VPS4A

Researchers have shown that lysosomes, key organelles for maintaining cellular stability, can be repaired once damaged by a process termed microautophagy. They identified molecules called STK38 and GABARAPs as key regulators of this process. Depletion of microautophagy regulators lead to increased cellular senescence and a shorter lifespan, indicating the importance of this process. This study is highly significant for the achievement of healthy aging and points toward new therapies for age-related diseases. To age or not to age! How does aging affect organisms on a cellular level? What mechanisms help cells survive self-inflicted or external harm? It is known that lysosomes -- critically important cellular structures -- are crucial for digesting damaged cellular components and pathogens, and maintain stability within cells and tissues. But can they also be repaired, and if so, how? In a study published this month in EMBO Reports, researchers from Osaka University and Nara Medical University have shown that damaged lysosomes are repaired by a mechanism called "microautophagy" and have identified two key regulators of this process. Microautophagy is one of the three main types of autophagy in most higher organisms. It is a regulated process by which cellular components that have become dysfunctional or are no longer required are broken down. Although it is assumed to be involved in defense mechanisms collectively called lysosomal damage responses, the details remain unknown. Lysosomes frequently become damaged and lysosomal dysfunction has been linked to accelerated aging and a shortened lifespan. In this study, the researchers tried to understand the repair mechanisms. To identify a novel regulator of lysosomal damage response, they focused a signaling pathway called Hippo pathway which controls multiple processes such as cellular growth. They knocked down individual components of the Hippo pathway in the human cells, and then observed whether the cells could respond to induced lysosomal damage. This screening revealed that a protein called Serine-threonine kinase 38 (STK38) is essential for the lysosomal damage response. They then found that STK38 works with a protein complex called the "endosomal sorting complex required for transport (ESCRT) machinery," which was already known to be linked to lysosomal repair. "STK38 recruits the protein 'vacuolar protein sorting 4' (VPS4) to damaged lysosomes and is crucial for disassembling the ESCRT machinery at the end of the repair process," explains lead author of the study Monami Ogura. They further found that lysosomal membrane repair by ESCRT machinery is mediated by microautophagy. They also identified that non-canonical lipidation of a subfamily of autophagy-related protein 8 (ATG8s) molecules -- the key autophagy proteins -- known as Gamma-aminobutyric acid receptor-associated proteins (GABARAPs) is required for this process. Lipidation, the process of modifying ATG8s with lipid extensions, is the main process involved in autophagy. In non-canonical lipidation ATG8s are lipidated into single-membrane endolysosomes, instead of double-membrane phagophore seen in canonical lipidation. The researchers showed that the GABARAPs are essential for the first step of the process of lysosomal repair. "We showed that non-canonical lipidation of ATG8s is crucial for the initial recruitment of the ESCRT machinery to damaged lysosomes and their subsequent repair," explains senior author Shuhei Nakamura. The team showed that depletion of the regulators of microautophagy increased the rate of senescent cells and shortened lifespan in C. elegans. Both STK38 and GABARAPs also have evolutionarily conserved roles, indicating the significance of this pathway in maintaining lysosomal integrity, healthy cellular function, and the prevention of cellular senescence and organismal aging. The detailed understanding provided by this study paves the way for increasing healthy aging and has great therapeutic value for the treatment of age-related diseases.

-- Conference Call and Webcast Scheduled for 5:00 p.m. ET on Monday, November 14, 2022 --SOUTH SAN FRANCISCO, Calif., Nov. 14, 2022 (GLOBE NEWSWIRE) -- Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision-oncology biopharmaceutical company, today announced its financial results for the third quarter ended September 30, 2022. “Earlier in the fourth quarter, we were very pleased to announce that we received FDA Fast Track designation for sapanisertib. This designation facilitates more frequent communication with the Agency, as well as a number of other benefits that could support our efforts to bring sapanisertib to patients in this area of high unmet need more quickly,” said Susan Molineaux, PhD, president and chief executive officer of Calithera. “Today we also share that we have experienced site activation delays on both our sapanisertib and mivavotinib trials, leading to slower than anticipated enrollment for both these programs. We expect initial data from these studies will not be available until mid-2023.” Third Quarter 2022 and Other Recent Highlights Received FDA Fast Track designation for sapanisertib (dual mTORC 1/2 inhibitor). In October, Calithera announced that sapanisertib has been granted Fast Track designation by the FDA for the treatment of adult patients with unresectable or metastatic squamous non-small cell lung cancer (sqNSCLC) whose tumors harbor the NRF2 mutation. Fast Track designation, which is designed to facilitate the development and expedite the review of therapeutic candidates with the potential to treat a serious or life-threatening condition where there is a major unmet medical need, provides a number of potential benefits including increased communication with the FDA, the ability to submit a marketing application on a rolling basis and the possibility of priority review. Began enrolling patients in Phase 2 trial evaluating sapanisertib in sqNSCLC. In July 2022, the Company began enrolling patients in its phase 2 clinical trial (NCT05275673) of the dual mTORC 1/2 inhibitor sapanisertib (CB-228) in patients with relapsed/refractory NRF2 (NFE2L2)-mutated sqNSCLC. The study is designed to confirm the selective activity of sapanisertib in NRF2-mutated tumors compared to wild-type tumors, and to refine dose in this biomarker-defined population. The primary endpoints of the study are investigator-assessed overall response rate (ORR) per RECIST v1.1, and safety. Calithera presented a trial-in-progress poster detailing the study design at the North American Conference on Lung Cancer in September 2022. Continued patient enrollment activities in Phase 2 trial evaluating mivavotinib (SYK inhibitor) in r/r non-GCB DLBCL. In June 2022, the Company began enrolling patients in its multicenter Phase 2 clinical trial (NCT05319028) evaluating mivavotinib (CB-659) in patients with relapsed/refractory non-germinal center B-cell like (non-GCB) diffuse large B-cell lymphoma (DLBCL). The main objectives of the study are to confirm previously observed single-agent activity in non-GCB DLBCL patients, evaluate activity according to MYD88/CD79b mutation status and refine dose/schedule in this patient population. The primary endpoints of the study are overall response rate (as assessed by an independent radiology review committee) and safety. Details of the Phase 2 study design were presented in a trial-in-progress poster at the Pan Pacific Lymphoma Conference in July. Continued to advance VPS4 program through lead optimization. Calithera continued to advance multiple vacuolar protein sorting-associated protein 4A (VPS4A) and VPS4B inhibitors through lead optimization and plans to share updates on this program by the end of 2022. Selected Third Quarter 2022 Financial Results Cash and cash equivalents totaled $34.1 million at September 30, 2022. Based on its current operating plan, the Company expects it has sufficient cash to fund its operations into the second quarter of 2023. The Company is currently evaluating all options for its programs, including strategic collaboration or licensing agreements and actively considering the sale of certain programs, in order to extend its cash runway. Research and development expenses for the third quarter 2022 were $6.5 million, compared to $11.6 million in the same period prior year. The decrease of $5.1 million was primarily due to decreases in the telaglenastat and CB-280 programs and investments in early stage research, partially offset by increases in the sapanisertib and mivavotinib programs. General and administrative expenses for the third quarter 2022 were $3.0 million, compared to $6.3 million in the same period prior year. The decrease of $3.3 million was primarily due to decreased personnel-related costs and legal expenses. Net loss was $9.8 million for the three months ended September 30, 2022. Conference Call Information Calithera will host an update conference call today, Monday, November 14, at 2:00 p.m. Pacific Time/5:00 p.m. Eastern Time. To register for dial-in access to the call, please use this link. To access the live audio webcast or the subsequent archived recording, visit the Investors section of the Calithera website at www.calithera.com. The webcast will be recorded and available for replay on Calithera’s website for 30 days. About Calithera Calithera Biosciences is a clinical-stage, precision oncology biopharmaceutical company developing targeted therapies to redefine treatment for biomarker-specific patient populations. Driven by a commitment to rigorous science and a passion for improving the lives of people impacted by cancer, Calithera is advancing a robust pipeline of investigational, small-molecule oncology compounds with a biomarker-driven approach that targets genetic vulnerabilities in cancer cells to deliver new therapies for patients suffering from aggressive hematologic and solid tumor cancers for which there are currently limited treatment options. Calithera is headquartered in South San Francisco, California. For more information about Calithera, please visit www.calithera.com. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "anticipate," "estimate," "intend," "poised" and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These statements include those related to the safety, tolerability and efficacy of Calithera’s product candidates, the overall advancement of Calithera’s product candidates in preclinical development and clinical trials, including the availability of initial data for the mivavotinib and sapanisertib trials by mid-2023, Calithera’s ability to potentially initiate registrational studies in biomarker-specific populations in DLBC and relapsed or refractory squamous NSCLC, the expectation that VPS4 inhibitors will be well-tolerated and have strong single-agent activity in tumors with certain mutations, Calithera’s plan to advance multiple VPS4 series through lead optimization and plan to share updates on this program by the end of the year, the unmet need in the treatment of patients with advanced disease, Calithera’s expectation that cash and cash equivalents will be sufficient to meet its current operating plan into the second quarter of 2023 and whether Calithera will be able to enter into strategic collaborations or licensing agreements or sell certain programs and sufficiently extend its cash runway. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. The potential product candidates that Calithera develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all. In addition, clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release. Such product candidates may not be beneficial to patients or be successfully commercialized. The failure to meet expectations with respect to any of the foregoing matters may have a negative effect on Calithera's stock price. Additional information concerning these and other risk factors affecting Calithera's business can be found in Calithera's periodic filings with the Securities and Exchange Commission at www.sec.gov. These forward-looking statements are not guarantees of future performance and speak only as of the date hereof, and, except as required by law, Calithera disclaims any obligation to update these forward-looking statements to reflect future events or circumstances. Calithera Biosciences, Inc. Selected Consolidated Statements of Operations Financial Data(in thousands) (unaudited) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2022 2021 2022 2021Revenue: License revenue $— $6,750 $— $9,750 Total revenue — 6,750 — 9,750 Operating expenses: Research and development 6,447 11,556 23,771 39,715 General and administrative 3,079 6,344 10,957 16,259 Total operating expenses 9,526 17,900 34,728 55,974 Loss from operations (9,526) (11,150) (34,728) (46,224)Other income (expense): Transaction costs allocable to warrant liabilities — — (475) — Change in fair value of warrants liabilities (453) — 2,253 — Interest and other income (expense), net 177 (22) 236 346 Other income (expense), net (276) (22) 2,014 346 Net loss $(9,802) $(11,172) $(32,714) $(45,878) Calithera Biosciences, Inc. Selected Consolidated Balance Sheet Financial Data (in thousands) (unaudited) September 30, December 31, 2022 2021Balance Sheet Data: Cash and cash equivalents$34,068 $59,537 Working capital 25,465 47,446 Total assets 37,083 64,756 Total liabilities 10,695 15,672 Convertible preferred stock 22,342 40,702 Accumulated deficit (505,680) (491,326)Total stockholders’ equity 26,388 8,382 CONTACTS:Stephanie Wong ir@Calithera.com 650.870.1063 INVESTORS:Burns McClellanLee Roth212.213.0006lroth@burnsmc.com MEDIA:Sam Brown, Inc.Hannah Hurdle805.338.4752hannahhurdle@sambrown.com

-- Conference Call and Webcast Scheduled for 5:00 p.m. ET on Monday, August 15, 2022 --SOUTH SAN FRANCISCO, Calif., Aug. 15, 2022 (GLOBE NEWSWIRE) -- Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision-oncology biopharmaceutical company, today announced its financial results for the second quarter ended June 30, 2022. “We continue to deliver on our commitment to efficiently advance our clinical programs, successfully initiating two new clinical trials and sharing program updates at two important medical conferences,” said Susan Molineaux, PhD, president and chief executive officer of Calithera. “We look forward to sharing data from the ongoing mivavotinib and sapanisertib phase 2 trials by the first quarter of 2023, as well as providing an update on the progress of our preclinical synthetic lethality VPS4 program by the end of 2022.” Second Quarter 2022 and Other Recent Highlights Initiated patient enrollment in phase 2 trial evaluating mivavotinib (SYK inhibitor) in r/r non-GCB DLBCL. In June, Calithera announced enrollment of the first patient in a multicenter phase 2 clinical trial (NCT05319028) evaluating the spleen tyrosine kinase (SYK) inhibitor mivavotinib (CB-659) in patients with relapsed/refractory non-germinal center B-cell like (non-GCB) diffuse large B-cell lymphoma (DLBCL), a DLBCL subpopulation that primarily comprises patients with activated B-cell like disease (ABC). The main study objectives are to confirm previously seen single-agent activity in non-GCB DLBCL patients, evaluate activity according to MYD88/CD79b mutational status, and refine dose/schedule in this patient population. The primary endpoints of the study are overall response rate as assessed by an independent radiology review committee and safety. Mivavotinib has the potential to be the first treatment specifically for non-GCB DLBCL, a population of patients with a historically poorer prognosis and therefore high unmet need, and potential to be the first treatment for a genetically-defined subset of ABC in patients with MyD88/CD79 mutations. Approximately 50% of all ABC DLBCL tumors have one or both of these mutations. Data from the ongoing phase 2 trial could position Calithera to initiate a study with registrational intent in biomarker-specific DLBCL populations. Calithera plans to share data from this trial by the first quarter of 2023.In July, Calithera presented a trial-in-progress poster at the Pan Pacific Lymphoma Conference detailing the design of this phase 2 study. Initiated patient enrollment in phase 2 trial sapanisertib (dual mTORC 1/2 inhibitor) in sqNSCLC. In July, Calithera announced enrollment of the first patient in a phase 2 clinical trial (NCT05275673) of the dual mTORC 1/2 inhibitor sapanisertib (CB-228) in patients with relapsed/refractory NRF2 (NFE2L2)-mutated squamous non-small cell lung cancer (sqNSCLC). The study is designed to confirm the selective activity of sapanisertib in NRF2-mutated tumors compared to wild-type tumors, and to refine dose in this biomarker-defined population. The primary endpoints of the study are investigator-assessed overall response rate (ORR) per RECIST v1.1, and safety. Data from this study could position Calithera to initiate a study with registrational intent in biomarker-specific sqNSCLC populations. Calithera plans to share data from this trial by the first quarter of 2023.Announced presentation of phase 1/2 data from sapanisertib/telaglenastat combination study. In a mini oral session at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC), Jonathan W. Riess, MD, MS, director of Thoracic Oncology and associate professor at UC Davis Comprehensive Cancer Center, presented dose-escalation findings from a multi-center phase 1/2 investigator-initiated study evaluating sapanisertib in combination with telaglenastat, an investigational glutaminase inhibitor, in biomarker-defined cohorts of patients with advanced non-small cell lung cancer (NSCLC). After evaluating five combination dosing levels in 13 patients, researchers determined that the sapanisertib/telaglenastat combination has a favorable tolerability profile at the recommended expansion dose. Early evidence of clinical benefit was observed in the dose-escalation cohort, including a partial response in a patient with NRF2-mutant squamous NSCLC and stable disease in a patient with KEAP1/NRF2-mutant adenosquamous NSCLC. As a next step, study investigators plan to enroll patients into one of four expansion cohorts evaluating sapanisertib plus telaglenastat in squamous NSCLC with and without NRF2 or KEAP1 mutations, and adenocarcinoma NSCLC with KRAS and KEAP1 or NRF2 mutations.Continued to advance VPS4 program through lead optimization. Calithera previously announced internal discovery of a novel series of small-molecule inhibitors of vacuolar protein sorting-associated protein 4A (VPS4A) and VPS4B, as well as the presentation of data validating the synthetic-lethal interaction between the gene paralogs at the American Association for Cancer Research (AACR) 2022 Annual Meeting. Calithera believes these VPS4 inhibitors are the first active, on-target inhibitors of VPS4. Potent, selective, and pharmacologically active VPS4 inhibitors are expected to be well-tolerated and have strong single-agent activity in tumors with these mutations. Calithera continues to advance multiple VPS4 series through lead optimization and plans to share updates on this program by the end of the year. Selected Second Quarter 2022 Financial Results Cash and cash equivalents totaled $41.8 million at June 30, 2022. Research and development expenses for the second quarter 2022 were $7.8 million, compared to $12.8 million in the same period prior year. The decrease of $5.0 million was primarily due to decreases in the telaglenastat and CB-280 programs, partially offset by increases in the sapanisertib and mivavotinub programs. General and administrative expenses for the second quarter 2022 were $3.6 million, compared to $4.5 million in the same period prior year. The decrease of $0.9 million was primarily due to decreased personnel-related costs. Other income, net for the second quarter 2022 was $2.3 million, compared to other expense of $4,000 in the same period prior year, primarily attributable to the decrease in fair value of warrant liabilities. Net loss was $9.1 million for the three months ended June 30, 2022. Conference Call Information Calithera will host an update conference call today, Monday, August 15, at 2:00 p.m. Pacific Time/5:00 p.m. Eastern Time. To register for dial-in access to the call, please use this link. To access the live audio webcast or the subsequent archived recording, visit the Investors section of the Calithera website at www.calithera.com. The webcast will be recorded and available for replay on Calithera’s website for 30 days. About Calithera Calithera Biosciences is a clinical-stage, precision oncology biopharmaceutical company developing targeted therapies to redefine treatment for biomarker-specific patient populations. Driven by a commitment to rigorous science and a passion for improving the lives of people impacted by cancer, Calithera is advancing a robust pipeline of investigational, small-molecule oncology compounds with a biomarker-driven approach that targets genetic vulnerabilities in cancer cells to deliver new therapies for patients suffering from aggressive hematologic and solid tumor cancers for which there are currently limited treatment options. Calithera is headquartered in South San Francisco, California. For more information about Calithera, please visit www.calithera.com. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "anticipate," "estimate," "intend," "poised" and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These statements include those related to the safety, tolerability and efficacy of Calithera’s product candidates, the overall advancement of Calithera’s product candidates in preclinical development and clinical trials, including Calithera’s plan to initiate two phase 2 clinical trials for mivavotinib and sapanisertib and plan to share data from these trials by the first quarter 2023, Calithera’s ability to potentially initiate registrational studies in biomarker-specific populations in DLBC and relapsed or refractory squamous NSCLC, the expectation that VPS4 inhibitors will be well-tolerated and have strong single-agent activity in tumors with certain mutations, Calithera’s plan to advance multiple VPS4 series through lead optimization and plan to share updates on this program by the end of the year, the unmet need in the treatment of patients with advanced disease, and management’s expectation that Calithera’s cash and cash equivalents will be sufficient to meet its operating plan through the second quarter of 2023. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. The potential product candidates that Calithera develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all. In addition, clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release. Such product candidates may not be beneficial to patients or be successfully commercialized. The failure to meet expectations with respect to any of the foregoing matters may have a negative effect on Calithera's stock price. Additional information concerning these and other risk factors affecting Calithera's business can be found in Calithera's periodic filings with the Securities and Exchange Commission at www.sec.gov. These forward-looking statements are not guarantees of future performance and speak only as of the date hereof, and, except as required by law, Calithera disclaims any obligation to update these forward-looking statements to reflect future events or circumstances. Calithera Biosciences, Inc. Selected Consolidated Statements of Operations Financial Data (in thousands) (unaudited) Three Months EndedJune 30, Six Months EndedJune 30, 2022 2021 2022 2021 Revenue: License revenue $— $3,000 $— $3,000 Total revenue — 3,000 — 3,000 Operating expenses: Research and development 7,758 12,820 17,324 28,159 General and administrative 3,618 4,487 7,878 9,915 Total operating expenses 11,376 17,307 25,202 38,074 Loss from operations (11,376) (14,307) (25,202) (35,074) Other income (expense): Transaction costs allocable to warrant liabilities (475) — (475) — Change in fair value of warrants liabilities 2,706 — 2,706 — Interest and other income (expense), net 68 (4) 59 368 Other income (expense), net 2,299 (4) 2,290 368 Net loss $(9,077) $(14,311) $(22,912) $(34,706) Calithera Biosciences, Inc. Selected Consolidated Balance Sheet Financial Data (in thousands) (unaudited) June 30, December 31, 2022 2021 Balance Sheet Data: Cash and cash equivalents$41,789 $59,537 Working capital 33,930 47,446 Total assets 45,558 64,756 Total liabilities 10,307 15,672 Convertible preferred stock 22,342 40,702 Accumulated deficit (495,878) (491,326) Total stockholders’ equity 35,251 8,382 CONTACTS:Stephanie Wong ir@Calithera.com650.870.1063 INVESTORS:Burns McClellanLee Roth212.213.0006lroth@burnsmc.com MEDIA:Sam Brown, Inc.Hannah Hurdle805.338.4752hannahhurdle@sambrown.com