On June 13, 2024 IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company developing innovative gamma-delta T cell therapies, reported updated data from its Phase 1 trial of INB-100 at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress (Press release, In8bio, JUN 13, 2024, View Source [SID1234644311]).

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The data from INB-100 demonstrated that 100% of evaluable leukemia patients (n=10) remained alive, progression-free, and in durable CR through one year as of May 31, 2024. Historically, published data demonstrated that up to ~50% of patients with hematologic malignancies undergoing HSCT with reduced intensity conditioning (RIC) relapse by one year and often succumb to the disease shortly thereafter. Two of the patients treated with INB-100 remain alive and relapse free for over three and a half years, and a third patient is now nearing three years. Furthermore, INB-100 has demonstrated for the first time, the in vivo expansion and persistence of a haplo-matched allogeneic, or donor-derived, cellular therapy at 365 days, with blood levels of gamma-delta T cells surpassing levels previously associated with greater survival.

The complete responses to date, combined with a favorable safety and risk profile demonstrating no dose limiting toxicities (DLTs), no cytokine release syndrome (CRS), no neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) and a lack of serious infections is encouraging for the treatment of hematological malignancies. One patient died of idiopathic pulmonary fibrosis, a known toxicity of transplants, without evidence of progression. Additionally, two patients with TP53 mutations, including one patient with Ph-acute lymphocytic leukemia (ALL) treated with seven prior treatment regimens and a patient with MDS/MPN syndrome, relapsed but remain alive. Leukemic relapse is the leading cause of death in patients undergoing HSCT, making relapse prevention a critical unmet need.

The trial has been expanded to enroll an additional ten patients at Dose Level 2 (DL2), the recommended Phase 2 dose. Enrollment and treatment of patients into the expansion cohort is ongoing, with updated data expected in late 2024 and 2025. IN8bio expects to discuss plans for a potential registrational trial for this indication with the U.S. Food and Drug Administration (FDA) in a Type B meeting this summer.

"These data demonstrate the potential of allogeneic INB-100 gamma-delta T cells to provide durable relapse-free periods for patients with high-risk or relapsed AML and other hematologic malignancies undergoing HSCT," said Trishna Goswami, MD, Chief Medical Officer of IN8bio. "100% of evaluable patients remain in complete remission at one year of follow-up. In this trial, the first three patients were high-risk or relapsed AML patients with complex cytogenetics, including trisomy of chromosome 8 and deletion of chromosome 7. All three patients are alive and progression free with one lost-to-follow-up at 42.4 months after they relocated away from the study site and out of state. Achieving these outcomes despite giving patients a RIC regimen, which carries a higher risk of relapse, in an older population with a median age of 68 is very encouraging. We look forward to advancing our novel gamma-delta T cell therapy for patients who need additional options."

"The emerging safety, efficacy and durability profile of this novel gamma-delta T cell therapy supports its potential to improve relapse free survival for patients with blood cancers following allogeneic stem cell transplantation," said Dr. Joseph P. McGuirk, Schutte-Speas Professor of Hematology-Oncology, Division Director, Hematologic Malignancies and Cellular Therapeutics, and Medical Director, Blood and Marrow Transplant, at The University of Kansas Cancer Center. "Approximately 25% of patients relapse within the first 100 days, and nearly half by one year post stem cell transplant, which remains the primary cause of treatment failure and mortality. The results of this clinical trial are very encouraging and hold promise that a novel cellular therapy using donor-derived gamma-delta T cells may prevent relapse, resulting in improved relapse-free survival for patients with hematologic malignancies."

Conference Call Details
IN8bio will host a conference call and webcast today, Thursday, June 13, 2024, at 4:15 pm ET to review the updated clinical data from the EHA (Free EHA Whitepaper) presentation. The webcast can be accessed by clicking this link and can also be accessed on the Events & Presentations page of the Company’s website. To participate in the live call, please register using this link. It is recommended that participants register at least 15 minutes in advance of the call. Once registered, participants will be informed of the dial-in number and will be provided a unique PIN.

About the INB-100 Phase 1 Trial
The Phase 1 clinical trial (NCT03533816) is an investigator-sponsored dose-escalation trial of allogeneic derived, gamma-delta T cells from matched related donors that have been expanded and activated ex vivo and administered systemically to patients with leukemia following HSCT approximately 15 to 30 days post engraftment. The single-institution clinical trial is being conducted at The University of Kansas Cancer Center (KUCC). The primary endpoints of this trial include safety and tolerability, and secondary endpoints include rates of GvHD, relapse rate and overall survival.

On June 13, 2024 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies for the treatment of cancer and other serious diseases, reported it will regain exclusive worldwide rights to plamotamab, a CD20 x CD3 bispecific T-cell engager, which Xencor advanced through Phase 1 clinical development in hematologic cancers (Press release, Xencor, JUN 13, 2024, View Source [SID1234644310]). In 2021, Xencor entered a collaboration and license agreement with Janssen Biotech, Inc. to develop and commercialize plamotamab and novel B-cell targeting bispecific antibodies designed to conditionally activate T cells through the CD28 co-stimulatory receptor. Xencor completed enrollment in a Phase 1 study of plamotamab in late 2023.

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Xencor has been notified that Janssen will terminate its rights to plamotamab under the collaboration and license agreement. Janssen has retained its rights to develop and commercialize B-cell targeting CD28 bispecific antibodies, including JNJ-9401 (PSMA x CD28) and JNJ-1493 (CD20 x CD28).

"Plamotamab is a Phase 2 ready, subcutaneously administered immune-cell directed cytotoxic antibody, and we will review its potential for addressing unmet medical needs," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "Xencor’s CD28 platform remains the subject of two collaborations with Janssen. JNJ-9401 and JNJ-1493 are clinical-stage CD28-targeting bispecific antibodies that J&J is currently developing in prostate cancer and B-cell malignancies, respectively, and both entered clinical development during the fourth quarter of 2023."

Under Xencor’s two collaboration agreements with Janssen, Xencor and Janssen conducted joint research activities to discover XmAb bispecific antibodies against CD28 and select targets, with Janssen maintaining exclusive worldwide rights to develop and commercialize licensed products identified from the research activities. Janssen has advanced JNJ-9401and JNJ-1493 into Phase 1 clinical studies.1,2

Xencor is eligible to receive additional development, regulatory and sales-based milestone payments, and tiered royalties on approved products in the high-single to low-double digit percent range of net sales. Upon clinical proof-of-concept for each program, Xencor has the right to opt-in to fund 20% of development costs (JNJ-9401) or 15% of development costs (JNJ-1493 or other B-cell targeting bispecifics) and to perform up to 30% of detailing efforts in the United States. If Xencor exercises these rights, the Company would then be eligible to receive tiered royalties in the low-double digit to mid-teen percent range.

References

ClinicalTrials.gov Identifier NCT06095089. "A Study of JNJ-87189401 Plus JNJ-78278343 for Advanced Prostate Cancer."
ClinicalTrials.gov Identifier NCT06139406. "A Study of JNJ-87801493 in Combination With T-Cell Engagers in Participants With B-cell Non-Hodgkin Lymphoid (NHLs) Cancer."
About Plamotamab

Plamotamab is an investigational XmAb bispecific antibody that contains both a CD20 binding domain and a cytotoxic T-cell binding domain (CD3). Engagement of CD3 by plamotamab activates T cells for highly potent and targeted killing of CD20-expressing cells.

Data presented from a Phase 1 clinical study of plamotamab in patients with B-cell malignancies indicated intravenously administered plamotamab was generally well tolerated and demonstrated encouraging clinical activity.

On June 13, 2024 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing novel solutions that treat urothelial and specialty cancers, reported 82.3% (95% CI, 75.9%, 87.1%) 12-month duration of response (DOR) data by Kaplan-Meier estimate (n=108) from its Phase 3 ENVISION trial in patients who achieved complete response (CR) at three months after the first instillation of investigational drug UGN-102 (mitomycin) for intravesical solution (Press release, UroGen Pharma, JUN 13, 2024, View Source [SID1234644309]). The ENVISION trial previously met its primary endpoint by demonstrating that patients treated with UGN-102 had a 79.6% (95% CI, 73.9%, 84.5%) CR rate at three months following the first instillation of UGN-102.

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The ENVISION Phase 3 study is investigating UGN-102 in patients with low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC). In addition to the 12-month data, the DOR Kaplan Meier estimates at 15 (n=43) and 18 (n=9) months were both 80.9% (95%CI, 73.9%, 86.2%).

"UGN-102 has demonstrated a strong clinical profile across multiple trials, with these latest results of 79.6% three-month complete response rate and 82.3% DOR at 12 months reinforcing its potential to be the first FDA-approved non-surgical option for treatment of LG-IR-NMIBC," said Liz Barrett, President and Chief Executive Officer of UroGen. "We estimate 82,000 patients suffer from this highly recurrent disease in the U.S. each year and may benefit from an innovative approach to treating their disease."

The most common treatment-emergent adverse events (TEAEs) in the ENVISION trial were dysuria, hematuria, urinary tract infection, pollakiuria, fatigue, and urinary retention. TEAEs were typically mild-to-moderate in severity. The ENVISION trial demonstrated a similar safety profile to that observed in other studies of UGN-102.

"These DOR findings continue to support the development of UGN-102 as a non-surgical alternative to the current standard of care of repeated surgeries for LG-IR-NMIBC, which can impact patients’ physical health and quality of life," said Sandip Prasad, MD, M.Phil., Director of Genitourinary Surgical Oncology, Morristown Medical Center/Atlantic Health System, NJ. "These results from the ENVISION study make me very optimistic about the opportunity for UGN-102, if approved, to provide another option for patients living with this highly recurrent disease."

"While LG-IR-NMIBC’s highly recurrent nature often means patients must undergo numerous surgeries throughout their lifetime, I am excited about the potential for patients to better manage the ongoing burden of this disease," said Mark Schoenberg, M.D., Chief Medical Officer, UroGen. "UGN-102, if approved, could provide a minimally invasive option for LG-IR-NMIBC patients whose existing treatment options currently center around repetitive surgeries."

In January 2024, UroGen initiated the submission of a rolling New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for UGN-102 as a treatment for LG-IR-NMIBC. The latest DOR data are expected to support the UGN-102 NDA, which the Company plans to complete in the third quarter of 2024, with a potential FDA decision as early as the first quarter of 2025.

UGN-102 ENVISION DATA Virtual Event

The Company is hosting a data event featuring a panel discussion with leading bladder cancer experts today, Thursday, June 13, 2024, at 11:00 a.m. Eastern Time to discuss results from the Phase 3 ENVISION clinical trial.

Please register for the webinar under the Events & Presentations section of the Company’s Investor Relations site (View Source).

Following the live webcast, a replay will be available on the Company’s website (View Source).

About UGN-102

UGN-102 (mitomycin) for intravesical solution is an innovative drug formulation of mitomycin, currently in Phase 3 development for the treatment of LG-IR-NMIBC. Utilizing UroGen’s proprietary RTGel technology, a sustained release, hydrogel-based formulation, UGN-102 is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using a standard urinary catheter in an outpatient setting by a trained healthcare professional. UroGen anticipates completing its NDA submission for UGN-102 in the third quarter of 2024 with a potential FDA decision as early as the first quarter of 2025.

About Non-Muscle Invasive Bladder Cancer (NMIBC)

In the U.S. bladder cancer is the second most common urologic cancer in men. LG-IR- NMIBC represents approximately 22,000 newly diagnosed bladder cancer patients each year and an estimated 60,000 recurrences annually among patients diagnosed from previous years. Bladder cancer primarily affects older populations with the median age of diagnosis 73 years and an increased risk of comorbidities. Guideline recommendations for the management of NMIBC include TURBT as the standard of care. Up to 70 percent of NMIBC patients experience at least one recurrence and LG-IR-NMIBC patients are even more likely to recur and face repeated TURBT procedures.

About ENVISION

The Phase 3 ENVISION trial is a single-arm, multinational, multicenter study evaluating the efficacy and safety of UGN-102 (mitomycin) for intravesical solution as primary chemoablative therapy in patients with LG-IR-NMIBC. The Phase 3 ENVISION trial completed target enrollment with approximately 240 patients across 56 sites. Study participants received six once-weekly intravesical instillations of UGN-102. The primary endpoint evaluated the CR rate at the three-month assessment after the first instillation, and the key secondary endpoint evaluated durability over time in patients who achieved a CR at the three-month assessment. Based on discussions with the FDA, UroGen anticipates completing its NDA submission for UGN-102 in the third quarter of 2024. Learn more about the Phase 3 ENVISION trial at www.clinicaltrials.gov (NCT05243550).

On June 13, 2024 Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company committed to advancing new standards of care for the frontline treatment of hematologic malignancies, reported that it will host a webcast event with medical experts to discuss the unmet need in higher-risk myelodysplastic syndrome (HR-MDS) and the opportunity for tamibarotene to transform the care of newly diagnosed patients with RARA gene overexpression (Press release, Syros Pharmaceuticals, JUN 13, 2024, View Source [SID1234644308]). The event will take place on Tuesday, June 25, 2024, from 11:00 a.m. – 12:30 p.m. ET.

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Syros is currently evaluating tamibarotene in SELECT-MDS-1, a pivotal Phase 3 clinical trial in HR-MDS patients with RARA overexpression, and in SELECT-AML-1, a Phase 2 clinical trial in unfit acute myeloid leukemia (AML) patients with RARA overexpression. Syros expects to report pivotal complete response data from the SELECT-MDS-1 trial by the middle of the fourth quarter of 2024 and will report clinical activity and tolerability data from a prespecified analysis of over 40 patients from the SELECT-AML-1 trial in the third quarter of 2024.

The webcast event will feature presentations from Amy DeZern, M.D., M.H.S., Professor of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Amer Zeidan, M.B.B.S., M.H.S., Chief, Hematologic Malignancies, Yale Cancer Center and Smilow Cancer Hospital; Associate Professor of Medicine (Hematology), Yale School of Medicine and David Sallman, M.D., Myeloid Section Head and Associate Member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute. The speakers will provide a disease overview of HR-MDS, including current therapies and approach to patient management, evaluation of patient outcomes in HR-MDS trials, and the emerging treatment landscape and ongoing areas of unmet need. In addition, members of Syros’ leadership team will provide an overview of RARA overexpression and tamibarotene’s mechanism of action, review the design of the pivotal SELECT-MDS-1 Phase 3 trial, and discuss previously presented clinical data supporting the development of tamibarotene for HR-MDS and the potential commercial opportunity.

There will be an opportunity for Q&A during the presentation. Participants can register for the live webcast here. For participants joining via conference call, please dial (800) 549-8228 (domestic) or (646) 564-2877 (international) and refer to conference ID 68622. In addition, a live webcast of the presentation will be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available following the presentation.

On June 13, 2024 Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, reported the generation and in vitro characterization of two novel drug candidates, SON-1411 (IL18BPR-FHAB-IL12) and SON-1400 (IL18BPR-FHAB), each containing a modified version of recombinant human interleukin-18 (IL-18BPR). SON-1411 is a proprietary bifunctional fusion protein consisting of IL-18BPR combined with single-chain wild-type IL-12, linked to Sonnet’s Fully Human Albumin Binding (FHAB) platform, which will replace SON-1410 as a development target (Press release, Sonnet BioTherapeutics, JUN 13, 2024, View Source [SID1234644307]). SON-1400 is a monofunctional fusion protein comprising the same IL-18BPR domain linked to the FHAB. FHAB extends the half-life and biological activity of linked molecules by binding native albumin in the serum and targets the tumor microenvironment (TME) through high affinity binding to glycoprotein 60 (gp60) and the Secreted Protein Acidic and Rich in Cysteine (SPARC).

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IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells and T cells. Systemic administration of IL-18 has been shown to have anti-tumor activity in several animal models. Moreover, tumor-infiltrating lymphocytes (TILs) express more IL-18 receptors than other T cells. However, IL-18 clinical trials have shown that, although it is well tolerated, IL-18 has poor efficacy in the treatment of cancers, most likely due in large part to the high co-expression of IL-18 binding protein (IL-18BP) in the TME. In particular, IL-18BP serves as a "decoy receptor" that binds to IL-18 with higher affinity, compared with the IL-18Rc complex, thereby causing a negative feedback loop with IL-18 and inhibiting IL-18-mediated TIL activation. Thus, there exists a potential for the discovery of IL-18 variant compositions that could harness the therapeutic potential of IL-18 for the treatment of cancers.

Sonnet’s strategy for amino acid modifications to rIL-18 was based on a compilation of literature review, 3D X-ray crystallography structures, and computer modeling analysis. Subsequently, certain IL-18 variant sequences were synthesized, engineered into expression constructs and manufactured at small scale in either CHO cell culture or E. coli. Highly purified milligram quantities of SON-1411 or SON-1400 were analyzed in vitro for IL-18Rc or IL-18BP binding activities, respectively, using the HEK-Blue and Bright-Glo Luciferase IL-18Rc reporter assays. In vitro results for at least one variant of IL-18 showed equivalent binding to the IL-18 Rc, compared to the wild-type IL-18 reference molecule, concomitant with no or reduced binding to IL-18BP.

"The development of a modified IL-18 has been a challenging scientific achievement. IL-18 is a key cytokine that, when combined synergistically with IL-12, has the potential to be an important therapeutic asset for oncology and cell-based therapy. We believe that these novel molecules combined with our proprietary FHAB platform are expected to demonstrate tumor targeting and longer half-lives, which in turn are expected to allow a therapeutic window for commercialization of these important oncology candidates", said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer.

"The known MOA of IL-18 inhibition by IL-18BP is reviving the importance of clinical applications of IL-18. IL-18BP has been shown to be elevated in cancer patients, thus negating the clinical use of IL-18. Sonnet is excited about the development of a novel bifunctional cytokine molecule, IL18BPR-FHAB-IL12, which contains a unique IL18 domain that does not bind the inhibitor IL-18BP but still maintains full IL-18 and IL-12 bioactivity. The clinical application of this bifunctional fusion protein could potentially expand immunotherapy applications for cancer patients" commented John Cini, Ph.D., Sonnet Chief Scientific Officer.

About SON-1411

SON-1411 is a candidate immunotherapeutic recombinant drug that is closely related to and will replace SON-1410, which links an unmodified single-chain human IL18 and an unmodified IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. The only difference between SON-1410 and SON-1411 is that in the latter, the IL-18 domain has been modified via mutagenesis to retain wildtype binding to the IL-18 receptor (IL-18 Rc) while inhibiting or abolishing binding to the IL-18 binding protein (IL-18 BP). The A10m3 scFv was selected to bind both at normal pH, as well as at the acidic pH that is typically found in the TME. The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of IL-18 and IL-12, as well as a variety of potent immunomodulators that can be added using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as SPARC and gp60, several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1411 is designed to deliver IL-18BPR and IL-12 to local tumor tissue, turning ‘cold’ tumors ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells.