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).

On December 12, 2022 Loxo@Lilly, the oncology unit of Eli Lilly and Company (NYSE: LLY), reported updated clinical data from the pirtobrutinib global Phase 1/2 BRUIN trial in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Richter transformation (RT), and Waldenström macroglobulinemia (WM) (Press release, Eli Lilly, DEC 12, 2022, View Source [SID1234625108]). Pirtobrutinib is an investigational, highly selective, reversible (non-covalent) inhibitor of Bruton’s tyrosine kinase (BTK). These data are featured in oral and poster presentations at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"These data presented at ASH (Free ASH Whitepaper) build on previous results with significantly longer follow-up and continue to expand on the body of evidence supporting pirtobrutinib as a potential treatment option for patients previously treated with a covalent BTK inhibitor across a range of B-cell malignancies," said Susan O’Brien, M.D., UCI Health hematology oncologist, Chao Family Comprehensive Cancer Center and professor of hematology/oncology at University of California, Irvine. "For patients with CLL/SLL, MCL, and Waldenström macroglobulinemia who have received the standard of care regimens, including covalent BTK inhibitors, treatment options are extremely limited. For patients with Richter transformation, there are no standard treatment options. These results show that pirtobrutinib may potentially help to address multiple areas of growing unmet need."

"We continue to be very excited by the results of pirtobrutinib across B-cell malignancies," said David Hyman, M.D., chief medical officer, Loxo@Lilly. "These data from the BRUIN Phase 1/2 trial provide further evidence that pirtobrutinib’s reversible binding mechanism and pharmacology may allow for extended targeting of the BTK pathway following treatment with a covalent BTK inhibitor. We are appreciative of the investigators and patients involved in the BRUIN study who have contributed to a better understanding of the potential of this medicine."

Key Data at ASH (Free ASH Whitepaper)

The BRUIN Phase 1/2 clinical trial is evaluating pirtobrutinib monotherapy in patients previously treated for MCL, CLL/SLL, or other non-Hodgkin lymphomas (NHL). The efficacy data being presented at ASH (Free ASH Whitepaper) for MCL and CLL/SLL are based on independent review committee (IRC) assessment while the efficacy data for RT and WM are based on investigator response assessments. The safety cohort consisted of all patients with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy as of the data cutoff date.

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

The BRUIN trial includes one of the largest prospective cohorts of BTK inhibitor pre-treated CLL/SLL patients ever studied. As of the July 29, 2022 data cutoff date, 247 patients with CLL/SLL had received a prior BTK inhibitor and enrolled prior to November 5, 2021, to ensure adequate follow-up. Patients had received a median of three prior therapies (range 1-11). In this dataset, pirtobrutinib demonstrated an overall response rate (ORR) of 82% (95% CI: 76.8-86.7) and median progression-free survival (PFS) of 19.6 months (95% CI: 16.9-22.1). In patients treated with both a prior BTK and BCL2 inhibitor (n=100, median of five prior lines of therapy), the ORR was 79% (95% CI: 69.7-86.5), and median PFS was 16.8 months (95% CI: 13.2-18.7). Response rates were consistent across all subgroups analyzed regardless of mutation status, age, or previous therapies.

Mantle Cell Lymphoma (MCL)

As of the January 31, 2022 data cutoff date, the primary analysis set consisted of the first 90 patients enrolled with MCL who had received a prior BTK inhibitor. Patients had received a median of three prior lines of therapy (range 1-8). In this dataset, pirtobrutinib demonstrated an ORR of 58% (95% CI: 46.9-68.1), a median duration of response (DoR) of 21.6 months (95% CI: 7.5-NE) and a median PFS of 7.4 months (95% CI: 5.3-12.5). Response rates were consistent regardless of number of prior lines of therapy and classes of prior therapy received.

Richter Transformation (RT)

The BRUIN trial also includes one of the largest prospective RT populations ever studied. As of the July 29, 2022 data cutoff date, 75 patients with RT were response evaluable, with 68 patients having received prior treatment for RT. Among these patients, the median number of prior lines of CLL therapy was two (range 0-11) and the median number of prior lines of RT therapy was two (range 1-7). The ORR for the 75 response-evaluable patients was 52% (95% CI: 40.2-63.7), and for the 68 patients previously treated for RT, the ORR was 50% (95% CI: 37.6-62.4). Among all response evaluable patients, median overall survival (OS) was 13.1 months (95% CI: 7.8-NE) and DoR was 5.6 months (95% CI: 2.5-NE), regardless of prior RT therapy.

Waldenström Macroglobulinemia (WM)

As of the July 29, 2022 data cutoff date, 80 patients with WM were response evaluable, with 63 patients having received prior treatment with a BTK inhibitor. Among the 63 patients, the median number of prior therapies was three (range 1-11). The major response rate (MRR) was 67% (95% CI: 53.7-78.0), including 15 (23.8%) very good partial responses and 27 (42.9%) partial responses. In patients who previously received both chemoimmunotherapy and a covalent BTK inhibitor (n=50), the MRR was 68% (95% CI: 53.3-80.5). Median PFS was 19.4 months (95% CI: 15.1-22.1) in patients who received previous treatment with a covalent BTK inhibitor (n=62).

Safety of Pirtobrutinib from the BRUIN Study

In the safety cohort of all pirtobrutinib-treated patients (n=773), the most frequent treatment-emergent adverse events (TEAE) (≥15%), regardless of attribution, were fatigue (29%), diarrhea (24%), and contusion (19%). The most frequent Grade ≥3 TEAE was neutropenia (20%). Low rates of Grade ≥3 TEAEs of hypertension (9%), hemorrhage (11%), and atrial fibrillation/flutter (3%) were observed. Overall, discontinuations due to a treatment-related adverse event occurred in 3% (n=20) of all patients. The safety profile was generally consistent across the populations studied.

Safety and Tolerability in Covalent BTK Intolerant Patients

The safety and tolerability of pirtobrutinib monotherapy in patients with relapsed or refractory B-cell malignancies who were intolerant to a prior covalent BTK inhibitor (n=127) was evaluated. Atrial fibrillation was among the most common adverse events (AE) that led to the discontinuation of a prior covalent BTK inhibitor, and in these patients (n=30), this AE recurred with pirtobrutinib treatment in two patients. Most patients did not experience high-grade recurrence of the other common AEs that led to discontinuation of a prior covalent BTK inhibitor, with the exception of neutropenia (in the patients in whom neutropenia recurred, 67% were Grade ≥3). No patient who discontinued a prior BTK inhibitor due to an AE had to discontinue pirtobrutinib for the same AE.

Loxo@Lilly is studying pirtobrutinib in multiple Phase 3 studies. Details on the trials can be found at lillyloxooncologypipeline.com or by visiting clinicaltrials.gov.

About Pirtobrutinib (LOXO-305)
Pirtobrutinib is an investigational, highly selective, reversible (non-covalent) Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). Pirtobrutinib was developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib was found to be highly selective – 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies. Interested patients and physicians can contact the Loxo@Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Phase 1/2 Trial

The BRUIN Phase 1/2 clinical trial is the ongoing first-in-human, global, multi-center evaluation of pirtobrutinib in patients previously treated for mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or other non-Hodgkin lymphomas (NHL).

The trial includes a Phase 1 dose-escalation phase, a Phase 1b combination arm, and a Phase 2 dose-expansion phase. The primary endpoint of the Phase 1 study is maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). Secondary endpoints include safety, pharmacokinetics (PK), and preliminary efficacy measured by overall response rate (ORR) for monotherapy. The primary endpoint of the Phase 1b study is safety of the drug combinations. The secondary endpoints are PK and preliminary efficacy measured by ORR for the drug combinations. The primary endpoint for the Phase 2 study is ORR as determined by an independent review committee (IRC). Secondary endpoints include ORR as determined by investigator, best overall response (BOR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and PK.

On December 12, 2022 Eagle Pharmaceuticals, Inc. (Nasdaq: EGRX) ("Eagle" or the "Company") reported that it has reached a settlement agreement with Accord Healthcare, Inc. ("Accord"). Eagle had asserted its Orange Book-listed patents against Accord related to Accord’s new drug application ("NDA") referencing BENDEKA. The settlement agreement provides that Accord has the right to market its product beginning January 17, 2028, or earlier based on certain circumstances. The settlement agreement is confidential and subject to review by the U.S. Federal Trade Commission and the U.S. Department of Justice.

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The settlement with Accord follows Eagle’s previously announced settlement with Hospira, Inc. ("Hospira") regarding two Orange Book-listed patents, which granted Hospira the right to market its product beginning January 17, 2028, or earlier based on certain circumstances.

"We are pleased with the settlement. Eagle intends to continue to expand and vigorously enforce its intellectual property rights around BENDEKA and our bendamustine franchise," stated Scott Tarriff, President and Chief Executive Officer of Eagle.