On January 23, 2023 TScan Therapeutics, Inc. (Nasdaq: TCRX), a clinical-stage biopharmaceutical company focused on the development of T cell receptor (TCR)-engineered T cell therapies (TCR-T) for the treatment of patients with cancer, reported that the U.S. Food and Drug Administration (FDA) has cleared its investigational new drug (IND) applications for T-Plex, TSC-204-A0201, and TSC-204-C0702 (Press release, TScan Therapeutics, JAN 23, 2023, View Source [SID1234626456]).

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T-Plex will now serve as the primary IND for TScan’s solid tumor program, enabling customized combinations of TCR-Ts to be administered to patients based on the targets and HLAs expressed in their tumors. The specific TCRs for each patient will be chosen from the Company’s ImmunoBank, consisting of high-affinity, naturally occurring TCRs that recognize a variety of prevalent cancer-specific targets and are associated with various common HLA types. Each unique TCR-T will be filed as a secondary IND and will reference the primary T-Plex IND.

In addition to the T-Plex IND, TScan filed secondary INDs for two initial TCR-T products, TSC-204-A0201 and TSC-204-C0702, that target melanoma-associated antigen 1 (MAGE-A1) on HLA types A*02:01 and C*07:02. MAGE-A1 is a cancer-associated antigen overexpressed in 45% of head and neck cancers and 50% of melanoma, cervical, and non-small cell lung cancers. TScan believes that TSC-204-C0702 is the first clinical program in MAGE-A1 for an HLA type other than A*02:01. With these INDs cleared, TScan is now working to open a multicenter Phase 1 clinical trial to establish the safety, preliminary efficacy, and feasibility of repeat dosing of multiplexed TCR-T. The trial will include patients with non-small cell lung cancer, melanoma, head and neck cancer, ovarian cancer, and cervical cancer.

"With the clearance of these three INDs, we believe we are the only company in the cell therapy field to have a clear clinical and regulatory path to develop multiplexed TCR-T cell therapy, which we see as critical for achieving durable responses in patients with solid tumors by overcoming resistance due to target or HLA loss. We will continue to rapidly build out our ImmunoBank, allowing us to deliver customized treatments tailored to each patient’s tumor biology," said Gavin MacBeath, Ph.D., Chief Scientific and Operations Officer. "We are now engaged in study start-up activities and look forward to sharing initial clinical data for the most advanced TCRs in this program by the end of 2023."

David P. Southwell, President and Chief Executive Officer continued: "Today marks the first three IND clearances for our solid tumor program and further validates the use of our proprietary platform to identify therapeutic TCRs suitable for clinical development. With the FDA clearance of T-Plex, along with two MAGE-targeting TCRs, we are now one step closer to bringing bespoke cell therapies to patients. We are continuing to build our ImmunoBank, with four more IND filings anticipated in 2023."

In the Phase 1 trial design, each TCR-T will initially be evaluated as singleplex therapy at two successive dose levels. Once single agent safety is established, each TCR becomes eligible for combination with any other TCR that has passed this threshold. The protocol has an interval 3+3 design, potentially allowing for a rapid path to multiplexing. The trial design also features a screening protocol, which pre-identifies patients whose tumors have a combination of targets and HLAs that would qualify them for the interventional study. The screening protocol is expected to initiate in Q2 2023.

On January 23, 2023 OncXerna Therapeutics, Inc. ("OncXerna"), a precision medicine company using an innovative RNA expression-based biomarker platform to predict patient responses to its targeted oncology therapeutic candidates, reported final results from a Phase 2 trial of bavituximab plus pembrolizumab in patients with previously untreated advanced hepatocellular carcinoma and new biomarker data demonstrating that the Xerna TME Panel clearly identified trial participants more likely to benefit from treatment (Press release, OncXerna Therapeutics, JAN 23, 2023, View Source [SID1234626455]). The data were featured in a poster that was presented on January 20, 2023 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI).

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The biomarker results presented at ASCO (Free ASCO Whitepaper) GI are from a planned analysis of tumor biopsies using the Xerna TME Panel, a novel RNA expression-based diagnostic panel that uses a machine learning-based algorithm to classify patients based on the interplay between angiogenic and immunogenic dominant biologies of the tumor microenvironment (TME). In the study featured in the ASCO (Free ASCO Whitepaper) GI poster, pre-treatment tumor biopsies were analyzed using the Xerna TME Panel and findings were correlated with objective tumor response to test the hypothesis that tumors with high immune scores (immune active or immune-suppressed TME subtypes [biomarker-positive]) are more likely to respond to bavituximab plus pembrolizumab than those with low immune scores (angiogenic or immune-desert TME subtypes [biomarker-negative]).

David Hsieh, M.D., Assistant Professor at University of Texas Southwestern Medical Center and lead investigator of the Phase 2 trial, commented, "Our newly reported clinical data in front-line liver cancer show a near doubling of response rate in the subset of patients classified as biomarker-positive by the Xerna TME Panel. The high response rate seen in these patients is rarely achieved in this challenging disease. Moreover, our patients are potentially more reflective of typical U.S.-based patients compared to those included in recent large, pivotal trials that enrolled the majority of their patients at sites outside of the U.S. We are therefore excited by the prospect of using this panel to optimize the care of patients with liver cancer."

Hagop Youssoufian, M.D., Chief Medical Officer of OncXerna Therapeutics and Adjunct Professor of Medicine at Brown University, commented, "The Xerna TME Panel has demonstrated remarkable consistency in identifying patients who are more likely to benefit from targeted and immune therapies across several malignancies. Although this was a proof-of-concept study, the responses noted in the biomarker-positive subgroup of patients in this lethal disease indicate substantial activity by comparison to the most active and contemporary combination therapies. This is the latest example of OncXerna’s longstanding commitment to utilize the Xerna TME Panel to bring the right medicines to the right patients."

A copy of the ASCO (Free ASCO Whitepaper) GI poster, entitled: "A phase II clinical trial of the phosphatidylserine targeting antibody, bavituximab in combination with pembrolizumab in patients with advanced hepatocellular carcinoma," will be available on the OncXerna website following the conclusion of the ASCO (Free ASCO Whitepaper) GI Symposium.

About the Phase 2 Trial

The trial featured in the ASCO (Free ASCO Whitepaper) GI poster was an investigator-sponsored, Phase 2, single arm study conducted at the University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center. The trial evaluated the combination of bavituximab and pembrolizumab in previously untreated patients with advanced hepatocellular carcinoma (HCC). The primary objective of the study was to determine the overall response rate (ORR) of the studied combination in patients with advanced HCC. Results showed bavituximab plus pembrolizumab was well tolerated, with no new safety signals, and that the studied combination induced objective tumor response in a meaningful subset of trial participants. Analysis of tumor biopsies showed that the response rate was enhanced in Xerna TME biomarker positive patients, while higher progressive disease rates were observed in biomarker negative patients. For more information on the trial, see Clinicaltrials.gov Identifier: NCT03519997.

About Bavituximab

Bavituximab is an antibody designed to reverse immune suppression by inhibiting phosphatidylserine (PS) signaling and is currently in Phase 2 clinical trials. The mechanism of action of bavituximab is to block tumor immune suppression signaling from PS to multiple immune cell receptor families (e.g., TIMs and TAMs). This biology is relevant across multiple types of solid tumors. Bavituximab is an investigational agent that has not been approved, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced gastric cancer.

About the Xerna TME Panel

The Xerna TME Panel uses proprietary RNA-based gene expression data and a machine learning-based algorithm to classify patients based on the interplay between angiogenic and immunogenic dominant biologies of the tumor microenvironment (TME). The Xerna TME Panel is an investigational assay that has not been approved and has not been demonstrated to be safe or effective for any use.

On January 23, 2023 Rain Oncology Inc. (NasdaqGS: RAIN), ("Rain"), a late-stage company developing precision oncology therapeutics with its lead product candidate, milademetan, an oral, small molecule inhibitor of the p53-MDM2 complex that reactivates p53, reported the publication of a peer-reviewed article titled, "A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients with Advanced Liposarcoma, Solid Tumors or Lymphomas" in the Journal of Clinical Oncology (Press release, Rain Oncology, JAN 23, 2023, View Source [SID1234626454]). Phase 1 clinical data in the paper highlight the activity and tolerability using intermittent dosing of milademetan across a range of tumor types including dedifferentiated liposarcoma (DD LPS), which represented the largest proportion of patients enrolled in the study (n=53).

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"An intermittent dosing schedule (260 mg qd, 3/14 days) of our highly selective inhibitor of the p53-MDM2 complex, milademetan, resulted in favorable safety and clinical activity in the Phase 1 trial in DD LPS patients," said Robert Doebele, MD, Ph.D., co-founder, president and chief scientific officer of Rain. "We view the prior data leveraging the intermittent dosing schedule as potentially offering a compelling risk/reward benefit, laying the foundation for our registrational Phase 3 MANTRA trial."

"Historical challenges with MDM2 inhibition identified cytopenias as a concern, for which intermittent dosing may provide a solution," said Richard Bryce, MBChB, Rain’s chief medical officer. "The intermittent dosing schedule identified may provide for a more favorable tolerability profile that we would expect to translate across a multitude of future therapeutic indications."

Key Article Highlights Include:

All liposarcoma patients enrolled in the Phase 1 trial exhibited the DD LPS subtype
Among DD LPS patients in the Phase 1 trial, median progression-free survival (mPFS) outcomes were maintained with intermittent dosing schedules (once daily [qd] on days 1-3 and 15-17 every 28 days; eg, 3/14 days) compared with extended (qd on days 1-21) / continuous (qd on days 1-28) schedules:
mPFS of patients across all doses/schedules (n=53): 7.2 months
mPFS of patients with 260 mg qd 3/14 intermittent schedule (n=16): 7.4 months
mPFS of previously treated patients with 260 mg qd 3/14 intermittent schedule (n=11): 8.0 months
mPFS of treatment-naïve patients in all doses/schedules (n=17): 14.6 months

Although all tested DD LPS patients had MDM2 gene amplification (n=22), mPFS in DD LPS patients did not differ by levels of key biomarkers including MDM2 or CDK4 copy number or by mRNA expression levels of MDM2, CDK4, or MDM4.
The preferred intermittent dosing schedule of milademetan (260 mg qd 3/14 days) mitigates dose-limiting hematologic adverse events while maintaining activity, leading to:
Marked reductions in occurrence and severity of grade 3/4 drug-related thrombocytopenia (15.8%; n=38) compared to extended/continuous schedules (36.2%; n=69) and
Fewer dose reductions (21.1%; n=8) and dose interruptions (15.8%; n=6) compared with extended/continuous schedules (23.3%; n=16 and 34.8%; n=24, respectively).
Preliminary single-agent activity with milademetan in DD LPS prompted the ongoing, randomized Phase 3 MANTRA trial (NCT04979442), with topline data anticipated in the first quarter of 2023.

About Milademetan

Milademetan (also known as RAIN-32) is an oral small molecule inhibitor of the p53-MDM2 complex that reactivates p53. Milademetan has demonstrated antitumor activity in an MDM2-amplified subtype of liposarcoma (LPS) and other solid tumors in a Phase 1 clinical trial, supported by a rationally designed dosing schedule to mitigate safety concerns and widen the potential therapeutic window of inhibition of the p53-MDM2 complex. Rain has completed enrollment in a Phase 3 trial of milademetan (MANTRA) in patients with LPS, and is evaluating milademetan in a Phase 2 tumor-agnostic basket trial in certain solid tumors (MANTRA-2). Rain anticipates commencing a Phase 1/2 clinical trial to evaluate the safety, tolerability and efficacy of milademetan in combination with Roche’s atezolizumab in patients with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and wildtype p53 advanced solid tumors (MANTRA-4), in the first quarter of 2023. Milademetan has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of LPS.

On January 23, 2023 Priothera, a late-clinical stage biotechnology company pioneering the development of its S1P receptor modulator compound mocravimod reported that the first patients have been enrolled in the pivotal MO-TRANS global Phase 2b/3 study evaluating mocravimod in AML patients undergoing allogeneic hematopoietic cell transplant (HCT) (Press release, Priothera, JAN 23, 2023, View Source [SID1234626453]).

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Mocravimod, a sphingosine 1 phosphate (S1P) receptor modulator which has been previously tested in multiple autoimmune indications, is being developed to enhance the curative potential of allogeneic HCT. Mocravimod has shown a clinically relevant benefit in an early clinical study in patients with hematologic malignancies undergoing allogeneic HCT.

Priothera is initiating the pivotal MO-TRANS global Phase 2b/3 study in Europe, Israel, the US and in additional Asian and Latin American countries, to assess the efficacy and safety of mocravimod as an adjunctive and maintenance therapy in AML patients undergoing allogeneic HCT. The double-blind, placebo-controlled study assesses relapse-free and overall survival of two dose levels of mocravimod in comparison to placebo. Topline data from this study are expected in 2025.

Marcos de Lima, M.D., is the Principal Investigator for the MO-TRANS global Phase 2b/3 trial. Dr. de Lima is professor of medicine at The Ohio State University College of Medicine and a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Prof de Lima said: "We are excited to be part of the important MO-TRANS global Phase 2b/3 study to investigate mocravimod, a potential new adjunctive and maintenance therapy for patients with Acute Myeloid Leukemia undergoing allogeneic Hematopoietic Cell Transplant. Maintenance therapy is fast becoming the new frontier in the treatment of AML and we are committed to bringing forth new innovative therapies to AML patients."

Elisabeth Kueenburg, M.D., Chief Medical Officer at Priothera, commented: "This MO-TRANS global Phase 2b/3 study builds on pre-clinical and clinical proof of concept studies which demonstrated mocravimod’s ability to improve survival outcomes for patients with hematological malignancies requiring allogeneic HCT. The mode of action has been well-established in autoimmune indications, but never in hematology. Mocravimod has the potential to be a first-in-class therapy in maintaining the graft-versus-leukemia effect, while preventing graft-versus-host disease, one of the most serious complications of allogeneic HCT. We expect this trial to deliver important clinical data supporting the registration of mocravimod in this indication."

Florent Gros, Co-Founder and CEO of Priothera, said: "Having successfully enrolled the first AML patients undergoing allogeneic HCT in our MO-TRANS global study represents a significant milestone for Priothera as we believe mocravimod has the potential to address a significant unmet need. Furthermore, we anticipate a strong uptake in patient enrollment with a significant number of patients currently being identified. We look forward to seeing topline results in 2025."

On January 23, 2023 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies (tumor infiltrating lymphocyte, TIL, and peripheral-blood lymphocyte, PBL), reported corporate, clinical, and regulatory updates (Press release, Iovance Biotherapeutics, JAN 23, 2023, View Source [SID1234626450]).

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CORPORATE UPDATE

Acquisition of Proleukin

Under a definitive agreement between Iovance and Clinigen Limited, Iovance will acquire worldwide rights to Proleukin (aldesleukin), an interleukin-2 (IL-2) product used to promote T-cell activity following TIL infusion. Iovance expects the benefits of this transaction to include immediate and future revenue, securing the IL-2 supply chain and logistics surrounding TIL therapy administration, and lower cost of goods and clinical trial expenses for Proleukin used with TIL therapies.

Terms of the agreement include an upfront payment of £166.7 million, a £41.7 million milestone payment upon first approval of lifileucel in advanced melanoma, and double-digit Proleukin global sales royalties from Iovance to Clinigen. The transaction is expected to close in the first quarter of 2023, subject to required regulatory approvals and clearances and other customary closing conditions.

Iovance is financing the acquisition with existing cash. As of January 20, 2023, Iovance’s unaudited cash position is approximately $477.0 million, which includes net proceeds from an at-the market (ATM) equity financing facility of approximately $227.1 million raised during the fourth quarter of 2022 and early 2023. In addition, Iovance has agreed to terms for a secured line of credit of up to $100 million from Quogue Capital. These proceeds are expected to fund the acquisition of Proleukin and Iovance’s operating plan well into 2024.

CLINICAL AND REGULATORY UPDATES

Lifileucel in Advanced Melanoma

TILVANCE-301 Phase 3 Confirmatory Trial: During the fourth quarter of 2022, Iovance reached agreement with the U.S. Food and Drug Administration (FDA) regarding the Phase 3 TILVANCE-301 trial of lifileucel in combination with pembrolizumab in frontline advanced melanoma. The TILVANCE-301 trial will randomize 670 patients and will investigate lifileucel in combination with pembrolizumab (experimental arm) compared with pembrolizumab monotherapy (control arm).

The FDA agreed to dual primary endpoints of objective response rate (ORR) to support accelerated approval and progression free survival (PFS) to support full approval of lifileucel in frontline advanced melanoma. The TILVANCE-301 confirmatory trial will also support full approval of lifileucel in post-anti-PD-1 advanced melanoma and is expected to be well underway at the time of potential BLA approval for lifileucel. Further details will be shared later in 2023.

Updated results from nearly 20 patients treated in Cohort 1A of the IOV-COM-202 trial of lifileucel in combination with pembrolizumab in frontline advanced melanoma remain consistent with previously reported data1 demonstrating robust ORR by RECIST 1.1 and durability of response. Additional data will be shared later in 2023 and continue to support the opportunity for lifileucel in frontline advanced melanoma.

Lifileucel in Anti-PD-1 Naïve Metastatic Non-Small Cell Lung Cancer (NSCLC)

IOV-COM-202 Cohort 3A: Confirmed ORR by RECIST 1.1 of 47% (n=8/17) was observed in patients treated with a combination of TIL therapy (LN-145) and pembrolizumab in Cohort 3A of the IOV-COM-202 trial. Responses were observed regardless of PD-L1 status. Safety was consistent with other studies of Iovance TIL therapies in combination with pembrolizumab. Study enrollment remains ongoing.

ORR by Clinical Subset: Cohort 3A comprises three distinct clinical subsets of anti-PD-1 naïve metastatic NSCLC: 1) treatment-naïve, 2) post-chemotherapy, and 3) EGFR-mutant after prior treatment with tyrosine kinase inhibitors (TKI). Response rates were highest in patients who were treatment-naïve (80% ORR; n=4/5) and post-chemotherapy anti-PD-1 naïve (43% ORR, n=3/7) compared with EGFR-mutant after prior treatment with TKI (20% ORR, n=1/5). Two patients achieved complete responses and remain on study (post-chemotherapy anti-PD-1 naive, n=1 and EGFR-mutant after prior treatment with TKI, n=1). The observed differences in ORR between the patient subsets are informing the design of a subsequent potential registration study. Detailed clinical results will be shared at a future medical meeting.

Regulatory Strategy: Iovance plans to meet with FDA in 2023 to discuss Cohort 3A results and a potential registration trial of lifileucel in frontline advanced NSCLC patients who are EGFR wild-type. The proposed design will be a frontline maintenance study of standard-of-care pembrolizumab and limited duration chemotherapy followed by treatment consisting of TIL therapy in combination with pembrolizumab compared with pembrolizumab monotherapy in responding patients. This design takes advantage of the findings of Cohort 3A and has the potential to offer frontline advanced NSCLC patients improved responses and PFS compared with single agent maintenance pembrolizumab.

BLA Submission

The rolling BLA submission for lifileucel in post-anti-PD-1 advanced melanoma commenced in August 2022 and is on track to complete during the first quarter of 2023.

Investor Webcast

Iovance will host a webcast on Monday, January 23, 2023, at 8:30 a.m. ET to discuss these corporate, clinical and regulatory updates. To participate in the webcast, please register at https://register.vevent.com/register/BIb01d5a16742c4d99b3dfe1b02bad8147. The live webcast and replay can be accessed in the Investors section of the company’s website at ir.iovance.com.