TERNS PHARMACEUTICALS, INC. The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our unaudited condensed consolidated financial statements and related notes included elsewhere in this Quarterly Report on Form 10-Q and our audited consolidated financial statements and related notes thereto included in our Annual Report on Form 10-K for the year endedDecember 31, 2021 , which was filed with theSEC onMarch 7, 2022 . In addition to historical financial information, this discussion contains forward-looking statements based upon current expectations that involve risks and uncertainties. Our actual results could differ materially from those anticipated in these forward-looking statements as a result of various factors, including those set forth under "Special Note Regarding Forward-Looking Statements" and "Risk Factors" and elsewhere in this Quarterly Report on Form 10-Q. Our fiscal year ends onDecember 31 each year.
Overview
We are a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases including oncology, obesity and non-alcoholic steatohepatitis (NASH). Our programs are based on mechanisms of action that have achieved proof-of-concept in clinical trials in indications with large unmet needs. The most advanced product candidates in our pipeline - TERN-701, TERN-601 and TERN-501 - were internally discovered. TERN-701 is our allosteric BCR-ABL tyrosine kinase inhibitor (TKI) that is in clinical development inChina for chronic myeloid leukemia (CML), a form of cancer that starts in bone marrow. TERN-601 is our small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist for metabolic diseases such as obesity, with the goal of initiating a first-in-human clinical trial in 2023. TERN-501 is our highly selective thyroid hormone receptor beta (THR-?) agonist for NASH in Phase 2a development. We expect our existing cash and cash equivalents to support our operations into 2025 and be sufficient to generate three key clinical data readouts from our three programs in CML, obesity and NASH. Additionally, we are conducting pre-clinical studies exploring TERN-201, our vascular adhesion protein-1 (VAP-1) inhibitor, in combination with immune checkpoint inhibitors for solid tumor indications, and have an ongoing discovery effort for the TERN-800 series of small-molecule glucose-dependent insulinotropic polypeptide receptor (GIPR) modulators for obesity.
TERN-701: Oral, allosteric BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia
TERN-701 is our proprietary, oral, potent, allosteric BCR-ABL TKI specifically targeting the ABL myristoyl pocket for chronic myeloid leukemia. CML is a form of cancer that begins in the bone marrow and leads to growth of leukemic cells. CML accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Inthe United States , the prevalence of CML is approximately 90,000 and is expected to reach 180,000 cases by 2030. In 2022, approximately 9,000 new cases of CML will be diagnosed, with a mortality rate of 1,200 patients expected. The standard of care (SOC) for CML includes active-site TKIs including imatinib, nilotinib, dasatinib, bosutinib and ponatinib. However, an unmet medical need remains due to (1) an increasing number of patients becoming refractory or intolerant to the current SOC, (2) BCR-ABL mutations that are difficult for active-site TKIs to treat (e.g., T315I), or (3) safety warnings for active-site TKIs used in CML patients who are resistant or intolerant to prior TKI therapy. Allosteric TKIs, which bind to the myristoyl-binding pocket, represent a new treatment class for CML and have the potential to address active-site TKI shortcomings, including off-target activity and limited efficacy against active site resistance mutations. Asciminib is the only allosteric TKI that has been approved by the FDA for use in third-line CML patients and is being evaluated in clinical trials for earlier lines of treatment. In a Phase 3 trial, asciminib was shown to be more than twice as effective as bosutinib, a second generation active-site TKI, in achieving a major molecular response (MMR) in third-line CML patients after 96 weeks of treatment (37.6% asciminib v. 15.8% bosutinib; p=0.001). The discontinuation rate after 96 weeks due to the lack of efficacy or adverse events in patients on asciminib was nearly half of the rate of patients on bosutinib (31.2% asciminib v. 60.5% bosutinib). Similar to asciminib, TERN-701 aims to address the limitations of active-site TKIs with the goal of achieving improved tumor suppression through a combination of (1) potent activity against BCR-ABL including a broad range of mutations, and (2) improved safety and tolerability profiles. As CML patient survival rates and treatment durations continue to increase, physicians are seeking additional efficacious CML therapies for patients whose tolerability, co-morbidity and/or drug-drug interaction profiles change over time, limiting their available treatment options and the effectiveness of mainstay therapies. We intend to initiate a clinical trial for TERN-701 in the second half of 2023 inthe United States , with potential interim top-line readouts from initial cohorts in 2024. We retain all worldwide development and commercialization rights for TERN-701 outside of greaterChina . InJuly 2020 ,Hansoh Pharmaceuticals in-licensed TERN-701 for development in the greaterChina region. TERN-701 is referred to byHansoh Pharmaceuticals as HS-10382. Hansoh is responsible for all development costs in the greaterChina region, including the ongoing Phase 1 trial. 21 -------------------------------------------------------------------------------- InMay 2022 , Hansoh initiated an open-label, multicenter, dose-escalation and expansion, first-in-human study in chronic or accelerated phase CML patients, who are resistant or intolerant to prior active-site BCR-ABL TKI treatment. The trial is comprised of two parts, with dose escalation being conducted in Part 1 to determine the maximum tolerated or maximum applicable dose followed by dose expansion in Part 2 of the trial, in which additional CML patients will be enrolled to receive one or more doses selected from Part 1. Part 2 of the trial will evaluate major cytogenetic response at six months as its primary endpoint, with key secondary endpoints including molecular response, hematologic response, measures of PK and an evaluation of safety and tolerability. The Phase 1 trial for TERN-701, which is conducted and funded by Hansoh inChina , is illustrated below: [[Image Removed: img254958980_0.jpg]]
TERN-601: Oral, small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist for obesity
We are also developing an oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of obesity known as TERN-601. Obesity represents a large unmet medical need, with recent studies estimating the aggregateU.S. national cost of obesity to exceed$260 billion . While approximately 50% of Americans meet the criteria for medical obesity, only 2% of adults receive therapies for weight loss. GLP-1R agonism has many potentially beneficial effects including increased insulin secretion by the pancreas, reduced glucagon secretion in the liver, slowed gastric emptying into the gut, increased sense of satiety in the brain and reduced inflammation. Synthetic GLP-1 peptides have been approved for obesity and diabetes. Semaglutide (Wegovy), a GLP-1R peptide agonist recently approved for chronic weight management in overweight or obese patients, appears to be expanding the primary care market for obesity treatment, as 75% of Wegovy patients are receiving anti-obesity medication for the first time. However, approved synthetic GLP-1R peptide agonists are biologic molecules with complex manufacturing processes and may require higher doses for weight loss than for management of diabetes. These GLP-1R peptide agonists also require frequent subcutaneous injections, and titration or drug holidays for management of their poor tolerability profiles. These barriers are likely to limit their widespread use for chronic weight management, particularly if efficacious oral treatments become available. We aim to develop small molecule, orally administered GLP-1R agonists with a convenient oral dosing schedule for the treatment of obesity. Our GLP-1R agonist program has screened more than 20,000 molecular permutations through our proprietary quantitative structure activity relationship (QSAR) model to identify several potentially suitable small-molecule scaffolds with potentially improved properties relative to other GLP-1R agonism-based approaches. We have optimized these series of compounds and identified structures that we believe are suitable for oral administration as a single-agent or in combination with other drug candidates within our pipeline, including small-molecule GIPR modulators. 22 -------------------------------------------------------------------------------- We designated a lead development candidate for our GLP-1R agonist program as TERN-601 in the fourth quarter of 2021. We are conducting IND-enabling activities for TERN-601 with the goal of initiating a first-in-human clinical trial in 2023 and receiving top-line data in 2024. We expect that the Phase 1 clinical program for TERN-601 will include a single ascending dose (SAD) trial in healthy volunteers and a multiple ascending dose (MAD) proof-of-concept trial in obese healthy volunteers and/or people with Type 2 diabetes that would potentially assess changes in body weight and glycemic control parameters, such as HbA1c. We also continue to evaluate other small-molecule GLP-1R agonists that have the potential to exhibit differentiated properties from TERN-601 and other GLP-1 product candidates.
TERN-501: Oral, thyroid hormone receptor-beta (THR-?) agonist for NASH
TERN-501 is an orally administered THR-? agonist with high metabolic stability, enhanced liver distribution and greater selectivity for THR-? compared to other THR-? agonists in development. InNovember 2021 , we announced positive top-line data from a Phase 1 clinical trial of TERN-501 in healthy volunteers with mildly elevated low-density lipoprotein (LDL) cholesterol. This Phase 1 trial included single ascending dose (SAD), multiple ascending dose (MAD) and drug-drug interaction (DDI) cohorts evaluating the safety, tolerability, pharmacodynamics and pharmacokinetics of TERN-501. In the SAD and MAD cohorts, single and multiple doses of TERN-501 were generally well-tolerated with a similar incidence of adverse events (AEs) across all TERN-501 treatment groups and placebo. All AEs were mild to moderate with no apparent dose relationship, no treatment-emergent serious AEs and no discontinuations of study or study drug due to any AE. There were no cardiac safety signals, no incidence of diarrhea and no differences between TERN-501 groups and placebo in change from baseline in heart rate, blood pressure or other vital signs. Thyroid function test results were consistent with THR-? agonists currently in clinical development, and there were no findings of clinical hyper- or hypo-thyroidism. There were no differences between placebo and any TERN-501 dose group in liver function abnormalities or mean change from baseline in liver transaminases at Day 15 in the MAD cohorts. TERN-501 demonstrated a predictable pharmacokinetic profile with low variability: study drug plasma exposures were linear and approximately dose-proportional with no overlap between dose strengths. Significant effects on sex hormone binding globulin (SHBG), a key pharmacodynamic marker of THR-? engagement linked to NASH histologic efficacy, were observed following treatment with TERN-501. The SHBG increases observed with 14 days of TERN-501 treatment were significant, dose dependent and have been associated with robust reductions in magnetic resonance imaging proton density fat fraction (MRI-PDFF) and NAFLD Activity Score in a precedent late-stage clinical NASH trial. The overall pharmacokinetic profile from this trial indicates that TERN-501 is well-suited for co-formulation with other small-molecule NASH agents as an oral, once-daily fixed dose combination. In the DDI cohort, the combination of TERN-501 and TERN-101, our liver-distributed, non-bile acid FXR agonist, was well-tolerated. Preliminary pharmacokinetic results support the co-administration of TERN-501 and TERN-101 in NASH patients, with no apparent need for dose adjustment. InApril 2022 , theU.S. Food and Drug Administration (FDA) cleared our investigational new drug (IND) application for our clinical-stage combination therapy candidates in NASH, including combinations of TERN-501 and TERN-101 as well as future studies of other potential combination therapy regimens. Under the IND, we are proceeding with a multicenter randomized, double-blind, placebo-controlled Phase 2a clinical trial in noncirrhotic NASH patients using a factorial design, which includes both monotherapy and combination arms of TERN-501 and TERN-101. This Phase 2a trial, known as the DUET trial, is expected to enroll approximately 140 adult patients with elevated body mass index (BMI ? 25 kg/m2) and NASH with fibrosis, but not cirrhosis, based on prior liver biopsy and/or imaging criteria and clinical criteria. All patients must have liver fat content measured by MRI-PDFF of ?10%, MRI corrected T1 (cT1) relaxation time of ? 800 msec, and meet other inclusion and exclusion criteria. The clinical trial includes a 12-week treatment period and a 4-week follow-up period. The primary endpoint will be the relative change from baseline in MRI-PDFF at Week 12 for TERN-501 monotherapy compared with placebo. Secondary endpoints include assessment of changes in PDFF (combination vs. placebo) and cT1 (TERN-501 monotherapy vs. placebo as well as TERN-501 and TERN-101 combination vs. placebo). Dosing in the DUET trial started inJuly 2022 , and top-line data are expected in the second half of 2023. The Phase 2a DUET trial design is illustrated in the figure below: 23 -------------------------------------------------------------------------------- [[Image Removed: img254958980_1.jpg]]
TERN-201: Oral, vascular adhesion protein-1 (VAP-1) inhibitor in combination with immune checkpoint inhibitors for solid tumors
TERN-201 is a highly-selective inhibitor of VAP-1 that has demonstrated sustained target engagement in clinical trials without the off-target liabilities associated with other VAP-1 inhibitors in development. As part of our oncology pipeline development, we are engaging in preclinical research to evaluate the use of TERN-201 in combination with immune checkpoint inhibitors for solid tumor indications. VAP-1 is an adhesion molecule and amine oxidase enzyme expressed on the surface of endothelial cells that supports rolling, adhesion, and transmigration of certain leukocytes into sites of inflammation. VAP-1 has also been associated with the recruitment of certain lymphocytes to several human tumors, including hepatocellular carcinoma and head and neck cancer, where VAP-1 expressed on tumor endothelium supports lymphocyte binding. Additionally, bioinformatic analyses have shown that VAP-1 expression is associated with poor prognosis of glioma patients. An analysis of various human cancers revealed that VAP-1 expression was a negative prognostic factor in patients with colorectal, renal, and urothelial cancers. In mouse models of melanoma and lymphoma, VAP-1 inhibition was also shown to decrease the number of CD11b-positive cells, which may suppress immune response, potentially resulting in the slowing of tumor growth. Efficacy of cancer immunotherapy utilizing immune checkpoint inhibitors such as anti-CTLA4 and PD-1/PD-L1 antibodies is often diminished by underlying immunosuppressive resistance to the therapies in the tumor microenvironment. VAP-1 may contribute to tumor progression through migration of such immunosuppressive myeloid cells. In a recent publication, VAP-1 inhibition was shown to reduce tumor growth in murine colon cancer models. Furthermore, synergistic effects were observed with VAP-1 inhibition in combination with anti-CTLA4 or anti-PD-1 antibodies.
TERN-800 Series: Discovery series of small-molecule glucose-dependent insulinotropic polypeptide receptor (GIPR) modulators for obesity
As part of our ongoing discovery efforts, we are evaluating a family of
small-molecule glucose-dependent insulinotropic polypeptide (GIP) receptor
modulators, designated as the TERN-800 series, for obesity. GIP is secreted in
response to nutrient ingestion to enhance meal-stimulated insulin secretion in a
glucose-dependent manner by activating its associated GIP receptor (GIPR) in
pancreatic beta cells and other cells in various tissues. In preclinical
studies, GIPR activation appears to reduce food intake and promote weight loss
when combined with its incretin partner GLP-1. The overlapping body
weight-lowering actions of both GIP and GLP-1 suggests that combining the
actions of these two peptide hormones may bolster glucose-lowering and
appetite-suppressing effects beyond those observed with individual agents.
In a preclinical study, two weeks of simultaneous administration of equimolar
amounts of a GLP-1R and a GIPR agonist reduced food intake, body weight, and fat
mass in mice to a greater extent than either agent alone. Late stage dual
GLP-1/GIP receptor agonists,
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tirzepatide (Lilly) and NNC0090-2746 (Novo Nordisk), have shown improved
glycemic control compared to GLP-1 agonist alone, and decreased body weight in
clinical trials. Additionally, a monomolecular combination of a GIPR
antagonist/GLP-1R agonist, AMG 133 (Amgen), enhanced the observed weight loss in
animal obesity models. In a Phase 1 clinical study of AMG 133, a single high
dose resulted in approximately 8 kilograms of weight loss.
Similar to our discovery process for GLP-1, we have synthesized small molecule
ligands targeting the GIP receptor and are currently assessing their activity at
relevant G-protein coupled receptors. We plan to combine GIPR modulators with
GLP-1 receptor agonists, such as TERN-601, for the treatment of obesity and
metabolic diseases. We believe our small molecules have the advantage of oral
bioavailability and the ability to dose adjust to achieve an optimal response.
Combining GIPR modulators with GLP-1 represents a promising strategy under
investigation for the treatment of obesity.
Since the commencement of our operations, we have devoted substantially all of
our resources to research and development activities, organizing and staffing
our company, business planning, raising capital, establishing and maintaining
our intellectual property portfolio, conducting preclinical studies and clinical
trials and providing general and administrative support for these operations. We
expect our cash and cash equivalents will be sufficient to fund our operating
expenses and capital expenditure requirements into 2025, including three
clinical data readouts from our three lead programs.
We do not have any product candidates approved for commercial sale, and we have
not generated any revenue from product sales. Our ability to generate product
revenue sufficient to achieve profitability, if ever, will depend on the
successful development and eventual commercialization of one or more of our
product candidates which we expect, if it ever occurs, will take a number of
years.
We will not generate any revenue from product sales unless and until we
successfully complete clinical development and obtain regulatory approval for
one or more of our product candidates. If we obtain regulatory approval for any
of our product candidates, we expect to incur significant expenses related to
developing our internal commercialization capability to support product sales,
marketing and distribution.
We do not own or operate, and currently have no plans to establish, any
manufacturing facilities. We rely, and expect to continue to rely, on third
parties for the manufacture of our product candidates for preclinical and
clinical testing, as well as for commercial manufacturing if any of our product
candidates obtain marketing approval. We believe that this strategy allows us to
maintain a more efficient infrastructure by eliminating the need for us to
invest in our own manufacturing facilities, equipment and personnel while also
enabling us to focus our expertise and resources on the development of our
product candidates.
The coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving. The
COVID-19 pandemic continues to impact countries worldwide, including the United
States and China where we have business operations. The extent of the impact of
the COVID-19 pandemic on our business, operations and development timelines and
plans remains uncertain, and will depend on future developments, including the
duration and spread of the outbreak and its impact on supply chains, our
development activities, planned clinical trial enrollment, future trial sites,
contract research organizations (CROs), third-party manufacturers and other
third parties with whom we do business, as well as its impact on regulatory
authorities and our key scientific and management personnel. The ultimate impact
of the COVID-19 pandemic or a similar health epidemic is highly uncertain and
will depend on future developments, including the duration and/or severity of
the outbreak, the impact of any resurgences and new variants that emerge,
actions by the government authorities to contain the spread of the virus, the
availability, adoption and effectiveness of any vaccines, and when and to what
extent normal economic and operating conditions can resume. To the extent
possible, we are conducting business as usual, with necessary or advisable
modifications to employee travel and to the on-site and in-person activities of
our personnel. We will continue to actively monitor the rapidly evolving
situation related to the COVID-19 pandemic and may take further actions that
alter our operations, including those that may be required by federal, state or
local authorities in the United States and China , or that we determine are in
the best interest of our employees and other third parties with whom we do
business. At this point, the extent to which the COVID-19 pandemic may affect
our business, operations and development timelines and plans, including the
resulting impact on our expenditures and capital needs, remains uncertain.
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--------------------------------------------------------------------------------Results of operations
The following table summarizes our results of operations for the three and nine
months ended
Three Months Ended Nine Months Ended September
September 30, 30,
(in thousands) 2022 2021 Change 2022 2021 Change
Results of Operations
Operating expenses:
Research and development $ 12,161 $ 7,153 $ 5,008 $ 28,959 $ 21,849 $ 7,110
General and administrative 5,131 4,715 416 16,242 14,133 2,109
Total operating expenses 17,292 11,868 5,424 45,201 35,982 9,219
Loss from operations (17,292 ) (11,868 ) (5,424 ) (45,201 ) (35,982 ) (9,219 )
Other income:
Interest income 499 49 450 782 115 667
Other (expense) income, net (14 ) 4 (18 ) (64 ) 30 (94 )
Total other income, net 485 53 432 718 145 573
Loss before income taxes (16,807 ) (11,815 ) (4,992 ) (44,483 ) (35,837 ) (8,646 )
Income tax expense (13 ) (20 ) 7 (40 ) (73 ) 33
Net loss $ (16,820 ) $ (11,835 ) $ (4,985 ) $ (44,523 ) $ (35,910 ) $ (8,613 )
Revenue
To date, we have not generated, and do not expect to generate for the
foreseeable future, any revenue from the sale of products. We may generate
revenue from pre-specified clinical, regulatory and sales milestones as part of
an exclusive option and license agreement for TERN-701 in greater China with
Hansoh Healthtech Co., Ltd. and Jiangsu Hansoh Pharmaceutical Group Company Ltd.
(collectively, Hansoh).
Research and development expenses
Research and development expenses consist of personnel-related expenses, including salaries, benefits and stock-based compensation expense, for personnel engaged in research and development functions. Research and development expenses also include clinical and nonclinical development of our product candidates. The increase in research and development expenses for the three months endedSeptember 30, 2022 , compared to the same period in 2021, was primarily due to a$3.8 million increase in clinical program expenses and a$1.2 million increase in personnel-related expenses due to higher headcount. The increase in research and development expenses for the nine months endedSeptember 30, 2022 , compared to the same period in 2021, was primarily due to a$3.7 million increase in personnel-related expenses due to higher headcount, a$3.3 million increase in clinical program expenses and a$0.1 million increase due to higher allocated facility-related and depreciation expenses to research and development expenses.
General and administrative expenses
General and administrative expenses consist of personnel-related expenses, including salaries, benefits and stock-based compensation expense, for personnel in administrative functions. General and administrative expenses also include professional fees for legal, patent, consulting, investor and public relations, accounting and tax services. The increase in general and administrative expenses for the three months endedSeptember 30, 2022 , compared to the same period in 2021, was primarily due to a$0.5 million increase in personnel-related expenses due to higher headcount. The increase was partially offset by a$0.1 million decrease in expenses related to professional services consulting. The increase in general and administrative expenses for the nine months endedSeptember 30, 2022 , compared to the same period in 2021, was primarily due to a$1.9 million increase in personnel-related expenses due to higher headcount and a$0.3 million increase in insurance and professional services consulting. These increases were partially offset by a$0.1 million decrease due to higher allocated facility-related and depreciation expenses to research and development expenses. 26
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Interest income
Interest income primarily consists of interest income on our marketable securities.
Interest income for the three months ended
Interest income for the nine months ended
Other (expense) income, net
Other (expense) income, net for the three months endedSeptember 30, 2022 was less than$0.1 million of expense, compared to less than$0.1 million of income for the same period in 2021. Other (expense) income, net for the nine months endedSeptember 30, 2022 was$0.1 million of expense, compared to less than$0.1 million of income for the same period in 2021. Income tax expense
Income tax expense for the three months ended
Income tax expense for the nine months ended
Liquidity and capital resources
Uses of cash
Our primary use of cash is to fund operating expenses, which consist primarily of research and development expenditures and general and administrative expenditures. Cash used to fund operating expenses is impacted by the timing of when we pay these expenses, as reflected in the change in our outstanding accounts payable and accrued expenses. We expect our existing cash and cash equivalents to be sufficient to fund our operating expenses and capital expenditures into 2025, including three clinical data readouts from our three lead programs. However, we continue to anticipate that our research and development expenses, general and administrative expenses and capital expenditures will remain significant to support our ongoing and planned activities. We expect to continue to incur net operating losses for at least the next several years.
Sources of liquidity
We have primarily funded our operations through proceeds from the issuance of shares of our common stock, convertible preferred stock and issuance of our convertible promissory notes. We have devoted substantially all of our resources to research and development activities, organizing and staffing our company, raising capital, establishing and maintaining our intellectual property portfolio, conducting preclinical studies and clinical trials and providing general and administrative support for these operations. Since our inception, we have not generated any revenue from product sales and we have incurred significant operating losses and negative cash flows from our operations. As ofSeptember 30, 2022 , we had an accumulated deficit of$226.6 million , a net loss of$44.5 million , negative cash flows from operations of$37.9 million , and cash, cash equivalents and marketable securities of$187.3 million .
In
InDecember 2020 , we issued and sold shares of our convertible preferred stock for gross proceeds of$87.4 million (including conversion of the$15.0 million of 2020 Notes and effective conversion of the$1.8 million bridge loan, plus accrued interest). InFebruary 2021 , we completed our initial public offering of 8,625,000 shares of our common stock, including the exercise in full by the underwriters of their option to purchase additional shares of common stock. The net proceeds from this offering were$133.0 million after deducting underwriting discounts and commissions and offering expenses. 27 -------------------------------------------------------------------------------- InMarch 2022 , we entered into a Sales Agreement withCowen and Company, LLC (Cowen), as sales agent, pursuant to which we have the ability to offer and sell, from time to time, through Cowen, shares of our common stock having an aggregate offering price of up to$75.0 million in an at-the-market offering. The shares are offered pursuant to our shelf registration statement on Form S-3 filed with theSecurities and Exchange Commission (SEC). There were no sales of our common stock pursuant to this agreement throughSeptember 30, 2022 . InAugust 2022 , we issued 12,250,000 shares of our common stock at a price of$2.42 per share and, to certain investors in lieu of common stock, pre-funded warrants to purchase 14,630,000 shares of common stock at a price of$2.4199 per pre-funded warrant. The purchase price per share of each pre-funded warrant represents the per share offering price for the common stock, minus the$0.0001 per share exercise price of such pre-funded warrant. Aggregate net proceeds were$60.7 million after deducting underwriting discounts and commissions and offering expenses. We believe that our existing cash and cash equivalents will be sufficient to fund our operating expenses and capital expenditure requirements into 2025. We will need substantial additional funding to support our operating activities.
Future funding requirements
We expect to incur significant expenses and operating losses for the foreseeable future as we advance the preclinical and clinical development of our product candidates. We expect that our research and development and general and administrative costs will remain significant for the foreseeable future in connection with conducting additional preclinical studies and clinical trials for our current and future research programs and product candidates, contracting with CROs and contract manufacturing organizations (CMOs) to support preclinical studies and clinical trials, expanding our intellectual property portfolio, and providing general and administrative support for our operations. As a result, we will need additional capital to fund our operations, which we may obtain from additional equity or debt financings, collaborations, licensing arrangements or other sources.
Our primary uses of cash are to fund our research and development activities, business planning, establishing and maintaining our intellectual property portfolio, hiring personnel, raising capital and providing general and administrative support for these operations.
We expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research and development of, continue or initiate clinical trials of, and seek marketing approval for, our product candidates. In addition, if we obtain marketing approval for our product candidates, we expect to incur significant commercialization expenses related to any approved products, marketing, manufacturing, and distribution to the extent that such sales, marketing and distribution are not the responsibility of potential collaborators. Furthermore, we expect to incur additional costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce, or eliminate our research and development programs or future commercialization efforts. Identifying potential product candidates and conducting preclinical studies and clinical trials is a time-consuming, expensive, and uncertain process that takes many years to complete, and we may never generate the necessary data or results required to obtain marketing approval and achieve product sales. In addition, our product candidates, if approved, may not achieve commercial success. Our commercial revenues, if any, will be derived from sales of product candidates that we do not expect to be commercially available for many years, if at all. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. Adequate additional financing may not be available to us on acceptable terms, or at all.
Cash flows
Operating activities
Net cash used in operating activities during the nine months endedSeptember 30, 2022 was$37.9 million and consisted primarily of our net loss of$44.5 million as well as a$2.9 million decrease from changes in operating assets and liabilities. This was partially offset by non-cash adjustments of$8.1 million of stock-based compensation,$0.6 million of net amortization of marketable securities,$0.4 million of depreciation and$0.4 million in amortization of operating lease assets. Net cash used in operating activities during the nine months endedSeptember 30, 2021 was$31.2 million and consisted primarily of our net loss of$35.9 million as well as a$2.0 million decrease from changes in operating assets and liabilities. This was partially offset by non-cash adjustments of$5.6 million of stock-based compensation,$0.4 million of depreciation and$0.7 million of net amortization on marketable securities. 28 --------------------------------------------------------------------------------
Investing activities
Net cash used in investing activities during the nine months endedSeptember 30, 2022 was$7.7 million and consisted primarily of$91.7 million in purchases of investments and$0.2 million in purchases of property and equipment. This was partially offset by proceeds from the sale and maturity of investments of$84.2 million . Net cash used in investing activities during the nine months endedSeptember 30, 2021 was$113.3 million and consisted primarily of$146.6 million in purchases of investments and$0.1 million in purchases of property and equipment. This was partially offset by proceeds from the sale and maturity of investments of$33.4 million . Financing activities Net cash provided by financing activities during the nine months endedSeptember 30, 2022 was$61.1 million and consisted of$61.1 million in proceeds from the issuance of common stock and pre-funded warrants in connection with theAugust 2022 Financing and$0.1 million of proceeds from the issuance of common stock under our employee stock purchase plan. This was partially offset by$0.1 million in payments of deferred offering costs. Net cash provided by financing activities during the nine months endedSeptember 30, 2021 was$134.4 million and consisted primarily of$136.4 million in proceeds from the issuance of common stock upon closing of the IPO inFebruary 2021 and$0.9 million of proceeds from stock option exercises. This was partially offset by$2.7 million in payments of deferred offering costs and a$0.2 million net payment on loans payable.
Critical Accounting Policies and Estimates
There have been no material changes to our critical accounting policies and use of estimates from those disclosed in our Annual Report on Form 10-K for the year endedDecember 31, 2021 . For a discussion of our critical accounting policies and use of estimates, refer to Management's Discussion and Analysis of Financial Condition and Results of Operations - Critical Accounting Policies and Significant Estimates in Part II, Item 7 of our Annual Report on Form 10-K for the year endedDecember 31, 2021 .
Recent Accounting Pronouncements
We are subject to several recently issued accounting pronouncements. Note 1 - Organization, Basis of Presentation, and Summary of Significant Accounting Policies - Recent Accounting Pronouncements which is contained in Part I, Item 1 of this Quarterly Report on Form 10-Q, describes these new accounting pronouncements and is incorporated herein by reference.
Off-balance sheet arrangements
We do not have any off-balance sheet arrangements (as defined by applicable regulations of theSEC ) that are reasonably likely to have a current or future material effect on our financial condition, results of operations, liquidity, capital expenditures or capital resources.
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