On June 29, 2023 Blue Earth Therapeutics, a Bracco company and emerging leader in the development of innovative next generation therapeutic radiopharmaceuticals, reported highlights from early clinical and preclinical studies of 177Lu-rhPSMA-10.1 by the Company and a collaborator at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting, June 24 – 27, 2023 (Press release, Blue Earth Therapeutics, JUN 29, 2023, View Source [SID1234632995]). 177Lu-rhPSMA-10.1 is an investigational radiohybrid (rh) Prostate-Specific Membrane Antigen-targeted therapeutic radiopharmaceutical for the treatment of prostate cancer. The presentations included results from an independent clinical study conducted by the University of Augsburg that investigated dosimetry and the therapeutic index for 177Lu-rhPSMA-10.1. Also being presented are results of Blue Earth Therapeutics’ preclinical studies that examined the therapeutic dose response of 177Lu-rhPSMA-10.1 and the therapeutic efficacy of 177Lu-rhPSMA-10.1 as compared to several other compounds. 177Lu-rhPSMA-10.1 is the first clinical candidate in Blue Earth Therapeutics’ oncology development program of advanced targeted therapeutic radiopharmaceuticals. An investigational Phase 1/2 clinical trial (NCT05413850) evaluating the safety, tolerability, dosimetry and anti-tumor activity of 177Lu-rhPSMA-10.1 in eligible men with metastatic castrate-resistant prostate cancer (mCRPC) is underway in the United States.

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"We are pleased to share these initial results from Blue Earth Therapeutics’ rhPSMA-10.1 program in prostate cancer with the nuclear medicine community at the SNMMI 2023 Annual Meeting," said David E. Gauden, D.Phil., Chief Executive Officer of the Company. "Our goal at Blue Earth Therapeutics is to deliver precise, targeted therapy specific to the patient’s condition. The radiohybrid PSMA theranostic technology platform enables molecules within the class to be modified and deployed for either diagnostic PET imaging or therapeutic applications, and can also be developed with both beta- and alpha-emitting therapeutic radioisotopes. Our lead therapeutic compound, 177Lu-rhPSMA-10.1, was carefully optimized during development with the aim of maximizing its therapeutic index by delivering high radiation doses to prostate cancer lesions while sparing normal tissues as far as possible. The preclinical efficacy results in prostate cancer xenografts reported here support a promising therapeutic profile for 177Lu-rhPSMA-10.1. They are further supported by the early clinical experience of our collaborators in Augsburg, where the team observed an average 3.3-fold higher tumor absorbed radiation dose compared to PSMA-I&T in a direct intra-patient comparison, without a proportional increase in radiation dose to the kidney."

Highlights of the presentations

Improved therapeutic index with the novel PSMA-ligand 177Lu-rhPSMA-10.1 compared to 177Lu-PSMA I&T – an intrapatient comparison

Results from an independent clinical study by BET collaborators at University Hospital Augsburg, Augsburg, Germany, were presented by Ralph Bundschuh, MD, PhD, Nuclear Medicine, Faculty of Medicine. The study was designed to evaluate and compare dosimetry and therapeutic indices for 177Lu-rhPSMA-10.1 and 177Lu-PSMA I&T. It included 4 patients with advanced, histologically confirmed metastatic castrate resistant prostate cancer, each patient received 177Lu-rhPSMA-10.1 (1.06 ± 0.05 GBq) and 177Lu-PSMA-I&T (1.09 ± 0.02 GBq), within 2 subsequent weeks. Dosimetry studies were performed to assess whole body uptake as well as, more specifically, uptake in salivary glands, kidneys, liver, spleen, bone marrow and up to 4 tumor lesions. The therapeutic index (TI), the ratio between mean dose to the metastases and the mean dose to the kidneys, was calculated for each patient.

The effective whole-body dose was found to be (0.038 ± 0.008) Sv/GBq for 177Lu-rhPSMA-10.1 and thus higher than for 177Lu-PSMA-I&T (0.022 ± 0.005) Sv/GBq, mainly due to 50% higher dose to the kidneys with (0.69 ± 0.30) Gy/GBq for 177Lu-rhPSMA-10.1 vs. (0.46 ± 0.11) Gy/GBq for 177Lu-PSMA-I&T. Bone marrow doses were (0.07 ± 0.06) Gy/GBq for 177Lu-rhPSMA-10.1 vs. (0.04 ± 0.04) Gy/GBq for 177Lu-PSMA-I&T, while doses to the salivary glands were (0.43 ± 0.18) Gy/GBq for 177Lu-rhPSMA-10.1 vs. (0.13 ± 0.04) Gy/GBq for 177Lu-PSMA-I&T. Tumor doses were significantly higher with 177Lu-rhPSMA-10.1 than 177Lu-PSMA-I&T. Across each evaluated lesion, 177Lu-rhPSMA-10.1 delivered an average of 3.3 times (1.2-8.3) higher tumor absorbed radiation dose. The TI was higher for 177Lu-rhPSMA-10.1 compared with 177Lu-PSMA-I&T (Patient 1, 43%, Patient 2, 213%, Patient 3, 70%, Patient 4, 6.4%) in all cases. Based on these initial results, the use of 177Lu-rhPSMA-10.1 has the potential to increase the tumor absorbed dose and improve the TI. An improved TI gives the option of maximizing tumor absorbed radiation doses, or, in earlier disease, reducing the radiation exposure to normal organs while still achieving an effective tumor dose. They noted that careful assessment of kidney and salivary gland organ function in prospective clinical trials is necessary.

Enhanced therapeutic response to 177Lu-rhPSMA-10.1 in preclinical models of prostate cancer

Caroline Foxton, Ph.D., Blue Earth Therapeutics, Oxford, UK, presented data from preclinical models of prostate cancer designed to evaluate the therapeutic response to 177Lu-rhPSMA-10.1 using several radiation dose levels, and compare the efficacy of 177Lu-rhPSMA-10.1 to 177Lu-PSMA-617 and 177Lu-PSMA-I&T. Results showed that in LNCaP xenografts a single dose of 177Lu-rhPSMA-10.1 significantly suppressed tumor growth (from day 11, p<0.05, to day 32, p<0.0001) and prolonged survival (p=0.001) at all doses tested (15, 30 or 45MBq) compared with controls. Tumor growth was significantly reduced with 30 MBq and 45 MBq compared with 15 MBq of 177Lu-rhPSMA-10.1 (from day 35, p=0.001, to day 49, p<0.0001), suggesting a dose-response effect. Median survival was 28 days for vehicle control and was not reached for the 177Lu-rhPSMA-10.1 groups at the study endpoint and all dose levels of 177Lu-rhPSMA-10.1 were well-tolerated.

In 22Rv1 xenografts, both 177Lu-rhPSMA-10.1 and 177Lu-PSMA-617 significantly suppressed tumor growth (from day 18 onwards, p<0.05, to day 35, p<0.0001) and prolonged survival (p≤0.01) compared with vehicle control. 177Lu-PSMA-I&T inhibited tumor growth to a lesser extent (from day 25 onwards, p<0.05, to day 35, p<0.0001). When compared with 177Lu-PSMA-I&T, 177Lu-rhPSMA-10.1 significantly reduced tumor growth from day 32 onwards (p<0.05) to day 49 (p<0.0001), whereas 177Lu-PSMA-617 significantly reduced tumor growth on day 49 only (p<0.05). Median survival was 33.5 days for vehicle control, 44 days for 177Lu-PSMA-I&T and was not reached for the 177Lu-rhPSMA-10.1 and 177Lu-PSMA-617 groups. All treatments were well-tolerated. The authors concluded that the analyses demonstrate significant therapeutic efficacy with 177Lu-rhPSMA-10.1 in prostate cancer xenografts, at clinically and sub-clinically equivalent dose levels. They noted that the promising therapeutic profile observed for 177Lu-rhPSMA-10.1 compared with 177Lu-PSMA-617 and 177Lu-PSMA-I&T further supports its clinical development.

About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA)

Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) compounds consist of a radiohybrid ("rh") Prostate-Specific Membrane Antigen-targeted receptor ligand, which attaches to and is internalized by prostate cancer cells, which can be radiolabeled with imaging isotopes for PET imaging, or with therapeutic isotopes for therapeutic use – providing the potential for creating a true theranostic technology. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Diagnostics received U.S. Food and Drug Administration approval for its radiohybrid PSMA PET diagnostic imaging product for use in prostate cancer in 2023. rhPSMA compounds for potential therapeutic use are investigational and have not received regulatory approval.

On June 29, 2023 ArteraAI, the developer of multimodal artificial intelligence-based predictive and prognostic cancer tests, reported the publication of data in the NEJM Evidence, validating the first-ever predictive AI biomarker of androgen deprivation therapy (ADT) benefit in prostate cancer (Press release, Artera, JUN 29, 2023, View Source [SID1234632994]).

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The study used novel deep learning methodology and histopathology image data from more than 5,000 patients across five Phase 3 randomized trials, with long-term follow-up. Patients in these trials were enrolled from over 100 centers across the US and Canada. The predictive AI biomarker was developed using datasets comprising about 20% African American patients. In past U.S.-based clinical trials, African American men have made up only 10.8% of prostate cancer trial participants.

"This is truly a milestone in the treatment for prostate cancer," said Dr. Daniel Spratt, MD, chairman and professor of radiation oncology at University Hospitals (UH) Seidman Cancer Center and Case Western Reserve University (CWRU), and one of the corresponding authors on the study. "With the first-ever predictive biomarker of ADT benefit in prostate cancer, created with AI, we are able to further realize the ability to create a personalized approach for the treatment of cancer."

In patients with localized prostate cancer, ADT can be added to radiotherapy if improved patient outcomes are anticipated. However, ADT is also known to have negative side effects ranging from loss of sexual function to potentially detrimental effects on cardiac and brain health. Some studies suggest many men do not need ADT as part of their treatment plan, and that radiotherapy alone is effective. If given the opportunity to leverage the biomarker, most intermediate-risk patients could potentially avoid the morbidity and financial burden associated with ADT.

"Keeping patients from undergoing a treatment that would not provide therapeutic benefit, especially one that could do more harm than good, is everything to a clinician," said Felix Feng, MD, Scientific Advisor to ArteraAI, Professor of Radiation Oncology, Urology, and Medicine at the University of California San Francisco, and corresponding author of the study. "The validation of this biomarker by this highly credible and trusted publication is a milestone. We celebrate this achievement while also looking ahead to how we can build upon this evidence to continue transforming care for men diagnosed with localized prostate cancer."

On June 29, 2023 Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported that the first patient has been dosed in its Phase I clinical trial that will test the safety and tolerability of the Company’s lead product candidate, CT-0508, a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M) in combination with Merck’s anti-PD1 therapy KEYTRUDA (pembrolizumab) for the treatment of HER2 overexpressing cancers (Press release, Carisma Therapeutics, JUN 29, 2023, View Source [SID1234632993]).

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Pre-clinical data presented at SITC (Free SITC Whitepaper) in 2022 demonstrated that the mice that received both therapies had improved tumor control, overall survival, and tumor microenvironment (TME) activation as compared to either treatment alone, indicating synergy and the capacity for CAR-M to sensitize solid tumors to checkpoint blockade.

This first patient’s cells were manufactured at the Novartis Cell Therapy Site in Morris Plains, New Jersey, following the successful completion of the tech transfer of CT-0508 to Novartis earlier this year. This is Carisma’s first clinical product to be manufactured and administered from this collaboration.

"We are excited by the progress being made on our CT-0508 clinical program with the dosing of the first patient in the combination study with KEYTRUDA," said Michael Klichinsky, PharmD, PhD, Co-Founder and Chief Scientific Officer at Carisma Therapeutics. "The CT-0508 monotherapy trial has demonstrated early clinical validation of the CAR-M mechanism of action, and we are eager to explore this sub-study to assess the potential synergistic effect of CAR-M therapy in combination with KEYTRUDA. The initiation of clinical manufacturing at Novartis’ GMP cell therapy site is also a meaningful step forward in progressing our overarching manufacturing strategy, and demonstrates our desire to work alongside best-in-class companies."

In January 2023, Carisma appointed nationally regarded cancer immunologist and oncologist, Dr. Padmanee Sharma, MD, PhD, to the company’s Scientific Advisory Board. The Company expects that Dr. Sharma’s scientific knowledge in immunotherapy will provide valuable guidance in the studies of CT-0508 and KEYTRUDA.

The clinical trial sub-study of CT-0508 in combination with KEYTRUDA has been initiated at multiple site locations in the U.S. and will enroll patients with different types of recurrent or metastatic cancers with HER2 overexpressing solid tumors. To learn more about this, please visit ClinicalTrials.gov (NCT04660929) or Carisma’s clinical trial website.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About CT-0508

CT-0508 is a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). It is being evaluated in a landmark Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers are not eligible for treatment with currently available HER2-targeted therapies or who do not respond to treatment. The trial is enrolling participants who have tumors of any anatomical origin, but with the commonality of overexpressing the HER2 receptor on the cell surface, which is the target for our CAR-M. The Phase 1 clinical trial is first-of-its-kind, marking the first time that genetically engineered macrophages are being studied in humans. The trial continues to enroll patients at seven clinical sites in the U.S., including (i) the University of Pennsylvania Abramson Cancer Center, (ii) the University of North Carolina Lineberger Comprehensive Cancer Center, (iii) the City of Hope National Medical Center, (iv) the MD Anderson Cancer Center, (v) the Sarah Cannon Cancer Research Institute, (vi) Oregon Health & Science University and (vii) Fred Hutchinson Cancer Center.

On June 29, 2023 Shasqi, Inc. ("Shasqi") a clinical stage biotech company, whose mission is to revolutionize cancer treatment with click chemistry, reported the expansion of its Click Activated Protodrugs Against Cancer (CAPAC ) platform with a pivotal manuscript describing the preclinical development of SQ2201, a novel cancer therapy (Press release, Shasqi, JUN 29, 2023, View Source [SID1234632992]). SQ2201 comprises a systemically administered tumor targeting agent that binds to the HER2 receptor (SQT01), paired with an MMAE protodrug (SQP22), which is activated at the site of the tumor via a click chemistry reaction. SQ2201 showed potent anti-tumor effects in mice that surpassed those seen with a biosimilar of disitamab vedotin, a conventional ADC which targets the same antigen and delivers the same payload. The manuscript is published in the peer-reviewed journal ACS Central Science.

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"By decoupling the targeting agent from the payload, our unique approach has the potential to expand on the promise of ADCs," said José M. Mejía Oneto, M.D., Ph.D., Shasqi CEO and founder. "Our systemic HER2 antigen targeting agent opens up a new area for our CAPAC platform, unlocking our library of payloads to the world of targeted therapeutics. We are excited to continue expanding the possibilities of our technology."

This work builds on the clinical validation achieved with SQ3370. In a phase 1 study, click chemistry was used to activate up to 12-times the conventional dose of doxorubicin, with a more favorable toxicity profile. Tumor localization of click chemistry in this instance was achieved through an intratumorally injected biopolymer. A phase 2 study is ongoing.

On June 29, 2023 HaemaLogiX Ltd, a clinical stage Australian biotech company developing novel immunotherapies for multiple myeloma, reported positive final results from a Phase IIb clinical study of its monoclonal antibody KappaMab in combination with lenalidomide and dexamethasone in kappa-type multiple myeloma patients who had relapsed or become refractory to other treatment options (Press release, HaemaLogiX, JUN 29, 2023, View Source [SID1234632991]).

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The final data has been published in the British Journal of Haematology. Key findings include:

A statistically significant overall response rate (ORR) of 83% and clinical benefit rate (CBR) of 93% in KappaMab + lenalidomide / dexamethasone (Case) was achieved compared to the matched Control cohort of lenalidomide + dexamethasone alone (ORR = 45%).
The median Overall Survival was not reached, with two patients remaining on therapy and continuing to respond, and with no evidence of detectable disease.
KappaMab’s previously established safety profile was reaffirmed, with no KappaMab related haematological toxicities or serious adverse effects.
KappaMab targets a receptor called Kappa Myeloma Antigen (KMA) found only on the surface of myeloma cells in kappa-type multiple myeloma patients and not on normal immune cells, which means normal immune cells are not damaged by the treatment.

The phase IIb study was initiated off the back of phase I, IIa, and preclinical data suggesting KappaMab may have a synergistic mechanism of action with lenalidomide, a drug sold under the trade name Revlimid, that forms standard of care for multiple myeloma. Lenalidomide is administered as both a monotherapy and with other drugs including dexamethasone, depending on the treatment approach and disease status.

"This study validates KMA as a highly specific target, and the ability to safely deliver KappaMab in combination with a mainstay treatment for multiple myeloma," HaemaLogiX CEO, Bryce Carmine, said:

"Patient response shows the combination of KappaMab with one of the most common multiple myeloma treatment approaches – lenalidomide and dexamethasone – outperforms that treatment approach alone.

"We are tremendously grateful to the investigators and to the patients who participated.

"We look forward to furthering the clinical progress of KappaMab with a clinical trial at a higher dose of KappaMab which will flow into a Phase IIb study investigating KappaMab in combination with pomalidomide and dexamethasone in patients who have relapsed or become refractory to other standard of care treatments."

This Phase IIb trial followed a Phase IIa open-label multiple dose trial to determine the safety and efficacy of multiple doses of KappaMab monotherapy in 19 relapsed and / or refractory patients who had received multiple prior treatments.

The phase IIb trial was a multi-centre trial led by Professor Andrew Spencer, which evaluated patient responses to KappaMab when combined with standard of care treatment compared to the standard of care drugs alone. The trial enrolled 40 patients with kappa-type myeloma who had previously been treated with one to three lines of drugs, and in which the disease was progressing. Along with positive efficacy results, the trial demonstrated an excellent safety profile with no patients experiencing KappaMab related serious side effects.