The following discussion and analysis should be read in conjunction with our consolidated financial statements and related notes included elsewhere in this Annual Report on Form 10-K. This discussion may contain forward-looking statements based upon current expectations that involve risks and uncertainties, including those set forth under the heading "Risk Factors" and elsewhere in this Annual Report on Form 10-K. Our actual results and the timing of selected events discussed below could differ materially from those expressed in, or implied by, these forward-looking statements.
We are a research and clinical development biopharmaceutical company focused on developing protease therapeutics to address unmet medical needs in disorders of the complement system or where complement components are associated with progression of the disease state. Proteases are an important class of enzymes, which are key natural regulators of many biological processes, including the complement system. We use our protease engineering platform to create improved or novel molecules for the treatment of diseases that result from dysregulation of the complement system. Our complement pipeline consists of a preclinical complement component 3 ("C3") degrader program for geographic atrophy ("GA") in dry age-related macular degeneration ("dAMD"), an improved Complement Factor I ("CFI") protease, CB 4332, for subcutaneous ("SQ") or intravitreal ("IVT") therapy to restore complement homeostasis in disease of overactive complement of CFI deficiencies, and proteases from our ProTUNE™ C3b/C4b degrader and ImmunoTUNE™ C3a/C5a degrader platforms designed to target specific disorders of the complement or inflammatory pathways. Historically, we also used our protein engineering platform to develop potential therapies for coagulation disorders, including marzeptacog alfa (activated) ("MarzAA"), a SQ administered next-generation engineered coagulation Factor VIIa ("FVIIa") for the treatment of episodic bleeding and prophylaxis in subjects with rare bleeding disorders, and dalcinonacog alfa ("DalcA"), a next-generation SQ FIX, both of which has shown sustained efficacy and safety in mid-stage clinical trials. The product candidates generated by our protease engineering platform are designed to have improved functional properties such as longer half-life, improved specificity and targeting, higher potency, and increased bioavailability. These characteristics potentially allow for improved safety and efficacy for SQ administration of recombinant complement regulators, or less frequently dosed intravitreal products than current therapeutics in development. Our current complement portfolio consists of the development candidates CB 4332 and CB 2782-PEG. CB 4332 is a wholly owned, first-in-class improved albumin-fused CFI molecule intended for prophylactic SQ or IVT administration in individuals with an imbalance in complement homeostasis or a CFI deficiency. CB 2782-PEG is a potential best-in-class C3 degrader product candidate in preclinical development for the treatment of dry AMD that we had licensed to Biogen. In
March 2022, we re-acquired the full rights to CB 2782-PEG adding to our promising portfolio, which includes CB 4332 our enhanced CFI development candidate. We have several engineered protease programs in discovery or early non-clinical development. These programs all target diseases caused by deficient regulation of the complement system and inflammation. In July 2021we commenced patient enrollment in the screening ("CFI-001") and natural history of disease ("CFI-002") studies to assess CFI blood levels in patients who have diseases related to CFI deficiency and identify those who might benefit from CB 4332 treatment ("ConFIrm" and "ConFIdence" studies, respectively). As of February 2022, we have completed enrollment of these studies. 64 --------------------------------------------------------------------------------
The following table summarizes our current development programs.[[Image Removed]]
We continue to experience operational and other challenges as a result of the COVID-19 global pandemic, which could delay or impact our development programs. See Note 7, Commitments and Contingencies, Other Recent Developments and Item 1A - Risk Factors for further discussion of the current and expected impact on our business and development programs.
Recent Development Program Updates
Our protease programs are designed to take advantage of nature's natural complement regulators that restore complement homeostasis and potentially treat a variety of complement-mediated disorders. We have several protease programs currently in preclinical discovery or early non-clinical development. These programs target diseases caused by aberrant regulation of the complement system including both ocular programs, specifically for dry AMD, and systemic complement disorders, all of which are wholly owned by Catalyst. The complement system is an enzyme-based innate immune defense system with the primary role of protecting the body from pathogens. The system is naturally regulated by proteases which is the basis for our approach to addressing complement-driven diseases. Deficient or excessive activation of the complement system may lead to severe disorders, including microthrombotic, autoimmune and/or immune-complex diseases, severe infectious diseases, and degenerative ophthalmic or neurologic diseases affecting a variety of tissues and organ systems. The absence of regulation can cause the complement system to become self-destructive or not provide the necessary protection when needed. The protease therapeutic candidates generated by our platforms are designed to correct or restore the missing balance in the complement system that drives several diseases. Proteases are uniquely poised to regulate key biological functions such as the complement system, either by promoting or limiting the cascade of events that leads to eventual clearing of foreign and damaged proteins, inflammation, and formation of the membrane attack complex, which is deposited on the surface of cells and drives their destruction. Compared with antibodies and small molecule inhibitors that generally require a sustained excess of therapeutic compound over that of the target, Catalyst's protease therapeutic candidates are based on natural regulatory proteins that are capable of rapidly engaging and modulating large quantities of target molecules, as each protease molecule can degrade many target molecules over their effective lifetime. This means that our proteases are ideal for regulating high abundancy targets such as complement proteins in a way antibodies and small molecule inhibitors cannot. 65 -------------------------------------------------------------------------------- CB 2782-PEG is an engineered pegylated C3 degrader previously licensed to Biogen that we designed with a best-in-class anti-C3 profile for geographic atrophy ("GA") in dry AMD. Dry AMD is an ocular disease that leads to vision loss and blindness for which there is currently no approved therapy. CB 2782-PEG degrades C3 in the eye reducing the steady state level of C3 activity. It is expected that maintaining low C3 levels in the eye can significantly slow disease progression and vision loss in patients with dry AMD. We have demonstrated in preclinical non-human primate models that we have the potential to reduce C3 levels in humans based on modeling studies for up to 3 months with a single intravitreal injection. In
September 2021, Apellis released the results of the DERBY and OAKS phase 3 trials for GA secondary to dry AMD, showing that once-monthly pegcetacoplan, a pegylated C3 targeted inhibitor, was safe and efficacious, meeting its primary endpoint in one trial and narrowly missing the primary endpoint in a second trial for reducing GA lesion growth over a 12-month period. Further subpopulation analyses demonstrated a greater effect of reducing GA lesion growth in those subjects with extrafoveal lesions at baseline. CB 2782-PEG provides a differentiated mechanism of action by degrading both C3 and one of its byproducts, C3a potentially offering not only less frequent dosing but a more efficacious mechanism than pegcetacoplan or other complement inhibitors in development for GA. In March 2022, Biogen terminated the license agreement and returned full rights to CB 2782-PEG. CB 4332 is an engineered albumin-fused version of the CFI protease with an extended half-life that can be dosed subcutaneously or intravitreally in individuals who would benefit from enhanced regulation of complement. CFI is the central regulator of the complement system and CB 4332 has the potential to address several mechanistically related diseases driven by complement imbalance such as: Lupus Nephritis ("LN"), Systemic Lupus Erythematosus ("SLE"), warm Autoimmune Hemolytic Anemia ("wAIHA"), atypical Hemolytic Uremic Syndrome ("aHUS"), C3 Glomerulonephritis ("C3G"), and Immune ComplexMembranoproliferative Glomerulonephritis ("IC-MPGN"), dry AMD and complete CFI deficiency ("CFID"), a rare immunodeficiency primarily affecting children. These are severe, chronic, life-threatening diseases that result in a significantly decreased quality of life for the afflicted individual. CB 4332 can be dosed subcutaneously for systemic diseases and has the potential for infrequent IVT injections for ophthalmic indications. As a key complement regulator, CFI has the potential to be used in several complement dysregulated diseases (e.g., those associated with hyperactive complement) in which additional upstream regulation may prove more effective than inhibiting specific downstream targets such as C3 or C5, where many of current molecules in development are targeted. Individuals with complete or significant absence of endogenous CFI may present with a variety of disease manifestations, such as recurrent invasive infections with encapsulated bacteria, but these patients are also at risk of developing autoimmune and/or immune-complex diseases such as chronic inflammation of the blood vessels of the brain, spinal cord, heart, or kidneys. No CFI replacement therapy, including for prophylactic use, has been approved, and patients often receive supportive care with lifelong antibiotic treatment, which may cause a range of additional problems. We have received pre-IND guidance from the FDA as well as Rare Pediatric Disease Designation of CB 4332 for treatment of CFI deficiency in January 2022. Low circulating serum CFI levels have been shown to be associated with rare CFI genetic variants and all forms of AMD ranging from early to late-stage manifestations. Studies have estimated the prevalence rates of CFI deficiency in GA to be approximately 20%, suggesting that CFI is a prognostic biomarker for progression of GA. Approximately 1 million individuals globally are predicted to have low serum CFI levels and may potentially benefit from targeted CFI therapy. Gyroscope released interim results from its FOCUS phase 1/2a trial for patients with GA and having rare CFI variants, showing that gene therapy with GT005, an AAV-delivered CFI rebalanced the overactivation of complement observed in the vitreous with sustained expression of CFI. The FOCUS data also showed that AAV-delivered CFI reduced complement biomarkers in the broader GA population who do not have a rare CFI genetic variant. We have additional early-stage complement discovery programs that target different proteins of the complement system including proteases from our ProTUNE™ C3b/C4b degrader and ImmunoTUNE™ C3a/C5a degrader platforms. These proteases are designed to target specific disorders of the complement or inflammatory pathways. The ProTUNE™ platform generates optimized, next-generation engineered CFI molecules that are selectively enhanced for potency and target engagement. We expect to nominate a development candidate and target indication from this platform in 2022. 66 --------------------------------------------------------------------------------
Coagulation Programs MarzAA MarzAA is a potent, subcutaneously administered, next-generation Factor VIIa variant. We commenced enrollment of a Phase 3 registrational trial of MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital hemophilia A or hemophilia B with inhibitors in
May 2021. We have discontinued this trial based on a number of factors, including challenges in enrollment resulting from the limited number of potential patients eligible to enroll in this trial, competition from competing approved therapies, delays in enrollment resulting from COVID-19, the capital requirements to complete the trial, and other factors. Patients enrolled in the study returned to their standard of care and completed all required safety assessments. In the patients enrolled to date, we have successfully treated bleeds with SQ MarzAA and have not observed any adverse events. We plan to report these data at an appropriate medical conference in the future. We had also begun enrollment of a Phase 1/2 trial of MarzAA for treatment of bleeding in individuals with Factor VII Deficiency, Glanzmann Thrombasthenia, and hemophilia A with inhibitors on emicizumab prophylaxis. We have discontinued this trial as well, in light of the difficulties in identifying and enrolling eligible patients, the capital requirements to complete the trial and other factors. We believe that a SQ recombinant Factor VIIa therapy, like MarzAA, has the potential to be an important treatment option for patients with various bleeding disorders and are exploring opportunities to license or sell MarzAA to another party for further development. DalcA DalcA is a next-generation SQ Factor IX product candidate for the prophylactic treatment of individuals with hemophilia B. An open-label, Phase 2b study was completed in 2020, demonstrating that FIX plasma activity levels were raised from severe to mild hemophilia B levels and maintained throughout the course of the study. We have received guidance from the FDA on the design of the registrational Phase 3 clinical trial, have the necessary data to support its initiation, and are exploring opportunities to license or sell DalcA to another party for further development.
Recent Manufacturing Updates
CB 4332 is an albumin-fused version of the CFI protease with an extended half-life that is designed to be a subcutaneous or intravitreal dosed therapy for people who would benefit from improved complement regulation.
Other Recent Developments COVID-19 Business Impact The global coronavirus pandemic has resulted in widespread requirements for individuals to work from their homes, strained medical facilities worldwide, and disruptions to certain pharmaceutical manufacturing and product supply chains. While our offices in
Californiahave reopened for all employees, we may experience future disruptions in applicable guidelines for workplace safety, necessitating a return to a remote working environment. We are also still experiencing operational and other challenges as a result of the COVID-19 global pandemic, which delayed our enrollment in MAA-304 and MAA-202, contributing to the decision to discontinue these trials, and which may delay or halt our other development programs. Recent Financing
In the first quarter of 2021, we issued and sold a total of 9,185,000 common shares (including 485,000 shares sold following the exercise of the underwriters’ over-allotment option) at a price of
We have no drug products approved for commercial sale and have not generated any revenue from drug product sales. From inception to
December 31, 2021, we have raised net proceeds of approximately $509.3 million, 67 -------------------------------------------------------------------------------- primarily from private placements of convertible preferred stock since converted to common stock, proceeds from our merger with Targacept, issuances of shares of common stock and warrants, including $83.5 millionin total cash receipts from our license and collaboration agreements. We have never been profitable and have incurred significant operating losses in each year since inception. Our net losses were $87.9 millionand $56.2 millionfor the years ended December 31, 2021and 2020, respectively. As of December 31, 2021, we had an accumulated deficit of $402.7 million. As of December 31, 2021, our cash, cash equivalents and short-term investments balance were $46.9 million. Substantially all our operating losses were incurred in our research and development programs and in our general and administrative operations. We expect to incur significant expenses and increasing operating losses for at least the next several years as we continue preclinical, manufacturing and clinical development, and seek regulatory approval for our drug candidates. Our operating losses may fluctuate significantly from quarter to quarter and year to year due to timing of preclinical, manufacturing, clinical development programs and regulatory guidance spending.
July 14, 2021, we promoted Grant Blouse, Ph.D., to chief scientific officer and Tom Knudsen, DVM, Ph.D., to senior vice president, corporate development. Howard Levy, M.B.B.Ch, Ph.D., M.M.M., chief medical officer, announced his plan to retire and transition to a senior clinical advisor role to Catalyst. On September 9, 2021(the "Effective Date"), we appointed Ms. Jeanne Y. Jewas a Class III director of Catalyst with a term to expire at the 2024 Annual Meeting of Stockholders. In connection with the appointment, the Board approved an increase in the size of the Board, from seven to eight members, effective as of the Effective Date. On October 13, 2021, Clinton Musil, the chief financial officer, resigned for personal reasons effective October 29, 2021. We promoted Seline Miller, the Company's controller, to senior vice president, finance. She will serve as the interim chief financial and principal accounting officer while the Company initiates a search for a successor.
Overview of financial operations
Licensing and Collaboration Revenue
License and collaboration revenue consist of revenue earned for performance obligations satisfied pursuant to our license and collaboration agreement with Biogen which was entered into in
December 2019. In consideration for the grant of an exclusive license and related know-how, we received an up-front license payment of $15.0 millionin January 2020, which was recorded in license revenue during the year ended December 31, 2020. We recognized collaboration revenue for reimbursable third-party vendor, out-of-pocket and personnel costs pertaining to the Biogen Agreement of $7.3 millionand $5.8 millionduring the years ended December 31, 2021and 2020, respectively. In March 2022, we received notice that Biogen is terminating the license and collaboration agreement. Under the terms of the Biogen Agreement, termination will be effective in May 2022.
We have not generated any revenue from the sale of pharmaceuticals and we do not expect to generate revenue from the sale of pharmaceuticals until we obtain regulatory approval and commercialize our product candidates.
Cost of license and collaboration
Cost of license and collaboration revenue consists of fees for research and development services payable to third-party vendors, and personnel costs, corresponding to the recognition of license and collaboration revenue from Biogen. Cost of license and collaboration revenue does not include any allocated overhead costs. In connection with the license revenue recognized from Biogen as discussed above in 2020, we paid Mosaic a
$3.0 millionsublicense fee and recorded such payment as cost of license. We recognized third-party vendor, out-of-pocket and personnel costs, most of which were reimbursable, pertaining to the Biogen Agreement of $7.4 millionand $6.1 millionduring the years ended December 31, 2021and 2020, respectively, and recorded such costs as cost of collaboration revenue. 68 --------------------------------------------------------------------------------
Research and development costs
Research and development expenses represent costs incurred to conduct research, such as the discovery and development of our product candidates. We recognize all research and development costs as they are incurred. Nonrefundable advance payments for goods or services used in research and development are deferred and capitalized. The capitalized amounts are then expensed as the related goods are delivered or services are performed, or until it is no longer expected that the goods or services will be delivered.
Research and development expenses mainly consist of the following items:
• employee-related expenses, which include salaries, benefits and stock-based compensation;
• laboratory and supplier expenses, including payments to consultants and
third parties, related to the execution of preclinical, non-clinical and
clinical studies; • the cost of acquiring and manufacturing preclinical and clinical materials and developing manufacturing processes;
• clinical trial costs, including third party clinical research costs
organizations; • performing toxicity and other preclinical studies; and • facilities and other allocated expenses, which include direct and
charges allocated to rent and maintenance of premises, depreciation
and depreciation and other supplies.
The table below details our internal and external costs for research and development for the period presented (in thousands). See Overview and Recent Development Program Updates for further discussion of the current research and development programs. Year Ended December 31, 2021 Hemophilia $ 25,791 Complement 24,698 Personnel and other 17,198 Stock-based compensation 1,202 Total research and development expenses $ 68,889 The largest component of our total operating expenses has historically been our investment in research and development activities, including the clinical and manufacturing development of our product candidates. We are focusing substantially all our resources and development efforts on our complement programs. Costs listed for our hemophilia and complement programs above consist of clinical trial, manufacturing and research costs. Our internal resources, employees and infrastructure, identified above as personnel and other, are generally not directly tied to individual product candidates or development programs. As such, we do not maintain information regarding these costs incurred for these research and development programs on a project-specific basis. We expect our aggregate research and development expenses will fluctuate during the next year as we continue to explore strategic opportunities for the clinical and manufacturing development of our programs. The global coronavirus pandemic may also delay and increase costs of our current development plans. On
May 20, 2016, we signed a development and manufacturing services agreement with AGC, formerly known as CMC ICOS Biologics, Inc., pursuant to which AGC will conduct manufacturing development of agreed upon product candidates. We will own all intellectual property developed in such manufacturing development activities that are specifically related to our product candidates and will have a royalty-free and perpetual license to use AGC's intellectual property to the extent reasonably necessary to make these product candidates, including commercial manufacturing. As of December 31, 2021, six GMP batches have been manufactured at AGC in addition to an engineering batch. The initial term of the agreement is ten years or, if later, until all stages under outstanding statements of work have been completed. Either party may terminate the agreement in its entirety upon written notice of a material uncured breach or upon the other party's bankruptcy, and we may terminate the agreement upon prior notice for any reason. In addition, each party may terminate the agreement in the event that the manufacturing development activities 69 -------------------------------------------------------------------------------- cannot be completed for technical or scientific reasons. We had firm work orders with AGC to manufacture MarzAA and DalcA to support clinical trials totaling $15.8 million. The payment obligations were fully paid off as of December 31, 2021. We also have firm work orders with AGC to perform certain manufacturing services related to our collaboration agreement with Biogen totaling $0.7 millionand the payment obligations remaining as of December 31, 2021were $0.3 million. In July 2021, we entered into two separate agreements, one for additional clinical trial services for MarzAA, and another for our screening and natural history of disease clinical studies related to CFI deficiency, with total payments of up to $3.2 millionand $6.5 million, respectively. In November 2021, we provided notice of intent to terminate our MarzAA manufacturing agreements and incurred charges of $3.8 millionto write-off prepaid manufacturing costs that will no longer be used for the clinical development of MarzAA. We can terminate the CFI agreement at our discretion and upon termination will be responsible to pay for those services incurred prior to termination plus reasonable wind-down expenses. On September 16, 2021, we signed a Manufacturing and Research and Development Studies Agreement to support the lyophilized drug product, CB 4332. The agreement will cover analytical method qualification to support GMP manufacturing. We have firm work orders related to this agreement totaling $0.2 millionand the payment obligations were fully paid off as of December 31, 2021. We also have a long-term clinical supply services agreement with Catalent Indiana, LLC("Catalent"). Catalent has facilities in the U.S.and Europeand conducts drug product development and manufacturing for MarzAA and DalcA. We successfully completed development work for a variety of vial sizes which supports flexible dosing. The process of conducting clinical trials necessary to obtain regulatory approval is costly and time consuming. We may never succeed in achieving marketing approval for our product candidates. The probability of success of each product candidate may be affected by numerous factors, including clinical data, competition, manufacturing capability and commercial viability. As a result, we are unable to determine the duration of and costs to complete our research and development projects or when and to what extent we will generate revenue from the commercialization and sale of any of our product candidates. Successful development of current and future product candidates is highly uncertain. Completion dates and costs for our research programs can vary significantly for each current and future product candidate and are difficult to predict. Thus, we cannot estimate with any degree of certainty the costs we will incur in the development of our product candidates. We anticipate we will determine which programs and product candidates to pursue and how much funding to direct to each program and product candidate on an ongoing basis in response to the scientific success of early research programs, results of ongoing and future clinical trials, our ability to enter into collaborative agreements with respect to programs or potential product candidates, as well as ongoing assessments as to each current or future product candidate's commercial potential.
General and administrative expenses
General and administrative expenses consist of personnel costs, allocated expenses and other expenses for outside professional services, including legal, human resources, audit and accounting services. Personnel costs consist of salaries, bonus, benefits and stock-based compensation. We incur expenses associated with operating as a public company, including expenses related to compliance with the rules and regulations of the
Securities and Exchange Commission("SEC") and Nasdaq Stock Market LLC("Nasdaq"), insurance expenses, audit expenses, investor relations activities, Sarbanes-Oxley compliance expenses and other administrative expenses and professional services. We expect such expenses to fluctuate as we continue to explore strategic opportunities for our programs. 70 --------------------------------------------------------------------------------
The following tables present our results of operations for the periods presented (in thousands, except percentages):
Year Ended December 31, 2021 2020 Change ($) Change (%) Revenue: License $ -
$ 15,100 $ (15,100 )* Collaboration 7,338 5,848 1,490 25 % License and collaboration revenue 7,338 20,948 (13,610 ) (65 )% Operating expenses: Cost of license - 3,102 (3,102 ) * Cost of collaboration 7,380 6,061 1,319 22 % Research and development 68,889 52,975 15,914 30 % General and administrative 18,963 16,180 2,783 17 % Total operating expenses 95,232 78,318 16,914 22 % Loss from operations (87,894 ) (57,370 ) (30,524 ) 53 % Interest and other income (expense), net (39 ) 1,129 (1,168 ) * Net loss $ (87,933 ) $ (56,241 ) $ (31,692 )56 % *Not meaningful
Licensing and Collaboration Revenue
License and collaboration revenues were
$7.3 millionand $20.9 millionfor the years ended December 31, 2021and 2020, respectively. In the year ended December 31, 2021, revenue consisted primarily of reimbursable collaboration expenses from our Biogen Agreement. In the year ended December 31, 2020, revenue consisted primarily of a license payment of $15.0 millionand reimbursable collaboration expenses of $5.8 millionfrom our Biogen Agreement.
Cost of license and collaboration
Cost of license and collaboration revenues were
$7.4 millionand $9.2 millionduring the years ended December 31, 2021and 2020, respectively. Cost of collaboration for the year ended December 31, 2021was primarily related to reimbursable third-party vendor and personnel costs we incurred pertaining to the Biogen Agreement. Cost of license for the year ended December 31, 2020was primarily the $3.0 millionsublicense fee we paid to Mosaic in connection with the recognition of the license revenue from Biogen. Cost of collaboration revenue for the year ended December 31, 2020was primarily reimbursable third-party vendor, out-of-pocket and personnel related costs we incurred pertaining to the Biogen Agreement.
Research and development costs
Research and development expenses were
$68.9 millionand $53.0 millionduring the years ended December 31, 2021and 2020, respectively, an increase of approximately $15.9 million, or 30%. The increase was due primarily to an increase of $9.3 millionin clinical manufacturing costs of which $3.8 millionrelated to the write-off of prepaid manufacturing costs as part of our restructuring, an increase of $3.9 millionin preclinical research, an increase of $2.1 millionin personnel-related costs which includes approximately $0.3 millionrelated to one-time severance costs associated with our restructuring, and an increase of $0.6 millionin facilities costs.
General and administrative expenses
General and administrative expenses were
Interest and other income (expenses), net
$1.2 milliondecrease in interest and other income (expense), net for the year ended December 31, 2021compared to the year ended December 31, 2020was primarily due to a decrease in interest income and due to the payment received in the first quarter of 2020 under an agreement associated with neuronal nicotinic receptor asset sold in 2016.
Recent accounting pronouncements
Refer to Note 3, Summary of Significant Accounting Policies, to our consolidated financial statements included within Item 8 of this Annual Report on Form 10-K for a description of recent accounting pronouncements adopted and not yet adopted for the year ended
December 31, 2021.
Cash and capital resources
December 31, 2021, we had $46.9 millionof cash, cash equivalents and short-term investments. During the year ended December 31, 2021, we had a $87.9 millionnet loss and $83.8 millioncash used in operating activities. We have an accumulated deficit of $402.7 millionas of December 31, 2021. Our primary uses of cash are to fund operating expenses, including 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 believe that our existing capital resources, including cash, cash equivalents and investments will be sufficient to meet our projected operating requirements for at least the next 12 months from the date of this filing. We have based this estimate on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we currently expect. We plan to continue to fund losses from operations and capital funding needs through future equity and/or debt financings, as well as potential additional asset sales, licensing transactions, collaborations or strategic partnerships with other companies. At the year ended December 31, 2021, we had effective registration statements on Form S-3 that enable us to sell up to $150.0 millionin securities subject to limitations under SECrules. The sale of additional equity or convertible debt could result in additional dilution to our stockholders. The incurrence of indebtedness would result in debt service obligations and could result in operating and financing covenants that would restrict our operations. Licensing transactions, collaborations or strategic partnerships may result in us relinquishing valuable rights. We can provide no assurance that financing will be available in the amounts we need or on terms acceptable to us, if at all. If we are not able to secure adequate additional funding we may be forced to delay, make reductions in spending, extend payment terms with suppliers, liquidate assets where possible, and/or suspend or curtail planned programs. Any of these actions could materially harm our business. In October 2021, we entered into the ATM Agreement with Piper Sandler, which provides that, upon the terms and subject to the conditions and limitations set forth in the ATM Agreement, we may elect to issue and sell, from time to time, shares of our common stock having an aggregate offering price of up to $50.0 millionthrough Piper Sandler acting as our sales agent. Under the ATM Agreement, Piper Sandler may sell the shares of common stock by methods deemed to be an "at the market" offering as defined in Rule 415 under the Securities Act of 1933, as amended, including sales made directly on the Nasdaq CapitalMarket or any other trading market for the common stock. Piper Sandler will use commercially reasonable efforts to sell the shares of common stock subject to the ATM Agreement from time to time, based upon our instructions (including any price, time or size limits or other customary parameters or conditions that we may impose). We will pay Piper Sandler a commission of 3.0% of the gross proceeds of any shares sold through Piper Sandler under the ATM Agreement; however, we are not obligated to make any sales of common stock. For the year ended December 31, 2021, no shares of common stock were sold under the ATM Agreement. 72 --------------------------------------------------------------------------------
The following table summarizes our cash flows for the periods presented (in thousands):
Year Ended December 31, 2021 2020 Cash used in operating activities
$ (83,755 ) $ (55,048 )Cash provided by investing activities 48,189 9,663 Cash provided by financing activities 49,553 60,376
Net increase in cash and cash equivalents
Cash flow from operating activities
Cash used in operating activities for the year ended
December 31, 2021was $83.8 million. The most significant component of our cash used was a net loss of $87.9 million. This included non-cash expense related to stock-based compensation of $3.4 millionand depreciation and amortization of $0.3 million. In addition, cash inflow of $0.5 millionwas attributable to the change in our net operating assets and liabilities primarily as a result of a $3.9 milliondecrease in prepaid and other assets, a $1.5 milliondecrease in accounts receivable, and a $0.5 millionincrease in accounts payable, offset by a $3.7 milliondecrease in accrued compensation and other accrued liabilities and a $1.8 milliondecrease in deferred revenue related to the Biogen Agreement. Cash used in operating activities for the year ended December 31, 2020was $55.0 million, due primarily to a net loss of $56.2 millionand a net change in our operating assets and liabilities of $2.6 million, due primarily to a $11.7 milliondecrease in accounts receivable and a $1.7 millionincrease in accounts payable, partially offset by a $13.0 milliondecrease in deferred revenue related to the Biogen Agreement and a $3.0 millionincrease in prepaid and other assets. This is partially offset by non-cash charges of $3.8 million.
Cash flow from investing activities
Cash provided by investing activities for the year ended
December 31, 2021was $48.2 million, due to $49.0 millionin proceeds from maturities of investments, offset by $0.8 millionin purchases of property and equipment. Cash provided by investing activities for the year ended December 31, 2020was $9.7 million, due to $107.6 millionin proceeds from maturities of investments, offset by $97.6 millionin purchases of short-term and long-term investments and $0.3 millionin purchases of property and equipment.
Cash flow from financing activities
Cash provided by financing activities for the year ended
December 31, 2021was $49.6 million, due to $49.3 millionin net proceeds from the issuance of common stock related to our public offering in the first quarter of 2021 and $0.3 millionin proceeds from ESPP purchases of common stock and stock option exercises. Cash provided by financing activities for the year ended December 31, 2020was $60.4 million, due to $32.0 millionin net proceeds from the issuance of common stock related to our public offering in February 2020, $28.0 millionin net proceeds from the issuance of common stock related to our public offering in June 2020, and $0.4 millionin proceeds from ESPP purchases of common stock and stock option exercises.
Critical accounting policies and estimates
The preparation of the consolidated financial statements and related disclosures in conformity with
U.S.generally accepted accounting principles ("GAAP") and the Company's discussion and analysis of its financial condition and operating results require the Company's management to make judgments, assumptions and estimates that affect the amounts reported in its consolidated financial statements and accompanying notes. Our significant accounting policies and methods used in preparation of the Company's consolidated financial statements are described in Note 3, "Summary of Significant Accounting Policies," of the Notes to the Consolidated Financial Statements of this Annual Report on Form 10-K. Management bases its estimates on historical experience and on various other assumptions it believes to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities. Actual results may differ from these estimates, and such differences may be material. 73 -------------------------------------------------------------------------------- Management believes the Company's critical accounting policies and estimates discussed below are critical to understanding its historical and future performance, as these policies relate to the more significant areas involving management's judgments and estimates.
License and collaboration agreements
We may enter into collaboration arrangements that fall under the scope Collaborative Arrangements (Topic 808) ("ASC 808"). We analyze collaboration arrangements to assess whether they are within the scope of ASC 808 to determine whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities. This assessment is performed throughout the life of the arrangement based on changes in the responsibilities of all parties in the arrangement. The accounting for some of the activities under collaboration arrangements may be analogized to ASC 606 for distinct units of accounting that are reflective of a vendor-customer relationship. Under ASC 606, in determining the appropriate amount of revenue to be recognized as we fulfill our obligations under its agreements, we perform the following steps: (i) identification of the promised goods or services in the contract; (ii) determination of whether the promised goods or services are performance obligations including whether they are distinct in the context of the contract; (iii) measurement of the transaction price, including the constraint on variable consideration; (iv) allocation of the transaction price to the performance obligations based on estimated selling prices; and (v) recognition of revenue when we satisfy each performance obligation. If a license to our intellectual property is determined to be distinct from the other performance obligations identified in the arrangement, we recognize revenues attributed to the license when the license is transferred to the customer and the customer is able to use and benefit from the license. For licenses that are bundled with other promises, we use our judgement to assess the nature of the combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time. At the inception of each arrangement that contains development milestones, we evaluate whether the development milestones included are considered probable of being reached and estimate the amount to be included in the transaction price using the most likely amount method. If it is probable that a significant revenue reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are not within our control or the licensee, such as regulatory approvals, are not generally considered probable of being achieved until those approvals are received. At the end of each reporting period, we re-evaluate the probability of achievement of any development milestones, and if necessary, adjust its estimate of the transaction price. Any such adjustments would be recorded on a cumulative catch-up basis, which would affect revenues and earnings in the period of adjustment. For research and development services, the Company elected the practical expedient to recognize revenue as the research and development services are invoiced. As the Company has a right to consideration from the collaboration agreement with Biogen, in an amount that corresponds directly with the value of the Company's performance completed to date for the research services, the Company recognized revenue related to the research services as invoiced, in line with the practical expedient in ASC 606-10-55-18. 74 -------------------------------------------------------------------------------- The transaction price is allocated to each performance obligation on a relative stand-alone selling price ("SSP") basis. We recognize revenue as or when the performance obligations under the contract are satisfied. As part of the accounting for these arrangements, we must develop assumptions that require judgment to determine the timing of recognition and the SSP for each performance obligation identified in the contract. The SSP for licenses are calculated using the residual approach if we have not yet established a price for such license and the license has not previously been sold on a standalone basis. Otherwise, selling prices for licenses are determined using an income approach model and include key assumptions such as: development timeline, revenue forecast, commercialization expenses, discount rate and probabilities of technical and regulatory success. To estimate the SSP for research and development services, we use a cost-plus margin approach.
We record accrued expenses for estimated costs of our research and development activities conducted by external service providers, which include the conduct of preclinical studies and clinical trials and contract manufacturing activities. We record the estimated costs of research and development activities based upon the estimated amount of services provided but not yet invoiced and includes these costs in other accrued liabilities in the consolidated balance sheet and within research and development expense in the consolidated statement of operations. These costs are a significant component of our research and development expenses. We record accrued expenses for these costs based on the estimated amount of work completed and in accordance with agreements established with these external service providers. We estimate the amount of work completed through discussions with internal personnel and external service providers as to the progress or stage of completion of the services and the agreed-upon fee to be paid for such services. We make significant judgments and estimates in determining the accrued balance in each reporting period. As actual costs become known, we adjust its accrued estimates. Stock-based Compensation We measure the cost of employee and director services received in exchange for an award of equity instruments based on the fair value-based measurement of the award on the date of grant and recognize the related expense over the period during which an employee or director is required to provide service in exchange for the award on a straight-line basis. The estimated fair value of equity awards that contain performance conditions is expensed over the term of the award once we have determined that it is probable that performance conditions will be satisfied. Determining the fair value of stock-based awards at the grant date requires judgment. We use the Black-Scholes option-pricing model to determine the fair value of stock options. The determination of the grant date fair value of options using an option-pricing model is affected by our assumptions regarding a number of variables including the fair value of our common stock, our expected common stock price volatility over the expected life of the options, expected term of the stock option, risk-free interest rates and expected dividends. We record stock-based compensation as a compensation expense, net of the forfeited awards. We elected to account for forfeitures when they occur. As such, we recognize stock-based compensation expense only for those stock-based awards that are expected to vest, over their requisite service period, based on the vesting provisions of the individual grants. See Note 10, Stock Based Compensation, to our consolidated financial statements included in this Annual Report on Form 10-K for more information. 75
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