FGF4

The viruses Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) have been linked to several cancers. For the first time, UNC School of Medicine scientists have discovered that these viruses use a human protein called barrier-to-autointegration factor 1, or BAF, to evade our innate immune response, allowing the viruses to spread and cause disease. These findings, published in Nature Communications, suggest that BAF and related proteins could be therapeutic targets to prevent these viruses from spreading and leading to cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, multicentric Castleman disease, nasopharyngeal carcinoma, and gastric cancer. "Viruses are in a constant battle with the cellular immune system, which includes the protein cyclic GMP-AMP synthase, or cGAS, which binds to viral DNA and sounds the alarm to trigger immune responses and fight the viral invaders," said senior author Blossom Damania, PhD, the Boshamer Distinguished Professor of Microbiology and Immunology and member of the Lineberger Comprehensive Cancer Center. "We've discovered that KSHV and EBV use a different host cell protein, BAF, to prevent cGAS from sounding the alarm." Viruses have evolved with humans for millions of years, so it's no surprise they've evolved tricks to evade our natural, or innate, immune responses. Finding out precisely how viruses do this is the basis for creating vaccines and therapeutics to overcome their tricks. In the case of KSHV and EBV, the expression of BAF is increased upon infection, suggesting that these viruses take advantage of this host protein to blunt the immune response to infection. In a series of experiments, Damanias lab found that BAF contributes to the degradation of the cGAS DNA sensor. With less cGAS protein available in the infected cell to detect DNA, the cells mount weaker immune responses, which allows these two viruses to replicate and spread more efficiently. "BAF enables EBV and KSHV to reactivate from latency, replicate, and make more of themselves," said first author Grant Broussard, a graduate student in the Genetics and Molecular Biology Curriculum at UNC Lineberger. "Our study highlights the prominent role that DNA detection pathways like the cGAS pathway play in controlling viral infection." He stressed that disrupting BAF activity with targeted therapies could reduce its immunosuppressive effects, thus restricting replication of these viruses to prevent the spread of disease. Damania, who is a Leukemia and Lymphoma Society Scholar and a Burroughs Wellcome Fund Investigator in Infectious Diseases, added, "Preventing lytic replication will prevent transmission of these viruses and also reduce the global cancer burden associated with these two viruses." Broussard, G., Ni, G., Zhang, Z. et al. Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency. Nat Commun 14, 434, 2023. doi: 10.1038/s41467-023-35898-2

First patient dosed in Phase 3 EFZO-FIT™ study in patients with pulmonary sarcoidosis; multiple centers in the U.S. are open for enrollment. Company to prioritize resources towards largest value driver efzofitimod program. Ended the third quarter 2022 with $79.6 million in cash, restricted cash, cash equivalents and investments. Company to host conference call and webcast today, November 10th, at 5:00 p.m. EST / 2:00 p.m. PST. SAN DIEGO, Nov. 10, 2022 (GLOBE NEWSWIRE) -- aTyr Pharma, Inc. (Nasdaq: LIFE), a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform, today announced third quarter 2022 results and provided a corporate update. “The third quarter saw the initiation of EFZO-FIT™, a global pivotal Phase 3 study of our lead therapeutic candidate, efzofitimod, in patients with pulmonary sarcoidosis, the most prevalent form of interstitial lung disease (ILD),” said Sanjay S. Shukla, M.D., M.S., President and Chief Executive Officer of aTyr. “Given current market conditions, we intend to focus our resources on the EFZO-FIT™ study, which is our largest value driver, to ensure a timely and successful completion of this study.” “As part of this prioritization, we have made the strategic decision not to use internal resources to initiate a Phase 1 study of ATYR2810 this year. The data we have generated for ATYR2810 firmly support its therapeutic potential in rare aggressive tumors, thus we intend to pursue alternative non-dilutive funding avenues, including academic collaborations, to advance this program.” Third Quarter 2022 and Subsequent Period Highlights Dosed the first patient in EFZO-FIT™, a global pivotal Phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of efzofitimod in patients with pulmonary sarcoidosis. This is a 52-week study consisting of three parallel cohorts randomized equally to either 3.0 mg/kg or 5.0 mg/kg of efzofitimod or placebo dosed intravenously once a month for a total of 12 doses. The study is currently enrolling and intends to enroll up to 264 subjects with pulmonary sarcoidosis at multiple centers in the U.S., Europe and Japan.Announced the publication of results of the Phase 1b/2a study of efzofitimod in patients with pulmonary sarcoidosis in the peer-reviewed medical journal CHEST. The study demonstrated that efzofitimod was safe and well-tolerated at all doses and exhibited a consistent dose response on key efficacy endpoints and improvements compared to placebo, including measures of steroid reduction, lung function, sarcoidosis symptom measures and inflammatory biomarkers.Received U.S. Food and Drug Administration (FDA) Fast Track designation for efzofitimod for the treatment of systemic sclerosis (SSc, or scleroderma)-associated ILD. Fast Track designation helps facilitate development and expedite the review of drugs to treat serious or life-threatening diseases with unmet medical need. Fast Track designation provides certain benefits, including enhanced interactions with the FDA throughout the development program, as well as eligibility for accelerated approval, priority review and rolling review.Presented a poster at the European Respiratory Society International Congress 2022 on findings for an antibody for immunohistochemical detection of neuropilin-2 (NRP2) protein, efzofitimod’s binding partner, in patient tissue samples. The antibody may provide a useful tool for patient selection or stratification for sarcoidosis, other ILD, oncology or other indications where NRP2 is implicated.Completed IND-enabling activities and received a notice of allowance for a patent for ATYR2810, a fully humanized monoclonal antibody targeting NRP2, in preclinical development for cancer.Announced a research collaboration with Dualsystems Biotech AG, a company specializing in custom proteomics, aimed at accelerating drug discovery and generating new therapeutics based on aTyr’s extensive intellectual property portfolio. Under the collaboration, which is exclusive with respect to tRNA related molecules, Dualsystems will utilize their proprietary receptor screening technology and research expertise to attempt to identify and validate 10 new target receptors for tRNA synthetases by 2025. aTyr previously worked with Dualsystems to identify fibroblast growth factor 4 (FGFR4) as the target receptor for a fragment of alanyl-tRNA synthetase (AARS). Third Quarter 2022 Financial Highlights and Cash Position Cash & Investment Position: Cash, restricted cash, cash equivalents and investments as of September 30, 2022, were $79.6 million.R&D Expenses: Research and development expenses were $9.9 million for the third quarter of 2022, which consisted of product development and manufacturing costs for the efzofitimod and ATYR2810 programs, as well as startup costs for the Phase 3 EFZO-FIT™ study.G&A Expenses: General and administrative expenses were $3.6 million for the third quarter of 2022.Shares Outstanding: Common shares outstanding were 29,009,382 as of September 30, 2022. Conference Call and Webcast DetailsaTyr will host a conference call and webcast today at 5:00 p.m. EST / 2:00 p.m. PST to discuss its financial results and provide a corporate update. Interested parties may access the call by registering here in order to obtain a dial in, personalized passcode and webcast information. Links to a live audio webcast and replay may be accessed on the aTyr website Events page at: http://investors.atyrpharma.com/events-and-webcasts. An audio replay will be available for at least 90 days following the event. About EfzofitimodaTyr is developing efzofitimod as a potential therapeutic for patients with fibrotic lung disease. Efzofitimod, a fusion protein comprised of the immunomodulatory domain of histidyl-tRNA synthetase fused to the FC region of a human antibody, is a selective modulator of neuropilin-2 that downregulates innate and adaptive immune response in inflammatory disease states. aTyr’s lead indication for efzofitimod is pulmonary sarcoidosis, a major form of interstitial lung disease. Clinical proof-of-concept for efzofitimod was recently established in a Phase 1b/2a multiple-ascending dose, placebo-controlled study of efzofitimod in patients with pulmonary sarcoidosis, which demonstrated safety and a consistent dose response and trends of benefit of efzofitimod compared to placebo on key efficacy endpoints, including steroid reduction, lung function, clinical symptoms and inflammatory biomarkers. aTyr is currently conducting EFZO-FIT™, a Phase 3 study of efzofitimod in pulmonary sarcoidosis event. About aTyraTyr is a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform. aTyr’s research and development efforts are concentrated on a newly discovered area of biology, the extracellular functionality and signaling pathways of tRNA synthetases. aTyr has built a global intellectual property estate directed to a potential pipeline of protein compositions derived from 20 tRNA synthetase genes and their extracellular targets. aTyr’s primary focus is efzofitimod, a clinical-stage product candidate which binds to the neuropilin-2 receptor and is designed to downregulate immune engagement in fibrotic lung disease. For more information, please visit www.atyrpharma.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are usually identified by the use of words such as “believes,” “expects,” “intends,” “may,” “plans,” “project,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by such safe harbor provisions for forward-looking statements and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements include statements regarding the expected number of patients to be enrolled in the EFZO-FIT™ study; the potential therapeutic benefits and applications of efzofitimod and our discovery programs; and timelines and plans with respect to certain development activities and development goals. These forward-looking statements also reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by these forward-looking statements, are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. Furthermore, actual results may differ materially from those described in these forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, the fact that NRP2 and tRNA synthetase biology is not fully understood, uncertainty regarding the COVID-19 pandemic, and geopolitical conflicts, including the risk of delays in our clinical trials, risks associated with the discovery, development and regulation of our product candidates, including the risk that results from clinical trials or other studies may not support further development, the risk that we may cease or delay preclinical or clinical development activities for any of our existing or future product candidates for a variety of reasons, the fact that our collaboration agreements are subject to early termination, and the risk that we may not be able to raise the additional funding required for our business and product development plans, as well as those risks set forth in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2022 filed with the SEC on November 10, 2022 and in our other SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. ATYR PHARMA INC. Condensed Consolidated Statements of Operations (in thousands, except share and per share data) Three Months Ended Nine Months Ended September 30, September 30, 2022 2021 2022 2021 (unaudited) Operating expenses: Research and development$9,867 $5,138 $27,898 $17,309 General and administrative 3,625 2,590 10,556 8,066 Total operating expenses 13,492 7,728 38,454 25,375 Loss from operations (13,492) (7,728) (38,454) (25,375)Total other income (expense), net 247 59 634 159 Consolidated net loss (13,245) (7,669) (37,820) (25,216)Net loss attributable to noncontrolling interest in Pangu BioPharma Limited 1 2 3 7 Net loss attributable to aTyr Pharma, Inc.$(13,244) $(7,667) $(37,817) $(25,209)Net loss per share, basic and diluted$(0.46) $(0.42) $(1.34) $(1.56)Shares used in computing net loss per share, basic and diluted 28,663,047 18,159,231 28,184,698 16,145,351 ATYR PHARMA INC. Condensed Consolidated Balance Sheets (in thousands) September 30, December 31, 2022 2021 (unaudited) Cash, cash equivalents, restricted cash and available-for-sale investments$79,613 $107,911 Other receivables 873 435 Property and equipment, net 1,275 543 Operating lease, right-of-use assets 6,971 1,267 Financing lease, right-of-use assets 768 — Prepaid expenses and other assets 6,555 5,381 Total assets$96,055 $115,537 Accounts payable, accrued expenses and other liabilities$10,398 $5,033 Current portion of operating lease liability 657 980 Current portion of financing lease liability 158 — Long-term operating lease liability, net of current portion 7,218 398 Long-term financing lease liability, net of current portion 618 — Total stockholders’ equity 77,006 109,126 Total liabilities and stockholders’ equity$96,055 $115,537 Contact:Ashlee DunstonDirector, Investor Relations and Corporate Communicationsadunston@atyrpharma.com

A new study confirms that idiopathic plasmacytic lymphadenopathy is an independent disease subtype of idiopathic multicentric Castleman disease. Idiopathic plasmacytic lymphadenopathy (IPL) is a clinical condition marked by an excessive amount of antibody production due to the proliferation of polyclonal plasma cells in the lymph nodes. At present, it is not clear if IPL is a subtype of idiopathic multicentric Castleman disease (iMCD)-not otherwise specified (NOS). In a new study, researchers from Okayama University have found clinicopathological evidence needed to establish a separate disease unit for IPL under iMCD-NOS. Multicentric Castleman disease (MCD) comprises a heterogenous group of rare disorders that exhibit generalized symptoms such as swelling of lymph nodes, anemia, fever, and fatigue. The causative factors underlying MCD include Kaposi sarcoma-associated herpesvirus (KSHV)/ human herpesvirus 8 (HHV8) infections. KSHV/HHV8-negative MCD without association with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes) syndrome are termed "idiopathic," i.e., diseases with no identifiable cause, and are thus referred to as "iMCD." At present, specific clinical manifestations or diagnostic criteria have not been identified for iMCD, which often results in treatment delay. iMCD is further classified as iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). With additional research efforts, iMCD-NOS, which is highly heterogenous, could be classified into various subtypes. Interestingly, a disease known as idiopathic plasmacytic lymphadenopathy (IPL), which is characterized by hypergammaglobulinemia, i.e., high levels of serum immunoglobulins, and histologically mature plasma cell proliferation in the lymph nodes, is considered a part of iMCD-NOS due to their clinicopathological similarity. However, till date, no study has validated if IPL has distinct clinicopathologic features compared to other iMCD-NOS. This motivated a team of researchers led by Assistant Professor Asami Nishikori, including Associate Professor Midori Filiz Nishimura, and Professor Yasuharu Sato from Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Japan to conduct a thorough clinicopathological examination of IPL and others in iMCD. Their findings were published on September 7, 2022, in the International Journal of Molecular Sciences. "We wanted to determine whether IPL has distinct and uniform clinicopathologic features compared to other subtypes (non-IPL) in iMCD-NOS," remarks Assist. Prof. Nishikori while discussing the motivation behind the study. The team analyzed lymph node specimens derived from 42 Japanese patients with lymph node involvement of iMCD-NOS, who met the consensus diagnostic criteria of iMCD and were negative for KSHV/HHV8 infections. Upon further examination, the team classified 34 of the 42 patients as the IPL group and the remaining 8 as the non-IPL group. On grading histological features such as vascularity, plasmacytosis (high proportion of plasma cells), atrophic and hyperplastic germinal centers (GCs), the team identified significant pathological differences between the specimens of the IPL and non-IPL groups. The IPL group demonstrated greater plasmacytosis and hyperplastic GCs compared to the non-IPL group. Conversely, the vascularity of the non-IPL group was higher than that of the IPL group. Clinically, the IPL group exhibited higher platelet count and serum antibody (immunoglobulin G) levels, with lesser fluid retention in pleural and/or abdominal cavity. The frequency of disease-specific autoantibody detection was also different between the groups. In addition, the clinical course and treatment responses in the two groups were also distinct. Upon treatment with tocilizumab, an anti-interleukin 6 receptor monoclonal antibody approved to treat iMCD in Japan, there was a significant improvement in the condition of patients with IPL. In contrast, patients with non-IPL responded poorly to the drug and showed progressed disease activity, requiring more intensive treatment. These findings were consistent with those of previous studies that suggest that the clinical course of IPL disease progression is slower as compared to the non-IPL group, and with a superior response to anti-IL-6 agents. Discussing these findings, Assist. Prof. Nishikori states "Given the heterogeneity of non-IPL cases, we must try to identify its primary cause. Molecular analysis could lead to a better understanding of disease pathology and the development of subsequent targeted therapies." To sum up, these findings have established IPL as a clinicopathologically uniform disease, which can be reclassified into an independent subtype of iMCD. So, what are the future implications of these findings? "It is critical that patients get the most out of any treatment modules. Studies on iMCD subtype-specific diagnostic biomarkers, treatment, and follow-up are thus warranted in the future to improve the clinical outcomes for these patients," concludes Assist. Prof. Nishikori.