On December 6, 2021 Adicet Bio, Inc. (Nasdaq: ACET), a biotechnology company discovering and developing first-in-class allogeneic gamma delta CAR T cell therapies for cancer and other diseases, reported positive interim data from its dose escalation Phase 1 study evaluating the safety and tolerability of ADI-001, Adicet’s investigational therapy targeting CD20 for the potential treatment of B-cell Non-Hodgkin’s Lymphoma (Press release, Adicet Bio, DEC 6, 2021, View Source [SID1234596495]).

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As of the November 22, 2021 data cutoff, six patients had been enrolled and received ADI-001. The first two patients enrolled in the lowest dose level tested did not reach the day 28 assessment and were not evaluable for efficacy per protocol. Three of the four evaluable patients achieved responses, including two complete responses (CR) and one partial response (PR) that investigators characterized as near complete response. Patients were heavily pre-treated, with a median of five lines of prior systemic therapy, including a patient who had received prior autologous CD19 CAR T,​ and achieved complete response following a single infusion of ADI-001 administered at the lowest dose level.

"We are extremely excited to see such profound early complete responses in our Phase 1 dose-finding study evaluating ADI-001 as monotherapy among patients with very advanced cancer starting at our first dose level of 30 million CAR+ cells," said Chen Schor, President and Chief Executive Officer of Adicet Bio. "Data to-date suggest that ADI-001 is highly clinically active. We look forward to reporting additional data in the first half of 2022 and to rapidly progressing our pipeline to realize the full potential of our gamma delta CAR T cell platform for patients."

"The unequivocal responses to ADI-001 in this heavily pre-treated patient population at such low dose levels are highly promising," said Sattva Neelapu M.D., Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "These data suggest that ADI-001 has the potential to be an effective treatment option for B cell malignancies if confirmed in further clinical testing. ADI-001 does not require gene editing and provides complementary innate, adaptive, and CAR mediated antitumor effects which may improve durability and minimize emergence of tumor resistance."

Of the four efficacy evaluable patients, three received ADI-001 at dose level one (30 million CAR+ cells) and one received ADI-001 at dose level two (100 million CAR+ cells). In dose level one, one patient achieved a CR, one patient achieved a PR that was characterized as near CR and one patient had progressive disease (PD). In dose level two, the first patient achieved a CR.

All evaluable patients had been heavily pre-treated with a median of five lines of prior systemic therapies. Of the three patients who achieved PR or better under Lugano 2014 criteria (ORR=75%, CR=50%), one had diffuse large B-cell lymphoma (DLBCL) with five prior lines of therapy including two cycles of anti-CD19 CAR T cell therapy, one had follicular lymphoma transformed into a large B-cell tumor with four prior lines of therapy, and the third had mantle cell lymphoma with five prior lines of therapy. These patients achieved two CRs and a near CR.

Overall, ADI-001 infusions were generally well-tolerated. No dose-limiting toxicities, graft vs host disease (GvHD), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) or grade 3 or higher Cytokine Release Syndrome (CRS) have been reported to-date, suggesting a potentially wide therapeutic window for ADI-001.

A significant increase in circulating IL-15 was observed during the 28-day window following lymphodepletion, potentially providing cytokine support for the proliferation of ADI-001​. Emergence of circulating ADI-001 in the blood was observed by quantitative polymerase chain reaction and by flow cytometry, demonstrating expansion of ADI-001 in patients​. Elevations in additional circulating cytokines, primarily IL-2 and IL-8 were observed during the first 14 days from dosing, consistent with the activation profile of ADI-001 and similar to the observed time-to-peak for cytokines previously reported in association with autologous alpha-beta CAR T cells. Importantly, no meaningful increases in IL-6 were seen in association with ADI-001, except for one patient who experienced COVID-19 infection, suggesting reduced likelihood for ICANS and high-grade CRS.

"It is remarkable to see our early preclinical studies translate to the clinic. The preliminary safety and efficacy data from low-dose ADI-001 collected to date indicate the potential for a broad therapeutic window. Without the need for gene editing and its associated safety concerns, our platform is designed to preserve the natural innate and adaptive anti-tumor activity of gamma delta CAR T cells, which we believe may lead to better durability," said Francesco Galimi, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Adicet Bio. "As we look to expand into additional cohorts, we plan to leverage our scalable off-the-shelf manufacturing process to meet future needs. We look forward to advancing our novel allogeneic gamma delta T cell pipeline for cancer patients."

Table 1: Summary of ADI-001 interim data from two dosing cohorts*:

Dose Level Age/Sex B-cell lymphoma subtypes # Prior lines of therapies Prior CAR T? Best Response (BOR) by Lugano Criteria (2014)
30 million CAR+ cells

62/F Transformed DLBCL​
(from chronic lymphocytic leukemia) 5 prior lines No PD
66/F Transformed high grade​
B cell tumor (from follicular lymphoma) 4 prior lines

No PR
(Near CR)
75M DLBCL 5 prior lines Yes (liso-cel) CR
100 million CAR+ cells 62/M Mantle cell lymphoma 5 prior lines No CR
*Efficacy evaluable patients as of November 22, 2021 database entry. Data are subject to further review and verification.

Webcast/Conference Call Information
Adicet will host a live presentation on Monday, December 6 at 8:30am EST to discuss the results. Dr. Sattva Neelapu from the University of Texas MD Anderson Cancer Center will participate in the event.

The live webcast of the presentation can be accessed under "Presentations & Events" in the investors section of the Company’s website at www.adicetbio.com or by dialing (877) 800-3802 (domestic) or (615) 622-8057 (international) and reference the conference ID 6952318. The archived webcast will be available on the Company’s website beginning approximately two hours after the event.

About ADI-001
ADI-001 is an investigational allogeneic gamma delta CAR T cell therapy being developed as a treatment for B-cell non-Hodgkin’s lymphoma. ADI-001 targets malignant B-cells via an anti-CD20 CAR and via the gamma delta innate and T cell endogenous cytotoxicity receptors. Gamma delta T cells engineered with an anti-CD20 CAR have demonstrated potent antitumor activity in preclinical models, leading to long-term control of tumor growth.

About the GLEAN Study
This Phase I study is an open-label, multi-center study of ADI-001 enrolling adults diagnosed with B cell malignancies who have either relapsed, or are refractory to at least two prior regimens. The primary objectives of the study are to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ADI-001, and to determine optimal dosing as a monotherapy. The study is expected to enroll approximately 75 patients. For more information about the clinical study design, please visit: www.clinicaltrials.gov (NCT04735471).

On December 6, 2021 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a platform-driven, clinical-stage biopharmaceutical company committed to transforming the discovery and development of novel antibody-based immunotherapies, reported clinical data on its anti-CTLA-4 monoclonal antibody, ADG116, and anti-CD137 agonist, ADG106, in two poster presentations at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) Congress 2021, to be held virtually and in Geneva, Switzerland from December 8 to 11, 2021 (Press release, Adagene, DEC 6, 2021, View Source [SID1234596494]). Both posters are available in the Publications section of the company’s website at www.adagene.com.

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In the first presentation of results from an ongoing dose-escalation trial of monotherapy in patients with advanced metastatic tumors, ADG116 demonstrated a strong safety profile and early signals of efficacy, including dose-dependent T-cell activation and tumor suppression in treatment-resistant "cold" and "warm" tumors such as pancreatic, ovarian and renal cell cancers.

Commenting on the findings, Dr. Gary Richardson, OAM, MBBS, FRACP, Group Director at Cabrini Health Research, Director at Szalmuk Family Department of Medical Oncology and Professor of Medicine at Monash University, Australia, "These encouraging clinical data demonstrate the promising safety profile of ADG116 monotherapy in patients with advanced solid tumors across 15 different tumor types, the majority of which are resistant to standard therapy. The most exciting thing about these results is that we have also seen the early signals of efficacy in ‘cold’ tumors such as pancreatic and certain gynecological cancers, which do not respond to current immunotherapies. We want to see this type of unique activity, which suggests that this treatment may look different and potentially better than the options we have available today."

Additionally, a separate poster presentation describing results of pharmacodynamic (PD) biomarker analyses reinforced the synergy and strong T-cell activation of ADG106 in combination with the anti-PD-1 antibody toripalimab.

A summary of data from both posters is included below.

ADG116

Key findings from the poster (#137P) titled "Phase 1 dose-finding study of a novel anti–CTLA-4 antibody ADG116 as monotherapy in patients with advanced solid tumors" include:

Clinical results from a global dose escalation and cohort expansion trial with sites in the U.S. and Australia (ADG116-1003) evaluated ADG116 monotherapy in 25 heavily pre-treated patients with advanced metastatic solid tumors, the majority of which are insensitive to immunotherapy:
Patients across 15 different tumor types were evaluated.
The majority (68 percent) received three or more lines of prior systemic therapy.
Nearly one quarter (24 percent) received prior immunotherapy treatment.
ADG116 monotherapy was well-tolerated up to 6 mg/kg with only Grade 1 or 2 treatment-related adverse events (TRAEs) observed; rash (20 percent) and pruritus (20 percent) were the most common.
In the ongoing 10 mg/kg cohort, a rash (Grade 3) and dose limiting toxicity event (Grade 4 hyperglycemia) occurred in a patient with renal cell carcinoma who relapsed on nivolumab. A significant increase in the patient’s CD8 T cells after one cycle of treatment showed that ADG116 is highly active for triggering T cell activation.
ADG116 treatment resulted in dose-dependent increases in peripheral CD8 and CD4 T cells, indicating immune activation by targeting the CTLA-4 pathway, starting at a dose as low as 0.03 mg/kg and becoming more striking at the 6 mg/kg and 10 mg/kg dose levels. In one example, a patient refractory to multiple cycles of pembrolizumab treated at 0.03 mg/kg showed increased CD8 and CD4 T cells.
In the dose escalation portion of the trial, four prolonged stable diseases were observed amongst these heavily pre-treated patients.
Of special note is a 22 percent tumor reduction observed in target lesions (after the data cut-off on October 15, 2021) following two cycles of ADG116 for a pancreatic cancer patient treated at 10 mg/kg. Only Grade 1 TRAEs were observed and the patient’s non-target lesion (23 x 12mm) disappeared. The patient continues on treatment.
Additionally, an ovarian cancer patient treated at 6mg/kg showed stable disease for more than 116 days with increased CD8 and CD4 T cells. The patient continues on treatment.
ADG116 demonstrated dose-proportional increases in drug exposure with a half-life supporting convenient dosing every three weeks.
The findings support that ADG116 has achieved the recommended dosing range as a single agent and for evaluation in combination therapy. The ADG116-1003 trial continues with dose escalation at 10 mg/kg, while cohort expansion has been initiated at 6 mg/kg.

Adagene is also advancing ADG116 in combination with anti-PD-1 therapy (pembrolizumab or toripalimab) and with its proprietary anti-CD137 agonist (ADG106). Further, the company is evaluating a second anti-CTLA-4 antibody, ADG126, using its SAFEbody precision masking technology in an ongoing phase 1 dose escalation as monotherapy. This reflects the company’s commitment to unlock the value of CTLA-4 as a proven target and the backbone of future immunotherapies.

ADG106

Key findings from the poster (#43P) titled "Assessment of Biomarker Kinetics for ADG106 (anti-CD137 agonist) as monotherapy or combined with toripalimab" include:

Results of PD biomarker analyses which demonstrated the synergistic effect of ADG106 in combination with an anti-PD-1 antibody, toripalimab, compared to ADG106 monotherapy at doses up to 3 mg/kg.
The combination of ADG106 with toripalimab resulted in a 2-fold greater immune activation versus ADG106 alone. These results were observed even amongst patients who failed prior anti-PD-1 and CTLA-4 therapies.
Soluble CD137 levels (sCD137) levels increased with immune activation suggesting this as a dose-dependent PD biomarker of T cell target engagement, which could be used to monitor potential clinical response.
ADG106 treatment alone and in combination with anti-PD-1 therapy also increased serum IFN-γ, IL-6, natural killer cells, and T-cell subsets.
Additional analyses demonstrate that the pharmacokinetic profile of ADG106 was not altered by the addition of toripalimab.
These findings highlight the synergistic activity of ADG106 in combination with the anti-PD-1 toripalimab for patients who failed anti-PD-1 and anti-CTLA-4 immunotherapies. This combination is being evaluated in the ongoing ADG106-1008 clinical trial, currently in a cohort dosing ADG106 at 3 mg/kg. The data support further exploration of combination therapy regimens with ADG106 at informed dose ranges for targeting biomarker enriched tumor types.

"The data presented today from two of our NEObody clinical programs show how we are creating transformative antibody-based immunotherapies that push the limits of antibody discovery and development, overcoming liabilities with some of the most promising yet challenging immuno-oncology targets today," said Peter Luo, Ph.D., Co-founder, Chief Executive Officer and Chairman of Adagene. "These findings strengthen confidence in our clinical pipeline and in the ability of our platform technologies to achieve unprecedented results that will ultimately benefit patient care."

About ADG116

This NEObody program, targeting a unique epitope of CTLA-4, is being evaluated in patients with advanced/metastatic solid tumors. ADG116 is designed to enhance efficacy by potent Treg depletion in the tumor microenvironment (TME) and maintain its physiological function by soft ligand blocking to address safety concerns associated with existing CTLA-4 therapeutics.

About ADG106

This NEObody program is a fully human ligand-blocking, agonistic anti-CD137 IgG4 monoclonal antibody (mAb) that is being evaluated in patients with advanced solid tumors and/or non-Hodgkin’s lymphoma.

On December 6, 2021 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that the first patient has been dosed in a Phase 1b/2 trial evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), in combination with elranatamab (PF-06863135) Pfizer’s investigational B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody, in patients with relapsed or refractory multiple myeloma (Press release, SpringWorks Therapeutics, DEC 6, 2021, View Source [SID1234596493]).

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Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of myeloma cells. In preclinical models, nirogacestat has been shown to increase the cell surface density of BCMA and reduce levels of soluble BCMA, thereby enhancing the activity of BCMA-targeted therapies, including CD3 bispecific antibodies.1,2

"We are very pleased to be dosing patients in this study, which is one of six collaborations evaluating the combination of nirogacestat with a BCMA-targeted therapy as part of our broader effort to explore our gamma secretase inhibitor’s role as a potential cornerstone of BCMA combination therapy," said Saqib Islam, Chief Executive Officer of SpringWorks. "Our goal is to improve treatment options for patients with multiple myeloma and we look forward to generating data with our collaborators to determine if adding nirogacestat can potentiate the activity of BCMA-directed therapies for these patients."

The Phase 1b/2 trial, which is one sub-study of Pfizer’s umbrella MagnetisMM-4 trial (NCT05090566), is an open-label study evaluating the safety, tolerability and preliminary efficacy of elranatamab in combination with nirogacestat in patients with relapsed or refractory multiple myeloma. The trial is being advanced pursuant to a clinical trial collaboration agreement between SpringWorks and Pfizer. Under the terms of the agreement, Pfizer is sponsoring and conducting the Phase 1b/2 study and is assuming all costs other than expenses related to the manufacturing of nirogacestat and certain expenses related to intellectual property rights. The companies have formed a joint development committee to manage the clinical study.

About Elranatamab

Elranatamab is an investigational B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody being investigated in relapsed or refractory multiple myeloma. Binding affinity to BCMA and CD3 has been optimized, to potentially elicit more potent T-cell-mediated anti-myeloma activity. Elranatamab is being investigated as a subcutaneous administration, which is intended to allow higher doses than intravenous administration without increasing adverse events.

Elranatamab has been granted Orphan Drug Designations by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of multiple myeloma. The U.S. FDA and EMA have also granted elranatamab Fast Track Designation for the treatment of patients with multiple myeloma who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and the PRIME scheme for the treatment of multiple myeloma, respectively.

About Nirogacestat

Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.

In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has six collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, two bispecific antibodies and a monoclonal antibody. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA therapies using a variety of preclinical multiple myeloma models.

Nirogacestat has received Orphan Drug Designation from the U.S. FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.

On December 6, 2021 MannKind Corporation (Nasdaq: MNKD), a company focused on the development and commercialization of inhaled therapeutic products for patients with endocrine and orphan lung diseases, reported that it will be participating in the Lytham Partners Winter 2021 Investor Conference taking place from December 13-16, 2021 (Press release, Mannkind, DEC 6, 2021, View Source [SID1234596492]). During the event, the Company’s Chief Executive Officer, Michael Castagna, PharmD, will be participating in a webcasted Fireside Chat discussing its vision for 2022 and Mr. Castagna and the Company’s Chief Financial Officer, Steven B. Binder will be conducting 1×1 virtual investor meetings.

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The webcasted Fireside Chat will be available for viewing at 11:00 AM ET on Monday, December 13, 2021, on the Company’s website at View Source The webcast will also be archived and available for replay.

To arrange a 1×1 meeting with management, please contact Lytham Partners at 1×[email protected] or register at www.lythampartners.com/winter2021invreg.

On December 6, 2021 PDS Biotechnology Corporation (Nasdaq: PDSB), a clinical-stage immunotherapy company developing novel cancer therapies based on the Company’s proprietary Versamune T-cell activating technology, reported the reopening of recruitment in the National Cancer Institute (NCI)-led Phase 2 clinical trial (NCT04287868) evaluating PDS0101 (Versamune-HPV16) in combination with two investigational immune-modulating agents in advanced HPV cancers (Press release, PDS Biotechnology, DEC 6, 2021, View Source [SID1234596490]).

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The suspension of recruitment was administrative in nature and was unrelated to any specific safety or efficacy concerns associated with the triple combination being studied. As a result, during the recruitment suspension, patients already enrolled in the study continued to receive scheduled treatment. The timing of clinical results from this trial is not expected to be affected by the pause in recruitment of new patients.

The trial is evaluating the novel triple combination in two groups of patients. Firstly, in second line treatment of recurrent or metastatic HPV-positive cancers including anal, cervical, head and neck, penile, vaginal, and vulvar cancers in patients who are naïve to checkpoint inhibitors and have not responded to at least one standard of care therapy. Secondly in third line treatment of the above recurrent or metastatic HPV-positive cancers in patients who have not responded to at least two standard of care therapies including checkpoint inhibitor treatment.

"We are pleased that the NCI, part of the National Institutes of Health, quickly obtained IRB approval to resume recruitment in this important trial. We believe the interim data demonstrated that this combination has the potential to significantly improve clinical outcomes for patients with advanced, refractory HPV16-positive cancers who have limited treatment options. Our approach of treating multiple types of cancer based on their molecular profiles rather than tissue location, may have the potential to provide safe Versamune-based treatment options to an expanded population of patients suffering from multiple types of cancer and at different stages of disease." said Dr. Lauren V. Wood, PDS Biotech’s Chief Medical Officer.

For patients interested in enrolling in this clinical study, please call NCI’s toll-free number 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615), email [email protected], and/or visit the website: View Source