Caribou Biosciences(US:CRBU)2023-03-08 16:00PART I Business Caribou Biosciences is a clinical-stage CRISPR genome-editing biopharmaceutical company developing allogeneic CAR-T and CAR-NK cell therapies Overview Caribou Biosciences is a clinical-stage CRISPR genome-editing biopharmaceutical company focused on developing transformative allogeneic CAR-T and CAR-NK cell therapies - Caribou Biosciences is a clinical-stage CRISPR genome-editing biopharmaceutical company dedicated to developing transformative therapies for patients with devastating diseases, utilizing its novel chRDNA technologies for high-precision genome editing2851163773 - The company is advancing a pipeline of allogeneic, or off-the-shelf, cell therapies from its CAR-T and CAR-NK platforms2851163773 - Key product candidates include CB-010 (anti-CD19 CAR-T with PD-1 knockout for r/r B-NHL, in Phase 1), CB-011 (anti-BCMA CAR-T with immune cloaking for r/r MM, in Phase 1), CB-012 (anti-CLL-1 CAR-T with checkpoint disruption and immune cloaking for r/r AML, in IND-enabling studies), and CB-020 (CAR-NK for solid tumors, preclinical)2718451711511652881166 Our CRISPR Hybrid RNA-DNA (chRDNA) Technologies Caribou's novel chRDNA technologies improve genome-editing specificity and efficiency for multiplex editing in advanced cell therapies - The chRDNA technologies use hybrid guides (RNA and DNA nucleotides) with Cas9 or Cas12a proteins for editing genomic DNA50325 - These chRDNA guides significantly improve genome-editing specificity by reducing off-target events compared to first-generation all-RNA guides50296 - The technology achieves high efficiency for on-target gene knockout and site-specific gene insertions, enabling robust multiplex editing, including multiple gene insertions (e.g., >60% of T cells with four intended edits for CB-011)5029454 Immune Cell Therapies Allogeneic CAR-T and CAR-NK cell therapies offer scalable, off-the-shelf solutions with enhanced antitumor activity, addressing autologous limitations - Autologous CAR-T cell therapies are limited by high production costs, scalability issues, limited patient access, and variable potency due to patient T-cell condition or prior treatments27300301331 - Allogeneic CAR-T or CAR-NK cell therapies offer advantages such as more efficient and scalable manufacturing, off-the-shelf availability, broad patient access, and the ability to engineer enhanced antitumor activity through genome editing282930230359 Our Strategy Caribou aims to be an integrated genome-edited therapy company, focusing on allogeneic cell therapies with enhanced antitumor activity - The company's overarching goal is to build an integrated company that discovers, develops, manufactures, and commercializes genome-edited therapies30 - Key strategic components include applying chRDNA technology to engineer allogeneic cell therapies with enhanced antitumor activity through checkpoint disruption and immune cloaking, developing new CAR-T therapies for hematologic malignancies, expanding into solid tumors with CAR-NK therapies, pursuing strategic collaborations, and reinforcing leadership in CRISPR genome editing30461703353271 - Armoring strategies for CAR-T cells include PD-1 knockout for checkpoint disruption and immune cloaking (removing PD-1 and overexpressing HLA-E) to sustain antitumor activity and reduce immune-mediated rejection3430964 Our Pipeline Caribou is advancing a pipeline of allogeneic CAR-T and CAR-NK cell therapies for hematologic malignancies and solid tumors, including two AbbVie programs - Caribou is developing a pipeline of allogeneic CAR-T and CAR-NK cell therapies for hematologic malignancies and solid tumors76340 Caribou Biosciences Pipeline | Product Candidate | Platform | Target | Indication | Development Stage | Designations | | :---------------- | :------- | :----- | :--------- | :---------------- | :----------- | | CB-010 | CAR-T | CD19 | r/r B-NHL | Phase 1 | RMAT, Fast Track, Orphan Drug | | CB-011 | CAR-T | BCMA | r/r MM | Phase 1 | | | CB-012 | CAR-T | CLL-1 | r/r AML | IND enabling | | | CB-020 | CAR-NK (iPSC-derived) | ROR1 | Solid Tumors | Preclinical | | | CAR-T Program 1 (AbbVie) | CAR-T | Undisclosed | Undisclosed | Preclinical | | | CAR-T Program 2 (AbbVie) | CAR-T | Undisclosed | Undisclosed | Preclinical | | CB-010 CB-010 is Caribou's lead allogeneic anti-CD19 CAR-T cell therapy with PD-1 knockout, in Phase 1 for r/r B-NHL - CB-010 is the first clinical-stage allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knockout, designed to prevent rapid CAR-T cell exhaustion and confer a better therapeutic index2717779 - The manufacturing of CB-010 involves three modifications: TCR knockout, site-specific anti-CD19 CAR insertion, and PD-1 knockout78342 - CB-010 is being evaluated in the ANTLER Phase 1 clinical trial for adults with aggressive relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL)7782246 - Initial data from dose level 1 (40x10^6 CAR-T cells) showed 6 of 6 patients achieved a complete response (CR) as best response, with 3 maintaining CR at six months and 2 at 12 months, and the therapy was generally well-tolerated91105107 CB-011 CB-011 is an allogeneic anti-BCMA CAR-T cell therapy with immune cloaking, in Phase 1 for r/r MM - CB-011 is the first anti-BCMA CAR-T cell therapy incorporating an immune cloaking approach, involving B2M knockout and B2M–HLA-E insertion, designed to reduce CAR-T cell rejection by patient T and NK cells45117101 - The manufacturing of CB-011 involves four genome edits: TCR knockout, site-specific humanized anti-BCMA CAR insertion, B2M knockout, and B2M–HLA-E fusion protein insertion1099811011199 - CB-011 is being evaluated in the CaMMouflage Phase 1 clinical trial for adults with relapsed or refractory multiple myeloma (r/r MM)108114143 - Preclinical in vitro data demonstrated that the B2M–HLA-E fusion protein reduces NK cell-mediated lysis and B2M knockout reduces T cell-mediated lysis, with in vivo mouse models showing CB-011 led to statistically significantly longer survival of tumor-bearing mice148242253 CB-012 CB-012 is an allogeneic anti-CLL-1 CAR-T cell therapy with checkpoint disruption and immune cloaking for r/r AML - CB-012 is an allogeneic CAR-T cell therapy targeting CLL-1 for r/r AML, incorporating both checkpoint disruption (PD-1 knockout) and immune cloaking strategies (B2M knockout and B2M–HLA-E insertion) through five genome edits17115153154126155127156 - CLL-1 is an attractive target for AML due to its expression on myeloid cancer cells and leukemic stem cells, and its absence on hematopoietic stem cells, preventing targeting of critical immune system components17152 - CB-012 is currently in IND-enabling preclinical studies, with a planned IND application submission for r/r AML in the second half of 202317130 - Preclinical animal models demonstrated that CB-012 significantly reduced tumor burden and increased overall survival, with the PD-1 knockout strategy enhancing survival131132134173 CB-020 CB-020 is Caribou's first CAR-NK cell product from edited iPSCs, targeting ROR1 for solid tumors in preclinical development - CB-020 is a CAR-NK cell product candidate derived from edited iPSCs, designed to target ROR1, an antigen expressed on multiple solid tumors and associated metastases174177 - The iPSC-derived NK cell platform allows for multiple, sophisticated genome edits to iPSCs before differentiation into iNK cells, enabling the generation of armored iNK cells135163176 - Preclinical data demonstrated that anti-ROR1 CAR-NK cells exhibited increased tumor cell killing in vitro and significantly reduced tumor burden in solid tumor xenograft models in vivo138168179180 - Armoring strategies for the CAR-NK platform include CBLB knockout for enhanced antitumor activity, membrane-bound IL-15/IL-15RA fusion for enhanced cytotoxicity, and immune cloaking (B2M knockout and B2M–HLA-E insertion) to reduce T cell-mediated killing and NK fratricide169182 Strategic Agreements Caribou engages in strategic collaborations and in-licenses key technologies to accelerate therapeutic development and maximize platform value - Caribou seeks strategic collaborations to accelerate therapeutic development and maximize the value of its genome-editing technologies18232 AbbVie Manufacturing Management Unlimited Company Caribou collaborates with AbbVie to develop two allogeneic CAR-T cell therapies, receiving upfront payments and potential milestones/royalties - Collaboration agreement with AbbVie (Feb 2021) to develop two allogeneic CAR-T cell therapies using Cas12a chRDNA genome-editing technology1831218 - Caribou conducts preclinical R&D and manufacturing for Phase 1 clinical trials, with AbbVie reimbursing these activities1831218 AbbVie Collaboration Financials | Item | Amount | | :------------------------------------- | :------------- | | Upfront cash payment | $30.0 million | | Equity investment | $10.0 million | | Potential developmental/regulatory milestones (per program) | Up to $150.0 million | | Potential sales-based milestones (per program) | Up to $200.0 million | | Global royalties on net sales | High-single-digit to low-teens percent range | Memorial Sloan Kettering Cancer Center Caribou exclusively licensed CLL-1 targeting IP from MSKCC for CB-012, involving upfront payments, milestones, and royalties - Exclusive license from MSKCC (Nov 2020) for fully human scFvs targeting CLL-1 for allogeneic CLL-1-targeted cell therapy (used in CB-012)1871631286 MSKCC Agreement Financials | Item | Amount | | :------------------------------------- | :------------- | | Upfront payment | Cash and shares of common stock | | Potential clinical/regulatory/commercial milestones | Up to $112.0 million | | Royalties on net sales | Low-to-mid-single-digit percent | | Aggregate success payments | Up to $35.0 million | - Success payments are based on multiples of Caribou's common stock fair market value compared to an initial share price of $5.1914, payable in cash or common stock1881631287 ProMab Biotechnologies, Inc. ("ProMab") Caribou acquired an anti-BCMA scFv from ProMab for CB-011, involving an upfront payment and potential low-single-digit royalties - Acquired a humanized scFv targeting BCMA and related patent family from ProMab (Jan 2020) for an upfront cash payment of $0.4 million193 - The anti-BCMA scFv is used in Caribou's CB-011 product candidate193 - Caribou will owe low-single-digit percent royalties on net sales of CB-011 if regulatory approval is received193 Pioneer Hi-Bred International, Inc. ("Pioneer," now Corteva Agriscience) Caribou cross-licensed CRISPR IP with Pioneer, acquiring the chRDNA patent family for an upfront payment and future obligations - Cross-licensed CRISPR intellectual property portfolios with Pioneer (July 2015)1971300 - Pioneer assigned the chRDNA patent family to Caribou in December 2020 for an upfront payment of $0.5 million1941305 Pioneer Agreement Financials (Caribou's Obligations) | Item | Amount | | :------------------------------------- | :------------- | | Upfront payment | $0.5 million | | Regulatory milestones (for therapeutic products) | Up to $2.8 million | | Sales milestones (over 4 therapeutic products) | Up to $20.0 million | | Sublicensing revenues (chRDNA patent family) | Percentage of revenue | Intellia Therapeutics, Inc. ("Intellia") Caribou obtained an exclusive license from Intellia for CRISPR-Cas9 technology for CB-010 manufacturing, with an upfront payment and potential milestones/royalties - Granted Intellia an exclusive worldwide license to certain CRISPR-Cas9 technology for human therapeutics (July 2014)1981296 - Leaseback Agreement (June 2021) granted Caribou an exclusive license to CRISPR-Cas9, including Cas9 chRDNAs, for manufacturing CB-0102081297 Intellia Leaseback Agreement Financials (Caribou's Obligations) | Item | Amount | | :------------------------------------- | :------------- | | Upfront cash payment | $1.0 million | | Potential future regulatory and sales milestones | Up to $23.0 million | | Royalties on net sales of CB-010 | Low-to-mid-single-digit percent | The Regents of the University of California ("UC") and the University of Vienna ("Vienna") Caribou holds an exclusive license from UC and Vienna for foundational CRISPR-Cas9 IP, involving annual fees, milestones, and sublicensing revenue - Exclusive worldwide license from UC and Vienna (April 2013) to the foundational CRISPR-Cas9 patent family (CVC IP)2091281 - The license is non-exclusive with respect to Dr. Charpentier's co-owned rights, as she has not granted Caribou any direct or indirect rights2099731281 - Caribou pays annual license maintenance fees, potential regulatory and clinical milestone payments up to $3.4 million, and a percentage of sublicensing revenue2091281 - Caribou reimburses UC for CVC IP prosecution and maintenance costs, with CRISPR Therapeutics AG reimbursing 50% of these costs under the IMA20912811285 Intellectual Property Caribou protects its genome-editing technologies and product candidates through a robust IP portfolio, including numerous patents and trade secrets - As of March 1, 2023, Caribou owns 59 issued U.S. patents (including 9 for Cas9 and Cas12a chRDNA technologies), 257 issued foreign patents, and 74 pending patent applications worldwide212 - The company also relies on trade secrets, know-how, continuing technological innovation, and in-licensing opportunities to maintain its competitive position214 - Patent terms in the U.S. and other countries are generally 20 years from the first non-provisional application filing date, with potential for Patent Term Adjustment (PTA) or Patent Term Extension (PTE) for FDA-approved biologics213445 Competition Caribou operates in a highly competitive biopharmaceutical industry, leveraging its chRDNA platform for competitive advantages in allogeneic cell therapies - The biopharmaceutical industry, especially genome editing and cell therapy, is characterized by intense investment and competition215217865 - Competitors include major pharmaceutical companies, established biotechnology firms (e.g., Beam Therapeutics, CRISPR Therapeutics, Editas Medicine, Intellia), and companies developing other genome-editing technologies (e.g., bluebird bio, Allogene Therapeutics, Precision BioSciences)215218223890 - Caribou believes its novel Cas12a chRDNA genome-editing platform offers competitive advantages through improved specificity, reduced off-target edits, and advanced multiplexed editing capabilities, aiming for superior allogeneic cell therapies with enhanced persistence218219 Manufacturing Caribou optimizes and transfers manufacturing processes to CMOs for cGMP-grade clinical material, focusing on GvHD risk reduction - Manufacturing processes for CB-010 and CB-011 have been optimized in-house and transferred to CMOs for cGMP-grade material production for Phase 1 clinical trials226231233 - The company relies on multiple CMOs for manufacturing individual components (chRDNA guides, Cas9/Cas12a proteins, AAV6 vectors) and the final CAR-T/CAR-NK cell products2455591003 - A critical step in the manufacturing process is the removal of residual TCR-expressing cells to reduce the likelihood of GvHD in patients227234 Government Regulation Caribou is subject to extensive and evolving legal and regulatory requirements for its product candidates, enforced by agencies like the FDA and EMA - Caribou is subject to extensive legal and regulatory requirements for research, development, testing, manufacturing, and commercialization of product candidates by agencies like the FDA and EMA86 - Product candidates are regulated as biological products (biologics) under the Public Health Service Act (PHSA) and the Federal Food, Drug, and Cosmetic Act (FDCA) in the United States8783 - The regulatory landscape for gene therapy and cell therapy products, especially novel genome-edited ones, is still developing and subject to frequent changes, creating uncertainty and potential for delays548549 Licensure and Regulation of Biologics in the United States U.S. biologics licensure requires preclinical testing, IND submission, clinical trials, cGMP manufacturing, and BLA approval by the FDA - Product candidates are regulated as biologics under the PHSA and FDCA by the FDA8783 - The approval process involves preclinical testing, IND submission, human clinical trials (cGCP), cGMP manufacturing, and BLA submission and approval84243492 - Failure to comply with requirements can lead to delays in clinical trials, regulatory review, approval, and administrative or judicial sanctions83 Preclinical Studies and Investigational New Drug Applications Preclinical testing under cGLP precedes IND submission to the FDA, which has 30 days to review before human trials can begin - Preclinical testing, including laboratory evaluations and formulation studies, must comply with the FDA's current Good Laboratory Practice (cGLP) regulations68493 - Results of preclinical tests, manufacturing information, and analytical data are submitted to the FDA as an IND application493 - The FDA has 30 calendar days to review an IND application; concerns raised during this period must be resolved before human clinical trials can commence, with potential for clinical holds493 Human Clinical Trials in Support of a BLA Clinical trials involve phased human testing under cGCP and IRB protocols, with extensive monitoring and reporting requirements for regulatory approval - Clinical trials involve administering product candidates to patients under qualified principal investigators, adhering to cGCP requirements and IRB-approved study protocols494502 - Trials typically progress through Phase 1 (safety, dose tolerance), Phase 2 (safety, efficacy, optimal dosage), and Phase 3 (expanded population, overall benefit-risk)507508511 - Regulatory agencies require extensive monitoring, auditing, and reporting, including annual progress reports and expedited IND safety reports for suspected unexpected serious adverse reactions (SUSARs)512 - Human gene transfer trials may be subject to Institutional Biosafety Committee (IBC) oversight, and the Food and Drug Omnibus Reform Act of 2022 requires diversity action plans for clinical trials505506 Compliance with cGMP and cGTP Requirements FDA inspects manufacturing facilities for cGMP compliance and cGTP for HCT/Ps, ensuring product quality and preventing communicable disease transmission - FDA inspects manufacturing facilities to ensure full compliance with cGMP requirements before BLA approval, ensuring consistent product quality514 - For human cells, tissues, and cellular and tissue-based products (HCT/Ps), compliance with cGTP is required to prevent the introduction, transmission, and spread of communicable disease517 - Material changes in manufacturing equipment, location, or process post-approval may result in additional regulatory review and approval516 Guidance Governing Gene Therapy Products FDA CBER regulates gene therapy products, issuing guidance on design, CMC, and risks, with long-term follow-up often recommended - The FDA defines gene therapy products as those mediating effects by transferred genetic material or altering host genetic sequences, regulated by CBER345 - FDA guidance documents provide recommendations for gene therapy products, including human genome editing and CAR-T cells, covering design, delivery, CMC, risk of unregulated proliferation, and off-site editing346 - Compliance with FDA guidance, though not legally binding, is likely necessary for product approval, and long-term follow-up (up to 15 years) for delayed adverse events is often recommended480 Clinical Trial Registry Caribou must register ongoing clinical trials and post results on public registries like ClinicalTrials.gov, with non-compliance leading to penalties - Caribou is required to register ongoing clinical trials and post results of completed clinical trials to public registries, such as ClinicalTrials.gov481992 - Disclosure includes product information, patient population, phase of investigation, clinical trial sites, and investigators481 - Failure to comply with reporting requirements can result in fines, adverse publicity, and civil and criminal sanctions992 Review and Approval of a BLA FDA reviews BLAs for safety, purity, and potency, involving in-depth review, advisory committees, and facility inspections before commercial marketing approval - The FDA approves a BLA if the product candidate is determined to be safe, pure, and potent, and the manufacturing facility meets standards348 - The review process includes an initial filing review, an in-depth review (10 months standard, 6 months priority), potential advisory committee consultation, and inspections of manufacturing and clinical sites347357243 - Approval authorizes commercial marketing with specific prescribing information; a complete response letter outlines conditions for approval, and the FDA may also require post-approval studies or Risk Evaluation and Mitigation Strategies (REMS)349358360 Fast Track, Breakthrough Therapy, Priority Review, and Regenerative Medicine Advanced Therapy Designations FDA offers expedited review programs for serious conditions with unmet needs, like RMAT and Fast Track for CB-010, to accelerate development - FDA offers expedited review programs (Fast Track, Breakthrough Therapy, Priority Review, RMAT) for products treating serious or life-threatening diseases with unmet medical needs361 - CB-010 has received RMAT designation for relapsed or refractory large B cell lymphoma (LBCL) and Fast Track designation for r/r B-NHL374 - These designations provide benefits like early interactions with FDA, timely advice, rolling review, and eligibility for accelerated approval, but do not change the standards for FDA approval361362371 Accelerated Approval Pathway Accelerated approval is granted for serious conditions based on surrogate endpoints, requiring post-marketing confirmatory studies to verify clinical benefit - Accelerated approval is granted for serious or life-threatening conditions based on surrogate or intermediate clinical endpoints that are reasonably likely to predict clinical benefit375376 - This pathway is commonly used for cancers where long-term clinical benefit is difficult to measure quickly377 - Accelerated approval is contingent on conducting post-approval confirmatory studies to verify clinical benefit; failure to do so can result in product withdrawal from the market377 Post-Approval Regulation Approved products face ongoing regulatory requirements, including adverse event reporting, manufacturing compliance, and potential for approval withdrawal or sanctions - Post-approval, products are subject to ongoing regulatory requirements, including reporting adverse reactions, manufacturing problems, and complying with advertising and promotional labeling386397 - Manufacturers must register with the FDA and undergo periodic inspections for cGMP compliance386 - Failure to maintain compliance or discovery of new problems can lead to approval withdrawal, post-marketing studies, REMS, product recalls, fines, or other sanctions389390396 Orphan Drug Designation Orphan drug designation for rare diseases grants 7 years of market exclusivity if first approved, as with CB-010 for follicular lymphoma - Orphan drug designation is for rare diseases (fewer than 200,000 US individuals or non-recoverable development costs)398 - Designation grants 7 years of market exclusivity if the product is the first approved for the same orphan indication398 - CB-010 was granted orphan drug designation for follicular lymphoma in 2022411 - Orphan drug designation does not expedite regulatory review, and the legal framework for exclusivity remains uncertain, potentially impacting future designations39976555 Pediatric Studies and Exclusivity PREA requires pediatric data for novel BLAs, with pediatric exclusivity adding six months of marketing protection for accepted data - PREA requires BLAs for certain novel products to contain data on safety and effectiveness in all relevant pediatric subpopulations, or sponsors must submit a pediatric study plan and may request deferrals or waivers412413414 - Pediatric exclusivity provides an additional six months of marketing protection to existing regulatory exclusivity if pediatric data, responsive to an FDA written request, is submitted and accepted415 - This exclusivity is not a patent term extension but extends the regulatory period during which the FDA cannot approve another application415 Biosimilars and Exclusivity BPCIA established an abbreviated biosimilar pathway, granting 12 years of exclusivity for reference products, though legal interpretations remain uncertain - The BPCIA created an abbreviated approval pathway for biosimilar biological products441 - A biosimilar application cannot be submitted until four years and approved until 12 years after the reference product's approval442 - Caribou believes its product candidates should qualify for the 12-year exclusivity, but legal interpretation uncertainty and potential congressional action could shorten this period557 Patent Term Extension Hatch-Waxman Amendments allow up to five years of PTE for new biologics, compensating for patent term lost during development and FDA review - The Hatch-Waxman Amendments permit a limited PTE of up to five years for patents covering new biologic products, compensating for patent term lost during development and FDA review445 - PTE cannot extend the remaining patent term beyond 14 years from the product's regulatory approval date, and only one patent covering an approved product is eligible445 - Eligibility for PTE requires exercising due diligence during the clinical phase and regulatory review process, and applying within applicable deadlines89912 Regulation and Procedures Governing Approval of Medicinal Products in Other Countries Marketing products outside the U.S. requires compliance with diverse and complex foreign regulatory requirements, which can be lengthy and vary significantly - Marketing products outside the U.S. requires compliance with numerous and comprehensive regulatory requirements of other countries and jurisdictions, including the EU and UK44678851 - The approval process varies significantly by country and can involve additional testing, with some countries requiring reimbursement price agreement before marketing44681 - FDA approval does not ensure approval by foreign regulatory authorities, and delays or inability to obtain foreign approvals could limit market potential and revenue generation446851 U.S. Export Control Licensing Requirements and Other U.S. and Foreign Trade Regulations, Sanctions Laws, Anti-Corruption, and Anti-Money Laundering Laws Caribou's international activities are subject to complex export controls, trade regulations, sanctions, and anti-corruption laws, with non-compliance risking severe penalties - Caribou's product candidates and international activities are subject to U.S. export control licensing requirements, foreign investment regulations, international trade laws (e.g., FCPA), sanctions laws, and anti-money laundering laws447476477895897 - Compliance with these complex laws is costly and critical, particularly when interacting with public officials or engaging in international collaborations896 - Violations can result in fines, criminal sanctions, facility closures, export license requirements, cessation of business activities in sanctioned countries, and damage to reputation and business prospects898 Coverage, Pricing, and Reimbursement Uncertainty in third-party payor coverage and reimbursement, along with governmental price regulation, could significantly impact product sales and profitability - Significant uncertainty exists regarding coverage and reimbursement for product candidates by third-party payors (government healthcare programs, commercial health insurers, managed care organizations) in the U.S. and other countries47848981861 - Payors determine coverage and reimbursement based on whether the product is a covered benefit, safe, effective, medically necessary, cost-effective, and not experimental490495 - Inadequate coverage or reimbursement rates, or governmental price regulation, could reduce physician utilization, deter patients, and materially adversely affect sales, results of operations, and financial condition49681885 Healthcare Law and Regulation Caribou is subject to complex fraud, abuse, and data privacy laws (e.g., HIPAA, GDPR), with violations leading to significant penalties and reputational harm - Healthcare providers and third-party payors are subject to fraud and abuse laws (e.g., AKS, False Claims Act, Beneficiary Inducement Statute) and data privacy/security laws (e.g., HIPAA, CCPA, GDPR)500509486487892901 - Compliance is complex and costly, with varying requirements across federal, state, and international jurisdictions, and violations can lead to significant penalties, including civil, criminal, and administrative sanctions83509892894 - The regulatory framework for data privacy is rapidly evolving, with stringent requirements under GDPR (EU) and CCPA (California), imposing obligations on data processing, consent, security, breach notification, and potential for substantial fines901487 Healthcare Reform U.S. healthcare reforms, including the ACA and IRA, aim to control drug pricing, potentially increasing development costs and reducing revenues - The U.S. healthcare industry is characterized by cost containment efforts, with federal and state proposals impacting pharmaceutical pricing and coverage520 - The Affordable Care Act and the Inflation Reduction Act of 2022 have introduced significant changes, including inflation rebates, Medicare Part D benefit caps, and drug price negotiation521522355366887 - These reforms could increase the difficulty and cost of obtaining approval and commercializing product candidates, potentially leading to lower reimbursement and reduced demand82862887 Additional Regulations Caribou is subject to federal and state environmental and hazardous substance laws, with non-compliance risking liability and significant costs - Caribou's business is subject to federal and state environmental protection and hazardous substance laws (e.g., OSHA, RCRA, TSCA)3681060 - These laws govern the use, handling, and disposal of various biological, chemical, and radioactive substances and wastes generated by operations3681060 - Contamination or injury from hazardous materials could result in liability for damages, governmental fines, and significant compliance costs3681060 Employee and Human Capital Resources Caribou had 137 employees as of March 2023, with 77% in R&D, focusing on attracting and retaining talent through an inclusive environment - As of March 1, 2023, Caribou had 137 employees, with 77% primarily engaged in research and development activities378 - 53% of research and development personnel hold one or more advanced degrees378 - The company focuses on attracting, motivating, and retaining talent through competitive compensation, comprehensive benefits, and an inclusive environment to support its pipeline and future goals381382 Diversity, Equity, and Inclusion Caribou is committed to DEI, with an Inclusion Committee driving initiatives; 53% of employees identify as female, and 49% as underrepresented - Caribou is committed to cultivating, fostering, and preserving a culture of diversity, equity, and inclusion (DEI)384 - An Inclusion Committee, formed in 2021, emphasizes DEI, provides diversity awareness and unconscious bias training, and works to identify gaps in hiring and retention practices391 Employee Diversity Metrics (as of March 1, 2023) | Metric | Percentage | | :------------------------------------- | :------------- | | Employees identifying as female | 53% | | Director-level and above identifying as female | 49% | | Employees identifying as member of at least one underrepresented group | 49% | | Director-level and above identifying as member of at least one underrepresented group | 40% | | Average age of employees | 40 years | Involvement in Our Community Caribou actively engages in community outreach, including STEM programs, and promotes environmental consciousness through various initiatives - Caribou actively participates in community outreach, including hosting and providing volunteers for STEM programs at local schools and universities393 - Employees receive eight hours of paid volunteer time each year for community activities393 - The company is environmentally conscious, offering commuter benefits, bicycle vouchers, EV charging, water filtration, and waste sorting to mitigate its environmental impact394 Information Available on the Internet Caribou communicates material information via its investor relations website, SEC filings, press releases, and public conference calls - Caribou announces material information via its investor relations website (https://cariboubio.com/investors), SEC filings, press releases, public conference calls, and webcasts402 - Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and other filings are available on the company's website and the SEC's website (http://www.sec.gov)[402](index=402&type=chunk) Risk Factors Investing in Caribou's common stock involves high risk due to early development, significant losses, and uncertainties in clinical, regulatory, and competitive landscapes - Investing in Caribou's common stock involves a high degree of risk, and investors should carefully consider the risks and uncertainties outlined404 - The company has incurred significant net losses since inception and anticipates continued losses, requiring substantial additional financing for product development and commercialization405406419 - Risks include the difficulty in predicting development time and cost for novel CRISPR chRDNA genome-editing technologies, potential failure of clinical trials, serious adverse events, and challenges in obtaining regulatory approval261450451453534 - Other significant risks involve intense competition, complex intellectual property landscape, reliance on third parties for manufacturing and clinical trials, and the volatility of the common stock market price921521827992598210741091 Risks Relating to Our Financial Position and Need for Additional Capital Caribou has incurred significant net losses and requires substantial additional financing, with failure to obtain it risking development delays or dilution - Caribou has incurred significant net losses since inception, with $99.4 million in 2022 and $66.9 million in 2021, and an accumulated deficit of $197.2 million as of December 31, 2022405406 - The company expects to incur significant expenses and net losses for the foreseeable future as it advances product candidates through development, expands R&D, and seeks regulatory approval4074091148 - Substantial additional financing is required, and failure to obtain it could delay or prevent development and commercialization, potentially causing dilution to stockholders or requiring relinquishment of rights260419426427430 - As of December 31, 2022, cash, cash equivalents, and marketable securities totaled $317.0 million, expected to fund the current operating plan for at least the next 12 months4211241187 Risks Relating to Our Business, Government Regulation, Technology, and Industry Caribou faces high risks of clinical failure, adverse events, regulatory uncertainty, intense competition, and compliance challenges due to its novel technology - Caribou's limited operating history and reliance on novel CRISPR chRDNA genome-editing technologies make it difficult to predict future performance, development time, and cost, with a high risk of failure in preclinical and clinical stages6261433434436450451 - Product candidates may cause serious adverse events (SAEs) or undesirable side effects, including injury and death, which could delay or prevent regulatory approval and limit commercial potential8453534535 - The regulatory approval process is expensive, time-consuming, and uncertain, especially for innovative cell therapies, and may be subject to changing requirements and guidance262543544548549 - The company faces significant competition from other biotechnology and pharmaceutical companies, which may develop or commercialize products more successfully, rendering Caribou's candidates non-competitive9215844865 - Business operations are subject to extensive healthcare regulatory laws (fraud, abuse, privacy), export controls, and trade regulations, with potential for penalties and reputational damage from non-compliance55476500868895 Risks Relating to Our Intellectual Property Uncertainty in patent enforceability, infringement claims, reliance on third-party licenses, and ongoing IP disputes pose significant risks to Caribou's IP protection - The strength of patents in biotechnology and genome editing is uncertain, and Caribou may not be able to obtain or maintain sufficient intellectual property protection for its technologies and product candidates1038265876878902903 - Third-party claims of intellectual property infringement could prevent or delay commercialization, leading to substantial litigation expenses, monetary damages, or the need for commercially unviable licenses281925926927929 - Caribou relies on licenses and assignments from third parties (e.g., MSKCC, ProMab, Pioneer, UC/Vienna), and failure to comply with contractual obligations could result in the loss of intellectual property rights or litigation38918939965967968 - Ongoing administrative patent proceedings related to foundational CRISPR-Cas9 intellectual property (CVC IP) could substantially impair Caribou's ability to receive licensing revenue and enter new licensing arrangements265972973975976 - Protecting trade secrets and know-how is difficult, and changes to patent law could diminish the value of patents, adversely affecting Caribou's competitive position214913951954977979 Risks Relating to Our Relationships with Third Parties Caribou's reliance on CMOs, CROs, and collaborators introduces risks of supply interruptions, quality issues, clinical trial delays, and partnership termination - Caribou relies on third-party CMOs and suppliers for materials and manufacturing of clinical product candidates, facing risks of supply issues, quality problems, and intellectual property disputes27995896698298310031005 - Dependence on CROs, clinical trial sites, and principal investigators to conduct clinical trials poses risks of delays, non-compliance with cGCPs, or compromised data quality263988989100810091011 - Collaborations, including the one with AbbVie, involve risks such as delays in timelines, insufficient resource allocation by collaborators, or termination, which can adversely affect milestone payments and royalties3129931012101310161043 - Reliance on healthy donor material for allogeneic CAR-T product candidates introduces risks related to donor cell quality, consistency, and procurement challenges9871007 Risks Relating to Employee Matters, Managing Growth, and Other Risks Relating to Our Business Caribou's success depends on retaining talent and managing growth, facing risks from cybersecurity breaches, employee misconduct, and product liability - Caribou's future success depends on its ability to retain executive officers and attract, retain, and motivate qualified personnel in a highly competitive industry11102310491050 - Anticipated growth requires continuous improvement of managerial, operational, and financial systems, and recruitment/training of additional personnel, posing significant challenges10261027105210531054 - Internal computer systems and those of third-party vendors are vulnerable to security breaches, which could disrupt development, compromise sensitive information, and expose the company to liability102810291030105510561058 - Risks include employee misconduct, non-compliance with regulatory standards, product liability lawsuits, and exposure to environmental, health, and safety laws103210331036105910601081 - The COVID-19 pandemic or other public health crises and geopolitical events may adversely impact business, preclinical studies, clinical trials, and financial markets106810691087 Risks Relating to Ownership of our Common Stock The market price of Caribou's common stock is volatile, influenced by clinical results and litigation, with reduced disclosure as an emerging growth company - The market price of Caribou's common stock has been, and may continue to be, volatile, leading to potential substantial losses for investors3910741091 - Stock price fluctuations are influenced by clinical trial results, regulatory decisions, competitor developments, financing efforts, and significant lawsuits10741075109210931113 - Caribou is subject to securities class action litigation, which can result in substantial costs and diversion of management's attention107611101093 - As an 'emerging growth company' and 'smaller reporting company,' Caribou utilizes reduced disclosure requirements, which may make its common stock less attractive to some investors1117111810971099 - Provisions in corporate documents and Delaware law may have anti-takeover effects, and failure to meet Nasdaq listing requirements could result in delisting1131124112511261127 Unresolved Staff Comments Caribou Biosciences has no unresolved staff comments from the SEC - There are no unresolved staff comments from the SEC1155 Properties Caribou leases approximately 71,735 square feet of R&D, lab, and office space in Berkeley, California, adequate for near-term needs - Caribou leases approximately 61,735 and 10,000 square feet of R&D, laboratory, and office space in Berkeley, California1132 - These leases expire in March 2031 and July 2032, respectively, with options for additional five-year extensions1132 - The company believes its existing facilities are adequate for near-term needs and that suitable additional facilities will be available in the future1111 Legal Proceedings Caribou is involved in a putative class action lawsuit challenging CB-010 disclosures, which the company intends to vigorously defend - A putative class action lawsuit was filed in February 2023 in the U.S. District Court for the Northern District of California against Caribou and certain officers/directors11571328 - The complaint challenges disclosures regarding CB-010's therapeutic effect and clinical/commercial prospects, alleging violations of Sections 11 and 15 of the Securities Act and Sections 10(b) and 20(a) of the Securities Exchange Act of 193411571328 - Caribou believes the lawsuit is without merit and intends to vigorously defend against it11571328 Mine Safety Disclosures Caribou Biosciences has no mine safety disclosures to report - Not applicable1134 PART II Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Caribou's common stock trades on Nasdaq, with 42 holders of record; no cash dividends have been paid, and IPO proceeds were $321.0 million - Caribou's common stock is traded on the Nasdaq Global Select Market under the symbol "CRBU"2561136 - As of March 3, 2023, there were approximately 42 holders of record of common stock1136 - The company has not declared or paid cash dividends and plans to retain future earnings for business operations11221137 - Net proceeds from the July 2021 IPO were $321.0 million, consistent with the planned use1139 Reserved This item is reserved and contains no information - This item is reserved and contains no information1141 Management's Discussion and Analysis of Financial Condition and Results of Operations This section reviews Caribou's financial condition, results of operations, liquidity, and critical accounting policies, highlighting significant net losses and future capital needs - Caribou is a clinical-stage CRISPR genome-editing biopharmaceutical company focused on allogeneic CAR-T and CAR-NK cell therapies1163 - The company has incurred net losses since inception, with $99.4 million in 2022 and $66.9 million in 2021, and an accumulated deficit of $197.2 million as of December 31, 20221148117 - Existing cash, cash equivalents, and marketable securities of $317.0 million as of December 31, 2022, are expected to fund operations for at least the next 12 months1241187 - Future funding requirements are highly uncertain and depend on clinical trial progress, regulatory approvals, and business expansion1197125 Overview Caribou, a clinical-stage CRISPR company, incurred significant net losses in 2022 and 2021, with existing cash expected to fund operations for 12 months - Caribou is a clinical-stage CRISPR genome-editing biopharmaceutical company focused on allogeneic CAR-T and CAR-NK cell therapies1163 Net Losses and Accumulated Deficit | Metric | Year Ended Dec 31, 2022 (in millions) | Year Ended Dec 31, 2021 (in millions) | | :-------------------- | :------------------------------------ | :------------------------------------ | | Net Losses | $99.4 | $66.9 | | Accumulated Deficit | $197.2 | $97.7 | - Expenses are expected to increase substantially due to advancing clinical trials, expanding R&D, seeking regulatory approvals, and operating as a public company114811691190 - As of December 31, 2022, cash, cash equivalents, and marketable securities totaled $317.0 million, expected to fund operations for at least the next 12 months1241187 Components of Results of Operations This section details Caribou's revenue, R&D, G&A, other income, and income tax components, with R&D expenses expected to increase significantly - Revenue is primarily generated from licensing and collaboration agreements, including upfront fees, maintenance fees, milestones, and royalties11911511562 - Research and development expenses, comprising internal (personnel, facilities) and external (CROs, CMOs, licenses) costs, are expensed as incurred and are expected to increase substantially11741175120 - General and administrative expenses include personnel, intellectual property, consulting, and allocated overhead costs, with reimbursements for patent costs reducing these expenses1178121 - Other income (expense) primarily consists of interest income, changes in the fair value of equity investments, and changes in the fair value of the MSKCC success payments liability122569 Comparison of the Years Ended December 31, 2022 and 2021 Caribou saw increased revenue and expenses in 2022 compared to 2021, driven by the AbbVie agreement and higher R&D and G&A costs Key Financial Performance Comparison (2022 vs 2021) | Metric | 2022 (in thousands) | 2021 (in thousands) | Change (2022 vs 2021) | | :----------------------------------- | :------------------ | :------------------ | :-------------------- | | Licensing and collaboration revenue | $13,851 | $9,598 | +$4,253 | | Research and development expenses | $82,230 | $52,255 | +$29,975 | | General and administrative expenses | $38,020 | $24,322 | +$13,698 | | Total other income | $7,048 | $377 | +$6,671 | | Net loss | ($99,421) | ($66,923) | -$32,498 | - Licensing and collaboration revenue increased by $4.3 million, primarily driven by a $4.0 million increase from the AbbVie Agreement11811203 - Research and development expenses increased by $30.0 million, mainly due to higher personnel-related expenses ($10.8 million), external CMO manufacturing and CRO clinical activities ($10.3 million), and other R&D expenses ($7.3 million)1204 - General and administrative expenses increased by $13.7 million, primarily from personnel-related expenses ($9.2 million, including $5.3 million in stock-based compensation) and public company operating costs ($2.6 million)1183 - Total other income increased by $6.7 million, mainly due to a $4.5 million increase in interest inco