Homozygous familial hypercholesterolemia

Following favorable FDA feedback for the treatment of liver disease, the company is preparing further pre-IND meetings with the FDA for the treatment of atherosclerosis and familial hypercholesterolemia SYRACUSE, NY / ACCESSWIRE / April 2, 2024 / Repair Biotechnologies, Inc. ( ) announced today that its lipid nanoparticle (LNP)/messenger RNA (mRNA) therapy has rapidly reversed the progression of atherosclerosis in mouse models applicable to both the rare genetic condition of familial hypercholesterolemia as well as atherosclerosis in the broader population. Repair Biotechnologies develops gene therapies based on the proprietary Cholesterol Degrading Platform (CDP) that safely break down excess free cholesterol inside cells. Excess free cholesterol is toxic to cells and contributes to the development of numerous conditions, including atherosclerosis and metabolic dysfunction-associated steatohepatitis (MASH). Established therapies that reduce LDL-cholesterol in the bloodstream have little effect on intracellular free cholesterol. "Unfortunately statins and PCSK9 inhibitors that reduce LDL-cholesterol in the blood exhibit little ability to reduce the size of established atherosclerotic lesions," said Mourad Topors, Chief Scientific Officer at Repair Biotechnologies. "Our studies in severely atherosclerotic mice demonstrate that LDL-cholesterol is the wrong target if the goal is the outright regression of plaque and dramatic reduction in risk of cardiovascular events. Instead, clearance of intracellular free cholesterol can potentially achieve these goals." Repair Biotechnologies scientists treated atherosclerotic APOE-null mice and LDLR-null mice over a period of six weeks with a CDP LNP-mRNA therapy, expressing therapeutic proteins that safely break down toxic free cholesterol in cells. APOE-null mice are a widely used, consensus model for atherosclerosis in the general population, while LDLR-null mice are the model for homozygous familial hypercholesterolemia, a genetic condition in which the LDLR gene suffers a loss of function mutation and which is characterized by greatly accelerated atherosclerosis. Both mouse models exhibited a dramatic reversal of atherosclerosis. Plaque in the aortic root of APOE-null mice exhibited a 19% drop in plaque lipids and a corresponding 23% increase in plaque collagen, indicating stabilization of soft, lipid-laden plaque that is prone to rupture. In LDLR-null mice, plaque obstruction of the aortic root was reduced by 17%, while treated mice exhibited a greatly improved capacity to run on a treadmill, a measure of cardiovascular health. "Our new results in atherosclerotic mice are as impressive as the results we achieved in mouse models of MASH," said Reason, co-founder and CEO of Repair Biotechnologies. "We are preparing for mid-2024 pre-IND meetings with the FDA for treatment of the rare genetic condition of homozygous familial hypercholesterolemia, as well as the treatment of atherosclerosis more generally. Our LNP-mRNA therapy is applicable in principle to the reversal of all forms of atherosclerosis." In high-fat diet mouse models of MASH, Repair Biotechnologies scientists have demonstrated as much as a 44% reduction in measures of liver fibrosis following eight weeks of CDP LNP-mRNA treatment. In March 2024, Repair Biotechnologies received favorable and comprehensive pre-IND feedback from the FDA. The company leadership looks forward to bringing this treatment to the clinic. Contact Information Reason CEO and Co-Founder press@repairbiotechnologies.com +1 315-299-2407 SOURCE: Repair Biotechnologies, Inc. View the original press release on newswire.com.

Approval extends treatment of Praluent to children aged 8 and older with heterozygous familial hypercholesterolemia (HeFH) TARRYTOWN, N.Y., March 11, 2024 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced the U.S. Food & Drug Administration (FDA) has extended the approval of Praluent® (alirocumab) as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C) lowering therapies to include pediatric patients aged 8 and older with heterozygous familial hypercholesterolemia (HeFH). “Many children with heterozygous familial hypercholesterolemia (HeFH) are able to substantially improve their LDL-C (bad cholesterol) with currently available therapies. But for those children whose LDL-C remains dangerously high, this approval is an important milestone as it gives these children and their families an additional option to help reduce and manage their LDL-C levels much earlier in their lives,” said Mary P. McGowan, M.D., Chief Medical Officer of the Family Heart Foundation. Familial hypercholesterolemia (FH) is an inherited condition caused by mutations in one of several genes that control how the body processes cholesterol, which can lead to very high levels of LDL-C (bad cholesterol). FH can come in two forms: HeFH, which develops when one mutated gene is inherited from one parent; and homozygous familial hypercholesterolemia (HoFH), which develops when a mutated gene is inherited from both parents. Praluent is approved to treat both children and adults with HeFH and adults with HoFH. The approval is based on a Phase 3, randomized multicenter trial evaluating pediatric patients aged 8 to 17 with HeFH, who had LDL-C levels of 130mg/dL or greater and were already being treated with lipid-lowering medications. Patients were randomized to receive Praluent (N=101) or placebo (N=52) every two or four weeks in two consecutive cohorts. Patients who received Praluent every four weeks had 31% lower LDL-C than placebo at 24 weeks (97.5% Confidence Interval: -45.0% to -17.9%; p<0.0001). Improvements in additional key lipid parameters were also observed. Results from the trial were recently published in the Journal of the American Medical Association Pediatrics. No new adverse reactions were identified in this trial, and the safety pro consistent with the safety pro in adults with HeFH. Across Praluent trials in patients with primary hyperlipidemia (N=2,476), the most common adverse reactions (≥5%) more frequently observed with Praluent than placebo have been injection site reactions (7%), and influenza (6%) and diarrhea (5%). “The approval of Praluent for the treatment of high cholesterol was a historic landmark achievement, as it was the first approved therapy targeting the genetically-validated PCSK9 target for heart disease,” said George D. Yancopoulos, M.D., Ph.D., Board co-Chair, President and Chief Scientific Officer at Regeneron, and a principal inventor of Praluent. “Praluent has made a meaningful impact in the treatment of adults with familial hypercholesterolemia, and we are proud that our innovation will now be able to help appropriate children with the heterozygous form of this disease manage their dangerously high levels of LDL-C.” About the Praluent HeFH Pediatric Trial The randomized multicenter Phase 3 trial consisted of a 24-week double-blind, placebo-controlled evaluating the efficacy and safety of Praluent in pediatric patients aged 8 to 17 years with HeFH (N=79). The primary endpoint was the percent change in LDL-C from baseline to week 24 in the Praluent and placebo treated patients. At baseline, patients were on a low-fat diet and being treated with background lipid-lowering therapy. In the trial, patients were randomized 2:1 to receive Praluent or placebo every 2 or 4 weeks. The Praluent dose was based on body weight. About Praluent Praluent inhibits the binding of PCSK9 to the LDL receptor and thereby increases the number of available LDL receptors on the surface of liver cells to clear LDL, which lowers LDL-C levels in the blood. Praluent was developed by Regeneron and Sanofi under a global collaboration agreement and invented by Regeneron using the company's proprietary VelocImmune® technology that yields optimized fully-human monoclonal antibodies. In the U.S., Praluent is currently indicated: to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease as an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C) lowering therapies in adults with primary hyperlipidemia including HeFH to reduce LDL-C as an adjunct to other LDL-C-lowering therapies in adults with HoFH to reduce LDL-C along with diet and other LDL-C lowering treatments in children aged 8 years and older with HeFH to reduce LDL-C In addition to the U.S., Praluent is approved in 60 countries, including the European Union, Japan, Canada, Switzerland and Brazil. About Regeneron’s VelocImmune Technology Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved fully human monoclonal antibodies currently available. This includes Evkeeza® (evinacumab-dgnb), REGEN-COV® (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent, Kevzara® (sarilumab), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). IMPORTANT SAFETY INFORMATION AND INDICATIONS INDICATIONS PRALUENT is an injectable prescription medicine used: in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization. along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia [HeFH]), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol. along with other LDL-lowering treatments in adults with a type of high cholesterol called homozygous familial hypercholesterolemia, who need additional lowering of LDL-C. along with diet and other LDL-C lowering treatments in children aged 8 years and older with HeFH to reduce LDL-C. It is not known if PRALUENT is safe and effective in children who are younger than 8 years of age or in children with other types of high cholesterol (hyperlipemias). IMPORTANT SAFETY INFORMATION Do not use PRALUENT if you are allergic to alirocumab or to any of the ingredients in PRALUENT. Before you start using PRALUENT, tell your healthcare provider about all of your medical conditions, including allergies, and if you are pregnant or plan to become pregnant or if you are breastfeeding or plan to breastfeed. Tell your healthcare provider or pharmacist about any medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. PRALUENT can cause serious side effects, including allergic reactions that can be severe and require treatment in a hospital. Stop using PRALUENT and call your healthcare provider or go to the nearest hospital emergency room right away if you have any symptoms of an allergic reaction including a severe rash, redness, hives, severe itching, trouble breathing, or swelling of the face, lips, throat, or tongue. The common side effects of PRALUENT include: redness, itching, swelling, or pain/tenderness at the injection site, flu or flu-like symptoms, diarrhea, muscle pain, muscle spasms and bruising. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Talk to your doctor about the right way to prepare and give yourself a PRALUENT injection and follow the “Instructions For Use” that comes with PRALUENT. In children aged 12 to 17 years, it is recommended that PRALUENT be given by or under the supervision of an adult. In children aged 8 to 11 years, PRALUENT should be given by a caregiver. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. Please click here for full Prescribing Information. About Regeneron Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for over 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases and rare diseases. Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world. For more information, please visit or follow Regeneron on LinkedIn. Forward-Looking Statements and Use of Digital Media This press release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (“Regeneron” or the “Company”), and actual events or results may differ materially from these forward-looking statements. Words such as “anticipate,” “expect,” “intend,” “plan,” “believe,” “seek,” “estimate,” variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of products marketed or otherwise commercialized by Regeneron and/or its collaborators or licensees (collectively, “Regeneron’s Products”) and product candidates being developed by Regeneron and/or its collaborators or licensees (collectively, “Regeneron’s Product Candidates”) and research and clinical programs now underway or planned, including without limitation Praluent® (alirocumab) for the treatment of pediatric patients aged 8 to 17 with heterozygous familial hypercholesterolemia; uncertainty of the utilization, market acceptance, and commercial success of Regeneron’s Products and Regeneron’s Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary), including the studies discussed or referenced in this press release, on any of the foregoing; the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron’s Product Candidates and new indications for Regeneron’s Products; the ability of Regeneron’s collaborators, licensees, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron’s Products and Regeneron’s Product Candidates; the ability of Regeneron to manage supply chains for multiple products and product candidates; safety issues resulting from the administration of Regeneron’s Products (such as Praluent) and Regeneron’s Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s Products and Regeneron’s Product Candidates in clinical trials; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron’s ability to continue to develop or commercialize Regeneron’s Products and Regeneron’s Product Candidates; ongoing regulatory obligations and oversight impacting Regeneron’s Products, research and clinical programs, and business, including those relating to patient privacy; the availability and extent of reimbursement of Regeneron’s Products from third-party payers, including private payer healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payers and new policies and procedures adopted by such payers; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron’s Products and Regeneron’s Product Candidates; the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators or licensees may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license, collaboration, or supply agreement, including Regeneron’s agreements with Sanofi and Bayer (or their respective affiliated companies, as applicable) to be cancelled or terminated; the impact of public health outbreaks, epidemics, or pandemics (such as the COVID-19 pandemic) on Regeneron's business; and risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings relating to EYLEA® (aflibercept) Injection), other litigation and other proceedings and government investigations relating to the Company and/or its operations, the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on Regeneron’s business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron’s filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2023. Any forward-looking statements are made based on management’s current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update (publicly or otherwise) any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise. Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron's media and investor relations website ( ) and its LinkedIn page ( ). Contacts: Media Relations Mary Heather Tel: +1 914-847-8650 mary.heather@regeneron.com Investor Relations Mark Hudson Tel: +1 914-847-3482 mark.hudson@regeneron.com

— CASGEVY™ approved in the U.S., European Union, Great Britain, the Kingdom of Saudi Arabia and Bahrain — — Clinical trials ongoing for next generation CAR T product candidates, CTX112™ and CTX131™ targeting CD19 and CD70, respectively — — Clinical trials ongoing for in vivo gene editing product candidates, CTX310™ and CTX320™ targeting ANGPTL3 and Lp(a), respectively — — Clinical trial ongoing for CTX211™, an allogeneic, hypoimmune, gene-edited, stem cell derived product candidate for the treatment of Type 1 Diabetes (T1D) — — Strengthened balance sheet with $280 million registered direct offering, bringing current cash position to >$2.1 billion — ZUG, Switzerland and BOSTON, Feb. 21, 2024 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today reported financial results for the fourth quarter and full year ended December 31, 2023. “2023 was a monumental year for CRISPR Therapeutics, with multiple milestones achieved across our pipeline, including the first-ever approval of a CRISPR-based gene-editing therapy in addition to entering the clinic with our first in vivo programs targeting cardiovascular diseases,” said Samarth Kulkarni, Ph.D., Chairman and Chief Executive Officer of CRISPR Therapeutics. “We continue to advance our next generation CAR T cell programs, CTX112 and CTX131, which have the potential to be best-in-class cell therapies for the treatment of both liquid and solid tumors. Additionally, we plan to initiate a clinical trial of CTX112 in systemic lupus erythematosus (SLE) in the first half of 2024, with the potential to expand into additional autoimmune indications in the future. We are excited about our first two in vivo programs that are now in the clinic, and also expect to nominate additional in vivo programs targeting both rare and common diseases mid-year. I am incredibly excited about the year ahead as we continue to innovate across our platform and execute on our clinical trials across various therapeutic areas, including oncology, autoimmune, cardiovascular and diabetes, setting up a catalyst-rich 12-18 months for the company.” Recent Highlights and Outlook Hemoglobinopathies and CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY has been approved in the U.S., E.U., Great Britain, Bahrain, and the Kingdom of Saudi Arabia (KSA) for the treatment of patients with either sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT). Nearly 35,000 patients are living with severe SCD or TDT in the U.S. and Europe alone. CASGEVY is the first therapy to emerge from a strategic partnership between CRISPR Therapeutics and Vertex Pharmaceuticals established in 2015. As part of an amendment to the collaboration agreement in 2021, Vertex now leads global development, manufacturing, regulatory and commercialization of CASGEVY with support from CRISPR Therapeutics.The regulatory submission for CASGEVY for both SCD and TDT is currently under review in Switzerland, with submission in Canada planned for the first half of 2024.Vertex reported progress on CASGEVY launch in the U.S. with the activation of 12 authorized treatment centers (ATCs) in the U.S. and the signing of an agreement with Synergie Medication Collective, a contracting organization which supports payors covering approximately 100 million people in the U.S., to provide access to CASGEVY. Additionally, Vertex is actively engaging with state Medicaid organizations to secure immediate reimbursement and coverage for CASGEVY.Outside the U.S., Vertex reported progress on the launch with the activation of three authorized treatment centers in the E.U. and one in KSA. Additionally, the French National Authority for Health (HAS) approved a request for the implementation of an early access program (EAP) for the use of CASGEVY to treat eligible people with TDT. Vertex is also pursuing an EAP submission for SCD in France and expects to hear the outcome of this decision in the coming months.CRISPR Therapeutics has two next-generation approaches that each have the potential to expand the addressable population with SCD and TDT significantly. CRISPR Therapeutics continues to advance its internally developed targeted conditioning program, an anti-CD117 (c-Kit) antibody-drug conjugate (ADC), through preclinical studies. Additionally, CRISPR Therapeutics has ongoing research efforts to enable in vivo editing of hematopoietic stem cells. This work, supported in part by a $14.5 million grant from the Bill & Melinda Gates Foundation, could obviate the need for conditioning altogether, expand geographic reach, and enable the treatment of multiple additional other diseases beyond SCD and TDT. Immuno-Oncology and Autoimmune Disease CRISPR Therapeutics’ next-generation allogeneic CAR T candidates reflect the Company’s mission of innovating continuously to bring potentially transformative medicines to patients as quickly as possible. Clinical trials are ongoing for CRISPR Therapeutics’ next-generation CAR T product candidates, CTX112™ and CTX131™, targeting CD19 and CD70, respectively. Emerging pharmacology data, including pharmacokinetics, indicate that the novel potency gene edits in CTX112 and CTX131 can lead to significantly higher CAR T cell expansion and functional persistence in patients compared to the first-generation candidates. Focusing efforts on these candidates will enable the Company to advance these potentially best-in-class CAR T therapies more efficiently and rapidly. The Company expects to provide a clinical update in 2024 for these next-generation candidates.CRISPR Therapeutics plans to initiate a clinical trial of CTX112 in systemic lupus erythematosus (SLE) in the first half of 2024, with the potential to expand into additional autoimmune indications in the future. Early clinical studies have shown that CD19-directed autologous CAR T therapy can produce long-lasting remissions in multiple autoimmune indications by deeply depleting B cells. The Company’s first generation allogeneic CD19-directed CAR T program has demonstrated that allogeneic CAR T cells can effectively deplete B cells in clinical trials in oncology settings, which supports the potential of CTX112 in autoimmune diseases.CRISPR Therapeutics is on track to initiate a Phase 1 trial of CTX131 in hematologic malignancies, including T- and B-cell malignancies, in the first half of 2024. CTX131 is currently in an ongoing clinical trial in solid tumors. In Vivo CRISPR Therapeutics continues to advance a pipeline of in vivo gene editing programs using lipid nanoparticle (LNP) delivery of Cas9 mRNA and a guide RNA (gRNA) to the liver. Its first two in vivo programs, CTX310™ and CTX320™, each aim to reduce expression of a validated target for cardiovascular disease. Beginning with these programs, CRISPR Therapeutics aims to transform the treatment paradigm for cardiovascular indications and beyond with potential one-time therapies that could recapitulate the proven benefit of targets validated by natural human genetics and other therapeutic modalities.A Phase 1 clinical trial is ongoing for CTX310, targeting angiopoietin-like 3 protein (ANGPTL3). In humans, naturally occurring loss-of-function variants of the ANGPTL3 gene are associated with reduced levels of serum lipids and reduced risk of atherosclerotic cardiovascular disease. The Phase 1 trial is open to patients with mixed dyslipidemias, homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, and severe hypertriglyceridemia.A Phase 1 clinical trial is ongoing for CTX320, targeting lipoprotein(a) (Lp(a)). Elevated Lp(a), which is associated with an increased risk of atherosclerotic cardiovascular disease, is present in approximately one in five people in the United States and around the world.CRISPR Therapeutics expects to nominate additional in vivo programs targeting both rare and common diseases this year, to be disclosed in mid-2024. Regenerative Medicine CRISPR Therapeutics continues to advance a Phase 1 clinical trial for CTX211™ for the treatment of Type 1 Diabetes (T1D). CRISPR Therapeutics remains committed to its goal of developing a beta-cell replacement product that does not require chronic immunosuppression.Vertex has non-exclusive rights to certain CRISPR Therapeutics’ CRISPR/Cas9 technology to accelerate development of potentially curative cell therapies for T1D. Vertex paid $170 million to CRISPR Therapeutics in upfront and milestone payments in 2023 as part of that licensing agreement, and CRISPR Therapeutics remains eligible for an additional $160 million in research and development milestones and would receive royalties on any future products resulting from this agreement. Other Corporate Matters In February 2024, CRISPR Therapeutics announced that it has entered into an investment agreement for the sale of approximately $280 million of its common shares to a select group of institutional investors in a registered direct offering, at a price per share of $71.50, representing a premium of greater than 10% to CRISPR Therapeutics’ 30-day volume-weighted average price. The financing is expected to close on or about February 27, 2024, subject to customary closing conditions. Fourth Quarter and Full Year 2023 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $1,695.7 million as of December 31, 2023, compared to $1,868.4 million as of December 31, 2022. The decrease in cash of $172.7 million was primarily driven by operating expenses, offset by payments received from Vertex in connection with a non-exclusive license agreement and related milestone, as well as interest income. Pro-forma cash, cash equivalents, and marketable securities were greater than $2.1 billion as of February 21, 2024, inclusive of a $200 million milestone received in January 2024 for the approval of CASGEVY and approximately $280 million in proceeds from the February 2024 registered direct offering.R&D Expenses: R&D expenses were $95.1 million for the fourth quarter of 2023, compared to $103.6 million for the fourth quarter of 2022. The decrease in R&D expense was primarily driven by reduced variable external research and manufacturing costs.G&A Expenses: General and administrative expenses were $16.5 million for the fourth quarter of 2023, compared to $21.2 million for the fourth quarter of 2022. The decrease in G&A expense was primarily driven by a decrease in external professional costs.Collaboration Expense: Collaboration expense, net, was $20.0 million for the fourth quarter of 2023, compared to $6.8 million for the fourth quarter of 2022. The increase of approximately $13.2 million in collaboration expense, net, was primarily driven by an additional $20 million licensing fee owed to Vertex in connection with the Amended and Restated Joint Development and Collaboration Agreement, offset by the fact that we reached the $110.3 million deferral limit on costs related to the CASGEVY program in the third quarter of 2023, whereas the limit was not reached until the fourth quarter of 2022.Net Income (Loss): Net income was $89.3 million for the fourth quarter of 2023, compared to a net loss of $110.6 million for the fourth quarter of 2022. About CASGEVY™ (exagamglogene autotemcel [exa-cel])CASGEVY™ is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients. About the CRISPR Collaboration and VertexCRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CASGEVY (exa-cel) represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing, and commercialization of CASGEVY and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics. Vertex is the manufacturer and exclusive license holder of CASGEVY™. About CTX112 CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 19, or CD19, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. About CTX131 CTX131 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX131 incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX131 is being investigated in a clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors. About in vivoOur lead investigational in vivo programs, CTX310 and CTX320, target angiopoietin-related protein 3 (ANGPTL3) and lipoprotein(a) (Lp(a)), respectively, two validated targets for cardiovascular disease, and we have initiated a Phase 1 clinical trial for both. About CTX211 CTX211 is an allogeneic, gene-edited, stem cell-derived investigational therapy for the treatment of T1D, which incorporates gene edits that aim to make cells hypoimmune and enhance cell fitness. This immune-evasive cell replacement therapy is designed to enable patients to produce their own insulin in response to glucose. About CRISPR TherapeuticsSince its inception over a decade ago, CRISPR Therapeutics has transformed from a research-stage company advancing programs in the field of gene editing, to a company with a diverse portfolio of product candidates across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine, cardiovascular and rare diseases. The Nobel Prize-winning CRISPR science has revolutionized biomedical research and represents a powerful, clinically validated approach with the potential to create a new class of potentially transformative medicines. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer and Vertex Pharmaceuticals. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts and San Francisco, California, and business offices in London, United Kingdom. To learn more, visit www.crisprtx.com. CRISPR THERAPEUTICS® standard character mark and design logo, CTX112™, CTX131™, CTX310™, CTX320™, CTX211™ and VCTX211™ are trademarks and registered trademarks of CRISPR Therapeutics AG. The CASGEVY™ word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks and registered trademarks are the property of their respective owners. CRISPR Therapeutics Forward-Looking StatementThis press release may contain a number of “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Kulkarni in this press release, as well as statements regarding CRISPR Therapeutics’ expectations about any or all of the following: (i) its plans for and its preclinical studies, clinical trials and pipeline products and programs, including, without limitation, manufacturing capabilities, status of such studies and trials, potential expansion into new indications and expectations regarding data generally; (ii) the data that will be generated by ongoing and planned clinical trials, and the ability to use that data for the design and initiation of further clinical trials; (iii) plans and expectations for the commercialization of, and anticipated benefits of, CASGEVY, including the anticipated patient populations eligible for CASGEVY in jurisdictions where it has been or may be approved; (iv) the sufficiency of its cash resources; (v) the expected benefits of its collaborations; and (vi) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words “believes,” “anticipates,” “plans,” “expects” and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the efficacy and safety results from ongoing clinical trials will not continue or be repeated in ongoing or planned clinical trials or may not support regulatory submissions; regulatory authorities may not approve exa-cel on a timely basis or at all; adequate pricing or reimbursement may not be secured to support continued development or commercialization of exa-cel following regulatory approval; clinical trial results may not be favorable; one or more of its product candidate programs will not proceed as planned for technical, scientific or commercial reasons; future competitive or other market factors may adversely affect the commercial potential for its product candidates; initiation and completion of preclinical studies for its product candidates is uncertain and results from such studies may not be predictive of future results of future studies or clinical trials; regulatory approvals to conduct trials or to market products are uncertain; uncertainties inherent in the operation of a manufacturing facility; it may not realize the potential benefits of its collaborations; uncertainties regarding the intellectual property protection for its technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics’ most recent annual report on Form 10-K, quarterly report on Form 10-Q and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law. Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com Media Contact:Rachel Eides+1-617-315-4493rachel.eides@crisprtx.com CRISPR Therapeutics AGCondensed Consolidated Statements of Operations(Unaudited, In thousands except share data and per share data) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 Revenue: Collaboration revenue $200,000 $6 $370,000 $436 Grant revenue 1,206 — 1,206 762 Total revenue 201,206 $6 $371,206 $1,198 Operating expenses: Research and development 95,144 103,555 387,332 461,645 General and administrative 16,479 21,169 76,162 102,464 Collaboration expense, net 20,000 6,823 130,250 110,250 Total operating expenses 131,623 131,547 593,744 674,359 Income (loss) from operations 69,583 (131,541) (222,538) (673,161)Total other income, net 19,997 11,490 71,816 22,661 Net income (loss) before income taxes 89,580 (120,051) (150,722) (650,500)(Provision) benefit for income taxes (233) 9,476 (2,888) 325 Net income (loss) 89,347 (110,575) (153,610) (650,175)Foreign currency translation adjustment 61 115 73 (80)Unrealized gain (loss) on marketable securities 8,649 6,501 17,487 (10,500)Comprehensive income (loss) $98,057 $(103,959) $(136,050) $(660,755)Net income (loss) per common share — basic $1.12 $(1.41) $(1.94) $(8.36)Basic weighted-average common shares outstanding 79,688,337 78,336,506 79,220,930 77,746,575 Net income (loss) per common share — diluted $1.10 $(1.41) $(1.94) $(8.36)Diluted weighted-average common shares outstanding 81,324,786 78,336,506 79,220,930 77,746,575 CRISPR Therapeutics AGCondensed Consolidated Balance Sheets Data(Unaudited, in thousands) As of December 31, 2023 December 31, 2022 Cash and cash equivalents $389,477 $211,885 Marketable securities 1,304,215 1,603,433 Marketable securities, non-current 1,973 53,130 Working capital 1,799,287 1,731,919 Total assets 2,229,571 2,243,057 Total shareholders' equity 1,882,803 1,875,479