue related to such transition, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 3, 2024, and its subsequent periodic reports filed with the SEC. In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/mycompany/). Contacts Ultragenyx Pharmaceutical Inc.InvestorsJoshua Higair@ultragenyx.com Ultragenyx Pharmaceutical Inc.Selected Statement of Operations Financial Data(in thousands, except share and per share amounts)(unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Statement of Operations Data: Revenues: Product sales$73,805 $42,179 $136,294 $86,408 Royalty revenue 73,221 46,331 119,565 51,213 Collaboration and license — 19,799 — 71,184 Total revenues 147,026 108,309 255,859 208,805 Operating expenses: Cost of sales 21,280 9,914 38,813 22,171 Research and development 161,503 164,949 339,990 330,647 Selling, general and administrative 80,604 81,403 158,764 158,049 Total operating expenses 263,387 256,266 537,567 510,867 Loss from operations (116,361) (147,957) (281,708) (302,062)Change in fair value of equity investments (3,991) 261 (245) (73)Non-cash interest expense on liabilities for sales of future royalties (15,960) (15,375) (31,807) (31,011)Other income, net 5,572 3,975 12,791 10,573 Loss before income taxes (130,740) (159,096) (300,969) (322,573)Provision for income taxes (858) (732) (1,313) (1,227)Net loss$(131,598) $(159,828) $(302,282) $(323,800)Net loss per share, basic and diluted$(1.52) $(2.25) $(3.54) $(4.58)Shares used in computing net loss per share, basic and diluted 86,580,516 70,897,991 85,433,443 70,639,015 Ultragenyx Pharmaceutical Inc.Selected Activity included in Operating Expenses(in thousands)(unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Non-cash stock-based compensation$39,363 $34,653 $76,297 $66,592 UX143 clinical milestone — $9,000 — $9,000 Ultragenyx Pharmaceutical Inc.Selected Balance Sheet Financial Data(in thousands)(unaudited) June 30, December 31, 2024 2023 Balance Sheet Data: Cash, cash equivalents, and marketable debt securities $874,490 $777,110 Working capital 691,774 451,747 Total assets 1,618,437 1,491,013 Total stockholders' equity 432,418 275,414