On November 3, 2023 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing viral immunotherapies to help patients fight cancer, reported initial positive interim survival and immunological biomarker data from the ongoing randomized phase 2 clinical trial of CAN-2409 plus valacyclovir (prodrug) together with standard of care (SoC) chemoradiation followed by resection for borderline resectable pancreatic ductal adenocarcinoma (PDAC) (Press release, Candel Therapeutics, NOV 3, 2023, View Source [SID1234636913]). Data were presented today in a poster session titled ‘Neoadjuvant CAN-2409+Prodrug Plus Chemoradiation for Borderline Resectable or Locally Advanced Non-Metastatic Pancreatic Adenocarcinoma (PDAC) at the 2023 Society for Immunotherapy (SITC) (Free SITC Whitepaper) Annual Meeting.

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"Given frequent recurrence and short survival with SoC chemotherapy for non-metastatic PDAC, effective new treatment options are urgently needed," said Garrett Nichols, MD, MS, Chief Medical Officer of Candel. "We are encouraged by the improved survival associated with CAN-2409 for the treatment of borderline resectable PDAC, demonstrated for the first time in a randomized clinical trial. CAN-2409 was generally well tolerated without significant additional local or systemic toxicity when added to SoC chemoradiation."

Data Highlights as of August 21, 2023 Data Cutoff, include:

Prolonged and sustained survival was observed after experimental treatment with CAN-2409 plus prodrug in patients with borderline resectable PDAC (n=13)
An estimated survival rate of 71.4% at both 24 and 36 months, observed in patients who received CAN-2409 regimen together with SoC chemoradiation prior to surgery, versus only 16.7% survival at 24 and 36 months in patients with SoC chemoradiation prior to surgery.
Importantly, 5 out of 7 patients who received CAN-2409 were still alive at the time of data cut-off, with two patients surviving more than 45 months from enrollment. Only one patient randomized to control SoC chemotherapy remained alive at data cut-off (alive at 43 months).
Median overall survival has not yet been reached in patients who received CAN-2409; median overall survival was 12.5 months in the control arm.
Disease course was altered after salvage chemotherapy with improved CA19-9 levels and ongoing survival in CAN-2409 arm, but not in control arm.
Data showed consistent and robust activation of immune response after dosing with CAN-2409
In pancreatic tissue of patients treated with CAN-2409 plus prodrug together with SoC (but not SoC alone), dense aggregates of CD8+ granzyme B positive cytotoxic T cells, dendritic cells, and B cells were observed in the tumor microenvironment.
Increased levels of soluble granzymes B and H as well as pro-inflammatory cytokines, including IFN-γ, were observed in peripheral blood after CAN-2409 treatment, but not with control treatment.
CAN-2409 was associated with a favorable tolerability profile
Addition of CAN-2409 regimen to SoC was generally well tolerated, with no reported dose-limiting toxicities, including no cases of pancreatitis.
"The failure of immunotherapy to improve outcomes in pancreatic cancer is attributed to the highly immunosuppressive tumor microenvironment, which is largely devoid of immune cells," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel. "The immunological changes induced by CAN-2409, as observed in the pancreatic tissue after dosing, suggest that CAN-2409 treatment can convert the immune desert microenvironment and enable the generation of an effective antitumoral response and improve survival."

Further details from the poster will be available at time of the SITC (Free SITC Whitepaper) embargo poster presentation lift on the Candel website at: www.candeltx.com/media

About the Phase 2 Clinical Trial of CAN-2409 in Non-Metastatic Pancreatic Cancer

In its current design, the randomized, open-label phase 2 clinical trial is designed to evaluate the safety, preliminary efficacy, and biologic activity of a 2-3 injection regimen of CAN-2409 plus prodrug (valacyclovir or acyclovir) in patients with borderline resectable pancreatic cancer who are being treated with neoadjuvant chemoradiation or stereotactic body radiation therapy. After amendment in 2022, when enrollment of patients with locally advanced PDAC was discontinued, the clinical trial is exclusively focused on borderline resectable disease. In a previously completed phase 1b clinical trial, a highly significant increase in the number of CD8+ tumor infiltration lymphocytes was demonstrated at the site of the tumor after CAN-2409 treatment.

About Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is a highly lethal malignancy, and is the fourth leading cause of cancer-related death in the United States among both men and women. Based on the National Cancer Institute, Surveillance, Epidemiology and End Results (SEER) database, pancreatic cancer is expected to account for 3.3% of all new cancer cases, with an estimated 64,050 new cases and estimated 50,550 deaths in 2023.1 Effective therapeutics for pancreatic cancer, including PDAC, which accounts for 90% of all pancreatic carcinomas2, are urgently needed.

Surgical resection offers the only chance of cure, thus a major therapeutic goal for subjects with non-metastatic disease is to achieve complete tumor resection. Surgical treatment (pancreaticoduodenectomy, also known as the Whipple procedure) or total or distal pancreatectomy (depending on tumor location) is generally the recommended treatment for patients diagnosed with resectable cancer; the addition of adjuvant chemotherapy has been shown to only slightly improve survival rates (20 to 23 months).2 To this end, there has been increasing use of neoadjuvant chemotherapy and chemoradiation regimens for subjects with borderline resectable pancreatic ductal adenocarcinoma. Neoadjuvant regimens are intended to debulk the tumor, thereby increasing the proportion of patients who may become eligible for surgical resection and achieve complete resection (i.e., resection with negative margins, designated ‘R0 resection’). Unfortunately, even when an R0 resection is initially achieved, cures remain elusive as most patients experience disease recurrence due to residual micrometastatic disease. In a recent meta-analysis of 20 studies representing 283 patients with borderline resectable PDAC, neoadjuvant FOLFIRINOX with or without radiotherapy, median OS was only 22.2 months (95% CI, 18.8 to 25.6 months).3

Immunotherapy with PD-1 antibodies with or without CTLA-4 antibodies has been uniformly unsuccessful in patients with PDAC due to the dense stroma that surrounds PDAC tissue and the absence of tumor infiltrating lymphocytes.

About CAN-2409

CAN-2409, Candel’s most advanced viral immunotherapy candidate, is an investigational off-the-shelf replication-defective adenovirus designed to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene to a patient’s specific tumor and induce an individualized, systemic immune response against the disease. HSV-tk is an enzyme that locally converts orally administered valacyclovir into a toxic metabolite that kills nearby cancer cells. The intratumoral administration results in the release of tumor-specific neoantigens in the microenvironment. At the same time, the adenoviral serotype 5 capsid protein elicits a strong pro-inflammatory signal in the tumor microenvironment. This is designed to create the optimal conditions to induce an individualized and specific CD8+ T cell mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity. Because of its versatility, CAN-2409 has the potential to treat a broad range of solid tumors. Encouraging monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and ICI have previously been shown in several preclinical and clinical settings. Furthermore, more than 950 patients have been dosed with CAN-2409 with a favorable tolerability profile to date, supporting the potential for combination with other therapeutic strategies without inordinate concern of overlapping adverse events. Currently, Candel is evaluating the effects of treatment with CAN-2409 in non-small cell lung cancer (NSCLC), borderline resectable pancreatic cancer, and localized, non-metastatic prostate cancer in ongoing clinical trials.

On November 3, 2023 Morphic Therapeutic (Nasdaq: MORF), a biopharmaceutical company developing a new generation of oral integrin therapies for the treatment of serious chronic diseases, reported corporate highlights and financial results for the third quarter 2023 (Press release, Morphic Therapeutic, NOV 3, 2023, View Source [SID1234636911]).

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"Morphic presented a comprehensive set of positive results from the 12-week induction phase of the EMERALD-1 study of MORF-057 in UC, showing consistent efficacy across-the-board for patients, while demonstrating no safety signals. These results are particularly impressive, given that enrollment was skewed towards the severe end of the spectrum of moderately-to-severely active UC. Notably, we continue to observe improvement in these difficult to treat patients beyond the induction phase of the study in 44-week data presented recently," commented Bruce Rogers, PhD, President of Morphic Therapeutic. "The Phase 2a study of MORF-057 clearly signaled everything we believed it would at this point in development and we are excited to continue enrolling patients in our ongoing EMERALD-2 Phase 2b study. On a separate note, what the company continues to accomplish, while Praveen is on medical leave, is a testament to the quality the team that he put in place, and we are all wishing him the very best in his continued recovery."

Third Quarter 2023 and Recent Corporate Highlights

Chief Executive Officer of Morphic Therapeutic, Praveen Tipirneni, MD, continues to improve while remaining on a medical leave of absence after suffering an emergent medical event in late September. Dr. Tipirneni is expected to return after he recovers.

In the EMERALD-1 Phase 2a trial of MORF-057 in UC, additional positive data, presented at UEGW 2023 and in a company conference call, indicate that in a moderately-to-severely-active UC population with severe disease burden, MORF-057:

•Continues to be generally well tolerated with no safety signal observed to date
•Achieved primary endpoint with high statistical significance in reduction of RHI of 6.4 points (p=0.0019)
•Showed clinical improvement consistently across key measures at week 12, including remission and response (mMCS remission of 25.7%; mMCS response of 45.7%)
•Demonstrated RHI change ≥7 points in 48.6% of patients and RHI remission in 22.9% of patients
•Led to clinical improvement in mMCS within the 12-week induction period for 76% of patients, including advanced therapy-experienced patients
•PK/PD results confirm those seen in healthy volunteer studies
◦Median RO >99% and sustained saturation at week 12
◦Predicted lymphocyte subset changes observed, consistent with engagement of α4β7
•Demonstrated deepening of clinical effect beyond the 12-week induction period, with symptomatic remission rates continuing to increase out to 44 weeks in both advanced treatment-naïve and advanced treatment-experienced patients

Ongoing MORF-057 EMERALD Phase 2 Development Program Updates

•Continued the 40-week maintenance phase of the EMERALD-1 study as planned
•EMERALD-2 global Phase 2b randomized, double-blind, placebo-controlled trial of MORF-057 in patients with moderate-to-severe UC continues to enroll as projected
▪The primary endpoint of EMERALD-2 is the clinical remission rate as measured by mMCS at 12 weeks and is expected to report in the first half of 2025
•The Phase 2b study of MORF-057 in Crohn’s Disease is anticipated to begin in the first half of 2024

MORF-057 Preclinical Studies

•Presented preclinical data on rational selection of combination therapy for inflammatory bowel disease (IBD) treatment using an established clinical mode at UEGW 2023
◦This study explored preclinical combination models in UC and preliminarily examined the potential utility and rationale of combining anti-inflammatory mechanisms with α4β7 integrin inhibition in IBD

Pipeline Programs
•Continued late-stage preclinical work in the MORF-088 small molecule αvβ8 inhibitor program, with initiation of clinical trials anticipated in the first half of 2024
◦αvβ8 inhibition holds promise as a novel mechanism to treat myelofibrosis, a rare blood cancer, because the αvβ8 integrin is an activator of TGF-β which is believed to play a central role in the pathogenesis of myelofibrosis

Financial Results for the Third Quarter 2023

•Net loss for the quarter ended September 30, 2023, was $36.2 million or $0.73 per share compared to net income of $30.0 million or $0.78 per share for the same quarter last year
•Revenue was $0 million for the quarter ended September 30, 2023, compared to $2.1 million for the same quarter last year due to the conclusion of the Company’s research and development collaborations with AbbVie and Janssen
•Research and development expenses were $34.4 million for the quarter ended September 30, 2023, as compared to $25.2 million for the same quarter last year. The increase was primarily attributable to higher manufacturing and development costs along with higher pre-clinical and phase 2 clinical trial costs to support our lead product candidate, MORF-057
•General and administrative expenses were $10.4 million for the quarter ended September 30, 2023, compared to $8.3 million for the same quarter last year. The increase was due to increased non-cash stock-based compensation expenses and higher payroll costs

As of September 30, 2023, Morphic had cash, cash equivalents and marketable securities of $725.1 million, compared to $731.4 million as of June 30, 2023. Based on its current operating plan, Morphic believes its existing cash, cash equivalents and marketable securities as of September 30, 2023, will be sufficient to fund operating expenses and capital expenditure requirements into the second half of 2027.

About MORF-057

Morphic is developing MORF-057 as a selective, oral small molecule inhibitor of the α4β7 integrin for patients with inflammatory bowel disease (IBD). α4β7 has been clinically validated as a target for the treatment of IBD by the success of the approved injectable antibody therapeutic vedolizumab. MORF-057, like vedolizumab, is designed to block the interactions between α4β7 on the surface of lymphocytes and the mucosal endothelial cell ligand MAdCAM-1, substantially reducing lymphocyte migration from the bloodstream into intestinal mucosal tissues and avoiding inflammation that is associated with IBD.

About the EMERALD-1 Study

EMERALD-1 (MORF-057-201) is an open-label multi-center phase 2a trial designed to evaluate the efficacy, safety, and tolerability of MORF-057 in adults with moderate to severe ulcerative colitis. The 35 patients enrolled in the main cohort of the EMERALD-1 study have been treated with 100 mg BID (twice daily) at sites in the United States and Poland. The primary endpoint of the trial was the change in Robarts Histopathology Index (RHI), a validated instrument that measures histological disease activity in ulcerative colitis at 12 weeks compared to baseline. Patients will continue for an additional 40 weeks of maintenance therapy followed by a 52-week assessment. Secondary and additional pre-specified measures in the EMERALD-1 study include change in the modified Mayo clinic score, safety, pharmacokinetic parameters and key pharmacodynamic measures including α4β7 receptor occupancy and lymphocyte subset trafficking.

About the EMERALD-2 Study

EMERALD-2 (MORF-057-202) is a global phase 2b randomized, double-blind, placebo-controlled trial of MORF-057 that is currently enrolling patients with moderate-to-severe ulcerative colitis. The primary endpoint of EMERALD-2 is clinical remission rate as measured by the Modified Mayo Clinic Score (mMCS) at 12 weeks. EMERALD-2 will also measure several secondary and exploratory endpoints based on the mMCS as well as histologic, pharmacokinetic and pharmacodynamic measures, and safety parameters. Patients in the EMERALD-2 study will be randomized to receive either 200 mg BID MORF-057, 100 mg BID MORF-057, a QD (once daily) dose of MORF-057, or a placebo dose. Following the 12-week induction phase, all patients will receive MORF-057 for 40-weeks of maintenance dosing. For more information about the EMERALD clinical trials of MORF-057, please click here.

On November 3, 2023 Kineta, Inc. (Nasdaq: KA), a clinical-stage biotechnology company focused on the development of novel immunotherapies in oncology that address cancer immune resistance, reported the presentation of new preclinical data on the company’s anti-CD27 agonist monoclonal antibodies (mAbs) at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting (Press release, Kineta, NOV 3, 2023, View Source;utm_medium=rss&utm_campaign=kineta-presents-new-preclinical-data-on-lead-anti-cd27-monoclonal-antibody-at-the-society-for-immunotherapy-of-cancers-sitc-38th-annual-meeting [SID1234636908]). Thierry Guillaudeux, Ph.D., Chief Scientific Officer of Kineta, presented the company’s poster revealing new preclinical data.

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"We are thrilled to share the growing body of preclinical evidence from our selected lead anti-CD27 antibody, including the compelling new tumor model data as a monotherapy and in combination with other checkpoint therapies demonstrating antitumor efficacy in multiple types of mouse models," said Dr. Guillaudeux. "We believe that our antibody has the potential to be a best-in-class, next-generation immunotherapy capable of addressing diverse types of solid and hematologic cancers."

Key highlights from the poster presentation:
Dr. Guillaudeux presented data from in vitro and in vivo assessments to identify anti-CD27 agonist antibody lead candidates. The lead agonist anti-CD27 mAbs demonstrated high affinity binding to both human and cynomolgus monkey CD27 and not to mouse CD27. Additionally, they exhibited high specificity against CD27 with no cross-reactivity detected against other members of the tumor necrosis factor receptor superfamily (TNFRSF).

Furthermore, the agonist anti-CD27 antibodies share a different and complementary binding site to CD27 than CD70 (CD27 natural ligand) and induced strong NFkB signaling in the absence or presence of cross-linking. The anti-CD27 antibody-mediated NFkB activation acted in synergy with CD70. The strong agonist proprieties of the company’s lead anti-CD27 antibodies were further demonstrated on T cell proliferation and activation as well as NK cell activation.

Lastly, Kineta’s selected lead anti-CD27 candidate demonstrated antitumor efficacy in vivo as a single agent and in combination with other immunotherapies in multiple solid and hematological mouse tumor models.

The poster presentation is available for viewing under Publications in the CD-27 section of the company’s website at www.kinetabio.com.

SITC Presentation Details:
Title: CD27 is a new promising T cell co-stimulatory target for the cancer immunotherapy – Development and selection of a lead anti-CD27 agonist antibody
Abstract Number: 1357
Date / Time: Friday, November 3 at 9:00 A.M. – 7:00 P.M. Pacific Time
Location: Exhibit Halls A and B1 – San Diego Convention Center

On November 3, 2023 Kineta, Inc. (Nasdaq: KA), a clinical-stage biotechnology company focused on the development of novel immunotherapies in oncology that address cancer immune resistance, reported financial results for the third quarter ended September 30, 2023 and provided a corporate update (Press release, Kineta, NOV 3, 2023, View Source [SID1234636906]).

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"We are thrilled to share the significant progress made during the third quarter of 2023, highlighted by announcing, in September, initial monotherapy data from our VISTA-101 clinical trial evaluating KVA12123 in patients with advanced solid tumors. Additionally, we initiated Part B of the study enrolling the first patient in combination with pembrolizumab" said Shawn Iadonato, Ph.D., Chief Executive Officer of Kineta. "We continue to execute the VISTA-101 trial on time and on budget as we remain laser focused on advancing this promising new immunotherapy for cancer patients."

RECENT CORPORATE HIGHLIGHTS

KVA12123

•
Announced positive KVA12123 monotherapy safety data from its ongoing Phase 1/2 VISTA-101 clinical trial in patients with advanced solid tumors
•
Enrolled the first patient in Part B of its VISTA-101 Phase 1/2 clinical trial evaluating the safety and tolerability of KVA12123 in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced solid tumors
•
Continued recruitment of new patients in monotherapy and combination cohorts in its ongoing VISTA-101 phase 1/2 clinical study evaluating KVA12123 as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

•
Announced new research agreement with Fred Hutchinson Cancer Center to evaluate VISTA expression as a potential biomarker in cancer patients from Kineta’s ongoing VISTA-101 Phase 1/2 clinical trial
•
Abstract accepted for KVA12123 poster presentation of monotherapy clinical data from VISTA-101 Phase 1/2 clinical trial at Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th annual meeting in November 2023 ("SITC 2023")
•
Thierry Guillaudeux PhD, Chief Scientific Officer of Kineta, co-authored a publication titled "Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights" in Frontiers in Oncology
•
Presented preclinical data on VISTA blocking KVA12123 at Immuno US 2023

CD27 monoclonal antibody (mAb) Program

•
Abstract accepted for poster presentation of preclinical data on lead anti-CD27 agonist mAb at SITC (Free SITC Whitepaper) 2023
•
Presented new preclinical data on lead anti-CD27 agonist antibody at AACR (Free AACR Whitepaper) special conference on tumor immunology and immunotherapy

Business

•
Closed $3 million registered direct offering priced at-the-market under Nasdaq rules in October 2023

ANTICIPATED FUTURE MILESTONES

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Initial KVA12123 monotherapy clinical safety, pharmacokinetic, receptor occupancy and biomarker data to be presented at SITC (Free SITC Whitepaper) 2023
•
Q2 2024:
o
Additional KVA12123 monotherapy safety and efficacy data
o
Initial KVA12123 and pembrolizumab combination therapy data

THIRD QUARTER AND YEAR-TO-DATE 2023 FINANCIAL HIGHLIGHTS

•
Cash position: As of September 30, 2023, cash was $7.6 million, compared to $13.1 million as of December 31, 2022. The decrease was primarily due to cash used for clinical trial development of KVA12123 as well as general corporate purposes, partially offset by $5.5 million net proceeds received from the registered direct offering in April 2023 and $5.0 million in cash received from the Merck milestone payment in July 2023. We believe our cash position as of September 30, 2023, together with the $2.7 million in cash received in October 2023 from the registered direct offering plus the committed proceeds of $22.5 million pursuant to the second closing of the private placement expected in April 2024, will be sufficient to fund operating expenses and capital expenditure requirements into early 2025.
•
Revenues: Total revenues were zero for the three months ended September 30, 2023 compared to $0.2 million for the three months ended September 30, 2022 and were $5.4 million for the nine months ended September 30, 2023 compared to $1.5 million for the nine months ended September 30, 2022. Revenues in 2023 were primarily due to our achievement of a development milestone under the Merck Exclusive License and Research Collaboration Agreement in the second quarter, which triggered a $5.0 million milestone payment. Revenues in 2022 were primarily due to research and development services from the Genentech Option and License Agreement, which was terminated in December 2022.
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Research and development (R&D) expense: R&D expenses were $1.9 million for the three months ended September 30, 2023 compared to $2.6 million for the three months ended September 30, 2022 and were $7.5 million for the nine months ended September 30, 2023 compared to $10.5 million for the nine months ended September 30, 2022. The decreases in R&D expenses were primarily due to lower activities for KVA12123 manufacturing and clinical study start up as the company began enrolling the first patient in the study, which occurred in April 2023. The company expects R&D expenses to increase over time this year as additional patients are enrolled and dosed.
•
General and administrative expense: General and administrative expenses were $2.1 million for the three months ended September 30, 2023 compared to $2.0 million for the three months ended September 30, 2022 and were $9.4 million for the nine months ended September 30, 2023 compared to $5.5 million for the nine months ended September 30, 2022. The increases were primarily due to higher personnel-related costs from non-cash stock-based compensation for stock options issued during 2023 and increased public company expenses such as professional services fees and insurance.
•
Net loss: Net loss was $5.3 million, or $0.46 per basic and diluted share, for the three months ended September 30, 2023, compared to a net loss of $5.7 million, or $1.14 per basic and diluted share, for the three months ended September 30, 2022. Net loss was $11.4 million, or $1.09 per basic and diluted share, for the nine months ended September 30, 2023, compared to a net loss of $16.5 million, or $3.42 per basic and diluted share, for the nine months ended September 30, 2022.

On November 3, 2023 Xilio Therapeutics, Inc. (Nasdaq: XLO), a clinical-stage biotechnology company discovering and developing tumor-activated immuno-oncology therapies for people living with cancer, reported initial safety, pharmacokinetic (PK), pharmacodynamic (PD) and anti-tumor activity data from its ongoing Phase 1/2 clinical trial evaluating XTX202, an investigational tumor-activated, engineered, beta-gamma IL-2, in late line patients with advanced solid tumors (Press release, Xilio Therapeutics, NOV 3, 2023, View Source [SID1234636905]). The data were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting in San Diego, CA being held on November 1-5, 2023.

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"The newly reported data from our Phase 1/2 clinical trial for XTX202 expands the evidence across our programs supporting clinical validation of our tumor-activated technology. We observed a disease control rate of 50% at higher doses (≥2.8 mg/kg) and 31% across all dose levels in a variety of advanced and IO refractory solid tumors, including cold tumors. Importantly, treatment-related adverse events were primarily Grade 1-2 with no evidence of vascular leak syndrome reported at any dose level, and two patients are continuing on treatment for more than one year, highlighting XTX202’s potential for long-term tolerability at high doses," said Katarina Luptakova, M.D., chief medical officer of Xilio. "In addition, an analysis of an on-treatment biopsy from a patient receiving 2.8 mg/kg of XTX202 demonstrated evidence of activation in the tumor with minimal active drug in peripheral circulation and also suggests that monotherapy doses at or above 2.8 mg/kg are approaching the optimal range to engage CD8+ T effector cell and NK cell expansion while continuing to avoid stimulation of regulatory T cells. Overall, these encouraging data support continued evaluation of XTX202 at a dose of 4.0 mg/kg in our Phase 2 trial of patients with metastatic renal cell carcinoma and unresectable or metastatic melanoma and the exploration of opportunities for combination therapy."

Investigator Dr. Howard Kaufman, M.D., FACS of Massachusetts General Hospital commented, "As opposed to the trademark toxicities associated with recombinant IL-2, the preliminary data from the XTX202 Phase 1/2 clinical trial demonstrate a marked difference in tolerability and the potential for long-term treatment at high doses for XTX202 that has not been possible previously with systemically active IL-2 molecules. These data showcase the importance of concentrating potent IO molecules directly in the tumor microenvironment and offer an encouraging signal for continued investigation of XTX202 monotherapy at high doses along with its broad combination potential with other mechanisms of action where the stimulation of CD8+ T cells and NK cells without expansion of regulatory T cells would be synergistic."

Data from the Ongoing Phase 1/2 Clinical Trial for XTX202

As of a data cutoff date of October 26, 2023, 62 patients with advanced solid tumors had been administered XTX202 in an outpatient setting. Fifty-four (54) patients were treated in Phase 1 monotherapy dose-escalation and dose-expansion at seven dose levels ranging from 0.27 mg/kg to 4 mg/kg administered once every three weeks (Q3W). Eight (8) patients were treated in Phase 2 monotherapy at a dose level of 1.4 mg/kg Q3W.

Patients enrolled in Phase 1 were heavily pre-treated, with 74% of patients previously treated with three or more lines of anti-cancer therapy and 69% of patients previously treated with an immunotherapy. All patients in Phase 2 had been previously treated with an immunotherapy. As of the data cutoff date, 20 patients were continuing treatment with XTX202 across the Phase 1/2 trial.

Preliminary Safety Data

Across all dose levels administered in the Phase 1/2 trial, 62 patients were evaluable for safety.

● No signs or symptoms of vascular leak syndrome were reported by investigators through the 4.0 mg/kg dose.
● XTX202 was generally well-tolerated. Treatment-related adverse events (TRAE) were primarily Grade 1 or 2, and no patients discontinued treatment due to a TRAE. Higher grade TRAEs were primarily asymptomatic laboratory abnormalities, and no Grade 5 TRAEs were reported by investigators.
● The most common TRAEs (≥10% incidence) of any grade reported by investigators across all dose levels were: fatigue (19%, no grade ≥3); pyrexia (18%, no grade ≥3); chills (16%, 2% grade 3); and lymphocyte count decreased (15%, 8% grade 3-4). Grade 3 TRAEs reported in one patient each (2%) were: diarrhea/colitis; myalgia; hypoxia; lymphopenia; and aspartate transferase (AST)/alanine transaminase (ALT) increased. Investigators reported two Grade 4 TRAEs of lymphocyte count decreased/lymphopenia, which were both transient (<3 days) and resolved without intervention, with both patients able to continue on treatment.
● Across all dose levels, only two patients (3%) had a dose reduction due to a TRAE, and only one dose-limiting toxicity was observed, which was a reversible and transient (<5 days) Grade 3 elevation of AST and ALT at the 1 mg/kg dose.
Preliminary Anti-Tumor Activity

Across all dose levels administered in the Phase 1/2 trial, 42 patients were evaluable for anti-tumor activity. Of these response-evaluable patients, 27 patients were treated at dose levels of 1.4 mg/kg or higher, including six patients treated at the 2.8 mg/kg dose level or higher.

● Data demonstrated evidence of a dose-dependent increase in disease control rate (DCR). Among the 42 response-evaluable patients treated across all dose levels, investigators reported stable disease (SD) of at least 9-weeks duration in 13 patients (31% DCR) across a range of solid tumors, including cold tumors: melanoma (n=3); renal cell carcinoma (RCC) (n=2); non-small cell lung cancer (n=2); colorectal cancer (n=2); and myoepithelial carcinoma, vaginal cancer, testicular cancer and squamous penile cancer (n=1 each). Among the six response-evaluable patients treated at the 2.8 mg/kg dose level or higher, investigators reported SD of at least 9-weeks duration in three patients (50% DCR).
● In addition, two patients were ongoing on treatment for more than one year as of the data cutoff date, including a treatment-refractory microsatellite stable colorectal cancer (MSS CRC) patient and an RCC patient, suggesting XTX202 was well-tolerated with repeated, long-term dosing in these patients.
Preliminary PK and PD Data

Preliminary PK analysis demonstrated limited XTX202 activation in peripheral circulation, including:

● Dose-proportional exposure for XTX202 with minimal levels of unmasked XTX202 detected in peripheral circulation that were consistent across dose levels.
● Approximately 15% activated XTX202 in the tumor based on an analysis of an on-treatment patient biopsy for a patient treated with XTX202 at the 2.8 mg/kg dose level as compared to <1% activated XTX202 in plasma across patients treated with XTX202 at the 2.8 mg/kg dose level for whom PK analysis was available. These data along with non-clinical pharmacology data suggest 2.8 mg/kg or higher monotherapy doses of XTX202 are approaching the optimal range to activate CD8+ effector T cells and natural killer (NK) cells in the tumor.
Consistent with IL-2 beta-gamma biology, preliminary PD analysis of four available on-treatment tumor samples showed an average increase >200% of CD8+ effector T cells in the tumor as compared to pre-treatment biopsies.

Poster Presentation

A copy of Xilio’s data presentation from the SITC (Free SITC Whitepaper) Annual Meeting for XTX202 is available in the "Our Approach—Publications and Presentations" section of the company’s website at www.xiliotx.com.

Clinical Development Plans for XTX202

XTX202 recently cleared dose level seven (4.0 mg/kg) in Phase 1 monotherapy dose-escalation, and Xilio recently opened enrollment at a second dose level of 4.0 mg/kg in the ongoing Phase 2 monotherapy trial for XTX202. Based on the initial monotherapy data for XTX202, Xilio also plans to explore opportunities for strategic partnerships to evaluate XTX202 as a combination therapy.

Key Upcoming Milestones

As previously reported, Xilio anticipates achieving the following milestones in 2023:

● Activate clinical trial sites for the Phase 1 dose escalation portion of the clinical trial evaluating XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4, in combination with atezolizumab in the fourth quarter of 2023
● Report preliminary Phase 1 safety data for XTX301, a tumor-activated, engineered IL-12, into the third dose level in the fourth quarter of 2023
In addition, subject to obtaining sufficient additional capital, Xilio reported plans to:

● Complete Phase 1 combination dose escalation and select a recommended Phase 2 dose for XTX101 in combination with atezolizumab in the second quarter of 2024
● Subject to the results of Phase 1 combination dose escalation, initiate a Phase 2 trial for XTX101 in combination with atezolizumab in patients with MSS CRC in the third quarter of 2024
● Report initial Phase 2 data for XTX101 in combination with atezolizumab in approximately 20 patients with MSS CRC in the fourth quarter of 2024 and in approximately 20 additional patients (40 patients total) in the first quarter of 2025
● Report Phase 2 monotherapy data for XTX202 in approximately 20 patients treated at the 4.0 mg/kg dose with metastatic RCC or unresectable or metastatic melanoma in the second quarter of 2024
● Report Phase 1 safety and PK/PD data for XTX301 in advanced solid tumors in the second half of 2024
Conference Call Information

As previously announced, Xilio Therapeutics will host a live conference call and webcast Monday, November 6, 2023 at 8:00 a.m. ET to review progress across its pipeline of tumor-activated molecules, including the Phase 1/2 clinical data presented for XTX202 at the SITC (Free SITC Whitepaper) Annual Meeting. The webcast may be accessed by clicking here. The webcast of the conference call will also be available under "Events and Presentations" in the Investors & Media section of the Xilio Therapeutics website at View Source The archived webcast will become available on the Xilio Therapeutics website approximately two hours after the conference call and will be available for 30 days following the call.

About XTX202 and the Phase 1/2 Clinical Trials

XTX202 is an investigational tumor-activated beta-gamma biased, engineered IL-2 molecule designed to potently stimulate CD8+ effector T cells and natural killer (NK) cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the tumor microenvironment (TME). The Phase 1 clinical trial for XTX202 is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of XTX202 as a monotherapy in patients with advanced solid tumors. The Phase 2 clinical trial for XTX202 is a multi-center, open-label trial designed to evaluate the safety and efficacy of XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic renal cell carcinoma who have progressed on standard-of-care treatment. Please refer to NCT05052268 on www.clinicaltrials.gov for additional details.