On May 8, 2024 Enveric Biosciences, Inc (NASDAQ: ENVB), a biotechnology company dedicated to the development of novel neuroplastogenic small-molecule therapeutics for the treatment of depression, anxiety, and addiction disorders, reported that it has signed a non-binding term sheet with an undisclosed biotechnology development and commercialization company ("Licensee") to exclusively out-license two patent families of Methods for Treating Breast Cancer and Other Cancers for development through additional discovery and preclinical stages using cannabinoids in combination with chemotherapeutic drugs to treat cancer (Press release, Enveric Biosciences, MAY 8, 2024, View Source [SID1234642874]).

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In an historic move on Tuesday April 30, 2024, the Biden administration moved to reschedule marijuana, one source of cannabinoids, as a Schedule III controlled substance. The action followed study by the U.S. Department of Health and Human Services ("HHS"), recommendations by both HHS and the Department of Justice ("DOJ"), and support from the U.S. Drug Enforcement Agency ("DEA") that acknowledge the medical benefits of this class of drugs. Enveric applauds the move by the Biden administration which enjoys bi-partisan Congressional support and advances the development of medical uses of much needed drugs.

Under the terms of the agreement with Enveric, the Licensee will receive an exclusive, global license to the methods, and devices and drugs developed to practice the methods, which feature using cannabinoids in combination with chemotherapeutic drugs and will assume responsibility for all future preclinical and clinical development on a royalty-bearing basis for all human and animal pharmaceutical applications.

Assuming certain conditions are met, the Licensee will pay Enveric a License Execution Fee and development and sales milestones up to $61 Million, and royalties (ranging from 2.5% up to 10%) on all future sales. The Licensee also has a cash Buyout Option.

Based on preliminary work performed by a renowned UK-based research hospital, it is believed that the methods of using novel treatment regimens that include cannabinoids combinations have potentially a significant impact for patients living with breast and other cancers. It is anticipated that the Licensee may advance these methods into the next stages of development, and further into clinical trials which would demonstrate a major value driver for both Enveric and the Licensee.

"We are excited to see the Licensee taking this innovative approach in effort to advance a novel treatment based on our discovery," said Joseph Tucker, Ph.D., Director and CEO of Enveric. "We look forward to partnering with the Licensee and are confident in their leadership to translate these discoveries into promising treatments for cancer patients. Importantly, this agreement further supports Enveric’s discovery capabilities and its ability to advance novel treatments for cancer and to make them available for others to pursue commercially outside the company with strong future potential upside to Enveric."

Breast Cancer alone has approximately 311,000 new cases diagnosed annually in the US, and over 4 million women have a history of, or are in treatment, for breast cancer in the US. The licensed methods also apply to many other forms of cancer that afflict millions more patients in the US.

On May 8, 2024 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of masked, conditionally activated biologic therapeutics, reported positive initial data from the ongoing CX-904 Phase 1a dose escalation clinical study, demonstrating a favorable safety profile and confirmed anti-cancer activity (Press release, CytomX Therapeutics, MAY 8, 2024, View Source [SID1234642873]). CX-904 is an investigational, masked, conditionally activated PROBODY T-cell engager designed to target the epidermal growth factor receptor (EGFR) on cancer cells and the CD3 receptor on T cells within the tumor microenvironment.

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"We are delighted to share these initial results today for CX-904, a highly innovative masked T-cell engager that embodies our vision at CytomX of transforming lives with safer, more effective therapies," said Sean McCarthy, D.Phil., chief executive officer and chairman of CytomX. "These data build on more than a decade of innovation at CytomX, and, we believe, open broad new possibilities for T-cell engagers across many targets and cancer types. For EGFR specifically, a target that is present on normal epithelial tissues, we are very encouraged to see CX-904 working as designed by eliciting meaningful tumor reductions in a very difficult to treat tumor type and with a favorable overall safety profile. We look forward to continuing to explore the potential of this exciting agent in multiple EGFR positive cancers and to determining longer term strategy with our global development partner, Amgen."

As of the April 16, 2024 data cutoff, the Phase 1 study had enrolled 35 patients with advanced metastatic solid tumor types that are generally known to express EGFR, including pancreatic, colorectal (CRC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), gastric, and esophageal cancers. Patients enrolled in the study were heavily pre-treated and had a median of 4 prior lines of therapy. As of the data cutoff, 19 patients were enrolled into initial non-step dosing cohorts with target doses ranging from 0.007 mg to 6 mg, and 16 patients were subsequently enrolled into step-dosing cohorts with target doses ranging from 5 mg to 10 mg and with tocilizumab prophylaxis. Enrollment into a cohort with a target dose of 15 mg is ongoing.

As of the cutoff date, CX-904 demonstrated a favorable safety profile that supports administration and monitoring of enrolled patients in an outpatient setting.1 There were no observed cases of CRS of any grade in step-dosing cohorts to-date. In non-step dosing cohorts, only Grade 1 CRS was observed in patients treated at the highest dose of 6 mg. Among all treated patients, the most common treatment-related adverse events (TRAEs) were rash, arthralgia, arthritis, pruritis, and vomiting, the majority of which were low grade, being observed in 14 (40%), 13 (37%), 5 (14%), 5 (14%) and 5 (14%) patients, respectively. Grade 3 TRAEs were tenosynovitis (n=1), arthralgia (n=2), arthritis (n=1), and rash (n=1).

Eight patients had measurable tumor reduction at data cutoff, including 2 of 6 efficacy-evaluable patients (33%) with pancreatic cancer with confirmed partial responses per RECIST 1.1. All 6 efficacy-evaluable patients with pancreatic cancer achieved disease control (objective response or stable disease). For the two patients with a confirmed partial response, one patient (6 mg target dose) achieved an 83% tumor reduction. The second patient (5 mg target dose) with a confirmed response achieved a 51% tumor reduction and remained on study treatment as of the data cutoff. In addition, a third pancreatic cancer patient maintained stable disease with no evidence of tumor growth through 3.5 months of study treatment and remained on treatment as of the data cutoff.

Preliminary pharmacokinetic and pharmacodynamic data were consistent with the PROBODY TCE mechanism of action, including maintained masking in circulation, and CD8+ T-cell margination and tumor infiltration.

CX-904 Phase 1a dose escalation and optimization continue, with future enrollment focused on determining a recommended Phase 2 dose, or doses. The Company expects to provide an additional Phase 1a dose escalation update by the end of 2024. These additional data will inform discussions with CytomX partner, Amgen, towards initiation of Phase 1b expansion cohorts in specific EGFR positive tumor types.

Conference Call & Webcast
CytomX management will host a conference call and simultaneous webcast today at 5 p.m. EDT (2 p.m. PDT) to discuss the first quarter 2024 results and provide an initial CX-904 Phase 1a clinical data update. Participants may access the live webcast of the conference call from the Events and Presentations page of CytomX’s website at View Source Participants may register for the conference call here and are advised to do so at least 10 minutes prior to joining the call. An archived replay of the webcast will be available on the company’s website for at least 30 days.

On May 8, 2024 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of masked, conditionally activated biologics, reported first quarter 2024 financial results and provided a business update (Press release, CytomX Therapeutics, MAY 8, 2024, View Source [SID1234642872]).

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"CytomX’s multi-modality PROBODY therapeutic pipeline encompasses some of the most exciting areas of current oncology R&D, including T-cell engagers, ADCs, and cytokines. CytomX’s leadership and continuous innovation in the field of masked, conditionally activated biologics ideally positions us to develop novel, potent therapies for cancer patients in key areas of unmet need," said Sean McCarthy, D.Phil., chief executive officer and chairman of CytomX.

McCarthy added, "CytomX entered 2024 executing to our plan and with substantial momentum, looking towards key data readouts from our multi-modality PROBODY therapeutic pipeline over the next 12 to 24 months. Our exciting announcement today of positive initial Phase 1a clinical data for CX-904 marks the beginning of this data-rich period and we look forward to making continued progress with our broad program of masked, PROBODY T-cell engagers and to also demonstrating clinical proof of concept for CX-2051 and CX-801, for which we anticipate initial Phase 1 data in 2025."

First Quarter Business Highlights and Recent Developments

Pipeline

CX-904, PROBODY T-cell-engager (TCE) targeted to EGFRxCD3, demonstrates a favorable safety profile and encouraging anti-cancer activity in Phase 1 dose escalation. Dose escalation continues.

CX-904 is a conditionally activated PROBODY TCE designed to target the epidermal growth factor receptor (EGFR) on cancer cells and the CD3 receptor on T cells within the tumor microenvironment. CX-904 is being evaluated in an ongoing Phase 1 study.

Today, the Company announced positive initial Phase 1 dose escalation data in heavily pre-treated patients with advanced metastatic solid tumor types that are generally known to express EGFR. 19 patients were initially enrolled into non-step dosing cohorts with target doses ranging from 0.007 mg to 6 mg. 16 patients were subsequently enrolled into step-dosing cohorts with target doses ranging from 5 mg to 10 mg and with tocilizumab prophylaxis. Dose escalation continues and enrollment into a cohort with a target dose of 15 mg is ongoing.

As of the April 16, 2024 data cutoff, CX-904 demonstrated a favorable safety profile including no observed cases of CRS of any grade in step-dosing cohorts and only Grade 1 CRS observed in patients treated at the highest non-step dose. The most common treatment-related adverse events (TRAEs) were arthralgia, arthritis, rash, pruritis, and vomiting, the majority of which were low grade.
Eight patients had measurable tumor reduction, including 2 of 6 (33%) efficacy-evaluable pancreatic cancer patients with confirmed partial responses per RECIST 1.1.
Preliminary pharmacokinetic and pharmacodynamic data were consistent with the PROBODY TCE mechanism of action, including maintained masking in circulation, and CD8+ T-cell margination and tumor infiltration.
CX-904 Phase 1a dose escalation and optimization continue, with future enrollment focused on determining a recommended Phase 2 dose.
The Company expects to provide an additional Phase 1a dose escalation update by the end of 2024. These additional data will help inform next steps along with partner Amgen, towards initiation of Phase 1b expansion cohorts in specific EGFR positive tumor types.
CX-2051, an EpCAM-directed PROBODY antibody drug conjugate, first patient dosed in Phase 1 in April 2024, initial data expected in 2025.

EpCAM is a promising oncology target with significant potential that is highly expressed across many indications including colorectal, gastric, endometrial, and ovarian cancers. EpCAM has been clinically validated by locally administered, previously approved cancer therapies. To date, systemically administered anti-EpCAM therapeutics have been unsuccessful due to toxicities in certain epithelial tissues. CX-2051 utilizes a cytotoxic payload that is a derivative of camptothecin, a topoisomerase-1 inhibitor, a class of drug that has shown potent clinical anti-cancer activity in the ADC context for multiple targets and cancer types. CX-2051 has demonstrated a wide predicted therapeutic index in multiple preclinical models, constituting an opportunity for broad clinical use in large patient populations.

In April 2024, the first patient was dosed as part of the Phase 1 dose escalation of CX-2051 in patients with solid tumors generally known to express EpCAM, including CRC. The first dose cohort in the CX-2051 Phase 1 study has been cleared and dose escalation continues.
The Phase 1 dose escalation study is following a Bayesian Optimal Interval (BOIN) design and is intended to demonstrate initial clinical proof of concept to inform a potential decision to move into dose expansion cohorts in 2025.
Initial data for CX-2051 is expected in the first half of 2025.
CX-801, a dually-masked PROBODY interferon-alpha 2b, advancing to Phase 1 in Q2 2024. Executed Clinical Collaboration Agreement with Merck (known as MSD outside of the US and Canada) to evaluate CX-801 in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab).

Interferon-alpha 2b is an immunotherapeutic cytokine that has demonstrated clinical activity and gained regulatory approval previously in multiple cancer types, including locally advanced or metastatic melanoma, renal cancer and bladder cancer. IFNα2b provides a potentially superior approach to activating anti-tumor immune responses compared to other cytokines but its clinical benefit has been limited to date by severe dose-limiting toxicities. CX-801 is an optimized, dually masked, conditionally activated IFNα2b, designed to have an expanded therapeutic index that has the potential to become a cornerstone of combination therapy for a wide range of tumor types.

Announced a clinical collaboration agreement with Merck to supply KEYTRUDA for a Phase 1 study of CX-801 in combination with KEYTRUDA.
CX-801 is anticipated to initiate Phase 1 dose escalation in patients with solid tumors including melanoma, renal, and head and neck squamous cell carcinoma in Q2 2024. The Phase 1 dose escalation will utilize a BOIN design to evaluate safety and signs of clinical activity for CX-801 monotherapy and for CX-801 in combination with KEYTRUDA.
Initial Phase 1 data for CX-801 is expected in 2025.
KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

CytomX continues to make progress in its R&D partnerships.

CytomX has multiple active research and development partnerships and more than 10 ongoing research programs with major biotechnology and pharmaceutical companies (Amgen, Astellas, Bristol Myers Squibb, Moderna and Regeneron). The majority of these programs are focused on masked, conditionally activated PROBODY T-cell engagers.

In Q1 2024, CytomX achieved $10.0 million in milestones under its multi-target T-cell Engager collaboration with Astellas related to two separate PROBODY TCE programs:

A $5.0 million milestone for the initiation of GLP toxicology studies for the first clinical candidate program in the collaboration.
A $5.0 million milestone for the nomination of the second clinical candidate in the collaboration.
2024 Priorities and Key Milestones:

CX-904 (EGFRxCD3):
CX-904 Phase 1a dose escalation and optimization continue, with future enrollment focused on determining a recommended Phase 2 dose or doses.
An additional Phase 1a dose escalation update is expected by the end of 2024.
A potential decision, to be taken with Amgen, to initiate Phase 1b expansion cohorts in specific EGFR positive tumor types is expected by the end of 2024.
CX-2051 (EpCAM):
Continued Phase 1 dose escalation in solid tumors with known EpCAM expression.
Initial Phase 1a data is expected in the first half 2025.
CX-801 (IFNα2b):
Initiation of Phase 1 dose escalation in solid tumors including melanoma, renal, and head and neck squamous cell carcinoma is expected by Q2 2024.
Initial Phase 1a data is expected in 2025.
Collaborations:
Continuation of T-cell engager focused drug discovery and development activities with Bristol Myers Squibb, Amgen, Astellas, and Regeneron.
Progress with Moderna on conditionally activated mRNA-based programs.
Potential additional pre-clinical and clinical milestones in 2024 and beyond.
Q1 2024 Financial Results

Cash, cash equivalents and investments totaled $150.3 million as of March 31, 2024, compared to $174.5 million as of December 31, 2023. The cash balance as of March 31, 2024, does not include the $10.0 million of Astellas milestone achievements earned in the first quarter of 2024.

Total revenue was $41.5 million for the three months ended March 31, 2024 compared to $23.5 million for the corresponding period in 2023. The increase in revenue was driven primarily by a higher percentage of work completion of existing targets under the BMS, Moderna and Regeneron agreements as well as the $10.0 million of milestones earned under the collaboration with Astellas.

Research and development expenses increased by $0.9 million for the three months ended March 31, 2024 to $22.1 million, compared to $21.2 million for the corresponding period of 2023. This was primarily due to increased laboratory contract services and manufacturing activities related to CX-904, CX-2051 and other wholly owned and partnered programs, as well as consulting, personnel and license related expenses, offset by decreased manufacturing activities for CX-801 program and winding down of clinical study activities related to the CX-2009 and CX-2029 programs.

General and administrative expenses decreased by $0.2 million for the three months ended March 31, 2024 to $7.8 million compared to $8.0 million for the corresponding period of 2023, primarily due to lower building rent as a result of partial sublease of the Company’s headquarters.

On May 8, 2024 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported new preclinical data presented at the 27th Annual Meeting of the American Society of Cell and Gene Therapy (ASGCT) (Free ASGCT Whitepaper) highlighting the Company’s approach to developing lipid nanoparticle (LNP) based delivery for in vivo ocular gene editing (Press release, CRISPR Therapeutics, MAY 8, 2024, View Source [SID1234642871]). In addition, CRISPR Therapeutics announced the expansion of its in vivo pipeline with two new programs. CTX340 and CTX450 utilize LNP-based delivery of CRISPR/Cas9 gene editing cargo to the liver, targeting angiotensinogen (AGT) for refractory hypertension and 5’-aminolevulinate synthase 1 (ALAS1) for acute hepatic porphyria (AHP), respectively.

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"Over the past two years, we have made significant progress on the development of our lipid nanoparticle platform for the delivery of CRISPR/Cas9 to the liver and are now in clinical trials with CTX310 and CTX320," said Samarth Kulkarni, Chief Executive and Chairman of the Board of CRISPR Therapeutics. "The expansion of our in vivo pipeline speaks to the scalability of the platform and the exceptional translation capabilities of our team. We continue to add programs to treat both common and rare diseases, as we look to broaden the number of areas where CRISPR could have transformational impact."

In Vivo Pipeline Expansion

CRISPR Therapeutics has established a proprietary LNP platform for the delivery of CRISPR/Cas9 to the liver. The first two in vivo programs utilizing this proprietary platform, CTX310 and CTX320, are directed towards validated therapeutic targets associated with cardiovascular disease, and are in on-going clinical trials. The addition of two more programs, CTX340 and CTX450, utilizing this LNP delivery technology demonstrates the modularity and scalability of the platform.

Refractory hypertension is a serious unmet medical need affecting approximately 1.5 million patients in the U.S. alone. CTX340 is designed to inhibit production of hepatic angiotensinogen (AGT), a validated target to modulate the renin-angiotensin-aldosterone system (RAAS) and normalize blood pressure durably with a one-time treatment. In preclinical studies, CTX340 showed ~60% liver editing and ~90% AGT protein reduction, resulting in sustained ~30 mmHg blood pressure (BP) reduction out to 3 months in the spontaneously hypertensive rat (SHR) model.
Acute hepatic porphyria (AHP) is a group of rare genetic diseases of heme biosynthesis. Symptomatic patients have acute attacks, characterized by debilitating neurovascular symptoms, as well as multiple chronic symptoms, such as pain. There are approximately 5,000 patients diagnosed with AHP in the U.S., although the disease remains underdiagnosed. CTX450 is specifically designed to inhibit production of ALAS1 in the liver, preventing accumulation of neurotoxic aminolevulinic acid (ALA) and porphobilinogen (PBG). In preclinical studies, CTX450 showed ~70% liver editing and ~97% ALAS1 protein reduction, resulting in reduction of ALA and PBG disease biomarkers to normal levels in an AHP mouse model.
CRISPR Therapeutics has initiated IND/CTA-enabling studies for CTX340 and CTX450 and expects to initiate both clinical trials in the second half of 2025.
ASGCT Presentation

In addition to expanding the liver-targeted in vivo pipeline, CRISPR Therapeutics reported initial data demonstrating its proprietary capabilities to deliver to and edit genes in the eye, opening a potential new focus area. The data will be presented today, May 8, 2024, from 3:00 p.m. – 3:15 p.m. ET at ASGCT (Free ASGCT Whitepaper) in an oral presentation entitled "Development of an In Vivo Non-Viral Ocular Editing Platform and Application to Potential Treatments for Glaucoma."
Glaucoma is the second leading cause of blindness worldwide. Mutations in the myocilin (MYOC) gene represent the most common genetic cause of glaucoma that affects approximately 150,000 people in the U.S. alone. In these patients, defective myocilin protein aggregates in the trabecular meshwork (TM) cells, leading to impaired outflow of aqueous humor from the anterior segment of the eye, resulting in elevated intraocular pressure. Patients with MYOC-associated glaucoma typically have an earlier onset and more rapidly progressive disease course than is seen with other causes of glaucoma. Pharmaceutical interventions carry a significant treatment burden resulting in reduced adherence to therapy and surgical interventions frequently do not lead to a durable resolution of elevated intraocular pressure (IOP). The Company has developed an LNP platform capable of delivering gene editing cargo to the TM cells in the eye. In today’s presentation, the Company presented data demonstrating efficient and specific delivery to TM cells in mouse, non-human primate, and ex vivo human eyes. The Company showed >90% editing of the MYOC gene in vitro with prioritized guide RNA, and ~90% reduction of surrogate protein expression in a mouse in vivo model after a single injection.

About In Vivo Programs

CRISPR Therapeutics has established a proprietary LNP platform for the delivery of CRISPR/Cas9 to the liver. The Company’s in vivo portfolio includes its lead investigational in vivo programs, CTX310 (directed towards angiopoietin-related protein 3 (ANGPTL3)) and CTX320 (directed towards lipoprotein(a) (Lp(a)), two validated therapeutic targets for cardiovascular disease, are in on-going clinical trials. In addition, the Company’s research and pre-clinical development candidates include CTX340 and CTX450, targeting angiotensinogen (AGT) for refractory hypertension and 5’-aminolevulinate synthase 1 (ALAS1) for acute hepatic porphyria (AHP), respectively.

On May 8, 2024 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported financial results for the first quarter ended March 31, 2024 (Press release, CRISPR Therapeutics, MAY 8, 2024, View Source [SID1234642870]).

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"This quarter, in addition the robust launch of CASGEVY, we are pleased to have nominated additional in vivo programs targeting both rare and common diseases to our portfolio based on promising preclinical data," said Samarth Kulkarni, Ph.D., Chief Executive Officer and Chairman of CRISPR Therapeutics. "Additionally, we continue to advance our portfolio of clinical trials across oncology, autoimmune, diabetes and cardiovascular indications in a capital efficient manner. With multiple data read-outs in the next 12-18 months, we are poised to broaden the number of patients that could potentially benefit from transformative gene-editing based therapies."

Recent Highlights and Outlook

Hemoglobinopathies and CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is approved in the U.S., Great Britain, the European Union (EU), the Kingdom of Saudi Arabia (KSA), and the Kingdom of Bahrain (Bahrain) for the treatment of both sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). Regulatory submissions for CASGEVY have been completed in both SCD and TDT in Switzerland and Canada; the submission in Canada was granted priority review. 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.

As of mid-April, more than 25 authorized treatment centers (ATCs) have been activated globally, including centers in all regions where CASGEVY is approved, and multiple patients have already had cells collected.

Vertex has signed multiple agreements with both commercial and government health insurance providers in the U.S. to provide access to CASGEVY. Vertex has also secured reimbursed access for eligible people with SCD or TDT in KSA and Bahrain, as well as for people with TDT in France through an early access program.

CRISPR Therapeutics has two next-generation approaches with the potential to significantly expand the addressable population with SCD and TDT. CRISPR Therapeutics continues to advance its internally developed targeted conditioning program, an anti-CD117 (c-Kit) antibody-drug conjugate (ADC), through preclinical studies. Additionally, the Company has ongoing research efforts to enable in vivo editing of hematopoietic stem cells. This work 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 Diseases

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 the Company’s next-generation CAR T product candidates, CTX112 and CTX131, targeting CD19 and CD70, respectively, across multiple indications. CTX112 and CTX131 both contain novel potency edits which can lead to significantly higher CAR T cell expansion and cytotoxicity, potentially representing best-in-class allogeneic CAR T products for these targets.

CTX112 is being developed for both oncology and autoimmune indications. In oncology settings, CTX112 is in a Phase 1/2 trial for CD19 positive relapsed or refractory B-cell malignancies, and the Company expects to report preliminary clinical data this year.

The Company remains on track to initiate a clinical trial for CTX112 in systemic lupus erythematosus (SLE) in the first half of this year, 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 effective depletion of B cells in oncology settings, which supports the potential for CTX112 in autoimmune diseases.

CTX131, CRISPR Therapeutics’ next generation CAR T targeting CD70, is currently in an ongoing clinical trial in solid tumors. The Company remains on track to initiate a clinical trial for CTX131 in hematologic malignancies in the first half of this year.

In Vivo

CRISPR Therapeutics has established a proprietary lipid nanoparticle (LNP) platform for the delivery of CRISPR/Cas9 to the liver. The first two in vivo programs utilizing this proprietary platform, CTX310 and CTX320, are directed towards validated therapeutic targets associated with cardiovascular disease, and are in ongoing clinical trials. Earlier today, the Company announced the addition of two additional preclinical programs, CTX340 and CTX450, utilizing this LNP delivery system, demonstrating the modularity and scalability of the platform.

Refractory hypertension is a serious unmet medical need affecting approximately 1.5 million patients in the U.S. alone. CTX340 is designed to inhibit production of hepatic angiotensinogen (AGT), a validated target to modulate the renin-angiotensin-aldosterone system (RAAS) and normalize blood pressure durably with a one-time treatment. In preclinical studies, CTX340 showed ~60% liver editing and ~90% AGT protein reduction, resulting in sustained ~30 mmHg blood pressure (BP) reduction out to 3 months in the spontaneously hypertensive rat (SHR) model.

Acute hepatic porphyria (AHP) is a group of rare genetic diseases of heme biosynthesis. Symptomatic patients have acute attacks, characterized by debilitating neurovascular symptoms, as well as multiple chronic symptoms, such as pain. There are approximately 5,000 patients diagnosed with AHP in the U.S., although the disease remains underdiagnosed. CTX450 is specifically designed to inhibit production of ALAS1 in the liver, preventing accumulation of neurotoxic aminolevulinic acid (ALA) and porphobilinogen (PBG). In preclinical studies, CTX450 showed ~70% liver editing and ~97% ALAS1 protein reduction, resulting in reduction of ALA and PBG disease biomarkers to normal levels in an AHP mouse model.

CRISPR Therapeutics has initiated IND/CTA-enabling studies for CTX340 and CTX450 and expects to initiate both clinical trials in the second half of 2025.

In addition to the pipeline updates expanding the liver-targeted in vivo pipeline, CRISPR Therapeutics reported initial data at the American Society of Gene and Cell Therapy Annual Meeting demonstrating its proprietary capabilities to deliver to and edit genes in the eye, opening a potential new focus area.

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. CRISPR Therapeutics remains eligible for development milestones and would receive royalties on any future products resulting from this agreement.

Other Corporate Matters

In March, CRISPR Therapeutics announced its proposal to elect Christian Rommel, Ph.D., to its Board of Directors at the Company’s annual general meeting to be held this year. Dr Rommel brings in-depth experience in successfully accelerating innovation and advancing drug candidates across a breadth of modalities and disease areas.

In February, CRISPR Therapeutics announced that it had 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.

First Quarter 2024 Financial Results

Cash Position: Cash, cash equivalents, and marketable securities were $2,108.1 million as of March 31, 2024, compared to $1,695.7 million as of December 31, 2023. The increase in cash was primarily driven by proceeds from the February 2024 registered direct offering, a $200.0 million milestone payment received from Vertex in connection with the approval of CASGEVY, proceeds from employee option exercises as well as interest income, offset by operating expenses.

R&D Expenses: R&D expenses were $76.2 million for the first quarter of 2024, compared to $99.9 million for the first quarter of 2023. 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 $18.0 million for the first quarter of 2024, compared to $22.4 million for the first quarter of 2023. The decrease in G&A expense was primarily driven by a decrease in employee related and stock-based compensation expense.

Collaboration Expense: Collaboration expense, net, was $47.0 million for the first quarter of 2024, compared to $42.2 million for the first quarter of 2023. The increase in collaboration expense, net, was primarily attributable to commercial and manufacturing costs.

Net Loss: Net loss was $116.6 million for the first quarter of 2024, compared to a net loss of $53.1 million for the first quarter of 2023.
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. 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.