On December 11, 2023 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 difficult-to-treat cancers and rare genetic diseases, reported updated encouraging safety and efficacy data from Mustang’s multicenter Phase 1/2 clinical trial of MB-106, a CD20-targeted, 3rd-generation autologous CAR T-cell therapy for patients with relapsed or refractory B-cell non-Hodgkin lymphomas ("NHL") and chronic lymphocytic leukemia ("CLL") (Press release, Mustang Bio, DEC 11, 2023, View Source [SID1234638432]). The data were presented during a poster session on December 9th (Abstract #2102) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting and build upon previously reported data from a single-institution Phase 1/2 clinical trial conducted at Fred Hutchinson Cancer Center ("Fred Hutch"). MB-106 is being developed in a collaboration between Mustang and Fred Hutch.

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"All nine patients have responded clinically to treatment in this multicenter trial and the safety and efficacy profile of MB-106 appears to be consistent with the original single-institution trial. It is especially encouraging that complete responses were observed in all patients with follicular lymphoma in this multicenter trial," said Mazyar Shadman, M.D., M.P.H., Study Chair, Innovators Network Endowed Chair at Fred Hutch, Associate Professor and physician at Fred Hutch and University of Washington. "One patient with follicular lymphoma who had six prior treatments including CD19-targeted CAR T-cell therapy experienced a complete response for the first time with no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS)."

Highlights from the data include:

o All patients responded clinically to treatment with MB-106 (n=9); 100% overall response rate for patients with follicular lymphoma ("FL") and Waldenstrom macroglobulinemia ("WM")
o 100% of patients with FL (n=5) had a complete response; 1 very good partial response and 2 partial responses were observed in WM patients (n=3); and the hairy cell leukemia variant ("HCL-v") patient experienced stable disease, with prolonged, ongoing independence from blood transfusions
o Complete responses observed in patients previously treated with CD19-targeted CAR T-cell therapy
o MB-106 has a tolerable safety profile in patients with indolent NHL, with no occurrence of CRS above grade 1, and no ICANS of any grade, despite not using prophylactic tocilizumab or dexamethasone
o Outpatient administration was allowed and found to be feasible
o MB-106 CAR T-cell expansion and persistence in patients was demonstrated

Efficacy (combined results for dose level 1 & 2)

Best Responses to Date1

Follicular Lymphoma
(n=5)

Waldenstrom
Macroglobulinemia
(n=3)

Overall response rate (ORR),2 n (%)

5 (100%)

3 (100%)

Complete response (CR), n (%)

5 (100%)

0

Very good partial response (VGPR),3 n (%)

N/A

1 (33%)

Partial response (PR), n (%)

0

2 (67%)

Minor response,3 n (%)

N/A

0

Stable disease (SD)

0

0

1. In WM patients, responses are evaluated using the 11th International Workshop on WM (IWWM) criteria (Treon, 2023). In lymphoma patients, PET-CT-based responses are evaluated using the Lugano Classification (Cheson, 2014).
2. ORR is the rate of PR or better in follicular lymphoma. ORR is the rate of minor response or better in WM.
3. VGPR and minor response are WM-specific response categories.
N/A = Not applicable

Safety

CRS and ICANS (combined results for dose level 1 & 2)

Grade 1

Grade 2

Grade 3

Grade 4

CRS, n (%)

5 (56%)

0

0

0

ICANS

0

0

0

0

● CRS = Cytokine release syndrome
● ICANS = Immune effector cell-associated neurotoxicity syndrome
● No related serious adverse events (SAEs) reported, apart from Grade 1 CRS.
● No prophylactic tocilizumab or dexamethasone was administered.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "Given the favorable data presented from the multicenter Mustang trial at ASH (Free ASH Whitepaper) and from the original single-institutional Fred Hutch trial, we anticipate finalizing a recommended Phase 2 dose level in early 2024 and moving ahead with the first ever registrational CAR-T trial focused on relapsed or refractory WM. As we plan for an End-of-Phase 1 meeting with the FDA in the first half of 2024 to solicit approval for the design of this trial, we are especially encouraged by the safety of the higher dose level of 1.0×107 CAR T-cells/kg which so far is indistinguishable from the safety of the lower dose level and which we have manufactured successfully for all 5 patients enrolled to date at the higher dose level. Following that meeting, we anticipate initiating a trial enrolling 58 patients across 20 sites in North America, with top-line data expected as early as mid-2026."

The data reported on nine patients from the indolent lymphoma arm of the multicenter clinical trial, including five patients with follicular lymphoma, three patients with Waldenstrom macroglobulinemia, and one patient with transfusion-dependent hairy cell leukemia variant. The patients had been treated with a median of 4 lines of prior therapy (range: 1-9), including 2 patients who had received prior CD19-directed CAR T-cell therapy and 1 patient who had received prior autologous stem cell transplant. The patients received one of two dose levels: dose level 1, 3.3×106 CAR T-cells/kg body weight, or dose level 2, 1.0×107 CAR T-cells/kg.

A link to the poster can be found on the Publications page of the Mustang Bio website here.

Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.

On December 11, 2023 During the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2023 held in Geneva, Switzerland, from December 6th to 8th, Qilu Pharmaceutical reported the latest results of the Phase I clinical trial for QLS31905 in patients with advanced solid tumors through a poster presentation (Poster No. 132P) (Press release, Qilu Pharmaceutical, DEC 11, 2023, View Source [SID1234638449]). The leading investigator of the study is Professor Lin Shen from the Peking University Cancer Hospital.

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QLS31905, developed by Qilu Pharmaceutical, is a bispecific T cell engager (BiTE) that targets Claudin18.2. The primary objective of this trial was to evaluate the safety, tolerability, and preliminary antitumor activity of QLS31905 in patients with advanced solid tumors.

Study Background and Design

Claudin18.2 is a highly specific cell surface molecule that is often abnormally expressed in primary gastric cancer as well as in other solid tumors such as pancreatic and esophageal cancers1,2. QLS31905 was designed to bind to Claudin18.2 on the surface of tumor cells and CD3 on the surface of T cells, leading to the sustained killing and lysis of tumor cells through the recruitment and activation of T cells near the tumor. This study enrolled patients with advanced solid tumors who had either failed standard treatments or for whom no standard treatment options were applicable or available. The trial consisted of two phases: dose escalation and dose expansion. In the dose-escalation phase, the accelerated titration and i3+3 designs were used. The dose levels of QLS31905 were incrementally increased, starting from 0.5 μg/kg once-weekly (QW), and escalated through 1.5 μg/kg QW, 5 μg/kg QW, 15 μg/kg QW, 45 μg/kg QW, 100 μg/kg QW, 200 μg/kg QW, 350 μg/kg QW, and up to 500 μg/kg biweekly (Q2W). The primary endpoints of this stage were the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), while secondary endpoints included safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity. The dose-expansion phase focused on the objective response rate (ORR) as its primary endpoint. Secondary endpoints in this stage were the disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

Study Results

As of July 17, 2023, a total of 52 patients had been enrolled in the clinical trial, including 31 patients with gastric cancer and 12 with pancreatic cancer. During the dose-escalation phase, 22 participants received QLS31905 at 0.5 μg/kg QW to 350 μg/kg QW. The administration of the 500 μg/kg Q2W dose level is currently ongoing. In the dose-expansion phase, 30 patients had been enrolled and received QLS31905 at dose levels of 200 μg/kg QW and 350 μg/kg Q2W.

In terms of safety, no DLTs occurred, and the MTD had not been determined yet. Among all the participants, 21 (40.4%) experienced grade 3 or higher treatment-related adverse events (TRAEs), 10 (19.2%) experienced serious TRAEs, and two (3.8%) experienced TRAEs leading to the discontinuation of the treatment. The most common TRAEs included fever, which was observed in 30 patients (57.7%), nausea in 26 (50.0%), and a decrease in white blood cell counts in 18 (34.6%). Notably, grade 3 or higher cytokine release syndrome was reported in two patients in the 350 μg/kg QW cohort.

Regarding efficacy, out of the 27 participants who were evaluable for efficacy, the ORR was 11.1%, and the DCR reached 63.0%. Three patients achieved partial response (PR) and exhibited moderate to high levels of Claudin18.2 expression, including two patients with pancreatic cancer and one with gallbladder cancer. Furthermore, among the 14 patients who experienced stable disease, 8 reported a reduction in the size of target lesions, and 7 showed moderate to high Claudin18.2 expression.

In summary, QLS31905 has demonstrated favorable safety, tolerability, and preliminary antitumor activity in patients with advanced solid tumors. The Phase II clinical trial are now in progress to further assess the efficacy and safety of QLS31905.

On December 11, 2023 Bristol Myers Squibb (NYSE: BMY) reported the results of two early studies evaluating combinations of potential first-in-class CELMoD agent golcadomide in non-Hodgkin lymphomas (Press release, Bristol-Myers Squibb, DEC 11, 2023, View Source [SID1234638465]). These data are being presented in separate posters (#4459, #4496, #1631) at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from December 9-12.

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"Golcadomide is a novel, oral CELMoD agent representing one of several compelling assets generated from our differentiated targeted protein degradation research platform," said Michael Pourdehnad, M.D., senior vice president, Head of Early Clinical Development, Hematology, Oncology and Cell Therapy Development, Bristol Myers Squibb. "In the studies being presented at ASH (Free ASH Whitepaper) 2023, golcadomide has shown potential warranting further evaluation in patients with first-line and previously treated large B-cell lymphomas. We are encouraged by the growing body of evidence for this purposefully designed lymphoma agent as we continue toward a registrational program."

CC-220-DLBCL-001

In the dose expansion phase of this Phase 1b study, patients were randomized 1:1 to golcadomide at one of two recommended Phase 2 dose levels (DL) (DL-1: 0.2 mg day 1-7, n=35; DL1: 0.4 mg day 1-7, n=37) plus R-CHOP-21 for a fixed duration of 6 cycles. A total of 65 (83.3%) patients completed 6 cycles of the combination with 13 discontinuing treatment.

There were 71 patients evaluable for efficacy, and results showed:

Overall response rate (ORR) at end of treatment rate was 84.5% in patients overall, with 87.9% of patients in the DL1 arm achieving a complete metabolic response (CMR) compared to 63.6% in the DL-1 arm.
Minimal residual disease negativity at the end of treatment was achieved in 93% (14/15) of patients treated with 0.4 mg of golcadomide plus R-CHOP compared to 70% (7/10) treated with 0.2 mg of golcadomide plus R-CHOP.
At both DL1 and DL-1, steady-state levels of golcadomide reduced Ikaros over 80%, to levels predicted to optimize tumor cell killing and to stimulate T and NK cells.
In the safety population (n=78), the majority of patients (98.7%) experienced at least one treatment-emergent adverse event (TEAE). Grade 3/4 TEAEs were primarily hematologic with neutropenia (89.7%), thrombocytopenia (42.3%) and anemia (32.1%) being the most common. Any grade febrile neutropenia was reported in 21.8% of patients. Median relative dose intensity of key R-CHOP components was maintained at >90%.

CC-99282-NHL-001

A separate poster detailed the efficacy and safety results from the dose expansion segment of a Phase 1/2 open-label study of two doses of golcadomide (0.2 mg, 0.4 mg) plus rituximab in relapsed/refractory patients with non-Hodgkin lymphoma. Patients were heavily pre-treated with a median number of 4 prior therapies (range 1-11), including 61% who had prior CAR T.

In patients evaluable for efficacy (n=26), the ORR was 42% (11/26) with 19% (5/26) achieving a complete response (CR). The median duration of response was 7.5 months (1.8-14.5). The ORR and CR rate was greater for patients in the 0.4 mg arm compared to the 0.2 arm (55% vs. 33% and 27% vs. 13%, respectively).

In the study, neutropenia was the most common TEAE of any grade, occurring in 50% of patients (22/44). Febrile neutropenia was observed in 2 patients, with 1 patient at each dose level. A total of 6 patients had serious adverse events with only pneumonia and pyrexia occurring in more than 1 patient (2 each). There were 4 deaths on treatment during the study with one considered related to the study treatment.

About Non-Hodgkin Lymphoma and Large B-Cell Lymphoma

Non-Hodgkin lymphoma (NHL) is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system.1 Diffuse large B-cell lymphoma (DLBCL) is a rapidly growing, aggressive disease and the most common form of non-Hodgkin lymphoma (NHL), accounting for one out of every three cases diagnosed.2 More than two-thirds of patients with DLBCL will not respond to or will relapse following second-line treatment. For patients who relapse or do not respond to initial therapies, conventional treatment options that provide durable remission are limited and median life expectancy is about six months, leaving a critical need for new therapies.

On December 11, 2023 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to naporafenib in combination with trametinib (MEKINIST) for the treatment of adult patients with unresectable or metastatic melanoma who have progressed on, or are intolerant to, an anti‑programmed death-1 (ligand 1) (PD‑(L)1)-based regimen, and whose tumors contain an NRAS mutation (NRASm) (Press release, Erasca, DEC 11, 2023, View Source [SID1234639350]). Naporafenib is an orally available, Phase 3-ready pan-RAF inhibitor with a potential first-in-class and best-in-class profile in NRASm melanoma and other RAS/MAPK pathway-altered solid tumors.

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FTD is designed to help drugs reach patients faster by facilitating the development and expediting the review of drugs with the potential to fill an unmet medical need by treating a serious or life-threatening condition. Programs that receive FTD benefit from early and frequent interactions with the FDA during the clinical development process and, if relevant criteria are met, the FDA may consider reviewing portions of a marketing application before the sponsor submits the complete application.

"The outcomes for patients with NRASm melanoma after frontline immunotherapy (IO) treatment are dismal with low response rates and short median progression free survival (mPFS). By contrast, as previously presented by Novartis at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 and as published in March 2023 by de Braud et al. in the Journal of Clinical Oncology, naporafenib in combination with trametinib has demonstrated strong and durable anti-tumor activity," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "We are now rapidly advancing clinical development of naporafenib in combination with trametinib in the post-IO setting in patients with NRASm melanoma with initiation of our pivotal Phase 3 SEACRAFT-2 trial expected in the first half of 2024. Receiving FTD further strengthens our ability to work closely with the FDA toward our goal of bringing this new therapy for difficult-to-treat melanoma to patients as soon as possible."

NRASm melanoma comprises 20-30% of all melanomas and is associated with a worse prognosis compared to other alterations. Effective treatment options are needed for patients following progression on frontline IO with anti-CTLA-4 and/or anti-PD-(L)1 antibodies. Currently, chemotherapy is the approved post-IO standard of care with a 7% objective response rate (ORR) and 1.5 months mPFS (historical Phase 3 data generated when the drug was administered in the front-line/second-line setting). While not approved in this indication in the United States, the MEK inhibitor binimetinib is used off label and demonstrated a 15% ORR and 2.8 months mPFS (historical Phase 3 data generated when the drug was administered in the front-line/second-line setting). There are currently no approved therapies that target NRAS mutations. Erasca recently reported that End of Phase 2 meetings with the FDA and European health authorities confirmed the SEACRAFT-2 Phase 3 trial design and provided clarity on the registrational pathway.

About SEACRAFT-2
SEACRAFT-2 is a randomized, pivotal Phase 3 trial that will evaluate the clinical efficacy of naporafenib in combination with trametinib (MEKINIST) compared to physician’s choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy) in the post-immunotherapy setting in patients with NRAS-mutated metastatic melanoma. Initiation of the SEACRAFT-2 trial is expected in H1 2024.

About Naporafenib
Naporafenib (formerly LXH254) is a potent and selective pan-RAF inhibitor, with a potential first-in-class and best-in-class profile. Naporafenib has been dosed in over 500 patients to date, whereby safety, tolerability, pharmacokinetics, and pharmacodynamics have been established in both monotherapy and select combinations. Clinical proof-of-concept (PoC) has been established for the combination with trametinib for patients with NRAS-mutant (NRASm) melanoma, which includes NRAS Q61X melanoma, and preliminary clinical PoC has been established for the combination with trametinib for patients with RAS Q61X in non-small cell lung cancer (NSCLC). Erasca plans to focus initially on advancing and securing regulatory approval for naporafenib plus trametinib in NRASm melanoma as part of the planned pivotal Phase 3 SEACRAFT-2 trial and in RAS Q61X tissue agnostic solid tumors as part of the Phase 1b SEACRAFT-1 trial, respectively. Erasca is also exploring additional combinations of naporafenib with other proprietary therapeutic agents in our pipeline. Naporafenib has received FDA Fast Track Designation for patients with advanced NRASm melanoma.

On December 11, 2023 Ferring Pharmaceuticals and Zürich-based microbiome translation company PharmaBiome reported a research & development collaboration to drive forward new microbiome-based biotherapeutics in the field of gastroenterology (Press release, Ferring, DEC 11, 2023, View Source [SID1234638417]).

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The deal provides Ferring with exclusive rights to develop, manufacture and commercialize next generation microbiome-based therapeutics within the field of gastroenterology arising out of the collaboration. The financial details of this deal are undisclosed.

"This agreement is the latest in Ferring’s long term mission to maximise the therapeutic potential of the gut microbiome for the benefit of patients. PharmaBiome’s unique technology enables identification and manufacturing of defined consortium live microbiome bio-therapeutics that could reverse microbiome dysbiosis linked to disease," said Carl Bilbo, Senior Vice President, Microbiome at Ferring Pharmaceuticals. "This collaboration is a successful example of our strategy to use external innovation to build our pipeline complementary to our in-house research; and we aim to do further collaborations to build a vibrant research community."

Tomas de Wouters, CEO, PharmaBiome said: "The trust of Ferring in our translational approach is an important validation of our work and a unique opportunity to accelerate the development of our rationally designed consortia with an experienced market leader in the microbiome therapeutic field. We are thrilled about the complementary expertise between our companies and look forward to a fruitful collaboration".

Based on two core technologies, PharmaBiome has developed a unique technology platform to select bacterial strains for the design of bacterial consortia as live biotherapeutic products with defined activities – the NicheMapTM and a co-cultivation approach that enables fast and scalable production. PharmaBiome’s programmes aim at a next generation of products that are independent of donor material and deliver exactly the consortium of bacterial strains with the desired activity and therapeutic effect ("defined consortia").

Ferring is the first company to successfully bring forward a first-in-class FDA approved live microbiome-based therapy to US patients. In addition, Ferring has the proven scale and ability to drive forward clinical trials and manufacture microbiome-based products in what is a pioneering field and has a long heritage within gastroenterology.