On April 13, 2022 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported that the company’s Chief Financial Officer, Andreas Emmenegger, and Chief Operating Officer, Michael Stumpp, will participate in the upcoming Kempen Life Sciences investor conference on April 20 & 21, 2022 (Press release, Molecular Partners, APR 13, 2022, View Source [SID1234612163]).

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Presentation Details:

Kempen Life Sciences Conference – company presentation

Wednesday, April 20, 2022, at 16:30 CET (10:30 AM EDT)
The corporate presentation will be made available through the Molecular Partners website.

On April 13, 2022 Neoleukin Therapeutics, Inc., "Neoleukin" (NASDAQ:NLTX), a biopharmaceutical company utilizing sophisticated computational methods to design de novo protein therapeutics, reported the presentation of preclinical data and a trial in progress overview for its immunotherapy candidate NL-201, an IL-2 and IL-15 agonist, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Neoleukin Therapeutics, APR 13, 2022, View Source [SID1234612162]).

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"The research presented by Neoleukin researchers highlights the potential for NL-201 to treat hematologic cancers. In addition, data generated by our academic collaborators demonstrate synergistic antitumor activity when NL-201 is combined with radiation therapy, including significant inhibition of tumor growth and increased survival in preclinical models," said Jonathan Drachman, M.D., Chief Executive Officer of Neoleukin. "We believe these data support the potential for NL-201 to provide broad benefit across a range of indications and in combination with other modalities of therapy to improve outcomes for cancer patients."

Details of the poster presentations are as follows:

NL-201, a de novoagonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models

Presenter: Justin Huard, Neoleukin Therapeutics
Abstract Number: 4227

NL-201 promotes in vitro cytotoxicity as a single agent and increases antibody-dependent cellular cytotoxicity (ADCC) in combination with anti-CD20 monoclonal antibody.
NL-201 monotherapy demonstrates antitumor activity in the human Pfeiffer xenograft lymphoma model.
NL-201 demonstrates robust monotherapy antitumor activity in the syngeneic murine A20 B cell lymphoma model and results in potent combination activity when NL-201 is combined with anti-PD-1 therapy.
These findings support the evaluation of NL-201 in a planned clinical study in patients with B cell lymphomas and other hematological malignancies.
NL-201, a de novo engineered IL2/IL15 mimic, synergizes with radiation to generate potent antitumor immunity

First author: Wen Jiang, M.D., Assistant Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center
Abstract Number: 2067

NL-201, in combination with radiotherapy (RT), is well-tolerated in murine models and elicits robust antitumor activity through both innate and adaptive responses, including in checkpoint resistant tumors and brain metastases.
NL-201 in combination with radiation therapy enhances activation of the cytosolic DNA sensor cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway.
The immune mechanisms triggered by NL-201 plus radiation result in superior tumor growth inhibition and survival in both localized and metastatic murine breast cancers.
Results support further investigation of this novel combination regimen in localized and metastatic cancers.
A first-in-human Phase 1 study of NL-201 in patients with relapsed or refractory cancer

First author: Aung Naing, M.D., Professor, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center
Abstract Number: CT250

The multinational, first-in-human, open-label Phase 1 trial of NL-201 monotherapy is assessing the safety profile, recommended Phase 2 dose and treatment schedule in patients with advanced and/or refractory solid tumors.
The primary objectives are to assess the safety and toxicity profile of NL-201 and define the recommended Phase 2 dose and treatment schedule.
Enrollment is ongoing at sites in North America and Australia (ClinicalTrials.gov Identifier: NCT04659629).
About NL-201

NL-201 is a de novo protein that acts as an agonist of the IL-2 and IL-15 receptors and is designed to expand cancer-fighting CD8 T cells and natural killer (NK) cells without any bias toward cells expressing the alpha receptor subunit (CD25). Preclinical data highlights the ability of NL-201 to stimulate and expand CD8+ and NK cells at very low doses with minimal impact on immunosuppressive regulatory T cells. Treatment with NL-201 in animal models was well-tolerated and induced durable, antitumor activity. Additionally, a low rate of immunogenicity was observed following five weekly doses of NL-201 in non-human primates.

On April 13, 2022 Mustang Bio, Inc. ("Mustang") (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, reported its plan to initiate a Phase I clinical trial combining CAR T cells and oncolytic virus for the treatment of recurrent glioblastoma (rGBM), supported by interim data from two ongoing investigator-sponsored Phase 1 clinical trials evaluating two clinical candidates, MB-108 (C134 oncolytic virus) and MB‐101 (City of Hope’s IL13Rα2‐targeted CAR T cell therapy) (Press release, Mustang Bio, APR 13, 2022, View Source [SID1234612160]). Preclinical data also presented support the safety of administering these two therapies sequentially in a regimen designated as MB-109. The data are from a late-breaking poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022.

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"The data presented at the AACR (Free AACR Whitepaper) Annual Meeting support the initiation of a Phase I clinical trial to evaluate combining locoregional delivery of MB-108 and MB-101 as an attractive strategy for improving outcomes for patients with rGBM. We are excited to build on the interim clinical safety and feasibility data for administering either single agent MB-101 or MB-108, as well as to take advantage of the potential of oncolytic viral therapy to make the tumor immunologically ’hot’ since clinical data suggest that CAR T cells may be more effective in an inflamed tumor microenvironment," said Christine Brown, Ph.D., Deputy Director, T Cell Therapeutics Research Laboratory, Professor, Departments of Hematology & Hematopoietic Cell Transplantation and Immuno-Oncology, and The Heritage Provider Network Professor in Immunotherapy at City of Hope, one of the largest cancer research and treatment organizations in the United States.

Outcomes presented by Dr. Brown from each of the clinical candidates are as follows:

MB‐101 (IL13Rα2‐targeted CAR T cell therapy)
City of Hope’s Phase 1 clinical trial (NCT02208362) evaluated the feasibility and safety of repetitive administration of locoregionally delivered MB-101 in 65 heavily pretreated patients with recurrent or refractory malignant glioma, the majority of which were rGBM. Following maximal surgical resection / biopsy, dose escalating schedules of MB-101 were administered weekly either intratumorally ("ICT"), intraventricularly ("ICV") to the cerebrospinal fluid, or to both sites (dual ICT/ICV). Infusions appeared to be well tolerated with clinically manageable flu-like symptoms and two grade 3 events (transient encephalopathy and ataxia) possibly related to the CAR T cells. Optimization of manufacturing and administration in the final cohort of 19 evaluable patients suggest MB-101 provides a possible survival benefit versus historical controls. Two patients with high levels of intratumoral CD3+ T cells pre-therapy achieved complete responses lasting 7.5 and 31+ months, respectively.

MB-108 (C134 oncolytic virus)
University of Alabama at Birmingham ("UAB") researchers are conducting a Phase 1 clinical trial (NCT03657576) evaluating MB-108 for rGBM that will enroll up to 24 patients. Today’s poster highlights one clinical trial participant who received a single infusion of MB-108 that was well-tolerated. MRI changes at approximately 7 weeks post-treatment could not discriminate between tumor progression and pseudoprogression. Therefore, the patient underwent tumor biopsy 7 weeks post treatment that showed necrotic areas in tumor after treatment with MB-108. Immune infiltrates, both treated and untreated, evaluated by flow cytometry at that time point suggested that MB-108-treated tumor regions exhibited T cell immune recruitment differences when compared to an untreated region, with increased numbers of CD3+ CD8+ effector T cells that express granzyme B and lower numbers of naïve T cells.

MB-109 (MB-101 (IL-13Rα2) + MB-108 oncolytic virus)
Preclinical data from orthotopic GBM models in nude mice show that pre-treatment with MB-108 re-shaped the tumor microenvironment by increasing immune cell infiltrates, and the overall treatment with MB-109 gave no adverse reactions. These data also show that MB-109 combination therapy could be safely administered at low doses and leads to tumor shrinkage. An upcoming Mustang-sponsored Phase 1 clinical trial will evaluate the safety, tolerability, feasibility and preliminary efficacy of MB-109 in patients with IL13Rα2-positive relapsed or refractory GBM and anaplastic astrocytoma. Correlative studies will evaluate whether the combination approach can modify the tumor microenvironment, facilitate CAR T cell trafficking, and mitigate tumor immune escape by antigen loss.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "Recurrent GBM remains a major challenge to treat with a median overall survival rate of 6 months. We thank Dr. Christine Brown for presenting the potential of our three clinical candidates at today’s AACR (Free AACR Whitepaper) Annual Meeting on behalf of the academic institutions researching these prospective treatment options. The MB-101 and MB-108 programs continue to enroll patients in Phase 1 clinical trials at City of Hope and UAB, respectively. Given the preclinical study outcomes, future efforts will include the combination therapy MB-109, for which we plan to file an Investigational New Drug application later this year."

About MB‐101 (IL13Rα2‐targeted CAR T cells)
MB-101 is an IL13Rα2-targeted CAR T cell therapy developed by Dr. Brown and her City of Hope colleagues for treating GBM. It is the first CAR T cell therapy to demonstrate complete responses in GBM based on City of Hope’s Phase 1 trial (NCT02208362), with Dr. Behnam Badie, Professor and Chief, Division of Neurosurgery, as the Principal Investigator. IL13Rα2 is a GBM-restricted receptor expressed abundantly on the majority of GBM tumors. Mustang is developing MB‐101 as an optimized CAR T product incorporating City of Hope’s enhancements in CAR design and T cell engineering to improve antitumor potency and T cell persistence. MB‐101 includes a second‐generation hinge-optimized CAR containing mutations in the IgG4 linker to reduce off‐target Fc interactions, the 4-1BB (CD137) co‐stimulatory signaling domain for improved persistence of CAR T cells and the extracellular domain of CD19 as a selection/safety marker. To further improve persistence, naïve and memory T cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion to reduce T cell exhaustion and maintain a memory T cell phenotype. Ongoing MB-101 malignant glioma clinical trials under City of Hope’s IND include a study in patients with leptomeningeal disease (NCT04661384) and a combination study with checkpoint inhibitors (NCT04003649).

About MB-108 (C134 oncolytic virus)
Developed by Dr. Kevin Cassady, Professor of Pediatrics at Nationwide Children’s Hospital, and his colleagues for the treatment of malignant brain cancers, MB-108 (C134 oncolytic virus) is a second-generation attenuated herpes simplex virus type 1 (HSV-1) oncolytic virus that has improved replication in tumors in murine models, but with a similar toxicity profile as its first-generation predecessors. MB-108 preferentially replicates in tumor cells over non-malignant cells, thereby killing the infected tumor cells and causing the tumor cell to act as a factory to produce new virus. MB-108 can also induce pro-inflammatory signals and chemotaxis, thereby theoretically improving CAR T infiltration into the tumor mass. In February 2019, Mustang entered into a licensing agreement with Nationwide Children’s Hospital for worldwide development rights to C134 oncolytic virus, including but not limited to developing MB-108 for the treatment of GBM, and a Phase 1 clinical trial is currently ongoing at the University of Alabama at Birmingham in patients with recurrent disease (NCT03657576), with Dr. James Markert, Professor and Chair, Department of Neurosurgery, as the Principal Investigator.

About MB-109 (MB-101 (IL-13Rα2) + MB-108 oncolytic virus)
MB-109 is Mustang’s designation for the treatment regimen combining MB-101 (IL13Rα2‐targeted CAR T cells) CAR T cell therapy with MB-108 (C134 oncolytic virus). The combination is designed to leverage MB-108 to make cold tumors "hot," as described above, and thereby improve the efficacy of MB-101 CAR T cell therapy. MB-108 oncolytic virus is first injected to infect tumor cells which, in turn, leads to reshaping of the tumor microenvironment (TME) through recruitment of endogenous CD8-positive effector T cells. This inflamed TME permits MB-101 CAR T cells injected into and around the tumor to better infiltrate into and throughout the tumor mass, undergo activation and effect tumor cell kill. Mustang intends to file a Phase 1 Investigational New Drug application for MB-109 combination therapy in the second half of 2022 for the treatment of IL13Rα2-positive relapsed or refractory GBM and anaplastic astrocytoma.

On April 13, 2022 ChemoCentryx, Inc., (Nasdaq: CCXI), reported the presentation of preclinical data and initial pharmacokinetic (PK) and pharmacodynamic (PD) data from the ongoing Phase I clinical study of CCX559 during a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, ChemoCentryx, APR 13, 2022, View Source [SID1234612159]).

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The PD-L1/PD-1 interaction is one of the major immune checkpoints that limits the ability of effector T cells to destroy cancer cells. As a potential next generation therapy, an orally administered small molecule inhibitor of PD-L1 could have advantageous properties compared to approved monoclonal antibodies, such as better penetration into solid tumors, reduced immunogenicity, lack of Fc-mediated side effects and convenience of oral administration.

Preclinical characterization has demonstrated that CCX559 is a potent inhibitor of PD-L1 that blocks binding to PD-1 and CD80 and prevents PD-L1 inhibition of T cell activation. During 2021, ChemoCentryx initiated a first-in-human Phase I dose escalation study to evaluate the safety, tolerability, PK and PD of CCX559 in patients with various types of advanced cancer. In this Phase I basket study, CCX559 is taken orally once per day at specified dose levels, starting at 30 mg and ranging to date to 120 mg.

In the AACR (Free AACR Whitepaper) poster titled, CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors: Initial Pharmacokinetic and Pharmacodynamic Results from the in Progress First-In-Human Trial (abstract #4147), ChemoCentryx reported initial data available to date from patients enrolled in the first three dose cohorts in the ongoing Phase I study. Patients received CCX559 once daily at doses of 30 mg, 60 mg and 120 mg. All patients receiving 120 mg of CCX559 (n=9) were included in the PK evaluation reported in the poster. PD data for seven of the 120 mg patients (i.e., those whose data were available at time of submission) were also presented.

PK evaluation shows human CCX559 exposure is in line with preclinical projections. The mean exposure at 120 mg CCX559 in patients is comparable to exposures with anti-tumor activity in preclinical models and sufficient for PD-L1 target coverage, the half-life of the drug (enabling predicted once daily dosing) was also in line with projections.
PD activity results from the first cycle of treatment indicate that CCX559 is immunomodulatory. CD4 and CD8 T cell proliferation increased in all dose groups; soluble PD-L1 levels in plasma were significantly increased in the 120 mg patients by the end of the first cycle of dosing; and plasma IFNγ, CXCL9, CXCL10 were increased in the majority of patients assessed at 120 mg.
The PD activity of CCX559 is consistent with approved antibody inhibitors of PD-L1, in the extent and kinetics of the observed Th1 responses.
ChemoCentryx expects to present additional findings from this ongoing Phase I study at major oncology conferences through 2022. During the second half of 2022, the Company plans to advance CCX559 into a Phase Ib/II clinical trial to measure anti-tumor effects of CCX559 more directly.

On April 13, 2022 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a clinical-stage precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported positive topline results from the registrational TRIDENT-1 study across all four ROS1-positive advanced non-small cell lung cancer (NSCLC) cohorts, as reported by Blinded Independent Central Review (BICR) (Press release, Turning Point Therapeutics, APR 13, 2022, View Source [SID1234612158]).

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"We are very encouraged by the topline results from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 by BICR shared today and continue to believe repotrectinib is a potentially best-in-class drug candidate for patients with ROS1-positive advanced NSCLC," said Athena Countouriotis, M.D., President and Chief Executive Officer. "The confirmed ORR data and 95% confidence intervals across all four cohorts remain strong, and the initial estimated Kaplan-Meier landmark analyses based on limited median follow-up of approximately 10 months for both duration of response and progression free survival in the TKI-naïve population are trending in the direction we had hoped for given this is the highest area of unmet medical need. We believe a differentiated profile is built upon a strong ORR and durability of response that could improve upon the current standard of care."

The primary objective of the TRIDENT-1 study is to determine the cORR based on BICR as assessed by RECIST 1.1, and the key secondary objectives include duration of response (DOR), progression free survival (PFS) and intracranial activity. The dataset utilizes a February 11, 2022 data cutoff date. The safety analysis included 380 treated patients from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 across all cohorts, of which 287 patients were treated at the Phase 2 dose. The efficacy analyses included pooled patients from Phase 1 across all dose levels with an identified ROS1 fusion by next generation sequencing at baseline and Phase 2 patients. All patients received at least one dose of repotrectinib with at least four months of follow-up, and the majority of responders had at least six months of DOR follow-up.

Pooled Phase 1 and Phase 2 Topline Efficacy Analyses by BICR
ROS1-positive TKI-Naïve NSCLC (EXP-1; n=71 (8 from Phase 1 and 63 from Phase 2)):

In the ROS1-positive TKI-naïve advanced NSCLC population (EXP-1: n=71), the cORR was 79% (n=56/71; 95% CI: 68, 88), with 4 patients (6%) achieving a complete response (CR) and 52 patients (73%) achieving a partial response (PR). The cORR does not include one patient in an unconfirmed partial response (uPR) with tumor regression of -38% on the last scan, who remained on treatment awaiting the next scan as of the data cutoff date.

DOR ranged from 1.4+ to 35.1+ months with probability of patients in a response at 6, 9, 12 and 18 months reflected in Table 1 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.2 months.

Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

PFS ranged from 0+ to 40.4+ months with probability of patients remaining progression free at 6, 9, 12 and 18 months reflected in Table 2 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.8 months.
Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

ROS1-positive TKI-Pretreated NSCLC (EXP-2, EXP-3, and EXP-4; n=100):

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI and prior platinum-based chemotherapy (EXP-2: n=26 (3 from Phase 1 and 23 from Phase 2)), the cORR was 42% (n=11/26; 95% CI: 23, 63), with 1 patient (4%) achieving a CR and 10 patients (38%) achieving a PR. Duration of response ranged from 3.6 to 18.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with two prior TKIs without prior chemotherapy (EXP-3: n=18 (1 from Phase 1 and 17 from Phase 2)), the cORR was 28% (n=5/18; 95% CI: 10, 54), with 1 patient (6%) achieving a CR and 4 patients (22%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI without prior chemotherapy (EXP-4: n=56 (3 from Phase 1 and 53 from Phase 2)), the cORR was 36% (n=20/56; 95% CI: 23, 50), with 4 patients (7%) achieving a CR and 16 patients (30%) achieving a PR. The cORR does not include two patients with an uPR who both had tumor regressions of -47% on their last scans, both of whom remained on treatment awaiting their next scans as of the data cutoff date. Duration of response ranged from 1.9+ to 17.8 months.

Across the ROS1-positive TKI-pretreated advanced NSCLC population (EXP-2, EXP-3 and EXP-4), 17 patients had an identified ROS1 G2032R solvent front mutation detected, of which the cORR was 59% (n=10/17; 95% CI: 33, 82), with 1 patient (6%) achieving a CR and 9 patients (53%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.
TRIDENT-1 Topline Safety Analyses
Repotrectinib was generally well tolerated in a total of 380 patients with a safety and tolerability profile that was consistent with previously reported findings. The most commonly reported treatment emergent adverse event remained dizziness (61% all grade), of which 76% of patients who reported dizziness had a maximum severity of grade 1. The safety profile was comparable among the 287 patients who were treated at the Phase 2 dose.

As previously guided, the company anticipates discussing the topline BICR data with the U.S. Food and Drug Administration (FDA) at a pre-NDA meeting this quarter. The company plans to present detailed study results, including intracranial activity, from the ROS1-positive advanced NSCLC cohorts of the TRIDENT-1 study, at a medical conference in the second half of 2022.

Webcast/Conference Call Information
Turning Point will host a webcast and conference call on April 13, 2022 at 8 a.m. ET / 5 a.m. PT to discuss these results. Athena Countouriotis, M.D., President and Chief Executive Officer of Turning Point Therapeutics, will host the virtual event for investors and will be joined by Mohammad Hirmand, M.D., Chief Medical Officer. In addition, Alexander Drilon, M.D., Chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, will also be available on the call.

The event will be accessible through the "Investors" section of www.tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 3197444. A replay will be available shortly after the live event through the "Investors" section of www.tptherapeutics.com.