On June 3, 2024 Mythic Therapeutics, a clinical-stage biotechnology company committed to the development of next-generation antibody-drug conjugate (ADC) therapies for the treatment of a wide range of cancers, reported initial dose escalation results from its ongoing Phase 1 KisMET-01 study evaluating its investigational cMET-targeting ADC, MYTX-011, in patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Mythic Therapeutics, JUN 3, 2024, View Source;utm_medium=rss&utm_campaign=mythic-therapeutics-presents-initial-dose-escalation-data-from-ongoing-phase-1-kismet-01-study-on-mytx-011-at-the-american-society-of-clinical-oncology-asco-annual-meeting [SID1234644019]).

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"The initial dose escalation results from our ongoing Phase 1 KisMET-01 study, coupled with the previously presented preclinical data are encouraging and underscore MYTX-011’s potential to serve patients with a broad range of cMET expression," said Gilles Gallant, BPharm, Ph.D., FOPQ, Chief Development Officer at Mythic Therapeutics. "ADCs have been a transformative class of treatment for patients impacted by cancer, but we know that there is a large population of patients with low-to-moderate target expression who are unlikely to benefit from them. These initial data potentially represent significant promise for patients who have historically been ineligible for treatment due to their level of target expression or tumor type, and we look forward to continuing our dose escalation and expansion study."

MYTX-011 is a novel cMET-targeted DAR 2 vcMMAE ADC with an antibody that has been engineered to have pH-dependent binding, which results in higher internalization and payload delivery to tumor cells with a range of cMET expression.

KisMET-01 (NCT05652868) is a multicenter, first-in-human study of MYTX-011 in patients with previously treated, locally advanced or metastatic NSCLC. The study is comprised of a Part 1 dose escalation in patients with NSCLC of any histology and regardless of cMET expression level, followed by Part 2 dose expansion in cohorts specified by cMET expression and histology. The primary objectives of Part 1 are to assess safety and tolerability and determine the recommended phase 2 dose. Secondary objectives include assessment of pharmacokinetics (PK) and preliminary anti-tumor activity.

As of April 30, 2024, 42 patients had been enrolled and received at least one dose of MYTX-011. Data from 41 patients was available by data cutoff and median follow-up was 15 weeks. Patients were dosed between 1.0 to 6.7 mg/kg on a once every three weeks schedule (Q3W). Treated patients had a median of three prior lines of therapy. As of data cutoff, PK data were available in patients who received doses 1.0 to 5.0 mg/kg. PK of MYTX-011 showed nearly dose proportional exposure up to 5.0 mg/kg. Little separation of ADC and total mAb concentration was noted, suggesting good stability of MYTX-011, supporting dosing every 3 weeks. MYTX-011 has been well tolerated with low incidence of common AEs associated with MMAE or cMET targeted therapeutics. No dose-limiting toxicity was reported, and dose escalation is ongoing. Given that dose escalation is ongoing and the overall median follow-up as of the data cutoff was 15 weeks, efficacy data will be presented in a future conference or publication.

"Patients with locally advanced or metastatic NSCLC who have not responded or become resistant to previous therapies represent an urgent unmet need," said Melissa Johnson, M.D., Director of Lung Cancer Research at Sarah Cannon Research Institute. "Observing the favorable safety, tolerability and PK of MYTX-011 across a diverse range of cMET-expressing patients is encouraging. We look forward to seeing additional safety and efficacy data from the Phase 1 study."

About MYTX-011

MYTX-011, an investigational cMET-targeting ADC, leverages Mythic’s innovative FateControl technology which is designed to allow ADCs to actively navigate inside of cells, potentially increasing delivery of anti-cancer agents to tumor cells with less impact on healthy cells. This breakthrough approach takes the next step beyond linker-payload technologies and is designed to improve ADC efficacy against a broad set of molecular targets and patient profiles. MYTX-011 is currently being evaluated in the Phase 1 KisMET-01 clinical trial, a first-in-human, open-label, multi-center, dose escalation and dose expansion study enrolling patients with locally advanced, recurrent or metastatic NSCLC (NCT05652868).

On June 3, 2024 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage company focused on the discovery and development of targeted biologic therapeutics with unique mechanisms of action (engineered toxin bodies or "ETBs") for cancer and immune-mediated disease, reported an update on its clinical-stage programs (Press release, Molecular Templates, JUN 3, 2024, View Source [SID1234644018]).

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Eric Poma, PhD., Chief Executive and Chief Scientific Officer of MTEM, stated, "ETBs are a potentially powerful therapeutic approach to selectively depleting immunosuppressive cells in oncology or eliminating self-reacting immune cells in severe immune-mediated diseases. The monotherapy activity we see with MT-6402 in relapsed/refractory solid tumor patients, and the clinical and ex vivo depletion of CD38+ immune cells seen with MT-0169 at well-tolerated doses underscore the potential of this platform across multiple diseases."

Company Pipeline Highlights

MT-6402 (PD-L1-targeting ETB)

Promising Single-Agent Activity: MT-6402 has shown monotherapy activity in heavily pre-treated patients who had previously progressed or were refractory to immuno-oncology therapy.
Head and Neck Cancer Responses: MTEM had previously reported that nine patients (seven evaluable) with head and neck squamous cell carcinoma ("HNSCC") had been treated in the Phase 1 dose escalation. Two heavily pre-treated patients with low PD-L1 expressing squamous cell carcinoma of the head and neck (HNSCC) had achieved partial responses with MT-6402 monotherapy. These patients remain in response and in good clinical condition, continuing treatment in cycles 21 and 12 (one cycle = 4 weeks), respectively. In addition, four of the HNSCC patients treated with MT-6402 had stable disease with two showing tumor reduction. All patients with tumor responses or tumor reduction had low PD-L1 expression (≤20% CPS).
New Lung Cancer Response: An unconfirmed partial response was observed in a non-small cell lung cancer ("NSCLC") patient with high PD-L1 expression in the Phase 1b monotherapy dose expansion study in solid tumor patients with high PD-L1 tumor expression (TPS≥50%). The patient achieved a partial response at the end of cycle 8 following sustained tumor reduction in prior assessments. A PET scan in cycle 8 showed no indications of active metastatic disease. This patient had previously progressed on chemotherapy, targeted therapy, and checkpoint therapy, including progression within six months on pembrolizumab + ramucirumab, before enrolling in the study. Three other NSCLC patients with high PD-L1 expression have been dosed in the Phase 1b expansion study. Two of these patients had progressive disease and one passed away from COVID and was not evaluable.
Favorable Safety Profile: To date, MT-6402 appears to be generally well-tolerated, with no drug-related adverse events exceeding grade 3.
Ongoing Enrollment: MTEM continues to enroll HNSCC patients with low PD-L1 expression (1-49%) and patients with solid tumors with high PD-L1 expression (≥50%).
MT-0169 (CD38-targeting ETB)

Clinical proof-of-concept supports the elimination of CD38+ cells in immune-mediated disease. Recent clinical data with CD38 antibodies have demonstrated the therapeutic potential of CD38+ immune cell clearance in several immune-mediated diseases. Despite these promising early data, a more potent mechanism of CD38+ immune cell depletion may provide greater clinical benefit.
Potent and unique mechanism of action. MT-0169 is designed to destroy CD38+ tumor or immune cells through internalization of CD38 and cell destruction via a novel mechanism of action (enzymatic ribosomal destruction and ER stress). In ex vivo cell kill assays, MT-0169 shows potency against plasma cells with IC50 activity in the picomolar or femtomolar range. Plasma cells are exceptionally sensitive to ER stress, making them uniquely susceptible to the MT-0169 mechanism of action. MT-0169 also shows potent activity against T-cells that express low levels of CD38. HLA-DR CD38+ T-cells have been implicated in many immune-mediated diseases.
Overcoming antibody resistance. The unique mechanism of action of MT-0169 and its lack of an Fc domain may avoid resistance mechanisms seen with CD38 antibodies like receptor downregulation or trogocytosis while allowing for combination approaches with FcRn-targeting therapies.
Clinical proof-of-concept with MT-0169. MTEM’s Phase 1 study in patients with relapsed or refractory multiple myeloma dosed at 5, 10, or 15 mcg/kg showed potent depletion of CD38+ immune cells with no drug-related adverse events of grade 3 or higher noted in these patients.
Planned clinical development with MT-0169. MTEM will continue to develop MT-0169 in hematology and is evaluating the potential of MT-0169 in severe immune-mediated diseases.
MT-8421 (CTLA-4 ETB)

Tumor microenvironment dismantling. MT-8421 is designed to potently destroy CTLA4+ Tregs, alleviating immunosuppression in the tumor microenvironment.
Pharmacodynamic effects observed early Phase 1 dose escalation. Three patients were dosed in the first cohort of the Phase 1 study at 32 mcg/kg. No drug-related adverse events of grade 3 or higher were observed. One patient had disease progression at the end of cycle 2. Two patients have stable disease and remain on study at cycle 8 and cycle 7, respectively (one cycle = four weeks). The two patients in stable disease showed peripheral depletion of Tregs and significant elevations in IL-2 while on therapy. One of the patients has a notable decrease in ctDNA.
Dose escalation continues. Enrollment is on-going in the second cohort of 48 mcg/kg for the Phase 1 study of MT-8421.

On June 3, 2024 TuHURA Biosciences, Inc. ("TuHURA"), a Phase 3 registration-stage immune-oncology company developing novel technologies to overcome resistance to cancer immunotherapy and Kintara Therapeutics, Inc. (Nasdaq: KTRA) ("Kintara"), a biopharmaceutical company focused on the development of new solid tumor cancer therapies, reported positive results from the primary analysis of TuHURA’s completed Phase 1b trial evaluating IFx-2.0 among patients with advanced or metastatic MCC or cSCC who exhibited primary resistance to immune checkpoint inhibitor (ICIs) therapy (Press release, Kintara Therapeutics, JUN 3, 2024, View Source [SID1234644016]).

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The abstract titled, "Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel Cell Carcinoma (MCC) and Cutaneous Squamous Cell Carcinoma (cSCC)," was presented by Andrew Brohl, MD, H. Lee Moffitt Cancer Center and Research Institute, in a poster presentation as part of the Melanoma/Skin Cancers session held at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

"It is encouraging that IFx-2.0 demonstrated the ability to overcome resistance to ICI in 63% of patients with advanced MCC, even in patients who progressed on both anti-PD1 therapy followed by anti-PD1/CTLA-4 combination therapy, many of whom also received chemotherapy and several investigational agents post ICI failure and prior to IFx-2.0 treatment," commented Dr. James Bianco, Chief Executive Officer of TuHURA.

The group that was of most interest were the seven (7) patients with ICI naïve, advanced MCC, who, prior to IFx-2.0 treatment, received no subsequent systemic or investigational therapies that may confound the ability to determine IFx-2.0’s contribution to overcoming primary resistance to ICI therapy. Five (5) of these 7 patients progressed within 3.8 months while receiving single agent anti-PD(L)-1 therapy. IFx-2.0 was administered as the immediate post ICI therapy. Following IFx-2.0 treatment, patients were rechallenged with an anti-PD(L)-1 agent. Four (4) of the 5 patients (80%) achieved a durable objective response (CR, pCR, 2 PRs) lasting, on average, 25 months, with 2 responses ongoing at 19 and 23 months.

The remaining 2 of 7 patients, after progressing on anti-PD-1 therapy, also received and progressed on combination anti-PD1/anti-CTLA4 therapy prior to IFx-2.0 treatment. Following IFx-2.0, 1 patient (50%) achieved a PR, ongoing at 6 months following rechallenge with single agent anti-PD-1 rechallenge.

The promising efficacy signal demonstrated in the Phase 1b study showing the potential for IFx-2.0 to overcome primary resistance to anti-PD(L)-1 therapy formed the rationale for TuHURA’s planned Phase 3 registration-directed clinical trial. The Phase 3 trial will examine IFx-2.0 as an adjunctive therapy with Keytruda (pembrolizumab, an anti-PD-1 agent) to improve tumor overall response rates when compared to Keytruda plus placebo in first line treatment of ICI naïve patients with advanced or metastatic MCC. This Phase 3 trial is expected to begin enrollment in 2H 2024 under the FDA’s Accelerated Approval Pathway.

TuHURA’s IFx-2.0 personalized cancer vaccine product involves the injection into a patient’s tumor of a small amount of pDNA that is designed to encode for an immunogenic bacterial protein that gets expressed on the surface of the patient’s tumor so that the surface of the tumor looks like a bacterium. By making the surface of a tumor look like a bacterium, IFx-2.0 is designed to use each patient’s tumor itself as the source of foreign neoantigens to prime and initiate a patient’s innate immune response against the tumor irrespective of whether the tumor escaped immune recognition prior to IFx-2.0 administration. In doing so, IFx-2.0 is designed to harness the power of the patient’s innate immune response, which has evolved over time to be conserved to detect foreign pathogens like bacterial proteins.

The primary objective of the Phase 1b study was to establish safety and feasibility of repeated administrations of IFx-2.0. The study met its primary safety objective: ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx-2.0, researchers performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge.

As reported at ASCO (Free ASCO Whitepaper), following completion of protocol directed therapy, 11 patients with MCC and 6 patients with cSCC who, prior to study entry, failed anti-PD(L)1 or anti-PD-1/CTLA-4 therapy, were re-treated with anti-PD(L)1 monotherapy or combination therapy as the immediate IFx-2.0 post-protocol therapy: pembrolizumab (7), nivolumab + ipilimumab (2), or avelumab (2) in MCC and cemiplimab (6) in cSCC. The study concluded that IFx-Hu2.0 is safe and well tolerated at weekly dosing repeated up to 3 weeks. In an exploratory post-hoc analysis, 7 of 11 MCC patients (63%) treated with standard of care ICI agents immediately following protocol therapy experienced durable disease control despite prior failure of this same drug class prior to protocol enrollment, suggesting an "immune priming" effect of study therapy. Based on this promising efficacy signal, a randomized study of pembrolizumab +/- IFx-Hu2.0 is planned in the advanced MCC 1st line setting.

For more information about TuHURA’s Phase 1b IFx-2.0 study, visit clinicaltrials.gov and reference identifier: NCT04160065.

As previously announced, TuHURA entered into a definitive agreement for an all-stock transaction with Kintara to form a company combining expertise and resources to advance a risk diversified late-stage oncology pipeline. In conjunction with the execution of the definitive agreement, TuHURA entered into subscription agreements for a $31 million financing. The combined company will focus on advancing TuHURA’s personalized cancer vaccine(s) and first-in-class bi-functional Antibody Drug Conjugates ("ADCs"), two technologies that seek to overcome the major obstacles that limit the effectiveness of current immunotherapies in treating cancer. The combined company is expected to operate under the name "TuHURA Biosciences, Inc." and to trade on The Nasdaq Capital Market under the ticker "HURA". The transaction is subject to customary closing conditions, including stockholder approval of both companies, and is expected to close in the third quarter of 2024.

On June 3, 2024 Keros Therapeutics, Inc. ("Keros") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments to treat a wide range of patients with disorders that are linked to dysfunctional signaling of the transforming growth factor-beta ("TGF-ß"), reported that Keros’ President and Chief Executive Officer Jasbir S. Seehra, Ph.D., will participate in a fireside chat presentation at the Goldman Sachs 45th Annual Healthcare Conference on Monday, June 10, 2024 at 2:40 p.m. Eastern time (Press release, Keros Therapeutics, JUN 3, 2024, View Source [SID1234644015]).

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A live audio webcast of the fireside chat presentation will be available at View Source and an archived replay will be accessible in the Investors section of the Keros website at View Source for up to 90 days following the conclusion of the event.

On June 3, 2024 IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company developing innovative gamma-delta (γδ) T cell therapies, reported encouraging preliminary clinical data of INB-200 at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on June 1, 2024 (Press release, In8bio, JUN 3, 2024, View Source [SID1234644014]).

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The preliminary data demonstrated that 92% of evaluable patients treated with INB-200 exceeded a median PFS of 7 months (median follow-up: 11.7 months) with concomitant temozolomide (TMZ), as of a data cutoff date of May 30, 2024. The survival data along with radiographic improvements are indicative of positive treatment effects, which highlight the potential of IN8bio’s genetically modified, chemotherapy-resistant gamma-delta T cells as a potential first-in-class therapy for patients with newly diagnosed glioblastoma (GBM).

The Phase 1 study assessed the safety and preliminary efficacy of the addition of DeltEx DRI gamma-delta T cells to maintenance therapy with TMZ. The trial assessed the administration of 1×107 cells per dose across three different dosing regimens increasing from a single dose delivered on cycle 1 day 1 during maintenance in Cohort 1, to three doses delivered on day 1 of cycles 1-3 in Cohort 2, to six doses delivered on day 1 of cycles 1-6 in Cohort 3. Thirteen patients have been enrolled and treated with INB-200, including three patients in Cohort 1 (1 dose), four patients in Cohort 2 (3 doses) and six patients in Cohort 3 (6 doses).

"For far too long, there has been little advancement for patients with GBM to improve their treatment outcomes," said Burt Nabors, M.D., Division Director, Neuro-oncology at the Heersink School of Medicine at the University of Alabama at Birmingham. "The addition of multiple intracranial injections of IN8bio’s DeltEx DRI gamma-delta T cells shows the potential for extending progression-free survival in this patient population when administered in combination with the current standard of care used to treat newly diagnosed glioblastoma patients."

The current standard of care for newly diagnosed glioma patients consists of primary resection, six weeks of daily chemoradiation therapy followed by six cycles of monthly maintenance TMZ therapy (Stupp regimen), which achieves a median PFS of 7 months and an overall survival (OS) of approximately 14 to 16 months. All of the patients in the Phase 1 study that received all of their protocol defined treatments with INB-200 exceeded a median PFS of 7 months, including one patient in Cohort 2 that remains alive and progression free for nearly three years.

"The safety profile of gamma-delta T cells continues to be strong across all three dose cohorts with no cell therapy-related toxicities such as immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome reported in patients receiving up to the maximum dose of six infusions of the therapy," said Trishna Goswami, M.D., Chief Medical Officer, IN8bio. "We are now dosing newly diagnosed patients in Arm A of the Phase 2 study with INB-400, evaluating up to six infusions of our autologous gamma-delta T cells in combination with the Stupp protocol."

The poster presentation at ASCO (Free ASCO Whitepaper) included promising activity and safety data for the fully enrolled trial, as of the data cutoff date of May 1, 2024.

Key findings from the ongoing Phase 1 study:

All patients who completed all protocol mandated doses surpassed a median standard-of-care PFS of 7 months, with a majority also exceeding the expected PFS based on their age and MGMT status of their tumors.
92% of evaluable patients treated with INB-200 for GBM exceeded a median PFS of 7 months achieved with the standard-of-care regimen (Stupp regimen).
One patient with an IDH-mutant glioma remains alive and progression free at 34.9+ months; IDH-mutant patients in a recently published clinical trial of an IDH inhibitor demonstrated a median PFS of 11.1 months in the control arm and 28.5 months in the experimental arm.
No treatment-related serious adverse events, dose-limiting toxicities, cytokine release syndrome, infusion reactions, or immune effector cell-associated neurotoxicity syndrome have been reported in any cohort.
The most common treatment emergent adverse events were Grade 1-2 toxicities consisting of white blood cell and platelet count decreases related to standard-of-care TMZ.
Preserved gamma-delta T cells were found in relapsed tumor 148 days after initial DRI infusion in one patient with paired biopsies, pointing to durability of DRI gamma-delta T cells.
Radiographic evaluation pre- and post-treatment included resolution of midline shift in one patient with evidence of changes in enhancement attributed to treatment effect in multiple patients. One subject was found to have a 36% decrease in a lesion attributed to positive treatment effect.
"As these encouraging results from our ongoing INB-200 Phase 1 study continue to mature, we look forward to reporting additional results from a long-term follow-up of cohort 3 at future medical meetings," said William Ho, CEO and co-founder, IN8bio.

Poster details:
Abstract #: 2042
Title: INB-200: Fully enrolled Phase 1 study of gene-modified autologous gamma-delta (γδ) T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ)
Presenter: Mina Lobbous, MBChB, MD, MSPH, University of Alabama at Birmingham
Session Name: Central Nervous System Tumors
Date and Time: Saturday, June 1, 2024 from 10:00 a.m. – 1:00 p.m. EDT
Poster Board: #341

The poster presentation is accessible on the Company’s website here.

About INB-200
INB-200 is a genetically modified autologous DeltEx DRI product candidate for the treatment of solid tumors. This novel platform utilizes genetic engineering to generate chemotherapy-resistant gamma delta T cells which can be administered concurrently with standard-of-care treatment in solid tumors. This is a powerful, synergistic investigational treatment approach designed to enable gamma-delta T cells to persist in the presence of chemotherapy and maintain their natural ability to recognize, engage and kill cancer cells.

INB-200 is the first genetically engineered gamma-delta T cell therapy to be administered to patients with solid tumors in an initial indication of GBM.