On December 12, 2022 Nektar Therapeutics (Nasdaq: NKTR) reported two presentations of NKTR-255 at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Nektar Therapeutics, DEC 12, 2022, View Source [SID1234625158]).

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NKTR-255 is an investigational IL-15 receptor agonist designed to boost antitumor immunity by increasing the proliferation and survival of natural killer (NK) and memory CD8+ T cells, thereby enhancing the formation of long-term immunological memory, which may lead to sustained antitumor immune response.

The study design of an upcoming Phase 2/3, randomized, double-blind, placebo-controlled, multicenter clinical trial of NKTR-255 following CD19-directed chimeric antigen receptor T (CAR-T) cell therapy in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) was presented by Miguel-Angel Perales, M.D., Chief, Adult Bone Marrow Transplant Service, at Memorial Sloan Kettering Cancer Center on Sunday, December 11th. Pre-clinical studies demonstrate that NKTR-255 can potentiate the effects of CAR-T therapies and a number of early clinical studies are currently underway to evaluate the role of NKTR-255 following CAR-T cell treatment for different hematologic malignancies.

Additionally, results from the ongoing Phase 1 study of NKTR-255 as a monotherapy and in combination with daratumumab in patients with R/R multiple myeloma (MM) or non-Hodgkin’s lymphoma (NHL) were presented by Krina Patel, M.D., Associate Professor, Department of Lymphoma-Myeloma, at the University of Texas MD Anderson Cancer Center on Monday, December 12th. The data showed that NKTR-255 resulted in an expansion and proliferation of NK cells following daratumumab’s on-target depletion of CD38-expressing NK cells.

"NKTR-255 administration one-day following dara resulted in a 4-fold expansion of the NK cells, returning NK cells to the same baseline level seen before dara administration. This exciting result shows that NKTR-255 can restore dara-induced NK cell depletion and may potentiate its ADCC mechanism. Moreover, NKTR-255 treatment resulted in NK cell expansion and induction of NK-cell activation markers across multiple cycles further validating NKTR-255’s effect," said Jonathan Zalevsky, Ph.D., Head of Research and Development at Nektar. "Additional work presented at ASH (Free ASH Whitepaper) highlights our new trial evaluating NKTR-255 as a unique potentiator of cellular therapy in a Phase 2/3 study in relapsed or refractory lymphoma patients who are seeking long-term efficacy from currently available CAR-T cell therapy."

2022 ASH (Free ASH Whitepaper) presentations are available for download at www.nektar.com/science/scientific-posters-and-presentations.

Key details and takeaways from the presentation are as follows:

Abstract 3335 (Trial in Progress): "A Phase 2/3, Randomized, Double Blind, Placebo-Controlled, Multicenter Study of NKTR-255 Vs Placebo Following CD-19 Directed CAR-T Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma", Perales M., et al.

Based on preclinical and clinical evidence, NKTR-255 has the potential to improve efficacy of currently approved cellular therapy by enhancing antitumor effect and durability of responses.
The upcoming Phase 2/3 study will enroll eligible patients with R/R LBCL who have received an FDA-approved CAR-T cell product. Patients will receive NKTR-255 intravenously, starting approximately 14 days following CAR-T therapy, with continued dosing every 21 days.
The primary objective of the Phase 2 portion of the study is to identify the dose of NKTR-255 for the Phase 3 portion of the study based on safety, tolerability, and complete response rate (CRR) at month 6, the primary efficacy endpoint.
Abstract 4652: "Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies", Patel K., et al.

NKTR-255 was well tolerated in heavily pre-treated patients with hematologic malignancies (NHL and MM) in doses up to 12 μg/kg and in combination with daratumumab in doses up to 9 μg/kg (in MM). The majority of treatment-related adverse events (TRAE) were low-grade, transient, and easily managed. The maximum tolerated dose (MTD) was not reached.
No new safety signals or overlapping toxicities were observed with the doublet and dose escalation is ongoing.
Early evidence of clinical activity was observed in this heavily pre-treated and highly refractory patient population with the doublet (NKTR-255 + daratumumab).
Peak fold-changes of ~17-fold NK cell and ~2-fold in CD8+ T cell expansion were observed in the first 2 cycles with NKTR-255 monotherapy doses up to 12 μg/kg. Sustained proliferative ability of NK and CD8+ T cells across multiple cycles indicated no evidence of tachyphylaxis.
Preliminary data from patients previously treated with off-the-shelf allogenic CAR-T cells indicate that allo-CAR-T cells persisted with NKTR-255 monotherapy, suggesting no alloreactivity to off-the-shelf allo-CAR-T cells.
With combination therapy, NK cell rescue was observed with sustained increases in NK and CD8+ T cells despite daratumumab’s on-target depletion of CD38 expressing NK cells.
About NKTR-255

NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body’s innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.

Preclinical and clinical findings suggest NKTR-255 has the potential to synergistically combine with antibody-dependent cellular cytotoxicity molecules as well as to enhance CAR-T therapies.

Nektar has initiated a Phase 1 dose escalation and expansion clinical study of NKTR-255 in adults with relapsed or refractory non-Hodgkin lymphoma or multiple myeloma (NCT04136756), as well as a Phase 1/2 clinical study of NKTR-255 in patients with relapsed or refractory head and neck squamous cell carcinoma or colorectal cancer (NCT04616196).

There are two ongoing investigator sponsored trials evaluating NKTR-255 following treatment with a CAR-T cell therapy. Fred Hutchinson Cancer Center is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19 CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphoma (NCT05359211), and Stanford University is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19/22 CAR-T cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (NCT03233854).

On December 12, 2022 TC BioPharm (Holdings) PLC ("TC Biopharm" or the "Company") (NASDAQ: TCBP) (NASDAQ: TCBPW), a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer treatment, reported its financial results for the first half ended June 30, 2022 and provided a shareholder update (Press release, TC Biopharm, DEC 12, 2022, View Source [SID1234625157]).

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"The current year has been an eventful time for TC BioPharm as we launched our Phase 2b in AML," said Bryan Kobel, Chief Executive Officer. "Since completing our IPO in early 2022, we have advanced testing of our lead drug, OmnImmune, are actively forging strategic relationships with key industry leaders and established a strong foundation capable of supporting long-term growth. I am pleased with the current trajectory of the Company and eager to leverage the many opportunities that lay before us, as we execute on our clinical strategy and business development efforts from the second half of 2022. I look forward to providing additional operational announcements in 2023 as we continue to focus on our primary goal of enhancing overall shareholder value through clinical inflection points and strategic efforts."

First Half 2022 Highlights

On February 15, 2022, the Company announced closing of its $17.5 million Initial Public Offering and began trading on the NASDAQ stock exchange under the ticker "TCBP"
Earlier this year, TC BioPharm formally announced positive interim data its Phase 1a/2b human study evaluating safety and tolerability of TCB-002, OmnImmune, the Company’s allogeneic unmodified gamma delta t-cell product, a novel therapeutic targeting the potential treatment of relapse/refractory Acute Myeloid Leukemia ("AML")
In March 2022, TC BioPharm received MHRA and Research Ethics Committee approvals to initiate phase 2B/3 Clinical Trials for the treatment of Acute Myeloid Leukemia
During the First Quarter 2022, the Company announced that orphan drug status had been granted for lead product OmnImmune
In June 2022, the Company announced the closing of a further offering raising $4.6 million before expenses
Financial results

Basic and diluted income/(loss) per share was £0.93 (or $1.13) and £0.76 (or $0.92) for the six months ended June 30, 2022, respectively, compared to (£6.79) and (£6.79) for the six months ended June 30, 2021, respectively. Total net income for the six months ended June 30, 2022 was £0.5 million (or $0.6 million), respectively, compared to a net loss of £2.6 million, for the same period in 2021.

For the six months ended June 30, 2022, our research and development expenses were £3.7 million (or $4.5 million), as compared to £2.9 million for the six months ended June 30, 2021. For the six months ended June 30, 2022, our administrative expenses were £4.1 million (or $5.3 million), compared to £0.9 million for the six months ended June 30, 2021. For the six months ended June 30, 2022, our administrative expenses related to preparing for a listing were £1.1 million (or $1.4 million), compared to £Nil for the six months ended June 30, 2021.

Cash and cash equivalents were £6.0 million or $7.3 million as of June 30, 2022 compared to £1.6 million as of December 31, 2021. We subsequently raised a further £6.0 million (or $7.3 million) in the November 2022 PIPE before deductions for estimated attributable expense of £0.7 million (or $0.9 million).

We maintain our books and records in pounds sterling. For the convenience of the reader, we have translated pound sterling amounts as of and for the period ended June 30, 2022 into U.S. dollars at a rate of £1.00 to $1.2162.

On December 12, 2022 PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on the development of next-generation antibody therapeutics, reported that the Company has entered into a clinical collaboration agreement with MSD (Merck & Co., Inc., Rahway, NJ., USA), to initiate a Phase I combination trial of PMC-309, a novel anti-VISTA (V-domain Ig suppressor of T cell activation) antibody, in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy (Press release, PharmAbcine, DEC 12, 2022, View Source [SID1234625156]).

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Under the terms of the agreement, PharmAbcine will sponsor a Phase I study in Australia to evaluate the safety and clinical efficacy of the combination therapy for the treatment of multiple advanced solid tumors, and MSD will supply KEYTRUDA.

"We are excited to announce another pipeline combination project in collaboration with MSD besides olinvacimab, our lead anti-VEGFR2 antibody, undergoing a Phase II study in combination with KEYTRUDA in mTNBC (metastatic Triple Negative Breast Cancer) patients," said Dr. Jin-San Yoo, CEO of PharmAbcine. "In preclinical studies, PMC-309 demonstrated significantly enhanced tumor growth reduction when used with an anti-PD-1 drug in in vivo mouse model compared to both monotherapies of PMC-309 and an anti-PD-1 drug. We look forward to the opportunity to investigate this approach in a clinical setting."

Dr. Yoo also added, "In comparison to the existing immuno-oncology drugs that directly activate T cells, PMC-309’s distinct mechanism of indirectly activating T cells by inhibiting immunosuppressive cells may represent a novel strategy for patients who do not respond well or have become resistant to the existing treatments and are in need of new therapies. "We are optimistic about PMC-309’s best-in-class potential, and we are particularly excited to continue to evaluate it in combination with KEYTRUDA, one of the key leading molecules in cancer immunotherapy."

Further details of agreement and clinical protocols were not disclosed.

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

About PMC-309

PMC-309 is a novel IgG1 anti-VISTA (V-domain Ig Suppressor of T cell Activation) antagonizing antibody that can be used for the treatment of various tumor types. By inhibiting VISTA, an immune checkpoint receptor mainly expressed on MDSC (Myeloid-Derived Suppressor Cells) and Tregs (regulatory T cells), it can play a pivotal role in maintaining the immunosuppressive environment around the tumor cells.

In the nonclinical studies, it has been discovered that PMC-309 can promote both innate immunity (monocyte activation, M1 macrophage proliferation) and adaptive immunity (T cell activation) unlike the existing drugs which show significant changes only in adaptive immunity. In addition, the in vivo data showed that PMC-309 demonstrated significantly improved tumor growth inhibition when used in combination with an anti-PD-1 drug compared to both monotherapies of PMC-309 and an anti-PD-1 drug. These findings suggest that PMC-309 can offer a new treatment strategy in immuno-oncology area as it can be used in combination with other drugs to improve their low-response rates.

The GLP-Toxicology studies were already completed, and no serious safety issues were observed. The Company plans to submit Clinical Trial Application in early 2023.

On December 12, 2022 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company) a leader in the development of targeted radiotherapies, reported high rates of Complete Remission (CR/CRi) and rates of measurable residual disease (MRD) negativity with improved overall survival in its Actimab-A CLAG-M combination trial in high-risk patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) (Press release, Actinium Pharmaceuticals, DEC 12, 2022, View Source [SID1234625154]). These data were detailed in an oral presentation at the 64th Annual ASH (Free ASH Whitepaper) Meeting & Symposium being held December 10-13, 2022 in New Orleans, Louisiana. The trial enrolled patients with intermediate and adverse cytogenetics including over 50% with a TP53 mutation and significant prior treatment with a median of 2 lines of therapy and over 57% having prior Venetoclax based therapy. The addition of Actimab-A to CLAG-M was well tolerated with expected toxicities.

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Dr. Sameem Abedin, Assistant Professor at Froedtert & Medical College Wisconsin and Principal Investigator of the Study, commented, "The high rates of MRD negativity and strong survival outcomes, especially in the TP53 mutant and Venetoclax treated patients, is highly encouraging and represents a significant improvement compared to available therapies for these patients. The patients enrolled on this trial have very difficult to treat AML and a dismal prognosis with an expected survival of 2 to 3 months or less. They also have very limited treatment options. High rates of 1-year survival are rare in these patients and 2-year survival is rarely achieved. With Venetoclax treatment becoming standard of care, it is critical that we find a therapy for the high percentage of patients who do not respond or relapse and therapies with better outcomes for all relapsed or refractory patients. Outside of this novel clinical trial, these patients would not have been considered for CLAG-M treatment as it would not be expected to have this type of effect in patients who had failed venetoclax based on our considerable prior experience with this regimen. Importantly, the combination was well tolerated with manageable toxicities and enabled a significant number of patients to proceed to transplant. These data support advancing the Actimab-A CLAG-M combination in a registration enabling study."

Overall Survival
Patients

12-month Overall Survival

24-month Overall Survival

All (n=23)

53 %

32 %

CRc MRD Negative (n=9)

89 %

48 %

TP53 mutation (n=13)

51 %

19 %

Prior Venetoclax (n=13)

59 %

32 %

1st/2nd Salvage (n=14)

61 %

49 %

Dr. Avinash Desai, Actinium’s Chief Medical Officer, commented, "As a first-in-class targeted radiotherapy, Actimab-A represents a novel treatment for patients with relapsed or refractory AML. Its differentiated mechanism of action attacks leukemia cells with a radioactive payload that the cancer cells have never been exposed to, which we believe is driving improved outcomes in these heavily pretreated and adverse cytogenetic patients. The high rates and deep remissions evidenced by the 75% measurable residual disease negativity are exciting and support the hypothesis of this combination. We are thrilled to show improved survival, especially in the TP53 mutant and Venetoclax treated patients who have dismal outcomes with expected survival of less than 3 months and few, if any, treatment options. With enrollment of this study complete, we look forward to leveraging the strong survival, MRD negativity and complete remission results to rapidly establish an efficient development and regulatory strategy."

MRD Negativity and Response Rates
MRD negativity was 75% in patients achieving CRc, assessed by multiparametric flow cytometry.
Response

Recommended Phase
2 Dose (n=8)

Prior Venetoclax
Therapy (n=13)

All Patients

(n=23)

CR

13 %

15 %

22 %

CRi

50 %

15 %

30 %

CRc (CR/CRi)

63 %

31 %

52 %

Bridged to BMT

50 %

75 %

64 %

Patient Characteristics
Patients received a median of two lines of prior therapy (Range: 1 – 5 lines)
57% received prior treatment with Venetoclax
67% of patients had adverse cytogenetics, 52% had TP53 mutations
52% of patients had secondary AML or treatment related AML

References:

1) Maiti et al. Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimens. Hematoligica 2021 Mar 1; 894-898

2) Ganzel et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience. American Journal of Hematology. 2018 Aug; 93(8): 1074–1081

On December 12, 2022 IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that it has submitted an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for initiation of a Phase 1/2 clinical trial to evaluate IDE161, a small molecule inhibitor of poly (ADP-ribose) glycohydrolase (PARG), for the treatment of patients having solid tumors with homologous recombination deficiency (HRD) (Press release, Ideaya Biosciences, DEC 12, 2022, View Source [SID1234625153]).

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"IDE161 has an attractive preclinical profile, including single-agent tumor regressions in PARP inhibitor-resistant BRCA1/2 xenograft models, and a favorable preliminary preclinical myelosuppression safety profile relative to certain approved PARP inhibitors. The IND submission for IDE161 is a significant milestone for IDEAYA and reflects our unique platform capabilities in synthetic lethality for target and biomarker identification, and drug discovery," said Michael White, Ph.D., Senior Vice President and Chief Scientific Officer, IDEAYA Biosciences.

"There remains a significant unmet medical need for patients having tumors with homologous recombination deficiencies, such as BRCA1/2, and IDE161 has a potential opportunity for clinical differentiation in patients who are non-responsive to PARP inhibitors or to platinum-based treatments," said Dr. Darrin M. Beaupre, M.D., Ph.D., Senior Vice President and Chief Medical Officer, IDEAYA Biosciences.

IDE161 is a potent, selective, potential first-in-class small-molecule inhibitor of PARG, a novel and differentiated target in the same clinically validated pathway as poly (ADP-ribose) polymerase (PARP). Subject to effectiveness of the IND following FDA review, IDEAYA plans to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of IDE161 as monotherapy in BRCA1/2-mutant breast and ovarian cancer patients.

IDEAYA owns or controls all commercial rights in IDE161, subject to certain economic obligations pursuant to its exclusive, worldwide license with Cancer Research UK and University of Manchester.

Additional information on IDE161, including scientific insights and clinical development opportunities, will be highlighted in an Investor R&D Day webcast being hosted by IDEAYA this morning, December 12, 2022, at 8:00 am – 9:30 am ET. Registration is available at View Source or View Source