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Theratechnologies Initiates Increased Dose Level in Phase 1 Clinical Trial of Sudocetaxel Zendusortide in Advanced Ovarian Cancer

On March 21, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported moving to the next dose level in Part 3 of its Phase 1 clinical trial of sudocetaxel zendusortide in patients with advanced ovarian cancer (Press release, Theratechnologies, MAR 21, 2024, View Source [SID1234641351]). The study’s Medical Review Committee (MRC) has deemed the dose level in the first cohort of patients safe and has approved initiation of the next cohort with an increased dose, in accordance with the updated dose optimization protocol. Study centers are now actively recruiting patients for the second cohort, with one patient already enrolled and treated with the higher dose.

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"We are encouraged by the safety and tolerability of the sudocetaxel zendusortide regimen in the first cohort of six patients in Part 3 of the Phase 1 trial," said trial investigator Ira Winer, M.D., Ph.D., FACOG, a member of the Gynecologic Oncology and Phase 1 Clinical Trials Multidisciplinary Teams at Karmanos Cancer Center and Associate Professor of Oncology at Wayne State University. "We will continue to enroll and monitor patients as we further investigate this novel peptide-drug conjugate in individuals with advanced, platinum-resistant ovarian cancer, a population with high unmet medical need."

Part 3 of the Phase 1 study is intended to assess the optimal dose and schedule of sudocetaxel zendusortide, which is being administered on three consecutive weeks followed by one week of rest on Days 1, 8, and 15 of each 28-day cycle. The dose for the initial six patients was 1.75 mg/kg/dose and the dose for the next cohort of patients is 2.50 mg/kg/dose. The MRC approved initiation of the second cohort following attainment of the threshold of one or less dose-limiting toxicities in the first cohort. The study’s updated protocol defines DLTs as any Grade 3 or greater toxicity, within the first cycle and any worsening of peripheral neuropathy to Grade 3 or 4 within a three-month period.

"Initiation of treatment at the next dose level is an important milestone for Part 3 of the Phase 1 study and will allow us to further characterize sudocetaxel zendusortide as a potentially viable therapy for individuals with advanced ovarian cancer," commented Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "We welcome discussions with potential partners interested in helping to advance development of this novel peptide-drug conjugate."

Theratechnologies completed enrollment of the first cohort of six patients in Part 3 of the Phase 1 trial in February 2024, and dosed the first patient in October 2023. The U.S. Food and Drug Administration (FDA) approved the amended trial protocol in June 2023. Further details about the study design, participation criteria and contact information for the sites can be found at: View Source

About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology

Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting peptide-drug conjugate, and the first compound to emerge from the Company’s broader licensed oncology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial.

Theratechnologies has established the SORT1+ Technology platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.

Satya to present preclinical profile of its PARG inhibitors at the 2024 American Association for Cancer Research (AACR) Annual Meeting – April 5-10, San Diego, CA

On March 21, 2024 Satya reported to present preclinical profile of its PARG inhibitors at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting – April 5-10, San Diego, CA (Press release, SATYA Pharma Innovations, MAR 21, 2024, View Source [SID1234641350]).

March 21, 2024
3:31 pm
Abstract title

Preclinical profile of novel and potent small molecule inhibitors of PARG

Poster number

7112

Session title

DNA Damage and Repair

Session date and time

April 10, 9:00 AM – 12:30 PM

Session category

Experimental and Molecular therapeutics

Abstract title: Preclinical profile of novel and potent small molecule inhibitors of PARG

Abstract:
Poly(ADP-ribose) glycohydrolase (PARG) is primary enzyme involved in the dePARylation process of DNA repair, specifically in the single strand break repair (SSBRs). PARG is a macrodomain protein with exo- and endo-glycohydrolase activity that liberates free ADP-ribose and PAR chains, respectively. It interacts with various Poly(ADP-ribose) polymerase (PARP) proteins to facilitate appropriate and timely DNA repair. The balance between PARP and PARG activity is essential for efficient DDR. Inhibition of PARG lead to altered DNA repair in cancer cells. We have identified highly potent PARG inhibitors with picomolar IC50 in biochemical assay. PARG is the primary enzyme for dePARylation and accounts for 90% of dePARylation activity. Treatment of HCC-1806 cells with PARG inhibitors showed dose dependent increase of PARylation signature, with sub micromolar IC50 . Compounds also demonstrate significant functional, anti-proliferative activity in ovarian and breast cancer cell lines besides a favourable ADME profile. Further pharmacokinetic and pharmacodynamic characterization of the identified hits is currently in progress.

Pyxis Oncology Provides Corporate Update and Reports Financial Results for Fourth Quarter and Full Year 2023

On March 21, 2024 Pyxis Oncology, Inc. (Nasdaq: PYXS), a clinical stage company focused on developing next generation therapeutics to target difficult-to-treat cancers, reported financial results for the year and quarter ended December 31, 2023, and provided a corporate update (Press release, Pyxis Oncology, MAR 21, 2024, View Source [SID1234641347]).

PYX-201, a first-in-concept tumor stroma targeting antibody-drug conjugate (ADC) against the stromal Extradomain-B Fibronectin (EDB+FN) target, has dosed 37 patients in 6 cohorts since initiating the Phase 1 trial in March 2023. PYX-201 recently cleared the 21-day Dose Limiting Toxicity (DLT) observation period for ten subjects in Cohort 6 at a dose of 5.4 mg/kg. The Dose Escalation Steering Committee (DESC) met on March 19, 2024, and voted to escalate dosing into Cohort 7 at a dose of 8 mg/kg.

PYX-201 has been well tolerated to date, with no significant evidence of target mediated toxicities experienced by the 37 subjects enrolled and dosed. Approximately 54% of subjects have experienced grade 2, and 6% of subjects have experienced grade 3 treatment emergent adverse events (TEAEs). No subjects have reported TEAEs leading to dosing delay or study drug discontinuation. Another 10-15 subjects are likely to be dosed at either Cohort 7 (8 mg/kg) or future higher dose level cohorts, should PYX-201’s profile continue to support further dose escalation.

As we continue to dose escalate, we are focusing ongoing enrollment on four tumor types of high interest, identified through the assessment of several factors, including, but not limited to, IHC target expression data, stromal volume, and unmet medical need: head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic ductal adenocarcinoma cancer (PDAC).

"We believe the encouraging PYX-201 safety profile observed to date likely reflects the specificity of target expression within tumor tissue and the potential for a wider therapeutic index given the novel mechanism of action within the tumor microenvironment," said Lara S. Sullivan, M.D., President and Chief Executive Officer of Pyxis Oncology. "The tumor stroma is a prominent component of many solid tumors, and we believe that PYX-201 could have broad utility in many cancer settings. The global study remains on track with continued investigator enthusiasm and ease of enrollment, and we look forward to announcing initial results in the fall of 2024 with final timing dependent on ongoing continued dose escalation and finalization of subject scans."

Dr. Sullivan added, "We are also continuing to enroll our Phase 1 study evaluating PYX-106, a fully human immunotherapy antibody candidate that is designed to block the activity of Siglec-15 in subjects with NSCLC and other tumors of interest. We look forward to initial results from this program in 2H 2024."

Program and Corporate Updates

•
PYX-201 in the PYX-201-101 trial: To date, 37 subjects have been dosed, and we are currently enrolling Cohort 7 at 8 mg/kg. In the fall of 2024, we plan to report efficacy, safety, pharmacokinetics (PK), pre-clinical insights, the plan for the next development phase, and the likely timing of associated catalysts.
•
PYX-106 in the PYX-106-101 trial: Phase 1 trial focusing on NSCLC and other tumor types. Study dosing is ongoing with 21 subjects dosed to date and Cohort 5 is fully enrolled at 8 mg/kg administered once every two weeks. Preliminary data is anticipated in 2H 2024.
•
In Feb. 2024, completed a $50M PIPE with participation from new and existing institutional investors, including Deep Track Capital, Ridgeback Capital Investments L.P., Blue Owl Healthcare Opportunities, Laurion Capital Management, and StemPoint Capital L.P. Pyxis Oncology intends to use the proceeds to fund the continued development of PYX-201 and for working capital and general corporate purposes.

Anticipated Upcoming Milestones

•
PYX-201: Report preliminary Phase 1 data and PK/PD results in fall of 2024
•
PYX-106: Report preliminary Phase 1 data and PK/PD results in 2H 2024

Full Year and Q4 2023 Financial Results

•
As of December 31, 2023, Pyxis Oncology had cash and cash equivalents, including restricted cash, and short-term investments of $120.8 million. Following the end of fiscal year 2023, we raised gross proceeds of $10.8 million via ATM offering and completed $50 million of private placement. Pyxis Oncology expects to have the resources to fund operations into 2nd half of 2026.
•
Research and development expenses were $49.6 million for the year ended December 31, 2023, compared to $86.1 million for the year ended December 31, 2022. The decrease was primarily due to a one-time payment of $17.3 million to acquire exclusive licensing rights for the FACT platform, one-time payment of $10 million to acquire licensing rights to PYX-106 and decrease in contract manufacturing costs for drug products and drug substances by $12.5 million in 2022. This decrease was partially offset by a $5.0 million increase in clinical trial related expenses for our ongoing Phase 1 clinical trials for PYX-201 and PYX-106.
•
General and administrative expenses were $32.6 million for the year ended December 31, 2023, compared to $37.4 million for the year ended December 31, 2022. The decrease was primarily related to a reduction in professional and consultant fees partially offset by higher personnel-related expenses, including stock-based compensation.
•
Net loss was $73.8 million, or ($1.85) per common share, for the year ended December 31, 2023, compared to $120.7 million, or ($3.65) per common share, for the year ended December 31, 2022. Net losses for the years ended December 31, 2023 and 2022, included $16.9 million and $15.8 million, respectively, related to non-cash stock-based compensation expense.
•
As of March 20, 2024, the outstanding number of shares of Common Stock of Pyxis Oncology was 58,133,375.

Key milestone for OXC-101 – study approval in South Africa

On March 21, 2024 Oxcia reported that it has obtained approval from the South African Health Products Regulatory Authority, (SAHPRA) for the start of the phase 1 / 2 study of OXC-101 in solid cancers, more specifically gynecological cancers, prostate cancer and head and neck cancer (Press release, Oxcia, MAR 21, 2024, View Source;utm_medium=rss&utm_campaign=key-milestone-for-oxc-101-study-approval-in-south-africa [SID1234641346]). The study will take place at two clinical sites in South Africa. Oxcia is now applying for ethical approval and sending in a protocol amendment. The study is estimated to start early to mid-summer.

"I am thrilled for this opportunity to build further clinical experience with OXC-101 and demonstrate safety and efficacy in less heavily pretreated patients than those treated so far" says Ulrika Warpman Berglund, CEO at Oxcia.

The clinical phase 1 / 2 study with OXC-101 in advanced solid cancers has already been extended in Sweden. Recruitment of patients with prostate and gynecological cancer is ongoing. The goal is to gather more clinical data with OXC-101 and align with regulatory agencies on the optimal effective dose and move into phase 2 development once capital has been secured.

For further information, please contact:

Ulrika Warpman Berglund, CEO

Phone: +46 (0) 73 270 96 05

Email: [email protected]

Briefly about OXC-101

OXC-101 is a "mitotic MTH1 inhibitor" and belongs to a completely new class of cancer drugs. It has potential for broad anticancer effect and suitability for large patient populations. It is given as a tablet. OXC-101 has demonstrated clinical benefits which supports further development in the phase 1 MASTIFF study.

OXC-101 makes intelligent use of the cancer cell’s inherent high levels of oxidative DNA damage and oxidative stress. OXC-101 stops cancer cell division by preventing microtubules from functioning. This generates additional oxidative stress (ie, ROS) and increased levels of oxidatively damaged DNA building blocks. By inhibiting MTH1, more damaged DNA building blocks remain and build into the DNA, causing even more DNA damage. The cancer cell can no longer handle the high levels of oxidative stress and DNA damage, resulting in the death of the cancer cell.

Nkarta Reports Fourth Quarter and Full Year 2023 Financial Results and Corporate Highlights

On March 21, 2024 Nkarta, Inc. (Nasdaq: NKTX), a clinical-stage biopharmaceutical company developing engineered natural killer (NK) cell therapies, reported financial results for the fourth quarter and year ended December 31, 2023 (Press release, Nkarta, MAR 21, 2024, View Source [SID1234641345]).

"Patients with severe autoimmune diseases deserve novel, effective treatments," noted Paul J. Hastings, President and CEO of Nkarta. "Recent academic studies have shown that CD19-directed cell therapy has the promise to be truly transformative, and we believe that NKX019 may replicate these early results with superior safety and accessibility. Our approach leverages the potential advantages of NK cells, including fludarabine-free lymphodepletion, deep and rapid B-cell depletion, and the added utility of on-demand dosing. Work with investigators, sites and patients is advancing rapidly, and we remain on track to initiate dosing in our clinical trial of NKX019 in refractory lupus nephritis in the first half of 2024."

Hastings continued, "The potential of NKX019 to transform the treatment landscape in autoimmune disease demands our focus. To support our early-mover advantage and advance this program, Nkarta has deprioritized the development of NKX101. This follows a planned interim evaluation of Phase 1 data from NKX101 that included 14 new patients with AML. While the safety profile remained encouraging, the response rate was meaningfully lower than that from the first 6 previously reported patients. We see promise in NKX101, but before pursuing further development or significant investment, we will evaluate options for optimizing future study design, dosing schedule and manufacturing. We are grateful for the support of the NKX101 investigators as well as their patients for their commitment and trust."

NKX019 in autoimmune disease

In October 2023, Nkarta announced the expansion of its pipeline to include autoimmune disease following the clearance by FDA of the IND application for NKX019 in lupus nephritis (LN).
The multi-center, open label, dose escalation clinical trial will assess the safety and clinical activity of NKX019 in up to 12 patients with refractory LN. Patients will receive a three-dose cycle of NKX019 at 1 billion or 1.5 billion cells per dose following lymphodepletion (LD) with single agent cyclophosphamide (cy), an agent with an established safety profile in systemic lupus erythematosus (SLE) and LN.
Nkarta plans to dose the first patient in the LN study in the first half of 2024.
NKX019 is highly active against B cells from patients with multiple autoimmune diseases, and Nkarta is evaluating additional indications for potential clinical investigation with NKX019.
NKX019 in non-Hodgkin lymphoma (NHL)

In October 2023, Nkarta announced a new cohort in its Phase 1 study of NKX019 in relapsed/refractory (r/r) NHL. The cohort (n=6) introduces a compressed dosing schedule, where patients receive NKX019 doses on Days 0, 3 and 7 following LD with fludarabine (flu) and cy. This regimen is designed to intensify exposure of NKX019 by dosing closer to LD. In addition, patients with ongoing cytopenias have the potential to receive NKX019 following LD with cy alone.
Nkarta expects to announce preliminary data from the NKX019 compressed dosing cohort in mid-2024.
Nkarta is no longer enrolling patients in the cohorts in which NKX019 was being administered on Days 0, 7 and 14 following LD. Future development of NKX019 in the NHL indication will be contingent on favorable outcomes from the compressed dosing cohort.
In June 2023, Nkarta presented preliminary clinical data based on a November 2022 data cut-off from its Phase 1 clinical trial of NKX019 in patients with r/r NHL at the annual meeting of the European Hematology Association (EHA) (Free EHA Whitepaper) and the International Conference on Malignant Lymphoma. 7 of 10 patients achieved complete response (70% CR rate) following treatment with NKX019 monotherapy at highest dose levels.
In January 2024, Nkarta reported that 4 of 4 patients with r/r NHL that relapsed after achieving CR following treatment with NKX019 were again able to achieve CR after re-treatment with NKX019. These outcomes suggest that relapse, when it occurs, may be attributable to mechanisms of NKX019 exposure and not resistance to NKX019.
NKX101 in acute myeloid leukemia (AML)

Nkarta announced today that it has closed patient enrollment in its clinical trial of NKX101 and deprioritized the program as part of a pipeline realignment that directs primary resources to its lead pipeline program, NKX019, for the treatment of autoimmune disease. This follows a recent review of preliminary safety and response data from patients with r/r AML that received NKX101 after LD comprising fludarabine and cytarabine (flu/Ara-C). The aggregate CR/CRi rate (5 of 20 patients) was lower than what had been observed in the first 6 patients in the cohort. The safety profile of NKX101 was consistent with previously reported data.
This announcement reflects the NKX101 clinical update that Nkarta had planned to report in the first half of 2024. Nkarta plans to present these data at a future medical conference.
In June 2023, Nkarta reported updated clinical data from its Phase 1 clinical trial evaluating NKX101 in patients with relapsed or refractory (r/r) AML. In the first 6 patients that received NKX101 after flu/Ara-C LD, 4 of 6 achieved CR/CRi as of the data cut-off on June 10, 2023. In a follow-up report on these 6 patients presented at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), of those patients who achieved CR/CRi, 3 of 4 remained in CR/CRi at 4 months as of the data cut off on October 31, 2023.
Fourth Quarter and Full Year 2023 Financial Highlights

As of December 31, 2023, Nkarta had cash, cash equivalents, and investments of $250.9 million, including restricted cash of $2.7 million.
Research and development (R&D) expenses were $96.8 million for the full year 2023 and $23.3 million for the fourth quarter of 2023. Non-cash stock-based compensation expense included in R&D expense was $8.0 million for the full year 2023 and $1.7 million for the fourth quarter of 2023.
General and administrative (G&A) expenses were $34.9 million for the full year 2023 and $7.9 million for the fourth quarter of 2023. Non-cash stock-based compensation expense included in G&A expense was $9.2 million for the full year 2023 and $1.8 million for the fourth quarter of 2023.
Net loss was $117.5 million, or $2.40 per basic and diluted share, for the full year 2023. This net loss includes non-cash charges of $26.5 million that consisted primarily of share-based compensation, depreciation, and an impairment charge against right-of-use assets that Nkarta plans to sublease. Net loss was $27.8 million, or $0.57 per basic and diluted share, for the fourth quarter of 2023.
Financial Guidance

Nkarta expects its current cash and cash equivalents will be sufficient to fund its current operating plan into 2026.
About NKX019
NKX019 is an allogeneic, cryopreserved, off-the-shelf immunotherapy candidate that uses natural killer (NK) cells derived from the peripheral blood of healthy adult donors. It is engineered with a humanized CD19-directed CAR for enhanced cell targeting and a proprietary, membrane-bound form of interleukin-15 (IL-15) for greater persistence and activity without exogenous cytokine support. CD19 is a biomarker for normal B cells as well as those implicated in autoimmune disease and B cell-derived malignancies.

About NKX101
NKX101 is an allogeneic, cryopreserved, off-the-shelf cancer immunotherapy candidate that uses natural killer (NK) cells derived from the peripheral blood of healthy donors. It is engineered with a chimeric antigen receptor (CAR) targeting NKG2D ligands on tumor cells. NKG2D, a key activating receptor found on naturally occurring NK cells, induces a cell-killing immune response through the detection of stress ligands that are widely expressed on cancer cells. NKX101 is also engineered with a membrane-bound form of interleukin-15 (IL-15) for greater persistence and activity without exogenous cytokine support.