On April 17, 2023 Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, reported the presentation of the latest preclinical data from the company’s GPR65 discovery program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Pathios Therapeutics, APR 17, 2023, View Source [SID1234630167]). The presentation included the public unveiling of PTT-4256, an internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65 that has demonstrated excellent drug-like properties and impressive monotherapy anti-tumour activity in preclinical models. The data were featured in a poster presentation at the AACR (Free AACR Whitepaper) annual meeting, being held April 14-19, 2023, in Orlando, Florida.

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Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of tumour associated macrophages (TAMs) that is triggered by a highly acidic tumour microenvironment (TME). It does so by targeting GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive TAM phenotype that prevents immune-mediated killing of cancer cells. Pathios’ internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumour types, positioning it as a unique immuno-oncology target for therapeutic intervention.

Data presented at AACR (Free AACR Whitepaper) highlighted the company’s discovery and advancement of PTT-4256, which exhibits high potency for GPR65 (IC50 < 1 nM in human macrophages) and more than a 500-fold selectivity for GPR65 over related receptors. In preclinical experiments, PTT-4256 was shown to be highly effective in counteracting the effects of low pH (i.e. high acidity) that polarizes human and mouse macrophages toward an immunosuppressive state. This PTT-4256-induced relief of immune suppression was associated with dose-dependent increases in a range of pro-inflammatory genes that are consistent with an anti-tumour immune response, evidence of an infiltration of T cells and natural killer (NK) cells into the TME, and prevention of the activation of immunosuppressive cytokines. Together, this activity led to impressive monotherapy efficacy for PTT-4256 in syngeneic mouse cancer models following oral dosing.

"Pathios’ identification of PTT-4256 represents the culmination of several years of diligent and sophisticated drug discovery work by our team of scientists. These efforts have produced a highly optimised compound supported by an extensive dataset illustrating that the molecule possesses all target attributes for testing our GPR65 inhibitor hypothesis in humans," said Stuart Hughes, Ph.D., Chief Executive Officer of Pathios. "Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024. As we look ahead to our entry into the clinic, we continue to be utterly compelled by the promise of this novel immuno-oncology target, in particular noting the human genetic validation which we believe sets GPR65 inhibition apart from other approaches in the field."

About Acidity in the Tumor Microenvironment
The acidic tumour microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumour associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes

On April 17, 2023 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of two preclinical data abstracts focused on its natural killer cell pipeline and proprietary manufacturing technology at the 2023 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Nkarta, APR 17, 2023, View Source [SID1234630166]).

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"Our AACR (Free AACR Whitepaper) presentations demonstrate the potential to combine our engineered, donor-derived NK cell therapies with monoclonal antibodies to extend and enhance the potency of both modalities," said James Trager, PhD, Chief Scientific Officer of Nkarta. "We have shown that our products maintain high levels of CD16 and that the binding of appropriate monoclonal antibodies to CD16 can expand the targeting and potency of CAR NK cells. Specifically, we’ve shown that NKX101, our clinical candidate engineered with an NKG2D-based CAR, can be combined with cetuximab to enhance activity towards EGFR-expressing tumor cells. We’ve also shown that CRISPR-mediated knockout of ADAM17, a suppressor of CD16 activity, can be used to further elevate ADCC, and to help maintain NK cell potency. These findings will be critical groundwork for developing successful therapeutic combinations that include treatment with CAR NK cells, particularly in solid tumor settings."

Nkarta’s 2023 AACR (Free AACR Whitepaper) posters will be available for download shortly after their scheduled presentation at View Source

ADAM17 knockout NK or CAR NK cells augment antibody dependent cellular cytotoxicity (ADCC) and anti-tumor activity
Abstract Number 890
April 16, 2023, 1:30 p.m. – 5:00 p.m. ET

In this study, ADAM17 KO CAR NK cells demonstrate improved ADCC and ADAM17 KO can enhance in vivo anti-tumor activity of CISH/CBLB KO CD70 CAR NK cells in relevant tumor models. ADAM17 KO NK cells maintain dramatically higher surface expression of CD16a and CD62L than control NK cells. ADAM17 KO CD19 CAR NK cells demonstrate higher cytotoxicity compared to control NK cells against Raji tumor cells in the presence of rituximab (anti-CD20). Similarly, ADAM17 KO CD70 CAR NK cells also possess enhanced cytotoxicity against 786-O tumor cells in the presence of the anti-EGFR antibody, cetuximab. Furthermore, ADAM17/CISH/CBLB triple KO CD70 CAR NK cells have improved antitumor efficacy in vivo in an HL60 AML xenograft model. These data support the further exploration of ADAM17 KO CAR NK cells for clinical application and to improve the efficacy of therapeutic antibodies in combination with the adoptive transfer of engineered NK cells.

Combination of anti-EGFR antibody cetuximab with NKX101, an allogeneic NKG2D-L targeting NK cell therapy, enhances potency and in vitro cytotoxicity against solid tumors
Abstract Number 3183
April 17, 2023, 1:30 p.m. – 5:00 p.m. ET

This study demonstrates that cetuximab, a human IgG1 antibody targeting epidermal growth factor receptor (EGFR) approved for the treatment of colorectal and head and neck cancers, increases the anti-tumor effect of NKX101 in a dose-dependent manner. Assessment of the interaction between NKX101 and cetuximab in vitro revealed that the two agents can combine to kill cancer cells in a synergistic manner. Blocking CD16 on NKX101 cells with a neutralizing antibody significantly decreases the potency of the combination, suggesting that the improvement in potency observed is a direct result of CD16-mediated ADCC activity. It was also demonstrated that common CD16 polymorphisms do not influence NKX101 ADCC activity. This study shows that the combination of an engineered allogeneic NK cell therapy, NKX101, with cetuximab leads to an increase in the specific killing of cancer cells in vitro and supports further investigation into this combination for the treatment of solid tumors.

On April 17, 2023 Nektar Therapeutics (Nasdaq: NKTR) reported a strategic reprioritization and cost restructuring plan that includes a new pipeline focus on immunology, as well as several cost reduction initiatives, which the company expects will significantly reduce future operating expenses and extend its cash runway into the middle of 2026 (Press release, Nektar Therapeutics, APR 17, 2023, View Source [SID1234630165]).

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Key elements of the new plan include:

● Prioritize REZPEG development: Nektar intends to work with Eli Lilly to ensure the continuation of REZPEG development whether it is under the existing Eli Lilly agreement or Nektar regains the rights to REZPEG. The Phase 1b data for REZPEG in atopic dermatitis previously presented at the EADV meeting in September 2022 showed that a dose-dependent improvement was observed in key efficacy measures of mean change in EASI, EASI-75, vIGA-AD scores, and Itch NRS ≥4-point improvement rates over placebo with 12 weeks of treatment. These improvements were observed for an additional 36 weeks following the 12-week treatment period. These proof-of-concept data show REZPEG’s ability to stimulate Tregs to target an immune system imbalance resulting in an improvement of disease activity in patients. The Phase 1b data were recently highlighted in a talk by Eric Lawrence Simpson, MD, FAAD at the 2023 American Academy of Dermatology (AAD) Annual Meeting on March 17, 2023 in the scientific session covering atopic dermatitis, as a potential future remittive therapy.

● Continue development of lead oncology asset, NKTR-255, while seeking a strategic development partner: As part of the strategic reprioritization, Nektar will continue its Phase 2 study of NKTR-255 in combination with cell therapies and the Phase 2 JAVELIN Bladder Medley Study with partner Merck KGaA while it explores strategic partnership options for NKTR-255. NKTR-255 is an investigational IL-15 receptor agonist designed to boost antitumor immunity by increasing the proliferation and survival of natural killer and memory CD8+ T cells and may have broad potential applicability across oncology indications.

● Continue core research programs in immunology: Nektar will continue to advance two preclinical pipeline candidates in auto-immune diseases including a new PEG-Colony Stimulating Factor (CSF1) program and a separate TNFR2 agonist antibody being developed in collaboration with Biolojic Design. The company plans to file an IND for at least one of these programs in 2024.

● Implement a cost restructuring plan: As part of the strategic reprioritization, Nektar also plans to reduce its San Francisco-based workforce by approximately 60%. Once the cost restructuring plan has been fully completed, the company is expected to have approximately 55 employees based in San Francisco. The company anticipates that its Huntsville manufacturing facility, which supports several large pharmaceutical partners, will continue to operate with its current staff. The restructuring also includes actions to reduce additional operating costs and is expected to be substantially completed by June 2023.

"Following a comprehensive review of our portfolio, we have made the decision to prioritize the advancement of our immunology programs," said Howard W. Robin, President and CEO of Nektar. "We intend to work with Eli Lilly either to continue REZPEG’s development in the clinic under our existing agreement or to regain the rights to REZPEG for Nektar. We believe the strong data generated for this asset demonstrates its potential as a remittive therapy in atopic dermatitis and sets the stage to move quickly into a Phase 2b study. REZPEG would be positioned as a novel potential therapeutic in a significant, growing biologic treatment landscape."

"The strategic initiative we announced today is intended to further streamline our operations and to extend considerably our cash runway into the middle of 2026," continued Robin. "Although the actions we are taking today are difficult, we are incredibly grateful for the contributions of the employees departing Nektar."

Nektar had cash, cash equivalents, and marketable securities of approximately $456 million as of March 31, 2023. These significant reductions in the company’s operating expenses, including personnel-related costs and external expenses, are expected to extend the company’s cash runway into the middle of 2026. Projected annual savings from the headcount reduction will be fully realized in 2024 and represent an annual savings of approximately $30 million. Nektar expects non-recurring cash payments of approximately $8 million, primarily in the second quarter of 2023 associated principally with the workforce reduction.

Executive Management Changes

As part of this initiative, Nektar also announced several changes to its executive team:

● Dr. Brian Kotzin, Nektar’s Chief Medical Officer, will be stepping down from his full-time role but will continue to serve in an ongoing role as a strategic advisor to the company. Dr. Mary Tagliaferri, current Chief Development Officer, will assume the role of Chief Medical Officer.

● Jillian Thomsen will be stepping down from her role as Chief Financial Officer (CFO) and will depart the company in June following a transition period. The company has appointed Sandra Gardiner to the role of acting CFO. Sandra is a skilled business and finance executive with over 30 years of financial and accounting experience. She is a partner at FLG Partners, a leading CFO services firm in Silicon Valley.

● Kevin Brodbeck, Nektar’s SVP of Technical Operations, will depart the company in June following a transition period. Ken Franke, current VP of Biologics Development & Manufacturing will assume Kevin’s responsibilities.

The company thanks its departing executives for their contributions to Nektar.

Conference Call Details to Announce First Quarter 2023 Financial Results:

Nektar will announce its financial results for the first quarter 2023 on Tuesday, May 9, 2023, after the close of U.S.-based financial markets. Howard W. Robin, President and Chief Executive Officer, will host a conference call to review the results beginning at 5:00 p.m. Eastern Time/2:00 p.m. Pacific Time.

The press release and live audio-only webcast of the conference call can be accessed through a link that is posted on the Home Page and Investors section of the Nektar website: View Source The web broadcast of the conference call will be available for replay through June 4, 2023.

To access the conference call, please pre-register at Nektar Earnings Call Registration. All registrants will receive dial-in information and a PIN allowing them to access the live call.

On April 17, 2023 Myricx Pharma (‘Myricx’), an oncology drug discovery company focused on developing precision medicines based on its N-myristoyltransferase (NMT) platform has unveiled its antibody drug conjugate (ADC) programme, presenting promising in vivo data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s Annual Meeting, AACR (Free AACR Whitepaper) 2023, April 14-19, Florida (Press release, Myricx Pharma, APR 17, 2023, View Source [SID1234630164]).

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NMT inhibitors (NMTi) have previously been shown to inhibit viability and growth of haematological cancers. Myricx’s novel highly potent NMTi are selectively cytotoxic in multiple cancer cell lines as well as exhibiting tumour regression in in vivo models of both haematological and solid cancers. Myricx has also developed a transcriptional signature which predicts cancer cell sensitivity to NMTi with high confidence.

Myricx’s advanced chemistry offers the potential for the development of NMTi as a novel payload on a wide range of existing linker and antibody ADC technologies. A unique feature of NMTi-ADCs is that they contain two targeting mechanisms: a monoclonal antibody (mAb) that targets the payload to antigen positive cancer cells; and selectivity for specific cancers with high intrinsic sensitivity to NMTi. Myricx has data elucidating the mechanism of this sensitivity.

Myricx’s most advanced ADC, MYX2449, is a selective and ultrapotent NMTi conjugated via a cleavable linker to trastuzumab (HER2+ mAb). Positive in vitro and in vivo data presented at AACR (Free AACR Whitepaper)2 demonstrate MYX2449 cytotoxic potency in selective cancer cell lines, anti-tumour efficacy in both high and low HER2 expressing cancers, with tolerability >10 times its efficacious dose in in vivo models.

As a proof of concept (PoC) for its NMTi-ADC approach, Myricx tested MYX2449 trastuzumab-NMTi ADC in in vivo models of gastric cancer (GC) and breast cancer (BC), as many of these cancers express HER2 and also express the NMTi sensitivity signature. MYX2449 delivered differentiated activity and improved efficacy compared to the gold standard ADC trastuzumab-deruxtecan in a GC model with excellent tumour shrinkage at 5mpk in the xenograft and excellent cyno tolerability at the highest dose, 20mpk. Similar efficacy was obtained in a BC xenograft model.

Encouraged by these positive PoC results, Myricx is now exploring a range of ADCs in further hard-to-treat solid cancers that express both the NMTi sensitivity signature and ADC-compatible antigens.

Myricx CEO Dr Robin Carr who presented the ADC-NMTi poster at AACR (Free AACR Whitepaper) said "NMT inhibitors represent a novel class of ADC payloads that can be exploited as targeted therapies in cancer. Based on our positive PoC data we believe that ADC-NMTi offer huge potential for selective cancer cell killing via its unique mechanism of action."

Myricx is a start-up from two of London’s leading biomedical research organizations, Imperial College London and the Francis Crick Institute. Myricx scientists and founding collaborators were the first to identify that inhibition of NMT is highly effective in the treatment of MYC-driven cancer models acting through the unfolded protein response (UPR). UPR stress is a known vulnerability of cancer and Myricx is now using its discoveries to build a proprietary pipeline of targeted cancer therapies. The company is developing NMTi as small molecule drugs as well as novel selective cytotoxic payloads for ADCs.

In addition to the poster on its lead ADC programme, scientists from Myricx’s collaborators presented two posters on Myricx’s small molecule programmes and NMT biology, including in vivo reprogramming of tumour-associated macrophages to an anticancer phenotype by modulating NMT activity1 and how deregulation of MYC-family proteins sensitizes cancers to NMT inhibition, resulting in the identification of NMTi sensitivity and mechanism.3

Professor Ed Tate, Myricx co-founder and lead author of the posters presented by the Imperial College London/Francis Crick Institute teams said "NMT is a hot emerging drug target in cancer and Myricx has developed high-quality proprietary chemical inhibitors of NMT that have led to breakthrough discoveries and unlocked an unexpected and unique mechanism of cancer cell killing, specific to cancers with vulnerabilities associated with the unfolded protein response. Furthermore, we have recently shown that NMTi has the potential to drive anti-tumour innate immune responses, including the reprogramming of tumour-associated macrophages in the tumour microenvironment.

"These discoveries alongside the massive potential of NMTi as a selective ADC payload pave the way for novel and highly efficacious treatments for patients."

1. Poster number: 439: From foe to friend: In vivo reprogramming of tumour-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity – presented by @Wouter Kallemeijn, Francis Crick Institute/Imperial College London
New Drug Targets 16 April 1:30 PM Section 16 board 3

2. Poster number: 2635: N-Myristoyltransferase (NMT) inhibitors as novel potent payloads for antibody drug conjugates – presented by our CEO @Robin Carr
Antibody Technologies session 17 April, 1:30 PM Section 13 board 3

3. Poster number: 4871: Dysregulation of MYC-family proteins sensitizes cancers to NMT inhibition: identification of NMTi sensitivity and mechanism – presented by @James Zhang, ICR/Imperial College London
Anticancer Approaches Targeting Signal Transduction Pathways 18 April 1:30 PM Section 13 board 14

On April 17, 2023 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported preclinical data supporting the potential use of farnesyl transferase inhibitors (FTIs) to treat various types of solid tumors in combination with targeted therapies, including KRASG12C inhibitors and anti-angiogenic tyrosine kinase inhibitors (TKIs) (Press release, Kura Oncology, APR 17, 2023, View Source [SID1234630163]). These data were featured in two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on Sunday, April 16 in Orlando. Copies of the posters are available on Kura’s website at www.kuraoncology.com/pipeline/publications.

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New preclinical data in the poster titled, ‘Tipifarnib synergizes with a TKI in clear cell renal cell carcinoma models,’ demonstrates the synergistic activity of tipifarnib and axitinib, a TKI approved to treat advanced renal cell carcinoma (RCC), in cell- and patient-derived RCC xenograft models. These data support the potential to administer an FTI in combination with a TKI for the treatment of RCC, and studies are ongoing to further evaluate the mechanistic basis of the synergy observed with the combination.

In addition, new findings were presented in the poster titled, ‘Combination of tipifarnib with KRASG12C inhibitors to prevent adaptive resistance,’ evaluating the effects of tipifarnib in combination with adagrasib and sotorasib in cell line and xenograft models of KRASG12C mutant non-small cell lung cancer (NSCLC). These data reveal that the addition of tipifarnib leads to significant tumor regression in xenograft models and suppresses mTOR signaling reactivation relative to treatment with the KRASG12C inhibitors alone. These results support further preclinical studies to determine the mechanism of action for the combination.

"Although targeted therapies have demonstrated meaningful clinical activity, including objective responses, across a range of solid tumors, over time adaptive resistance almost invariably emerges, limiting the ability of the targeted therapies to drive sustained clinical benefit. Yesterday, we presented encouraging preclinical data that highlight the potential for FTIs to prevent or delay emergence of resistance to certain classes of targeted therapies," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "We believe these promising preclinical data strongly support our rationale to combine KO-2806 with KRASG12C mutant inhibitors and TKIs in NSCLC and RCC, respectively."

In parallel to the clinical evaluation of tipifarnib, the Company is advancing KO-2806, a potent inhibitor of farnesyl transferase that was designed to improve upon potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. The Company expects to initiate the Phase 1 first-in-human study (FIT-001) later this year to assess safety, tolerability and preliminary antitumor activity of KO-2806 as a monotherapy and in combination with other targeted therapies in adult patients with advanced solid tumors. Following completion of the dose escalation as a monotherapy, Kura plans to evaluate KO-2806 in dose escalation combination cohorts in advanced solid tumors.