On November 6, 2023 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported financial results for the third quarter ended September 30, 2023 (Press release, CRISPR Therapeutics, NOV 6, 2023, View Source [SID1234637018]).
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"The third quarter marked significant progress across our broad clinical pipeline of potentially curative gene edited therapies," said Samarth Kulkarni, Ph.D., Chief Executive Officer and Chairman of the Board of CRISPR Therapeutics. "We are excited about the upcoming PDUFA date for exa-cel, which could potentially bring a transformative therapy to patients living with sickle cell disease. If approved, exa-cel would be the first CRISPR-based medicine available to patients in the U.S., highlighting the groundbreaking opportunity of this technology to treat people with serious diseases. Additionally, we are excited to initiate clinical trials for our in vivo programs, adding a new pillar to our clinical portfolio. We remain well positioned and well capitalized to bring several transformative medicines for patients suffering from serious diseases."
Recent Highlights and Outlook
Hemoglobinopathies
In October, the U.S. Food and Drug Administration’s (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee completed their meeting for exagamglogene autotemcel (exa-cel) for the treatment of sickle cell disease (SCD) in people ages 12 and older with recurrent vaso-occlusive crises (VOCs). Exa-cel is the first potential therapy to emerge from a strategic partnership between CRISPR Therapeutics and Vertex Pharmaceuticals.
In November, it was announced that two abstracts (details below) on exa-cel clinical data have been accepted for oral presentations at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. The updated clinical data will include additional patients with longer follow-up duration from pivotal Phase 3 trials demonstrating exa-cel’s potential as a one-time functional cure for SCD and transfusion-dependent beta thalassemia (TDT). The accepted abstracts are available online on the ASH (Free ASH Whitepaper) website.
Abstract #1052 entitled "Exagamglogene Autotemcel for Severe Sickle Cell Disease" will be an oral presentation on Monday, December 11 at 4:45 pm PST.
Abstract #1053 entitled "Exagamglogene Autotemcel for Transfusion-Dependent Βeta-Thalassemia" will be an oral presentation on Monday, December 11 at 5:00 pm PST.
CRISPR Therapeutics and Vertex Pharmaceuticals previously announced that the FDA accepted the Biologics License Applications (BLAs) for exa-cel for severe SCD and TDT. The FDA has granted Priority Review for SCD and Standard Review for TDT and assigned Prescription Drug User Fee Act (PDUFA) target action dates of December 8, 2023, and March 30, 2024, respectively. In the U.S., exa-cel has been granted Fast Track, Regenerative Medicine Advanced Therapy (RMAT), Orphan Drug and Rare Pediatric Disease designations.
A marketing authorization application for exa-cel has also been submitted to the Saudi Food and Drug Authority (SFDA). Exa-cel is the first investigational medicine to receive Breakthrough Designation from the SFDA, reflecting the high unmet need for patients with SCD and TDT in the Kingdom of Saudi Arabia.
The Phase 1/2/3 CLIMB-111 and CLIMB-121 studies and the CLIMB-131 long-term follow-up study are ongoing in patients 12 years of age and older.
Two global Phase 3 studies of exa-cel are ongoing for patients 5 to 11 years of age with TDT or SCD.
CRISPR Therapeutics continues to advance its anti-CD117 (c-Kit) antibody-drug conjugate (ADC), its internal targeted conditioning program, in preclinical studies. This targeted conditioning agent has the potential to significantly expand the patient population that can benefit from exa-cel.
Immuno-Oncology
Clinical trials are ongoing for CTX110 and CTX112, CRISPR Therapeutics’ first and next-generation allogeneic chimeric antigen receptor T cell CAR T) investigational therapies targeting CD19 in B-cell malignancies. Based on encouraging preliminary data, CTX110 was granted RMAT designation by the FDA.
Clinical trials are ongoing for CTX130 and CTX131, CRISPR Therapeutics’ first and next-generation allogeneic CAR T investigational therapies targeting CD70 in T cell malignancies and solid tumors. Based on encouraging preliminary data, CTX130 was granted RMAT designation by the FDA.
Earlier this month, CRISPR Therapeutics presented new preclinical data at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting demonstrating the continued advancement of its immuno-oncology programs and platform.
Regenerative Medicine
CRISPR Therapeutics and ViaCyte continue to collaborate on their existing gene-edited allogeneic stem cell therapies for the treatment of diabetes under the terms of their collaboration. The clinical trial for VCTX211 for the treatment of T1D is ongoing.
In Vivo
CRISPR Therapeutics continues to progress its in vivo platform, focused on lipid nanoparticle (LNP)-based delivery to the liver and extrahepatic tissues. The Company continues to advance multiple in vivo programs directed towards cardiovascular indications and beyond.
CRISPR Therapeutics initiated a Phase 1 clinical trial for CTX310, targeting angiopoietin-like 3 protein (ANGPTL3). Natural history studies have shown that individuals with natural loss-of-function variants of ANGPTL3 have lower triglyceride levels, lower LDL-C levels, and a lower risk of coronary artery disease, validating targeting ANGPTL3 for the treatment of atherosclerotic cardiovascular disease (ASCVD).
Additionally, CRISPR Therapeutics continues to advance CTX320, an investigational program targeting lipoprotein(a) (Lp(a)) and remains on track to enter the clinic in the first half of 2024. High levels of Lp(a) are an independent and causal risk factor for ASCVD. CTX310 and CTX320 have the potential to shift the treatment paradigm for ASCVD with a single-dose, potentially life-long durable editing approach.
In November, CRISPR Therapeutics announced preclinical data from the Company’s investigational programs for the treatment of cardiovascular disease at the American Heart Association (AHA) Scientific Sessions 2023. The data will be presented on Saturday, November 11, 2023, in two oral sessions, entitled "CTX310: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces ANGPTL3 Protein and Triglyceride Levels in Non-Human Primates After a Single Dose" and "CTX320: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces Lipoprotein(a) Levels in Non-Human Primates After a Single Dose."
Beyond CTX310 and CTX320, CRISPR Therapeutics is advancing additional programs utilizing in vivo delivery to address both rare and common diseases.
In October, CRISPR Therapeutics received a new grant from the Bill & Melinda Gates Foundation to research in vivo gene editing of hematopoietic stem and progenitor cells (HSPCs). The grant builds upon CRISPR Therapeutics’ proprietary gene editing technology and expertise in editing HSPCs and contributes to efforts to accelerate transformative medicines for global health.
Other Corporate Matters
In October, CRISPR Therapeutics announced its proposal to elect Sandy Mahatme, LL.M. to its Board of Directors at the Company’s upcoming annual general meeting to be held in 2024. Mr. Mahatme, LL.M., brings a considerable breadth of experience to CRISPR Therapeutics gained from his senior roles at industry-leading companies and has a strong track record of success in finance, business development and corporate strategy.
Third Quarter 2023 Financial Results
Cash Position: Cash, cash equivalents, and marketable securities were $1,739.8 million as of September 30, 2023, compared to $1,868.4 million as of December 31, 2022. The decrease in cash of $128.6 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.
R&D Expenses: R&D expenses were $90.7 million for the third quarter of 2023, compared to $116.6 million for the third 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 $18.3 million for the third quarter of 2023, compared to $27.0 million for the third 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 $23.4 million for the third quarter of 2023, compared to $38.9 million for the third quarter of 2022. The decrease of approximately $15.5 million in collaboration expense, net, was due to the fact that we reached the $110.3 million deferral limit on costs related to the exa-cel program in the third quarter of 2023, whereas the limit was not reached until the fourth quarter of 2022.
Net Loss: Net loss was $112.2 million for the third quarter of 2023, compared to a net loss of $174.5 million for the third quarter of 2022.
About exagamglogene autotemcel (exa-cel)
Exa-cel is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited cell therapy that is being evaluated for patients with SCD or TDT, in which a patient’s own hematopoietic stem cells are edited to produce 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. The elevation of HbF by exa-cel has the potential to reduce or eliminate painful and debilitating VOCs for patients with SCD and alleviate transfusion requirements for patients with TDT. Earlier results from these ongoing trials were published in The New England Journal of Medicine in January of 2021 and presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Congress in 2022 and the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in 2023.
Exa-cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. FDA for both TDT and SCD. The FDA has accepted the Biologics License Applications (BLAs) for exa-cel and assigned Prescription Drug User Fee Act (PDUFA) action dates of December 8, 2023, for SCD and March 30, 2024, for TDT.
In the EU, exa-cel has been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both SCD and TDT. In the U.K., exa-cel has also been granted an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the Medicines Healthcare products Regulatory Agency (MHRA). In Europe, the Marketing Authorization Applications (MAAs) for exa-cel were submitted in December 2022 and validated by the EMA and MHRA in January 2023.
About CLIMB-111 and CLIMB-121
The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after exa-cel infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.
About CLIMB-131
The ongoing long-term, open-label trial, CLIMB-131, is designed to evaluate the safety and efficacy of exa-cel in patients who received exa-cel in CLIMB-111, CLIMB-121, CLIMB-141, CLIMB-151 or CLIMB-161. The trial is designed to follow participants for up to 15 years after exa-cel infusion.
About CLIMB-141 and CLIMB-151
The ongoing Phase 3 open-label trials, CLIMB-141 and CLIMB-151, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 2 to 11 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now open for enrollment and currently enrolling patients ages 5 to 11 years with the plan to extend to ages 2 to less than 5 years at a later date. Each trial will enroll approximately 15 patients. Patients will be followed for approximately two years after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.
About CLIMB-161
The ongoing Phase 3b trial, CLIMB-161, is to support expansion of our manufacturing footprint after initial potential approval and launch. This trial will enroll approximately 12 patients with either TDT or with SCD, characterized by recurrent VOCs, ages 12 to 35 years. Patients will be followed for approximately one year after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.
About the CRISPR Collaboration and Vertex
CRISPR 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. 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 exa-cel and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics.
About CD19 Candidates
CTX110 is a wholly-owned, healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting cluster of differentiation 19, or CD19, and CTX112, a next-generation, wholly-owned, investigational, allogeneic CAR T product candidate targeting CD19, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. Both CTX110 and CTX112 are being investigated in ongoing clinical trials designed to assess the safety and efficacy of the applicable product candidate in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. CTX110 has been granted RMAT designation by the FDA.
About CD70 Candidates
CTX130 is a wholly-owned, healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting cluster of differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies, and CTX131, a next-generation, wholly-owned, investigational allogeneic CAR T product candidate targeting CD70 in a basket of solid tumors, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. The safety and efficacy of CTX130 is being evaluated in two independent clinical trials, one for the treatment of relapsed or refractory T or B cell malignancies and on for the treatment of relapsed or refractory clear cell renal cell carcinoma. 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. CTX130 has been granted Orphan Drug designation for the treatment of T cell lymphoma by the FDA and RMAT designation for the treatment of relapsed or refractory Mycosis Fungoides and Sézary Syndrome (MF/SS), types of cutaneous T cell lymphoma (CTCL).
About VCTX211
VCTX211 is an allogeneic, gene-edited, stem cell-derived investigational therapy for the treatment of T1D, which incorporates additional gene edits that aim to further enhance cell fitness. This immune-evasive cell replacement therapy is designed to enable patients to produce their own insulin in response to glucose.