Hyperargininemia

Pictured: A rare disease awareness ribbon with a diverse representation of people/iStock, nambitomo Arginase 1 deficiency, or ARG1-D, is a rare, inherited disorder occurring in approximately 1.1 in 1 million live U.S. births. While born with normal function, by the age of two, patients with the condition have progressive deterioration in their physical ability due to the gradual accumulation of arginine and ammonia in the blood. The nervous system is particularly sensitive to high levels of ammonia, Stephen Cederbaum, a UCLA professor emeritus who has studied ARG1-D for more than 50 years, told BioSpace. Untreated, children progressively deteriorate, experiencing spasticity and developmental delays. There is currently no disease-modifying treatment for ARG1-D. Stephen Cederbaum So it may have seemed like welcome news for ARG1-D patients and their families when an experimental drug, pegzilarginase, developed by Aeglea BioTherapeutics, was found to rapidly and sustainably lower arginine levels and elicit improvements in mobility. A novel, recombinant human arginase 1 enzyme, pegzilarginase led to a statistically significant 80% reduction in mean plasma arginine—a key biomarker—in the pivotal Phase III PEACE trial; 90.5% of patients treated with the enzyme achieved normal plasma arginine levels compared to none on placebo. Then, last June, the company received a Refusal to File letter from the FDA in response to its Biologics License Application for pegzilarginase. The FDA requested more data to support its efficacy—particularly evidence showing that plasma arginine and metabolite reduction could predict clinical benefit in patients with ARG1-D. Aeglea has since sold the rights to the drug to its European partner, Immedica Pharma, but a group of experts is appealing to the FDA to give it another shot. These experts, including Cederbaum, believe the FDA should leverage its accelerated approval pathway, which allows the regulator to exercise flexibility when a treatment proposed for a serious disease or condition demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. “What we’re appealing [for] is accelerated approval,” said Cederbaum, who served as a one-time consultant to Aeglea and has followed the drug’s saga closely. “Given what we now know, and what has been demonstrated for us . . . when we get some of these patients back on therapy, they’re going to be the living proof that [pegzilarginase] really does help.” Barriers to Approval The reason the PEACE trial failed to meet the FDA’s bar for approval, Cederbaum said, is that many of the patients were older and had been diagnosed symptomatically only after severe and irreversible brain damage had occurred. PEACE enrolled 32 patients two years and older. Cederbaum and his colleagues have collected video evidence showing that participants in Aeglea’s extension trials have deteriorated since going off of pegzilarginase. “In one case, a patient had not gotten particularly better, but when he got off the enzyme, he really just collapsed,” Cederbaum said. While the team feels they have substantial evidence to go back to the FDA, “what we’re now lacking is a supply of enzyme and a company to champion this.” Cederbaum said he believes the FDA’s skepticism regarding pegzilarginase comes down to the question: has it been proven that increased levels of arginine and ammonia are the cause of ARG1-D and that bringing these levels down to normal is absolutely certain to be beneficial? The answer to that question, he said, is no. But “There is a mechanism now for dealing with this uncertainty, and that is accelerated approval.” Emil Kakkis Emil Kakkis, founder, president and CEO of Ultragenyx, a company that develops medicines for patients with rare and ultrarare diseases but has no direct involvement with Aeglea or Immedica, told BioSpace he got involved with the campaign for the drug’s approval because “I felt like arginase, if anything, is a poster child for the failure to use accelerated approval correctly at FDA.” When asked by BioSpace if the FDA would consider showing flexibility in the case of pegzilarginase, an agency representative declined to comment on this case specifically but said that the FDA “recognizes the importance of facilitating the development of, and access to, safe and effective treatment options for life-threatening and severely debilitating diseases with unmet medical needs, such as arginase 1 deficiency. “As such, we apply flexibility in these situations to address the particular challenges posed by each disease while upholding our regulatory standards,” the representative said. While Kakkis said the FDA requested a trial longer than six months, he noted that getting 30 patients into a trial “was already a miracle.” With “a handful of patients” in the U.S. and at a cost of $300,000 to $500,000 per patient per year, it would be impossible to conduct another trial, he said. The only reason Aeglea was able to fund a pivotal trial with 30 patients is that when the company started in 2013, “the stock market was up in the biotech space, and they were able to raise money to work on a disease this rare.” Today, he said, that money doesn’t exist, and there is no way for a company to see a return on its investment. The other problem with a longer trial, Kakkis said, is “If within six months, you know that the treated group is 90% normalized, it’s kind of unethical to keep the other group on placebo for a long period of time.” Kakkis recommended that the FDA consider data from the open-label extension (OLE) study of Aeglea’s Phase I/II trial, where 13 patients were treated with pegzilarginase plus standard-of-care for 96 weeks. In an abstract of the study, published this year, the authors concluded that “clinically meaningful improvements in functional mobility” increased with continued pegzilarginase treatment. At the time of Aeglea’s BLA submission, 56-week data from this study was available. The BLA also included data from the ongoing OLE of the PEACE trial. A Fundamental Problem Kakkis is the author of Saving Ryan, which documents his race—along with Ryan’s father, Mark Dant—to gain approval for the first-ever treatment for mucopolysaccharidoses (MPS), a group of inherited lysosomal storage disorders. “From that experience . . . I fundamentally recognized that there is a problem at FDA with dealing with ultra-rare diseases: scientifically knowing what to do with them, interpreting data and just a sort of cynical attitude,” he said. The MPS treatment, Aldurazyme, was eventually developed by BioMarin and Genzyme and won FDA approval in 2003, “But honestly, it barely made it,” Kakkis said, due to what he called “obstruction of biomarker acceptance” by the regulator. In 2009, Kakkis founded the EveryLife Foundation to accelerate innovation for rare diseases, which launched a campaign called CureTheProcess. The campaign, Kakkis said, focused on increasing FDA expertise in reviewing rare disease drugs and encouraging the regulator to accept alternative study designs and biomarkers “when the science underpinning them is very strong.” The FDA representative said the agency “recognizes the unique challenges in rare disease product development and encourages drug developers to consider and discuss with FDA alternative study designs and biomarkers” for the development of these drugs. Pegzilarginase is currently under review by the European Medicines Agency, and when announcing the sale of the rights to pegzilarginase to Immedica, Aeglea president and CFO Jonathan Alspaugh said the Swedish company would “seek to continue the dialogue with the FDA to discuss a path forward for [the drug] in the United States.” Kakkis said the regulatory acceptance of biomarkers is critical in ultra-rare diseases. When dealing with a disease marker that represents the underlying disease, he said, “It’s not a random secondary measure. It’s actually the source of the disease.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and X @chicat08.

Acquisition of Spyre's assets and concurrent oversubscribed $210.0 million private investment positions the company to advance a potentially best-in-class inflammatory bowel disease (IBD) portfolio, including α4b7 and TL1A programs Sale of legacy pipeline candidate, pegzilarginase, further streamlines operations and increases focus on IBD strategy $236.7 million of cash and cash equivalents and restricted cash as of June 30, 2023 WALTHAM, Mass., Aug. 11, 2023 /PRNewswire/ -- Aeglea BioTherapeutics, Inc. ("Aeglea" or the "Company") (NASDAQ:AGLE), a biotechnology company advancing a pipeline of antibody therapeutics with the potential to transform the treatment of inflammatory bowel disease ("IBD"), today announced second quarter 2023 financial results and provided program and corporate updates. "With the acquisition of Spyre Therapeutics and concurrent financing, we are in a privileged position to create meaningful new medicines for patients with IBD and build an industry-leading development organization," said Cameron Turtle, DPhil, Chief Operating Officer of Aeglea. "Our pipeline of differentiated and potentially best-in-class IBD programs, including a4b7 and TL1A, combined with a strategy to investigate therapeutic combinations and precision medicine approaches, offers the possibility to transform the treatment of this chronic and debilitating disease." "In parallel, we have made significant progress streamlining the organization with the sale of pegzilarginase and pivoting our operations and strategy around the new IBD assets," said Jonathan Alspaugh, President and Chief Financial Officer of Aeglea. "We are working to rapidly advance our co-lead product candidates with an expectation of initiating clinical studies for both SPY001 and SPY002 in 2024." Recent Program and Corporate Updates Corporate Completed the asset acquisition (the "Acquisition") of Spyre Therapeutics, Inc. ("Spyre"), a privately held biotechnology company with a pipeline of antibody therapeutics possessing the potential to transform the treatment of IBD alongside its research partner, Paragon Therapeutics, Inc. ("Paragon") Raised $210.0 million in gross proceeds (before deducting approximately $12.7 million in placement fees and other offering expenses) through a sale of Series A non-voting convertible preferred stock (the "Series A Preferred Stock") in a private placement to a group of investors. IBD Portfolio With the Acquisition, Aeglea shifted its focus to the development of a potentially best-in-class IBD portfolio including: SPY001 – a highly potent and selective anti-α4β7 monoclonal antibody engineered with half-life extension technology and formulated for high concentration, convenient dosing. SPY001 is currently progressing through IND-enabling studies and is expected to enter first-in-human ("FIH") studies in the first half of 2024. Data from a healthy volunteer study are expected by the end of 2024. SPY002 – a highly potent and selective anti-TL1A monoclonal antibody engineered with half-life extension technology. TL1A has emerged as one of the most promising targets in IBD and broader immunology indications. We expect to begin FIH studies of the SPY002 program in the second half of 2024 with healthy volunteer data expected in the first half of 2025. Pegzilarginase Sold global rights to pegzilarginase in development for Arginase 1 Deficiency to Immedica Pharma AB ("Immedica") for $15.0 million upfront cash proceeds and up to $100.0 million of contingent milestone payments. The sale of pegzilarginase to Immedica supersedes the previous license agreement between the companies. Marketing Authorisation Application for pegzilarginase is under review by the European Medicines Agency. The milestone payments are contingent on formal reimbursement decisions by national authorities in key European markets and pegzilarginase approval by the FDA, among other events. Net proceeds of the sale are to be distributed to holders of contingent value rights ("CVR") pursuant to the terms of the CVR Agreement dated July 7, 2023 by and between the Company and a rights agent. Second Quarter 2023 Financial Results As of June 30, 2023, Aeglea had available cash and cash equivalents and restricted cash of $236.7 million, including the $210.0 million in gross proceeds from the private placement offering in June 2023. Aeglea recognized development fee and royalty revenues of $0.7 million in the second quarter of 2023, as a result of its license and supply agreement with Immedica for the commercial rights to pegzilarginase in Europe and several countries in the Middle East. The revenues recorded in the second quarter of 2023 are related to drug supply and royalties from an early access program in France. Aeglea recognized $0.6 million for the second quarter of 2022 in development fee revenues. Research and development expenses totaled $17.4 million for the second quarter of 2023 and $15.4 million for the second quarter of 2022. The increase was primarily related to restructuring costs net of savings and an increase in reimbursable costs under the Paragon Agreement (as described below). General and administrative expenses totaled $12.1 million for the second quarter of 2023 and $7.7 million for the second quarter of 2022. This increase was primarily due to restructuring costs, net of savings. Acquired in-process research and development expenses totaled $130.5 million for the second quarter of 2023 and no expenses for the second quarter of 2022. As the Spyre assets have no alternative use, the net assets acquired are expensed in the period acquired. Change in the fair value of forward contract liability expense was $58.2 million for the second quarter of 2023 and no expenses for the second quarter of 2022. The stock consideration provided in the Acquisition was not issued until July 7, 2023. Accordingly, the Company recognized a forward contract liability to represent the contractual obligation to issue stock as of June 30, 2023. The increase in expense represents the change in fair value between June 22, 2023 (the Acquisition date) and June 30, 2023 for the redeemable Series A Preferred Stock. Net loss totaled $217.1 million and $22.3 million for the second quarter of 2023 and 2022, respectively, which includes non-cash stock compensation expense of $1.9 million and $2.0 million for the second quarter of 2023 and 2022, respectively. About Aeglea BioTherapeutics In June 2023, Aeglea completed the asset acquisition of Spyre and shifted its disease focus to IBD. Aeglea is advancing a pipeline of antibody therapeutics with the potential to transform the treatment of IBD. The approaches combine novel antibody engineering, rational therapeutic combinations, and precision immunology approaches to maximize efficacy, safety, and convenience of treatments for IBD. For more information, please visit . Follow Aeglea BioTherapeutics on social media: @aegleabio and LinkedIn. About the Paragon Agreement In May 2023, Spyre entered into an antibody discovery option and license agreement with Paragon (the "Paragon Agreement"). As part of the Paragon Agreement, Paragon identifies, evaluates and develops antibodies directed against certain mutually agreed therapeutic targets of interest to the Company. The arrangement currently includes four selected targets: α4β7, TL1A, IL-23, and an undisclosed fourth target. Subsequent to the Acquisition, the Company has exercised its option for the α4β7 program and will be granted an exclusive license to develop, manufacture and commercialize the antibody and products directed to the target, and plans to exercise its option for the other programs upon development candidate selection. From time to time, the Company can choose to add additional targets to the arrangement by mutual agreement with Paragon. Safe Harbor / Forward Looking Statements This press release contains "forward-looking" statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "believe," "continue," "goal," "expect," "may," "intend," "potential," "will" and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what the Company expects. Examples of forward-looking statements include, among others, statements the Company makes regarding any future payouts under the CVR, its ability to achieve the expected benefits or opportunities and related timing with respect to the Acquisition or to monetize any of its legacy assets, its future results of operations and financial position, its business strategy, its potential growth opportunities, its preclinical and future clinical development activities, the efficacy and safety profile of its product candidates, the potential therapeutic benefits and economic value of its product candidates, and the timing and results of preclinical studies and clinical trials, and other statements that are not historical fact. Actual results may differ materially from those indicated by such forward-looking statements. Factors that could cause actual results to differ include, but are not limited to, risks that the Company may not obtain stockholder approval of the conversion rights of the Series A Preferred Stock, the Company may fail to achieve the expected benefits or opportunities and related timing with respect to the Acquisition or to monetize any of its legacy assets, the Company's existing cash resources may not be sufficient to fund its future planned operations, the impact of macroeconomic conditions, including inflation, increasing interest rates and volatile market conditions, current or potential bank failures, as well as global events, including the ongoing military conflict in Ukraine and geopolitical tensions in China on the Company's operations, and the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates. Additional risks and uncertainties regarding the Company's business can be found in the section titled "Risk Factors" in the Company's Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 filed with the United States Securities and Exchange Commission ("SEC"), and future filings and reports that the Company makes from time to time with the SEC. The information contained in this press release is as of the date of this release, and the Company undertakes no duty to update forward-looking statements contained in this press release except as required by applicable laws. SOURCE Aeglea BioTherapeutics, Inc.

The tides may be changing for Aeglea after some tough decisions earlier in the year. Aeglea BioTherapeutics may be turning a corner. The biotech has managed to sell off its rare metabolic disease asset—which the FDA denied approval for last year—to Immedica Pharma for $15 million cash and the potential to make up to $100 million in milestones. Swedish pharma Immedica has snapped up global rights to Aeglea’s pegzilarginase, an investigational recombinant human enzyme designed to treat Arginase 1 Deficiency (ARG1-D), a rare metabolic disease. Last year, the company received a refusal to file letter from the FDA after asking for approval of pegzilarginase. In the letter, the drug agency requested more efficacy data and further information about chemistry manufacturing and controls. Now, the Massachusetts-based biotech has managed to offload worldwide rights to Immedica for $15 million upfront and up to $100 million in milestone payments that are contingent on formal reimbursement decisions by national authorities in European markets and FDA approval, among other events. The sale overrides a previous licensing agreement between the two in which Immedica held licensing rights for the asset in European and Middle Eastern markets. Immedica will continue development efforts for pegzilarginase and hopes to gain European market approval, Aeglea Chief Financial Officer Jonathan Alspaugh said in a July 27 release. Immedica will also maintain discussions with the FDA about a path forward for pegzilarginase in the U.S., according to Alspaugh. It could mean that Aeglea’s streak of bad luck is turning around. The biotech seemed all but shuttered early this year after disappointing data from rare disease med pegtarviliase prompted a third round of layoffs in a one-year period. The company shed almost all remaining staff, leaving only 10 employees standing, and was exploring its strategic alternatives. It turns out one of those alternatives was taking a seat at the buyer’s table. In late June, the rare disease company said it was pivoting to immunology, acquiring Spyre Therapeutics in a stock swap deal. The deal gave Aeglea access to the Paragon Therapeutics spinout's long-acting antibodies aimed at immunology, including two parallel lead programs set to enter the clinic in 2024. Both assets are being developed to treat inflammatory bowel syndrome. Around the same time, Aeglea also drew in $210 million via a private placement, money that’s expected to extend the company’s cash runway into 2026.