On December 12, 2022 Ichnos Sciences Inc., a global clinical-stage biotechnology company developing innovative multispecific immune cell engager antibodies in oncology, shared data during an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition supporting the advancement of its first-in-class TREATTM1 trispecific antibody, ISB 2001, to a first-in-human clinical trial. Both IND and CTN filings are planned during the first quarter of calendar year 2023 and preparations for a Phase 1 clinical trial in relapsed/refractory multiple myeloma (RRMM) are under way (Press release, Ichnos Sciences, DEC 12, 2022, View Source [SID1234625116]).

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During the oral session on Saturday, December 10, Mario Perro, PhD, Vice President of Oncology Research at Ichnos Sciences, showed the benefits of the design of ISB 2001, a BCMAxCD38xCD3 trispecific antibody based on Ichnos’ proprietary BEAT2 platform, which promotes strong avidity induction and enables efficient and potent killing of multiple myeloma (MM) cells. Dual targeting with ISB 2001 may overcome escape mechanisms associated with BCMA and CD38 therapeutic antibodies, including approved T cell engagers.

More specifically, the data presented show that the design of ISB 2001 results in higher tumor cell killing potency compared to other treatment options, including teclistamab, alnuctamab, and EM-801, in ex vivo cytotoxicity assays with smoldering MM, newly diagnosed MM, RRMM and plasma cell leukemia. Additionally, these data support the potential benefit of ISB 2001 for RRMM patients who may experience decreased effectiveness of other treatments due to target downregulation mechanisms or presence of high levels of inhibitory soluble factors.

"Tremendous need remains for innovative and effective treatments for patients with multiple myeloma, and while some treatments may initially be effective, developed resistance and relapse are unfortunately common over time," said Cyril Konto, M.D., President and Chief Executive Officer of Ichnos. "We are pleased to have the opportunity to present data at ASH (Free ASH Whitepaper) showcasing the potential for ISB 2001 to overcome mechanisms that lead to disease progression, and excited about advancing this asset to clinical trials in 2023. Beyond multiple myeloma, preclinical data presented for ISB 1442 provide a strong rationale in acute myeloid leukemia, and we plan to initiate a Phase 1 study for this indication in 2023."

Preclinical data on ISB 2001 presented at ASH (Free ASH Whitepaper) include:

Higher killing potency of tumor cell lines across varying expressions of both BCMA and CD38 compared to teclistamab, alnuctamab and EM-801;
Superior potency of ISB 2001 relative to teclistamab, with 100 percent complete responses resulting in tumor elimination in multiple myeloma in vivo models;
Superior cytotoxicity over teclistamab in ex vivo assays in patient bone marrow aspirates representing different stages of MM progression;
Increased potency in vitro when compared to the combination of daratumumab and teclistamab;
Reduced inhibition by soluble factors (sCD38, sBCMA, APRIL) when compared to teclistamab, alnuctamab and EM-801, ensuring tumor-killing potency is maintained; and
Half-life of more than 7 days in mice, suggesting acceptable dosing regimen in clinic.
In addition to the oral presentation on trispecific antibody ISB 2001 described above, Ichnos was selected for three poster presentations of data on other pipeline assets:

1. Initial Results of Dose Escalation of ISB 1342, a Novel CD3xCD38 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (link), presented by Sanjay Mohan, MD, on Sunday, December 11:

Showed that treatment with ISB 1342 was well tolerated at the evaluated Q1W dose levels up to cohort 109 (2µg/kg priming, 8µg/kg targeted dose), that observed CRS events were moderate and manageable with supportive care, and that no increased risk of infection has been observed
Dose escalation continues with participants enrolling in additional cohorts

2. Preclinical Evaluation of ISB 1442, a First-in-Class CD38 and CD47 Bispecific Antibody Innate Cell Modulator for the Treatment of AML and T-ALL (link), presented by Stefano Sammicheli, PhD, on Sunday, December 11:

Showed that ISB 1442 induces killing of acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL) cell lines in multiple in vitro assays, and has superior activity to daratumumab in AML and T-ALL cell lines expressing intermediate or low CD38 expression
Demonstrated more frequent killing of AML blasts and a trend of higher potency compared to monospecific anti-CD38 daratumumab or anti-CD47 (5F9)

3. A Phase 1/2, First-in-Human, Multicenter, Open-Label, Dose Escalation and Dose-Expansion Study of Single-Agent ISB 1442 in Patients with Relapsed/Refractory Multiple Myeloma (link), to be presented by Tony Jiang, MD PhD on the evening of Monday, December 12:

Provides an overview of the ongoing Phase 1/2 study (NCT05427812)

All four of Ichnos’ presentations and corresponding data will be available for review on the Ichnos website (link). More information about the three oncology assets highlighted at the meeting, and the rest of Ichnos’ pipeline can be found at this link.

On December 12, 2022 HTG Molecular presented its corporate presentation (Presentation, HTG Molecular Diagnostics, DEC 12, 2022, View Source [SID1234625114]).

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On December 12, 2022 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported results from an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on longer follow-up data from the IMerge Phase 2 clinical trial of imetelstat, the Company’s first-in-class telomerase inhibitor, in lower risk myelodysplastic syndromes (MDS) (Press release, Geron, DEC 12, 2022, View Source [SID1234625111]). The data in the presentation focused on the patients who achieved greater than one-year sustained continuous transfusion independence and included their baseline characteristics, clinical benefits and observed safety profile.

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"Achievement of one year or more uninterrupted transfusion independence represents significant clinical benefit given the high transfusion burden of the patients in the IMerge Phase 2 trial," said Faye Feller, M.D., Executive Vice President, Chief Medical Officer of Geron. "The durability of transfusion independence, which was correlated to decreases in mutated cells with variant alleles, provide strong evidence of disease modification with imetelstat treatment. If the data from the Phase 2 are confirmed by the top-line results from IMerge Phase 3, which we expect in early January 2023, imetelstat could transform the lower risk MDS treatment landscape."

Longer Follow-Up Data from IMerge Phase 2 Clinical Trial in Lower Risk MDS

IMerge Phase 2 is an open label, single arm study to assess the efficacy and safety of imetelstat in transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (lower risk MDS), who are relapsed or refractory to prior treatment with erythropoiesis stimulating agents (ESAs). The primary efficacy endpoint is 8-week transfusion independence (TI) rate, which is defined as the proportion of patients achieving red blood cell TI during any consecutive eight weeks since entry into the trial. Secondary endpoints include 24-week TI rate and duration of TI.

The oral presentation at ASH (Free ASH Whitepaper) described the 29% (11/38) of patients in IMerge Phase 2 who achieved ≥1 year sustained continuous TI with imetelstat. The median time on study for these patients was approximately 4.8 years with a median treatment duration of approximately 2.4 years. For these 11 patients, the median TI duration was approximately 1.8 years, which is the longest reported to date with imetelstat. In addition, these patients experienced increases in hemoglobin ≥3g/dL. Furthermore, these 11 patients represented 69% of the ≥8-week TI responders and 92% of the ≥24-week TI responders. As such, attainment of 24-week TI was indicative of the likelihood to achieve TI ≥1 year.

New efficacy data related to the 16% (6/38) of patients in IMerge Phase 2 who were relapsed/refractory to ESAs and had also been treated previously with luspatercept are as follows:

50% (3/6) of these patients achieved ≥8-week TI
67% (2/3) of those ≥8-week TI responders also achieved ≥24-week TI
100% (2/2) of those ≥24-week TI responders also achieved >1 year TI
Safety findings for the 11 patients were consistent with the overall patients in the target population, including resolution of each of Grade 3/4 thrombocytopenia and neutropenia to Grade 2 or lower within 4 weeks for >97% of patients in the >1 year TI population.

Mutation data were available for nine of the 11 patients, and 89% had a reduction in SF3B1 variant allele frequency (VAF) while 56% achieved greater than or equal to 50% VAF reduction. Reduction in VAF correlated with longer TI duration (median, >20 months) and shorter time to onset of TI (median, <10 weeks). These correlations, along with the clinical benefits of durable continuous TI and meaningful rises in hemoglobin, provide strong evidence of disease modification for imetelstat’s unique mechanism of action as a telomerase inhibitor.

Imetelstat Presentations in Myelofibrosis (MF) and Acute Myeloid Leukemia (AML)

Preclinical Data in AML

An oral presentation described results from non-clinical in vitro and in vivo experiments of imetelstat using AML cell lines and AML patient samples. The experiments found that imetelstat promotes the formation of polyunsaturated fatty acids-containing phospholipids which cause excessive levels of lipid peroxidation and oxidative stress in AML cells, potentially leading to programmed cell death. The mechanistic insights from this preclinical work could be leveraged to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat and may result in significant delay of relapse in AML.

Trials in Progress Posters in MF

MYF3001, or IMpactMF (NCT04576156), is a Phase 3, randomized (2:1), open label multicenter study of imetelstat compared with best available therapy (BAT) in approximately 320 adult patients with Intermediate-2 or High-Risk MF whose disease has relapsed after or is refractory to janus associated kinase inhibitor, or JAKi, treatment. The primary endpoint is overall survival and secondary endpoints include symptom and spleen response rates at Week 24, progression-free survival, clinical response assessments, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones. Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia and Asia. The study is actively enrolling.

MYF1001, or IMproveMF (NCT05371964), is a single arm, open label, two-part Phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat in combination with ruxolitinib as a frontline treatment in patients with Intermediate-1 or -2 or High-risk MF (frontline MF). In both parts, patients will receive ruxolitinib followed by imetelstat. Part 1 will enroll up to 20 frontline MF patients who, at the time of enrollment, have received an optimized dose of ruxolitinib, to which imetelstat treatment will be added at increasing dose levels based on safety and tolerability. The primary purpose of Part 1 is to identify a safe dose for treating frontline MF patients with a combination of imetelstat and ruxolitinib. If a safe dose is identified in Part 1, participants in Part 2 will be JAKi naïve and will receive treatment with ruxolitinib after screening and enrollment at a starting dose based on standard-of-care or local prescribing information. Treatment with single-agent ruxolitinib will continue for at least 12 weeks, including four consecutive weeks at a stable dose prior to the addition of imetelstat. Part 2 is designed to confirm the safety profile of imetelstat in combination with ruxolitinib and to evaluate for preliminary clinical activity of the combination. Part 1 is open for enrollment, with approximately three sites planned in North America.

The presentations or abstracts from the 2022 ASH (Free ASH Whitepaper) Annual Meeting are available at www.geron.com/r-d/publications.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from Phase 2 clinical trials provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis stimulating agent, and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment.

On December 12, 2022 Genmab A/S (Nasdaq: GMAB) reported that it will hold its 2022 R&D Update and ASH (Free ASH Whitepaper) Data Review Meeting today, December 12, 2022 at 8:00 PM Eastern Time (7:00 PM CST / 1:00 AM GMT on December 13) (Press release, Genmab, DEC 12, 2022, View Source [SID1234625110]). The event will take place live at the Four Seasons New Orleans in New Orleans, Louisiana, Plimsole Ballroom B. Those wishing to attend in person may register on site.

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The event can also be attended via webcast. To register for the webcast, click here. Webcast viewers may submit questions during the Q&A portion of the live webcast via the webcast player. An archive of the webcast will be available on Genmab’s website. The webcast will be conducted in English.

This meeting is not an official program of the ASH (Free ASH Whitepaper) Annual Meeting.

On December 12, 2022 Enterome, a clinical stage company developing first-in-class immunomodulatory drugs based on its gut bacterial Mimicry drug discovery platform, reported completion of patient enrollment in its Phase 2 clinical trial (ROSALIE) evaluating its lead OncoMimics candidate, EO2401, in combination with an immune checkpoint inhibitor (nivolumab) +/- an anti-VEGF therapy (bevacizumab) in patients with first progression/recurrence of glioblastoma, an aggressive form of brain cancer (Press release, Enterome, DEC 12, 2022, View Source [SID1234625109]).

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The Phase 2 trial (NCT04116658) is an open-label, multicenter study assessing the safety, tolerability, immunogenicity and preliminary efficacy of EO2401. A total of 100 patients have started treatment in the different study cohorts at 10 clinical sites in Europe and the US. Initial and highly promising immunological and clinical results were obtained in 2022 and presented at leading clinical oncology meetings during 2022.

Prof. David Reardon, MD, Clinical Director for Dana-Farber Cancer Institute, discussed the key takeaways from the ROSALIE study on The ASCO (Free ASCO Whitepaper) Post. The video can be viewed here.

OncoMimics immunotherapies are designed to activate pre-existing effector memory T cells that target bacterial (non self) peptides, which are strongly cross-reactive against selected Tumor-Associated Antigens (TAAs) expressed on tumoral cells, resulting in a rapid targeted cytotoxic response against cancer. EO2401 combines three OncoMimics peptides mimicking IL13Ra2, BIRC5 and FOXM1, TAAs present in aggressive cancers such as glioblastoma, combined with the helper peptide UCP2 (Universal Cancer Peptide 2).

"The completion of enrollment in ROSALIE moves us one step closer to establishing OncoMimics immunotherapies as potential breakthrough drugs for treating aggressive forms of cancer, resisting today’s most effective treatments, in broad patient populations," said Pierre Bélichard, co-founder and Chief Executive Officer of Enterome. "Thanks to the eagerness and dedication among global investigators, and an impressive effort from our team, we were able to enroll 100 patients within the projected timeframe. I consider it a remarkable achievement for the first immune-oncology study ever sponsored and conducted by Enterome. We extend our sincere thanks to the patients, caregivers, clinical investigators and staff who are participating in the ROSALIE trial, and we look forward to presenting further results in 2023."

Key highlights from the Phase 2 ROSALIE trial presented during 2022 were:

Data published to date confirm that EO2401 in combination with nivolumab +/- bevacizumab is well tolerated with a safety profile consistent with the safety profiles of nivolumab and bevacizumab, with the addition of local administration site reactions.

EO2401 in combination with nivolumab generated strong systemic immune responses through activation of specific effector memory CD8+ T cells, correlating with clinical efficacy.

As compared to the administration of EO2401 in combination with nivolumab without the addition of the anti-edema compound bevacizumab, the symptom-driven addition of low-dose, time-limited, bevacizumab (LDB) resulted in longer treatment durations (median treatment duration 3.2 months with LDB vs 1.4 months without LDB), and some improvement of efficacy (ORR 20% vs 8.7%, median PFS 3.6 months vs 1.6 months).
In a subsequent cohort, the addition of continuous standard bevacizumab (as labelled in the USA) to EO2401 in combination with nivolumab further improved median treatment duration (to 5.5 months), objective response rate (to 55%), and median PFS (to 5.5 months).

With a median follow-up of 15.4 months median survival for EO2401 in combination with nivolumab and bevacizumab has reached 14.5 months.

CD8+ T cells against at least one of the EO2401 peptides was detected in 26 out of 28 patients with some patients exhibiting up to 5% of circulating specific CD8+ T cells. Memory-specific CD8+ T cell responses were observed as early as two weeks after the first administration and maintenance of a strong and stable immune response could be detected for more than 10 months.

Clinical and immunological data from ROSALIE have been presented at five different scientific meetings in 2022: ASCO (Free ASCO Whitepaper), ESMO (Free ESMO Whitepaper), EANO, SITC (Free SITC Whitepaper) and SNO. Further updates on the trial were presented last week at the ESMO (Free ESMO Whitepaper) IO Annual Congress which took place in Geneva (Switzerland).