On April 1, 2024 Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical-stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported financial results for the fourth quarter, and full year ended December 31, 2023, and provided a business update (Press release, Carisma Therapeutics, APR 1, 2024, View Source [SID1234641660]).

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"Clinical data generated with CT-0508 in Study 101 has shown that CAR-M is well-tolerated, feasible to manufacture and biologically active in HER2 positive solid tumors. Combining this data set with the multiple potential advantages we’ve seen preclinically around a monocyte-based approach gives us confidence that CT-0525 may be a significant advancement in CAR-M treatment," said Steven Kelly, President and Chief Executive Officer of Carisma. "We have therefore made the decision to focus our resources on the clinical development of the product we believe is best suited to deliver benefit to patients with significant unmet need."

Mr. Kelly continued, "We have also undertaken a careful review of our business and prioritized our other pipeline programs on those with the greatest overall potential and near-term milestones. This prioritization enables us to reduce expenses and streamline operations, including a restructuring of our workforce. I want to express my sincere gratitude to those impacted by the workforce reduction for their invaluable contributions to our mission and their dedication to helping patients."

Reprioritization Plan, Pipeline Updates, and Upcoming Milestones:

Ex Vivo Oncology

· Anti-human epidermal growth factor receptor 2 (Anti-HER2) Program

o The Company’s goal to identify a registrational profile for the product candidate in its anti-HER2 program in 2025 remains unchanged.

o In Study 101, CT-0508, a chimeric antigen receptor macrophage (CAR-Macrophage), was well-tolerated, remodeled the tumor microenvironment (TME), and induced anti-tumor T cell immunity in patients with HER2 3+ tumors that achieved stable disease, despite suboptimal dose and a patient population with exhausted T cells.

o In late March 2024, Carisma made the decision to prioritize CT-0525, a chimeric antigen receptor monocyte (CAR-Monocyte), as the development candidate in its anti-HER2 program due to the potential for a CAR-Monocyte to have an approximately 2,000-fold increase in total exposure compared to a CAR-Macrophage. As a result, the Company believes that CT-0525 will be able to build on CT-0508’s observed clinical anti-tumor activity.

· CT-0525 (Anti-HER2 CAR-Monocyte)

o In November 2023, Carisma announced the clearance of its Investigational New Drug application (IND) by the U.S. Food and Drug Administration (FDA) for CT-0525.

o The Company expects to treat the first patient in the CT-0525 Phase 1 clinical study in the second quarter of 2024 and to report initial data from the study by year-end 2024.

· CT-0508 (Anti-HER2 CAR-Macrophage)

o In September 2023, the Company reported preliminary data from 14 patients in the open label Phase 1 clinical study of CT-0508 (Study 101) designed to evaluate the safety, tolerability and manufacturing feasibility of CT-0508 along with several customary secondary endpoints.

o The Company has also enrolled six patients in a Study 101 substudy evaluating the co-administration of CT-0508 and pembrolizumab, a programmed cell death protein 1 (PD-1) checkpoint inhibitor, evaluating the safety and tolerability of the co-administration, along with several customary secondary endpoints.

o While the Company will continue all study operations for subjects enrolled in Study 101, it plans to stop recruitment of new patients into the study and its substudies, and expects to report data from the substudy evaluating the co-administration of CT-0508 and pembrolizumab in the second quarter of 2024.

· CT-1119 (Anti-Mesothelin CAR-Monocyte)

o The Company has elected to pause further development of CT-1119 as part of its reprioritization plan, pending additional financing.

In Vivo Oncology

· Oncology (CAR-M + mRNA/LNP; Moderna Collaboration)

o In November 2023, Carisma presented pre-clinical data from its in vivo program demonstrating that chimeric antigen receptor macrophages and monocytes (CAR-M) can be directly produced in vivo, successfully redirecting endogenous myeloid cells against tumor-associated antigens using mRNA/LNP. The data demonstrated feasibility, tolerability, and efficacy of in vivo CAR-M against metastatic solid tumors.

o In December 2023, the Company announced the nomination of the first lead candidate in its collaboration with Moderna Tx, Inc., which will target an antigen present on a solid tumor with significant unmet medical need.

Fibrosis and Immunology

· Liver Fibrosis

o Pre-clinical proof of concept data from the fibrosis program is targeted for the second quarter of 2024.

Corporate Updates

· As a result of the pipeline reprioritization and corporate restructuring, Carisma plans to reduce its workforce by approximately 37% in the second quarter of 2024.

· On April 1, 2024, Carisma announced the appointment of John Hohneker, M.D. to the Board of Directors of the Company, effective April 1, 2024. Dr. Hohneker brings over 30 years of extensive experience in drug development and leadership across the biotech and pharmaceutical sectors. The Company concurrently announced the resignation of Chidozie Ugwumba from Carisma’s Board of Directors, also effective April 1, 2024.

Fourth Quarter and Full Year 2023 Financial Results

· Cash and Cash Equivalents: As of December 31, 2023, Carisma had cash and cash equivalents of $77.6 million.

· R&D Expenses: Research and development (R&D) expenses were $19.4 million and $74.1 million for the fourth quarter and full year ended December 31, 2023, respectively, compared to $18.1 million and $56.6 million for the fourth quarter and full year ended December 31, 2022, respectively. The increase of $17.5 million year-over-year was primarily due to a $8.4 million increase in direct costs associated with pre-clinical development of CT-0525, a $4.4 million increase in personnel costs due to growth in research and development employee headcount, a $2.7 million increase in the Company’s facilities and other expenses resulting from increased laboratory space and laboratory supplies from expanded clinical and pre-clinical work, a $1.3 million increase due to costs associated with growth and expansion of pre-clinical activities towards submission of an IND for CT-0525, and a $0.9 million increase in direct costs associated with the pre-clinical development related to CT-1119, partially offset by a $0.2 million decrease in direct costs associated with CT-0508. The Company expects its research and development expenses to decrease in 2024 as it implements the revised operating plan, including a reduction in workforce, prioritization of CT-0525 and a pause in development of CT-1119. The Company expects that its expenses will increase again in future years as it continues to advance its clinical trials and potentially progress additional product candidates.

· G&A Expenses: General and administrative (G&A) expenses were $7.3 million and $29.5 million for the fourth quarter and full year ended December 31, 2023, respectively, compared to $1.0 million and $9.4 million for the fourth quarter and full year ended December 31, 2022, respectively. The increase of $20.1 million year-over-year was primarily attributable to a $9.2 million increase in personnel costs and a $7.5 million increase in professional fees. The increase in personnel costs was primarily due to non-recurring severance and other costs associated with the merger with Sesen Bio, Inc. on March 7, 2023 ("Merger") of $4.6 million, and higher personnel costs as a result of an increase in headcount to support operating as a public company of $4.6 million. The increase in professional fees primarily consisted of $5.3 million in costs associated with activities to support the transitioning to and operating as a public company and protecting the Company’s IP portfolio, along with $2.2 million in legal fees and communication fees associated with the Merger. Insurance and taxes increased $2.1 million as a result of costs associated with operating as a public company, such as director and officer insurance. Facilities and supplies increased $0.8 million due to office expenditures resulting from an increased footprint, and other expenses increased $0.5 million. The Company expects that its general and administrative expenses will decrease in 2024 as its 2023 expenses included a significant amount of non-recurring costs related to the Merger and as it implements its revised operating plan, including reducing its workforce and decreasing expenses related to non-essential activities.

· Net Loss: Net loss was $86.9 million and $61.2 million for the years ended December 31, 2023, and 2022, respectively.

Outlook

Carisma anticipates that its cash and cash equivalents of $77.6 million as of December 31, 2023, combined with the expected cost savings from implementing the revised operating plan, are sufficient to sustain its planned operations into the third quarter of 2025.

About CT-0525

CT-0525 is a first-in-class, ex vivo gene-modified autologous chimeric antigen receptor-monocyte (CAR-Monocyte) cellular therapy intended to treat solid tumors that overexpress human epidermal growth factor receptor 2 (HER2). It is being studied in a multi-center, open label, Phase 1 clinical trial for patients with advanced/metastatic HER2-overexpressing solid tumors that have progressed on available therapies. The CAR-Monocyte approach has the potential to address some of the challenges of treating solid tumors with cell therapies, including tumor infiltration, immunosuppression within the tumor microenvironment, and antigen heterogeneity. CT-0525 has the potential to enable significant dose escalation, enhance tumor infiltration, increase persistence, and reduce manufacturing time compared to CT-0508.

About CT-0508

CT-0508 is an ex vivo gene-modified autologous chimeric antigen receptor-macrophage (CAR-Macrophage) cellular therapy intended to treat solid tumors that overexpress HER2. It is being evaluated in a Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment. The Phase 1 clinical trial marks the first time that engineered macrophages are being studied in humans.

On April 1, 2024 RS Oncology reported two abstracts with comprehensive preclinical and translational data in support of their lead clinical oncology compound RSO-021, have been accepted for poster presentations at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), taking place April 5-10, 2024 in San Diego (Press release, RS Oncology, APR 1, 2024, View Source [SID1234641659]). RSO-021 is a first-in-class peroxiredoxin 3 (PRX3) covalent inhibitor that disables a critical antioxidant defense system in the mitochondria of tumor cells. Results from the completed Phase 1 clinical trial (clinical trials.gov #NCT05278975) will be an oral presentation on June 3rd, at the upcoming ASCO (Free ASCO Whitepaper) meeting in Chicago. Currently patients are being recruited to the Phase 2 dose expansion cohorts of the MITOPE clinical trial.

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"Covalent inactivation of PRX3 by RSO-021 represents a viable anticancer approach by targeting a universal tumor vulnerability of oxidative stress. The results we present at the AACR (Free AACR Whitepaper) Annual Meeting will highlight fundamental tumor cell features that are exploitable by this novel treatment." said Brian Cunniff, Chief Scientific Officer of RS Oncology.

Approximately 90% of mesotheliomas and 15-20% of solid tumors present with malignant pleural effusion (MPE) at late stage leaving the patients with poor prognoses and limited options. RSO-021 is a local therapy for patients with MPE arising from mesothelioma or advanced metastatic tumors. "The discoveries presented at AACR (Free AACR Whitepaper) highlight tumor cell features that are associated with sensitivity to RSO-021, providing a potential strategy to maximize patient response to RSO-021", added George Naumov, Chief Operations Officer of RS Oncology.

Details of the poster presentations:

Title: First-in-class peroxiredoxin 3 (PRX3) inhibitor RSO-021 triggers mesenchymal-to-epithelial transition in mesothelioma

Presenter: Brian Cunniff, CSO of RS Oncology

Session Category and Title: Experimental and Molecular Therapeutics – Other Cellular Mechanisms for Anticancer Drug Action

Session Date and Time: Tuesday Apr 9, 2024 9:00 AM – 12:30 PM

Location: Poster Section 29

Abstract Number: 4716

Title: SLC7A11 modulates sensitivity to the first-in-class mitochondrial peroxiredoxin 3 inhibitor thiostrepton (RSO-021) via a ferroptosis independent pathway

Presenter: Brian Cunniff, CSO of RS Oncology

Session Category and Title: Molecular/Cellular Biology and Genetics- Cellular Stress Responses 1

Session Date and Time: Sunday Apr 7, 2024 1:30 PM – 5:00 PM

Location: Poster Section 16

Published Abstract Number: 384

The full abstracts will be published on March 22, 2024, in an online-only proceedings supplement to the AACR (Free AACR Whitepaper) journal, Cancer Research.

On April 1, 2024 Quince Therapeutics, Inc. (Nasdaq: QNCX), a late-stage biotechnology company developing an innovative drug delivery technology designed to leverage a patient’s own biology to deliver rare disease therapeutics, reported an update on the company’s development pipeline and announced financial results for the fourth quarter and fiscal year ended December 31, 2023 (Press release, Quince Therapeutics, APR 1, 2024, View Source [SID1234641658]).

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"With the acquisition of EryDel S.p.A. in October last year, we have successfully shifted our strategic focus to become a Phase 3 biotechnology company dedicated to securing regulatory approval for our lead product, EryDex, for the treatment of patients with Ataxia-Telangiectasia (A-T)," said Dirk Thye, M.D., Quince’s Chief Executive Officer and Chief Medical Officer. "With $75.1 million cash on hand, we expect to have sufficient funding to complete our Phase 3 clinical trial, in addition to supporting the expansion of EryDex into other indications and our Autologous Intracellular Drug Encapsulation (AIDE) technology platform into new products. By pioneering the delivery of drugs encapsulated in a patient’s own red blood cells, we are working to redefine the standard of care, first for chronic corticosteroid therapy, and later for other drugs, that will meaningfully improve the quality of life for rare disease patients."

Pivotal Phase 3 NEAT Clinical Trial

Completed the majority of study start up activities related to the company’s pivotal Phase 3 NEAT (Neurologic Effects of EryDex on Subjects with A-T; IEDAT-04-2022/NCT06193200) clinical trial.
NEAT is an international, multi-center, randomized, double-blind, placebo-controlled study to evaluate the neurological effects of the company’s lead asset, EryDex (dexamethasone sodium phosphate [DSP] encapsulated in autologous red blood cells), in patients with A-T.
On track to meet expectations to begin enrollment in the NEAT study during the second quarter of 2024.
Pivotal Phase 3 NEAT clinical trial will be conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food & Drug Administration (FDA).
Plan to enroll approximately 86 patients with A-T ages six to nine years old (primary analysis population) and approximately 20 patients with A-T ages 10 years or older.
Participants will be randomized (1:1) between EryDex or placebo and treatment will consist of six infusions scheduled once every 21 to 30 days. The primary efficacy endpoint will be measured by the change from baseline to last visit completion in rescored modified International Cooperative Ataxia Rating Scale (RmICARS).
Participants who complete the full treatment period, complete study assessments, and provide informed consent will be eligible to transition to an open label extension study.
Expect to report Phase 3 NEAT topline results in the second half of 2025 with a potential NDA submission in 2026, assuming positive study results.
Quince estimates there are an aggregate of approximately 10,000 patients with A-T in the U.S., U.K., and EU4 countries.
There are currently no approved therapeutic treatments for A-T and the market represents a $1+ billion peak commercial opportunity globally based on the company’s internal estimates and assumptions.
Scientific, Pipeline, and Corporate Updates

Detailed EryDex’s optimized delivery of DSP encapsulated in red blood cells with a comparison of company data relative to published corticosteroid pharmacokinetic and biodistribution information. Red blood cells have several characteristics that make them a potentially ideal vehicle for drug delivery, including potentially better tolerability, enhanced tissue distribution, reduced immunogenicity, and prolongation of circulating half-life. Learn more here.
Intend to investigate other potential indications for EryDex where chronic corticosteroid treatment is – or has the potential to become – a standard of care if there were not corticosteroid-related safety concerns. This evaluation process is expected to span across ataxias, neuromuscular indications, hematology, cancer, and autoimmune diseases, with a focus on rare diseases.
Plan to evaluate additional potential applications of Quince’s proprietary AIDE technology platform using drugs and biologics targeted at rare and debilitating diseases to further expand the company’s drug development pipeline.
Targeting participation at several A-T related global ataxia and neurology scientific congresses in 2024, in addition to ongoing engagement of global patient advocacy groups as enrollment of the Phase 3 NEAT study progresses.
Strong Cash Position Expected to Support Meaningful Clinical Milestone

Reported $75.1 million in cash, cash equivalents, and short-term investments as of December 31, 2023. Quince expects its existing cash runway to be sufficient to fund the company’s capital efficient development plan into 2026.
Expect to fully fund lead asset, EryDex, through Phase 3 NEAT topline results and prepare for a potential NDA submission in 2026, assuming positive study results. This includes approximately $20 million for the NEAT study and approximately $15 million in direct trial costs for the open label extension.
Evaluate potential strategic partnerships to out-license ex-U.S. regional territories to extend operational runway to support potential NDA approval of EryDex, as well as further advance other potential indications and programs discovered using the AIDE platform.

On April 1, 2024 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company working to develop the world’s most potent vaccines, reported that it has commenced an underwritten public offering of shares of its common stock (or pre-funded warrants to purchase common stock in lieu thereof) and accompanying common warrants to purchase common stock (or pre-funded warrants to purchase common stock in lieu thereof) (Press release, Gritstone Bio, APR 1, 2024, View Source [SID1234641657]). All of the shares of common stock, pre-funded warrants and accompanying common warrants are being offered by Gritstone bio. The proposed offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

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TD Cowen and Evercore ISI are acting as the joint book-running managers for the proposed offering.

The securities are being offered by Gritstone bio pursuant to a registration statement on Form S-3 (File No. 333-263455) previously filed and declared effective by the Securities and Exchange Commission ("SEC"). A preliminary prospectus supplement and accompanying base prospectus relating to and describing the terms of the proposed offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement and accompanying base prospectus may also be obtained, when available, from: TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, NY 10017, by telephone at (855) 495-9846 or by email at [email protected]; or Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, by telephone at (888) 474-0200, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 1, 2024 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company working to develop the world’s most potent vaccines, reported positive preliminary data from the ongoing, signal seeking Phase 2 portion of the Phase 2/3 study evaluating GRANITE, its personalized neoantigen cancer vaccine, in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC) (Press release, Gritstone Bio, APR 1, 2024, View Source [SID1234641656]). The randomized, controlled, open-label study is designed to quantify the clinical benefit of maintenance therapy with GRANITE (GRT-C901/GRT-R902) in combination with immune checkpoint blockade in addition to fluoropyrimidine/bevacizumab versus fluoropyrimidine/bevacizumab alone. Overall progression free survival (PFS) data show an early trend in benefit for GRANITE patients (HR=0.82, [95% CI, 0.34-1.67]; 62% censored) and extended PFS benefit in high-risk patients (HR=0.52 [95% CI, 0.15-1.38]; 44% censored), in whom progression occurs faster. Circulating tumor DNA (ctDNA) analysis over several months of treatment shows the expected relationship with disease progression and favors GRANITE, while short-term ctDNA response analysis (molecular response as defined per protocol) did not demonstrate a difference between study arms. Gritstone bio successfully manufactured GRANITE product candidate for every eligible patient (i.e., 100% vaccine manufacturing success rate).

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"Today’s preliminary Phase 2 results are highly encouraging and represent the first randomized trial evidence, albeit early, that a personalized neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumor. The overall trend of PFS improvement in GRANITE recipients is great to see, and the exploratory PFS hazard ratio of 0.52 in the high-risk group, a more mature dataset, is a striking signal," said Andrew Allen, MD, PhD, Co-founder, President & CEO of Gritstone bio. "Pioneering new spaces carries inherent risks, and with regard to defining molecular response, we simply got it wrong. ctDNA levels in both arms decreased on chemotherapy for longer than we anticipated, generating similar short-term molecular response rates across arms and rendering our protocol measure of ctDNA change uninformative. Fortunately, long-term analysis demonstrates the expected correlation of ctDNA with clinical benefit and favors GRANITE patients. We believe these preliminary findings put us in a strong position to share mature PFS data in the third quarter and then enter regulatory discussions regarding Phase 3. The growing body of evidence favoring GRANITE in this trial, including positive PFS and long-term ctDNA trends in both high and low-risk populations, is exciting and suggests GRANITE is working in this notoriously underserved patient population."

"Up to 97% of patients with metastatic colorectal cancer, the second most common cause of cancer death, are MSS. Unlike patients with melanoma and lung cancer, they have not benefited from standard immunotherapies such as checkpoint inhibitors. These preliminary results indicate that GRANITE is inducing a potentially significant immune response in a disease that has been felt to be immunologically cold," said J. Randolph Hecht, MD, Professor of Clinical Medicine and Director of the UCLA GI Oncology Program and an investigator in the GRANITE Phase 2/3 study. "The PFS difference, particularly in a poor prognosis group of patients, indicates the potential for clinical benefit and provides the rationale for a confirmatory Phase 3 trial, about which I am very excited. Furthermore, we are learning how to better analyze ctDNA continuously to study the efficacy of this novel immunotherapy. Expanding the scope of immunotherapy to a broader spectrum of cancer patients is the ‘holy grail’ of oncology, especially for MSS colorectal cancer. While early, these promising results suggest GRANITE has potential to deliver clinically meaningful benefit in MSS-CRC and other cold tumors."

Key Findings from Preliminary Phase 2 Data in Front-Line Metastatic MSS-CRC
Clinical data cut as of March 8, 2024; ctDNA data cut as of March 12, 2024

One hundred and four (104) patients were randomized (1:1) in the study: Sixty-seven (67) patients (39 GRANITE arm, 28 control arm) are included in the treated analysis below. Thirty-six patients have left the study prior to randomized treatment primarily due to early progressive disease or withdrawal of consent, and one patient has yet to begin study treatment start. Demographics and clinical characteristics were balanced between arms (stage, sidedness, presence of liver metastases), with approximately 75% of patients having liver metastases.

Progression Free Survival (PFS)

Early trend in PFS benefit was observed for GRANITE recipients
Hazard ratio of 0.82 ([95% CI, 0.34-1.67]; 62% censored) in all patients
Hazard ratio of 0.52 ([95% CI, 0.15-1.38]; 44% censored) in high-risk patients1 (>90% have liver metastases). Median PFS of 12 months (GRANITE) vs. 7 months (control).
1High-risk subgroup defined as baseline ctDNA above the median value (2%) for the control group (ctDNA quantified as mean variant allele frequency [VAF] at time of study randomization). This analysis was performed on 44 patients who received study treatment (control and GRANITE arms) and have available baseline ctDNA data.
GRANITE and control arms begin separating 1-2 months after initiation of GRANITE treatment, consistent with expected kinetics of GRANITE-induced immune response
Biomarker Results – Circulating Tumor DNA (ctDNA)

Short-term molecular response (>30% reduction in ctDNA using single time-point analysis, defined per protocol) is uninformative due to unanticipated continuation of ctDNA drop beyond induction chemotherapy.
Molecular response, similar in both arms (30% [6/20] in vaccine arm; 42% [5/12] in control arm)
Long-term ctDNA responses align with PFS trends and favor GRANITE vs. control patients
Analysis in the high-risk group1 shows that between first blood draw (time of randomization) and last blood draw (most recent study visit), ctDNA shifted from high (>2% VAF) to low (≤2% VAF) in 56% (9/16) of GRANITE patients vs 22% (2/9) of control patients. Progressive disease was observed in 44% (7/16) vs 78% (7/9), respectively, within this group.
Analysis in patients whose ctDNA was negative after induction chemotherapy, a low-risk group, favors GRANITE. Sustained ctDNA negativity was observed in 67% (6/9) of GRANITE recipients vs 38% (3/8) control patients. Progressive disease was observed in 11% (1/9) and 38% (3/8) of these patients, respectively.
Safety and Tolerability

GRANITE demonstrated a favorable safety and tolerability profile
Vast majority of adverse events (AEs) were Grade 1/2
Common AEs were mild systemic and local effects typically associated with any potent vaccine (i.e., transient flu-like illness)
No patients discontinued study treatment due to an AE
A presentation reviewing these results has been added to the Presentations page of Gritstone’s website, View Source