NELFCD

Janus kinase is a family of proteins that play a significant role in immune responses by transmitting signals from over 50 different cytokines, thus potentially serving as a target for treating autoimmune diseases.  However, available JAK inhibitors currently lack specificity in inhibiting cytokine signaling, leading to some adverse reactions. Therefore, the next-generation inhibitors need to maintain their efficacy while avoiding adverse events. Within the JAK family, JAK3 is a narrow-spectrum member that only regulates γc cytokines, thus becoming an ideal potential target. The Janus kinase family has four subtypes: JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2), which transmit signals through the JAK/STAT pathway. JAK1, JAK2, and TYK2 are widely expressed, while JAK3 is mainly expressed in lymphatic tissues and is a selective regulator of lymphocyte development, playing a crucial role in the immune system. JAK3 selectively binds to a cytokine receptor subunit (common γ-subunit or γc chain). To date, 51 drugs targeting JAK3 have been discovered, covering 74 different indications. The number of associated research and development organizations has reached 66. Clinical trial data shows that there are 199 clinical trial results related to JAK3 targeted drugs. Furthermore, research and development of JAK3 targeted drugs have received widespread attention and protection, with currently 5,385 patent applications related to JAK3 targeted drugs. To support the progress of JAK3 targeted drug research, there have been 2,031 published papers, providing essential references for further research. Competitive LandscapeAccording to the Synapse Database, drugs targeting the JAK3 are being extensively developed, covering multiple therapeutic areas, with a particular focus on autoimmune diseases. For rheumatoid arthritis, there are currently 20 drugs in development, and for ulcerative colitis and atopic dermatitis, there are 10 and 8 drugs respectively under development. Key DrugRitlecitinib is an irreversible inhibitor targeting JAK3. Pfizer plans to conduct Phase II clinical trials (NCT05743244) for type 1 diabetes in 2023, making Ritlecitinib one of the fastest progressing JAK3 selective inhibitors currently.  Ritlecitinib exerts its inhibitory activity by covalently binding with the Cys909 residue in JAK3, enhancing its selectivity for JAK3. Its IC50 for JAK3 is 33.1 nM, whereas it barely has any inhibitory activity for JAK1, JAK2, and TYK2 (IC50 >10,000 nM). Furthermore, Ritlecitinib also functions by inhibiting Th1 and Th17, achieved by suppressing the production of IFNγ (IC50 = 48 nM) and IL-17 (IC50 = 269 nM). The mechanism of JAK inhibitors in the treatment of Inflammatory Bowel Disease (IBD) is by blocking the communication between immune cells. In May 2018, the FDA approved the oral small molecule inhibitor Tofacitinib for the treatment of moderate to severe ulcerative colitis. Tofacitinib can inhibit JAK1 and JAK3, thus blocking the downstream JAK/STAT signaling pathway and regulating DNA transcription. The selective JAK1 inhibitor Itacitinib showed good efficacy in patients with acute graft versus host disease (aGVHD), but research on its indications for pancreatic cancer, plaque psoriasis, and rheumatoid arthritis was discontinued due to side effects.  Whether selective JAK3 inhibitors can reduce the side effects of widespread cytokine suppression has at least been confirmed by phase I clinical data from Ritlecitinib. Moreover, no significant adverse cardiac events (MACE), deaths, or opportunistic infections were observed in the study. In September last year, regulatory authorities in the United States and Japan respectively approved the TYK2 inhibitor deucravacitinib for the treatment of moderate to severe plaque psoriasis. Deucravacitinib also became the first selective inhibitor to be marketed in the TYK2 signaling pathway. This successful market case again demonstrates the potential for drug development in the JAK/STAT pathway.  After 30 years of research, the understanding of this pathway has deepened, and research on the function of JAK kinase subtypes has gradually deepened, and the marketed drugs have developed from early non-selective inhibitors to inhibitors with high selectivity for two subtypes or a certain subtype. Whether a JAK3 highly selective inhibitor can be successfully marketed like the TYK2 inhibitor still needs time to verify.

Janus Kinase Plays a Critical Role in Immune Responses by Transmitting Signals from Over 50 Cell Factors, Making It an Attractive Therapeutic Target for Autoimmune Diseases. However, Currently Available JAK Inhibitors are Accompanied by Some Adverse Reactions Due to Their Lack of Selectivity in Inhibiting Cytokine Signals. Therefore, The Next Generation of Inhibitors Need to Avoid Adverse Events While Maintaining Therapeutic Effectiveness. Among the JAK Family Members, JAK3, which Only Regulates a Narrow Spectrum of γc Cytokines, Emerges as a Potential Ideal Target. Synergistic Signaling Pathway of JAK1 and JAK3 on γc Cytokine ReceptorIn the Janus kinase family of non-receptor tyrosine kinases, there are four subtypes, JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2), which send out signals through the JAK/STAT pathway. JAK1, JAK2, and TYK2 are ubiquitously expressed, while JAK3 is mainly expressed in lymphoid tissues and is a selective regulator in lymphocyte development, playing roles in the immune system that make JAK3 an attractive target for treating autoimmune diseases. JAK3 selectively binds to a single subunit of cytokine receptors, called common γ-subunit or γc chain. JAK3, in conjunction with JAK1, is involved in signal transmission initiated by 6 cytokines (interleukin-2, -4, -5, -7, -15, and -21), which are essential in immune homeostasis. An example of the key role of JAK3 in autoimmune diseases is X-linked severe combined immunodeficiency (X-SCID). Mutations in JAK3 or γc cytokines can result in X-SCID, a pediatric emergency condition that leads to severe infections and diarrhea and requires immediate hematopoietic stem cell transplantation (HSCT) or gene therapy. The Discovery Process and Structural Characteristics of JAK3 InhibitorsA difference in the amino acid sequence between JAK3 and other JAK members is the presence of a cysteine residue in the ATP binding pocket, which is replaced by a serine residue in the other three subtypes, providing a structural biology basis for designing highly selective JAK3 inhibitors. In 2000, Brown and others at AstraZeneca first reported the discovery process of JAK3 selective inhibitors, initially using enzyme-linked immunosorbent assay (ELISA) to conduct high-throughput screening of >200,000 compounds at a test concentration of 10µM. A series of 2-aminoethyl ketone (AEKs) compounds were synthesized, including the most effective compound 1 (JAK3 IC50 80nM, [ATP] = 2µM). It was found however, under experimental conditions, compound 1 could decompose, and it had previously been reported that AEKs could undergo reverse Michael addition reaction. After preparing and evaluating more stable AEKs, their JAK3 activity was found to be lower, possibly due to the AEKs decomposing under ELISA experimental conditions, generating highly active naphthyl ethylene ketone, which might interact covalently with JAK3 protein. When the most effective compound 1 was found to have a half-life of 36 minutes under experimental conditions and the possible decomposition product was 2, this was confirmed. Compound 2 was subsequently tested, revealing its JAK3 IC50 also as 80nM ([ATP] = 2µM), demonstrating that the decomposition product was actually the active inhibitor. Decomposition of Compound 1 (AEK) to Acetone via Reverse Michael Addition ReactionSubsequent JAK3 Selective Inhibitors Retain the Enone Fragment: Differential Effects of Cyanide Introduction on Reversibility, Increased Acidity of Cα Hydrogens, Product Instability, and Conversion of Irreversible Cysteine Addition to Reversible Addition. The Advantages of Reversible Covalent Inhibitors include Prolonged Inhibition Duration, Lower Effective Concentration, and Reduced Off-Target Toxicity. Mechanism of Covalent Bond Formation between Cysteine Residues and Electrophilic Warheads: (A) Irreversible (B) ReversibleRitlecitinib is an irreversible inhibitor of JAK3. As of March 2023, according to the information obtained from Synapse using the keyword 'Ritlecitinib', the phase II clinical trials for both monotherapy and combined therapy for rheumatoid arthritis have failed. The ulcerative colitis indication is in phase III clinical trials, Crohn's disease is in phase II clinical trials, and Pfizer plans to initiate a phase II clinical trial (NCT05743244) for type I diabetes in 2023. This is currently the fastest progressing JAK3 selective inhibitor.  The inhibitory activity of Ritlecitinib is mediated by its interaction with the Cys909 residue in JAK3. Covalent binding enhances the compound's selectivity for JAK3. Ritlecitinib inhibits JAK3 with an IC50 of 33.1 nM, and exhibits no activity against JAK1, JAK2, and TYK2 (IC50>10,000 nM). It also suppresses Th1 and Th17, achieving this by inhibiting the production of IFNγ (IC50=48 nM) and IL-17 (IC50=269 nM). JAK inhibitors treat IBD by blocking communication between immune cells. In May 2018, the FDA approved tofacitinib for the treatment of moderate to severe UC. Tofacitinib is an oral small molecule inhibitor, which inhibits JAK1 and JAK3, disrupting the downstream JAK/STAT signaling pathway, thereby regulating DNA transcription. The selective JAK1 inhibitor itacitinib has shown good therapeutic effects in patients with aGVHD, but due to side effects, several indications such as pancreatic cancer, plaque psoriasis, and rheumatoid arthritis have been discontinued. Whether selective JAK3 inhibitors can reduce the side effects caused by broad inhibition of cytokines has been validated by at least the phase I clinical data from ritlecitinib. No major adverse cardiovascular events (MACE), deaths, or opportunistic infections were observed in the study. Representative Covalent Inhibitors of JAK3Current Status of Target JAK3According to Synapse, at this stage, nearly 50 varieties of this target (including multiple targets) are distributed in "pre-clinical to various stages of clinical trials", developing almost 74 types of indications and the focus of clinical trials points towards autoimmune diseases (particularly rheumatoid arthritis and enteritis). The focus of clinical trials is primarily on Phase I (single target), and the number of related patents exceeds 5300 (comprehensive target). SummaryResults from cellular experiments have repeatedly proven that, beyond the JAK1/JAK3 heterodimer pairs, the solitary inhibition of JAK3 is necessary for cancelling the downstream signal of γc chain cytokines. Covalent inhibitors of JAK3 also demonstrate stability in human whole blood and mouse liver microsomes. This stability allows certain compounds to show treatment effects in in vivo inflammation models after oral administration.  Pfizer's Ritlecitinib is presently the most advanced. Though the clinical trials for Rheumatoid Arthritis have failed, clinical trials for Ulcerative Colitis are still in progress, and new explorations in stage II clinical trials for Type I Diabetes have commenced. However, difficulties persist. Rigel's R348, targeting ophthalmic diseases, has been declared a failure. Creabilis SA's CT 340 has made no progress in phase II clinical trials. Theravance's compound, TD-5202, entered clinical trials as early as 2020, but reports of adverse reactions during phase I trials were revealed at the 28th United European Gastroenterology Conference. Currently, it remains in Phase I. In February of this year, Theravance announced a temporary halt in the development of inhaled JAK inhibitors and layoffs of 17%, casting a shadow over TD-5202's future. OST-122, capable of inhibiting both JAK3 and TYK2, is presently progressing normally in Phase II.  Last September, the US and Japanese regulatory authorities approved the TYK2 inhibitor Deucravacitinib for the treatment of moderate to severe plaque psoriasis. This oral medication from Bristol Myers Squibb is also the first selective inhibitor of the TYK2 signaling pathway to be approved. The successful launch of Deucravacitinib once again validates the druggability of the JAK/STAT pathway. The functions of the JAK kinase in this pathway, which has been studied for 30 years, are becoming increasingly clear. Drugs have advanced from early pan inhibitors to highly selective inhibitors that target two subtypes or a single subtype. The success of JAK3 selective inhibitors in obtaining market approval, like TYK2 inhibitors, remains to be verified with time. Reference 1.Stefan A. Laufer,et al, Recent Developments in JAK3 Inhibition: Isoform Selectivity by Covalent Targeting of Cys909.http://dx.doi.org/10.1016/j.bmcl.2017.07.079. 2.Glynn Addison,et al, Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3)  Inhibitors.Mini-Reviews in Medicinal Chemistry, 2019, 19, 1531-1543. 3.Hans-Günter Zerwes,et al, Selective inhibitors of the Janus Kinase Jak3 – are they effective?http://dx.doi.org/10.1016/j.bmcl.2014.08.046.

New CPI-818 Predictive Biomarker Enables Selection of Lymphoma Patients Most Likely to Benefit from Treatment Conference Call Today at 4:30 p.m. ET / 1:30 p.m. PT BURLINGAME, Calif., March 28, 2023 (GLOBE NEWSWIRE) -- Corvus Pharmaceuticals, Inc (Corvus or the Company) (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, today provided a business update and reported financial results for the fourth quarter and year ended December 31, 2022. “Heading into 2023, we are building momentum for CPI-818, our ITK inhibitor, which we believe is well positioned to provide a platform opportunity across cancer and immune diseases,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “This includes a growing body of clinical and preclinical data supporting ITK inhibition across a range of indications. The most encouraging data is in oncology, where enrollment in our Phase 1/1b trial in T cell lymphoma has accelerated and has enabled us both to increase the number of patients treated at the optimum dose and to identify a predictive biomarker that we believe will enrich for patients most likely to benefit from treatment with CPI-818. Looking forward, we are focused on achieving value driving milestones for CPI-818 including interim T cell lymphoma clinical data at upcoming medical meetings and additional preclinical data with CPI-818 in solid tumors at the upcoming AACR meeting in April. In addition, we have upside potential from ciforadenant and mupadolimab, the clinical development of which are primarily being advanced and funded by partners.” Business Update and Strategy Prioritized Program: CPI-818 (selective ITK inhibitor) CPI-818 for T Cell Lymphoma CPI-818 Phase 1/1b clinical trial results presented at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2022 provided clinical data and in vivo evidence supporting its ongoing development as a therapy for T cell lymphoma and its potential in autoimmune and allergic diseases. Key data from the presentation include: As of September 2, 2022, there were 1 complete response (CR), 1 nodal CR and 2 partial responses (PR) in 11 evaluable patients in the 200 mg twice per day cohort (identified optimal dose). An additional PR was seen in a patient receiving the 600 mg twice per day dose. No dose limiting toxicities were observed in 43 patients enrolled across four dosing cohorts, and a maximally tolerated dose was not reached at doses as high as 600 mg twice per day. The 200 mg dose was shown to induce Th1 skewing and both Th2 and Th17 blockade based on findings in peripheral blood samples from several patients and in vitro data demonstrated that it did so in a dose-dependent manner that supported the selection of the 200 mg twice per day optimum dose. The findings of the human and preclinical studies suggest that CPI-818 enhances anti-tumor immunity representing a potentially novel approach to immunotherapy. Enrollment in the 200 mg cohort has accelerated and is ongoing. As of February 23, 2023, 20 patients were enrolled, including 13 evaluable for tumor response. There have been 1 CR of 24 months duration, 1 equivocal CR awaiting confirmatory PET scan of 13+ months duration (a previous PR), 1 nodal CR of 21 months duration and 1 PR of 7 months duration. Ten patients continue on therapy, including seven that have not yet been evaluated for tumor response. The swimmer and waterfall tumor plots for these patients are shown below. New CPI-818 predictive biomarker: Corvus has identified a biomarker associated with response to CPI-818. CPI-818 induces a host anti-tumor cell mediated immune response that requires normal functioning T cells. Data from the 200 mg cohort in the Phase 1/1b clinical trial indicates that a minimum absolute lymphocyte count (ALC) above 900 per cubic milliliter of blood is required for tumor response and disease control. Four of eight patients with ALC above 900 have objective responses (those four patients are described above), all eight have disease control (stable disease, PR, CR) and the median progression free survival (PFS) is 28.1 months. No objective responses were seen in five patients (0 of 5) with ALC below 900 and the PFS is 2.1 months. The ALC biomarker is routinely measured, is consistent with CPI-818’s presumed mechanism of action and is present in about 70% of patients based on the Company’s experience to-date. This biomarker has been incorporated as an eligibility criterion in the ongoing Phase 1/1b clinical trial. Figure 1: Swimmer Plot for Patients in the 200 mg Dose Cohort of the CPI-818 Phase 1/1b Clinical Trial for T Cell Lymphoma. The plot shows the tumor response and duration (months) for patients with various tumor histologies, which are shown on the chart and defined as follows: PTCL-NOS, peripheral T cell lymphoma not otherwise specified; CTCL-SS, cutaneous T cell lymphoma Sezary; CTCL-MF, cutaneous T cell lymphoma mycosis fungoides; AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic T cell lymphoma and NKTCL, natural killer T cell lymphoma. The tumor response evaluation are labeled on the chart and are defined as follows: CR, complete response; equivocal CR; PR, partial response; SD, stable disease; PD, progressive disease. Arrows indicate that treatment with CPI-818 is continuing as of the February 23, 2023 data cut-off. Figure 2: Waterfall Plot for Patients in the 200 mg Dose Cohort of the CPI-818 Phase 1/1b Clinical Trial for T Cell Lymphoma. The plot shows the best percent change in tumor volume in the evaluable patients from the same group shown in Figure 1. Corvus recently received a communication from the U.S. Food and Drug Administration (FDA) regarding its clinical development plans for CPI-818. Based on the current enrollment rate of its ongoing Phase 1/1b clinical trial, the Company believes that the number of patients treated in this clinical trial would provide adequate safety and preliminary efficacy data to inform the design of a registration Phase 3 randomized clinical trial. As recommended by the FDA, the Company plans to meet with the FDA to discuss such a clinical trial; it is anticipated that this meeting will take place later this year. Reprioritization of CPI -818 for Atopic Dermatitis Based on recent progress and data supporting the ongoing development of CPI-818 for T cell lymphoma and other cancers, Corvus has decided to delay its plans to initiate a Phase 1 clinical trial in atopic dermatitis. This decision allows the Company to conserve cash and intensify its focus on T cell lymphoma, which could include conducting a potentially registrational, randomized Phase 3 trial. While Corvus is pausing development of CPI-818 for the treatment of atopic dermatitis, the Company will continue to investigate the potential role of CPI-818 in immune diseases through its ongoing and planned preclinical research and external collaborations. CPI-818 for HIV In February 2023, researchers from The University of California San Francisco-Bay Area Center for AIDS Research (UCSF) presented new data at the 30th Annual Conference on Retroviruses and Opportunistic Infections demonstrating the potential of CPI-818 to reduce the need for chronic human immunodeficiency virus (HIV) therapy. The data further highlights the broad therapeutic opportunity for ITK inhibition with CPI-818. Based on this positive data, the UCSF team plans to continue studying the potential for ITK inhibition to be developed within antiproliferative and “block-and-lock” HIV cure strategies. Partner Led Programs: Ciforadenant (adenosine 2a receptor inhibitor) and Mupadolimab (anti-CD73) The Kidney Cancer Research Consortium (KCRC) is enrolling a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The clinical trial is expected to enroll up to 60 patients and initial data is anticipated before the end of 2023. Angel Pharmaceuticals, Corvus’ partner in China, is enrolling patients in a Phase 1/1b clinical trial of mupadolimab in patients with non-small cell lung cancer (NSCLC) and head and neck squamous cell cancers. In this clinical trial, patients will receive mupadolimab monotherapy or in combination with pembrolizumab. Financial Results As of December 31, 2022, Corvus had cash, cash equivalents and marketable securities totaling $42.3 million. This compared to cash, cash equivalents and marketable securities of $69.5 million as of December 31, 2021. Corvus expects full year 2023 net cash used in operating activities to be between approximately $19 million and $22 million, resulting in a projected cash balance of between $20 million and $23 million as of December 31, 2023. Based on its current plans, Corvus expects its cash to fund operations into 2024. Research and development expenses for the three months and full year ended December 31, 2022 totaled $4.1 million and $24.5 million, respectively, compared to $4.8 million and $29.1 million for the same periods in 2021. In the fourth quarter of 2022, the decrease of $0.7 million was primarily related to a decrease in personnel costs. The net loss for the three months ended December 31, 2022 was $9.8 million compared to a net loss of $9.2 million for the same period in 2021. Total stock compensation expense for the three months ended December 31, 2022 was $0.6 million compared to $0.7 million for the same period in 2021 and the non-cash loss from the Company’s equity method investment in Angel Pharmaceuticals was $4.6 million for the three months ended December 31, 2022 compared to $2.6 million for the same period in 2021. Conference Call Details Corvus will host a conference call and webcast today, Tuesday, March 28, 2023, at 4:30 p.m. ET (1:30 p.m. PT), during which time management will provide a business update and discuss the fourth quarter and full year 2022 financial results. The conference call can be accessed by dialing 1-844-825-9789 (toll-free domestic) or 1-412-317-5180 (international) or by clicking on this link and requesting a return call and using the conference passcode 3154152. The live webcast may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus' website for 90 days. About Corvus Pharmaceuticals Corvus Pharmaceuticals is a clinical-stage biopharmaceutical company. Corvus’ lead product candidate is CPI-818, an investigational, oral, small molecule drug that selectively inhibited ITK in preclinical studies and is in a multicenter Phase 1/1b clinical trial in patients with several types of T cell lymphomas. The Company’s second clinical program, ciforadenant (CPI-444), is an oral, small molecule inhibitor of the A2A receptor that is in an open-label Phase 1b/2 clinical trial. Its third clinical program, mupadolimab (CPI-006), is a humanized monoclonal antibody directed against CD73 that has exhibited immunomodulatory activity and activation of immune cells in preclinical and clinical studies. For more information, visit . About CPI-818 CPI-818 is an investigational small molecule drug given orally that has selectively inhibited ITK (interleukin-2-inducible T cell kinase) in preclinical studies. It was designed to block malignant T cell growth and to modulate immune responses. ITK, an enzyme, is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell lymphomas and leukemias, as well as in normal immune function. Recent clinical data in T cell lymphomas suggests that CPI-818 has the potential to control differentiation of T helper cells and enhance immune responses to tumors. Interference with ITK signaling also can modulate immune responses to various antigens. Optimal doses of CPI-818 have been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of Th2 related cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. The immunologic effects of CPI-818 lead to what is known as Th1 skewing and is made possible by the high selectivity of CPI-818 for ITK. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with T cell lymphomas, solid tumors, and in patients with autoimmune and allergic diseases. The Company is conducting a Phase 1/1b trial in patients with refractory T cell lymphomas that was designed to select the optimal dose of CPI-818 and evaluate its safety, PK, target occupancy, immunologic effects, biomarkers and efficacy. Interim data from the Phase 1/1b clinical trial of CPI-818 for T cell lymphoma demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, and identified a dose that maximally affects T helper cell differentiation. About Ciforadenant Ciforadenant (CPI-444) is an investigational small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine triphosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. About Mupadolimab Mupadolimab (CPI-006) is an investigational, potent humanized monoclonal antibody that is designed to react with a specific site on CD73. In preclinical studies, it has demonstrated immunomodulatory activity resulting in activation of lymphocytes, induction of antibody production from B cells and effects on lymphocyte trafficking. While there are other anti-CD73 antibodies and small molecules in development for treatment of cancer, such agents react with a different region of CD73. Mupadolimab is designed to react with a region of the molecule that acts to stimulate B cells and block production of immunosuppressive adenosine. Mupadolimab is being studied in combination with pembrolizumab in a Phase 1b/2 clinical trial in patients with advanced head and neck cancers and in patients with NSCLC that have failed chemotherapy and anti-PD(L)1 therapy. It is postulated that the activation of B cells will enhance immunity within the tumors of these patients, leading to improved clinical outcomes. About Angel Pharmaceuticals Angel Pharmaceuticals is a privately held biopharmaceutical company developing a pipeline of precisely targeted investigational medicines for cancer, autoimmune, infectious and other serious diseases in China. Angel Pharmaceuticals was launched through a collaboration with U.S.-based Corvus and investments from investors in China. Angel Pharmaceuticals licensed the rights to develop and commercialize Corvus’ three clinical-stage candidates – CPI-818, ciforadenant and mupadolimab – in greater China and obtained global rights to Corvus’ BTK inhibitor preclinical programs. Under the collaboration, Corvus currently has a 49.7% equity stake in Angel Pharmaceuticals excluding 7% of Angel’s equity reserved for issuance under the Angel ESOP, and Corvus has designated three individuals on Angel’s five-person Board of Directors. For more information, visit . Forward-Looking Statements This press release contains forward-looking statements, including statements related to the potential safety and efficacy of CPI-818, ciforadenant and mupadolimab; the Company’s ability and its partners’ ability, as well as the timing thereof, to develop and advance product candidates into and successfully complete preclinical studies and clinical trials, including the Company and Angel’s Phase 1/1b clinical trial of CPI-818 and the Company’s planned meeting with the FDA to discuss a registration clinical trial with CPI-818 for T cell lymphoma later this year; the design of clinical trials, including the target number of patients to be enrolled; the timing of the availability and announcement of clinical data and certain other product development milestones; the estimated amount of net cash used in operating activities for 2023 and its ability to fund operations into 2024. All statements other than statements of historical fact contained in this press release are forward-looking statements. These statements often include words such as “believe,” “expect,” “anticipate,” “intend,” “plan,” “estimate,” “seek,” “will,” “may” or similar expressions. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond the Company’s control. The Company’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to, risks detailed in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission on or about the date hereof, as well as other documents that may be filed by the Company from time to time with the Securities and Exchange Commission. In particular, the following factors, among others, could cause results to differ materially from those expressed or implied by such forward-looking statements: the Company’s ability to demonstrate sufficient evidence of efficacy and safety in its clinical trials of CPI-818, ciforadenant and mupadolimab; the accuracy of the Company’s estimates relating to its ability to initiate and/or complete preclinical studies and clinical trials; the results of preclinical studies and interim data from clinical trials not being predictive of future results; the unpredictability of the regulatory process; regulatory developments in the United States, and other foreign countries; the costs of clinical trials may exceed expectations; the Company’s ability to accurately estimate the amount of net cash used in operating activities for 2023 and cash on hand providing funding into 2024 and the Company’s ability to raise additional capital. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and the timing of events and circumstances and actual results could differ materially from those projected in the forward-looking statements. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and the Company undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. The Company’s results for the quarter and year ended December 31, 2022 are not necessarily indicative of its operating results for any future periods. CORVUS PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except share and per share data) Three Months Ended December 31, Year Ended December 31, 2022 2021 2022 2021 (unaudited) Operating expenses: Research and development $ 4,080 $ 4,788 $ 24,468 $ 29,115 General and administrative 1,586 2,022 8,097 9,515 Total operating expenses 5,666 6,810 32,565 38,630 Loss from operations (5,666 ) (6,810 ) (32,565 ) (38,630 ) Interest income and other expense, net 318 (8 ) 654 (15 ) Gain from sale of property and equipment 22 - 22 - Sublease income - related party 148 141 587 235 Loss from equity method investment (4,638 ) (2,559 ) (10,005 ) (4,831 ) Net loss $ (9,816 ) $ (9,236 ) $ (41,307 ) $ (43,241 ) Net loss per share, basic and diluted $ (0.21 ) $ (0.20 ) $ (0.89 ) $ (1.03 ) Shares used to compute net loss per share, basic and diluted 46,553,511 46,551,954 46,553,511 41,854,110 CORVUS PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) Year ended December 31, 2022 2021 Assets Cash, cash equivalents and marketable securities $ 42,303 $ 69,451 Operating lease right-of-use asset 2,217 3,190 Other assets 1,843 2,548 Investment in Angel Pharmaceuticals 21,877 34,266 Total assets $ 68,240 $ 109,455 Liabilities and stockholders' equity Accounts payable and accrued liabilities and other liabilities $ 9,524 $ 8,646 Operating lease liability 2,601 3,647 Stockholders' equity 56,115 97,162 Total liabilities and stockholders' equity $ 68,240 $ 109,455 INVESTOR CONTACT: Leiv Lea Chief Financial Officer Corvus Pharmaceuticals, Inc. +1-650-900-4522 llea@corvuspharma.com MEDIA CONTACT: Sheryl Seapy Real Chemistry +1-949-903-4750 sseapy@realchemistry.com Photos accompanying this announcement are available at: Figure 1: Swimmer Plot for Patients in the 200 mg Dose Cohort of the CPI-818 Phase 1/1b Clinical Trial for T Cell Lymphoma. The plot shows the tumor response and duration (months) for patients with various tumor histologies, which are shown on the chart and defined as follows: PTCL-NOS, peripheral T cell lymphoma not otherwise specified; CTCL-SS, cutaneous T cell lymphoma Sezary; CTCL-MF, cutaneous T cell lymphoma mycosis fungoides; AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic T cell lymphoma and NKTCL, natural killer T cell lymphoma. The tumor response evaluation are labeled on the chart and are defined as follows: CR, complete response; equivocal CR; PR, partial response; SD, stable disease; PD, progressive disease. Arrows indicate that treatment with CPI-818 is continuing as of the February 23, 2023 data cut-off. Figure 2: Waterfall Plot for Patients in the 200 mg Dose Cohort of the CPI-818 Phase 1/1b Clinical Trial for T Cell Lymphoma. The plot shows the best percent change in tumor volume in the evaluable patients from the same group shown in Figure 1.