On December 11, 2021 Aleta Biotherapeutics, a privately held immuno-oncology company focused on transforming cellular therapeutics to allow a broad spectrum of cancer indications to be targeted, reported a summary of ALETA-001 preclinical results from a poster being presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held in Atlanta, Georgia and in a virtual platform on December 11-14, 2021 (Press release, Aleta Biotherapeutics, DEC 11, 2021, View Source [SID1234596854]).

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The presentation featured preclinical data that support the upcoming Phase 1/2 clinical trial of ALETA-001 being run in collaboration with Cancer Research UK. ALETA-001 is a multifunctional biologic for injection that contains an anti-CD20 llama VHH linked to an optimized CD19 protein and further linked to an anti-albumin llama VHH. Extensive preclinical in vitro modeling demonstrated that ALETA-001 specifically binds to CD20-positive/CD19 negative lymphoma cells with high affinity, thereby densely coating these cancer cells with the CD19 protein. In the presence of anti-CD19 CAR T cells, ALETA-001 mediated cytotoxicity against CD19 negative lymphoma cells at sub-nM concentrations. The administration of ALETA-001 and anti-CD19 CAR T cells in vivo eliminated systemic CD19 negative lymphoma that otherwise produced lethal disease at doses of ALETA-001 as low as 0.5mg/kg. Further, upon stopping dosing in the in vivo lymphoma model, 40% of ALETA-001-treated animals did not relapse through day 43, more than 2 weeks after the last dose, suggesting apparent cures. Additionally, excess ALETA-001 did not interfere with cytotoxicity. ALETA-001 is designed to be administered to patients who have received CAR19 T cell therapy and who fail to achieve a complete response at the time of their first clinical evaluation, or who relapse from a complete response thereafter. Clinical trial development is underway in collaboration with Cancer Research UK.

On December 11, 2021 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor program in B-cell lymphomas in a poster session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta, Georgia (Press release, Schrodinger, DEC 11, 2021, View Source [SID1234596853]). MALT1 is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia. Schrödinger has identified novel MALT1 inhibitors that demonstrate strong anti-tumor activity across multiple tumor models, including cell- and patient-derived xenograft models, and combination potential with other agents, including standards of care such as ibrutinib.

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"We are pleased that our data strongly underscore the therapeutic potential of our MALT1 inhibitors and present an opportunity to advance a potential best-in-class MALT1 inhibitor into the clinic," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery R&D at Schrödinger. "We are on track to submit the IND for our MALT1 development candidate to the FDA in the first half of 2022."

The data presented suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), with the possibility of expanding into other B-cell lymphomas such as mantle cell lymphoma (MCL). Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with Bruton’s tyrosine kinase (BTK) inhibitors to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas.

Additional Details About the Study

The presentation, "Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered using Schrodinger’s proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the ABC-DLBCL cell lines, such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL cell line-derived xenograft (CDX) models, the company’s representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. The representative MALT1 inhibitor, when tested in LY2298 patient-derived xenograft (PDX) models, demonstrates similar results. In addition, the representative MALT1 inhibitor was explored in a CDX model derived from a mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition as a single agent. Taken together, these data strongly underscore the therapeutic potential of Schrödinger’s MALT1 inhibitors and support further evaluation of a potential best-in-class MALT1 inhibitor in clinical trials.

On December 11, 2021 Orca Bio, a clinical-stage biotechnology company developing purified, high-precision cell therapies for the treatment of cancer, autoimmune diseases and genetic blood disorders, reported positive clinical data on its lead investigational cell therapy, Orca-T, were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Orca Bio, DEC 11, 2021, View Source [SID1234596852]). The data presented on 109 patients with at least 90 days of follow-up in combined data from the Phase 1b and Phase 2 trials showed significantly higher graft-versus-host disease-free, relapse-free survival (GRFS) rates compared to patients who received standard of care.

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"The lower rates of graft versus host disease and improved relapse-free survival suggest Orca-T has the potential to become a safer and more effective treatment option for patients living with serious blood cancers," said Ivan Dimov, Ph.D., cofounder and chief executive officer of Orca Bio. "We are further encouraged by the validation of our platform as we advance Orca-T into our pivotal Phase 3 trial, a significant step toward potential commercialization and, most importantly, to helping more patients in need."

Findings presented today in an oral presentation included pooled results from the single-center Phase 2 and multi-center Phase 1b trials from 109 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, myelofibrosis and other hematological malignancies. Median follow-up for these patients was 617 days (single-center) and 209 days (multi-center). For comparison purposes, a contemporary, propensity-matched cohort of 95 matched patients undergoing standard of care allogeneic hematopoietic stem cell transplant (alloHSCT) served as the standard of care cohort ("SOC cohort"). Results demonstrated that:

Patients who received Orca-T had a GRFS of 74%. When comparing this non-randomized data to the SOC cohort, the difference was significant (74% vs. 34%; p<0.0001).
Orca-T showed the potential for lower rates of moderate-to-severe chronic graft versus host disease (GvHD) at 1 year post-transplant (3% vs. 43%; p<0.0005).
Overall survival rates with Orca-T (90% vs. 78%; p<0.03) and rates of chronic-GvHD-free survival (87% vs. 45%; p<0.0001) were improved.
Orca-T was manufactured reliably and delivered with vein-to-vein times of 72 hours or less across the continental U.S.
In a poster presentation at ASH (Free ASH Whitepaper), Orca Bio also shared an analysis of treatment impact in patients with myelofibrosis. The analysis compared eight patients with myelofibrosis who were treated with Orca-T with six patients who underwent standard of care (SOC) alloHSCT. Regression of marrow fibrosis to myelofibrosis grade 0 or 1 was observed by Day 100 post-transplant in all eight Orca-T recipients, but was observed in only one of the six SOC patients. Additionally, Orca-T recipients had lower incidence of acute and chronic GvHD.

Along with the positive Phase 1b/2 results, Orca Bio announced that it has completed a successful end of Phase 2 meeting with the U.S. Food and Drug Administration and plans to commence a Phase 3 trial for Orca-T in early 2022.

The full presentation is available on www.orcabio.com.

About Orca-T
Orca-T is an investigational high-precision allogeneic cellular therapy consisting of infusions containing regulatory T-cells, conventional T-cells and CD34+ stem cells derived from peripheral blood from either related or unrelated matched donors. Orca-T has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration and is being studied to treat multiple hematologic malignancies.

On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that new analyses illustrating responses that first-line treatment with DARZALEX▼ (daratumumab)-based regimens may be able to achieve, including a potential survival benefit for daratumumab in combination with lenalidomide and dexamethasone (Rd).1,2 Updated data from the randomised Phase 2 GRIFFIN study in transplant-eligible patients and real-world evidence in transplant-ineligible patients were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596850]). Data from the GRIFFIN study will also be featured in the Highlights of ASH (Free ASH Whitepaper) programme.

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"Despite treatment advances, multiple myeloma remains a complex, currently incurable blood cancer. The latest clinical trial data and real-world evidence presented for daratumumab at ASH (Free ASH Whitepaper) shines a light on the potential of daratumumab-based combinations and sequencing approaches in the first-line, to tackle this complexity and improve patient outcomes," said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "At Janssen, we are committed to developing transformative treatment regimens that address individual patient needs and offer physicians options which they have not had before, as we work towards our longer-term goal of curing multiple myeloma."

Updated Phase 2 GRIFFIN data of investigational daratumumab quadruple regimen for newly diagnosed transplant-eligible patients1

Updated results from the GRIFFIN study, now with a median follow-up of 38.6 months, were presented in an oral session (Abstract #79). The data show improved outcomes with the addition of daratumumab to bortezomib (VELCADE), lenalidomide (Revlimid) and dexamethasone (VRd), followed by daratumumab plus lenalidomide (R) maintenance therapy, in transplant-eligible patients.1 Key findings included:

The rate of stringent complete response (sCR) favoured daratumumab-VRd compared to VRd alone (66 percent versus 47.4 percent; p=0.0096).1,3
Minimal residual disease (MRD) negativity rates at a threshold of 10-5 remained significantly higher in patients treated with daratumumab-VRd versus VRd alone (64.4 percent versus 30.1 percent; p<0.0001).1, 3
Whilst this study was not powered for progression-free survival (PFS), at 36 months, the PFS rate trended toward favouring daratumumab-VRd compared to VRd alone (88.9 percent versus 81.2 percent).1
At the median follow-up of 38.6 months, median progression-free survival (mPFS) had not been reached in either arm.1
No new safety concerns were observed with longer-term follow up.1
"These updated findings from the GRIFFIN study are promising when adding daratumumab to VRd in the treatment of newly diagnosed, transplant-eligible multiple myeloma," said Jacob Laubach†, M.D., M.P.P, Clinical Director of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and GRIFFIN study investigator.

Additional analyses of daratumumab-based regimens for the treatment of transplant-ineligible newly diagnosed multiple myeloma2

Research shows that 50 percent of transplant-ineligible patients will not receive a second line of therapy.2 An oral presentation at ASH (Free ASH Whitepaper) 2021 highlighted clinical sequencing scenarios in patients with newly diagnosed transplant-ineligible multiple myeloma, utilising data from the Phase 3 MAIA study, including attrition rates, and real-world evidence from the Flatiron Health electronic health record-derived de-identified database* (Abstract 118).2 Researchers explored survival outcomes based on clinical sequencing scenarios using daratumumab first in combination with Rd, compared to when bortezomib was administered first in combination with Rd.2 Results from this modelled analysis suggest a potential for a survival benefit when patients received daratumumab in first-line treatment versus saving it for later.2 Future research is required to generate clinical data to confirm these results.2

A second presentation of real-world evidence data provided additional insights on sequencing, based on results from a retrospective, observational cohort study evaluating patients from the Flatiron database who received first-line daratumumab-Rd (Abstract #1979).4 The analysis indicated that the real-world patient population was similar to that of the MAIA study population, with an early trend of PFS similar to that observed in the MAIA study.4

A post-hoc analysis of the Phase 3 MAIA study, focusing on patients with renal impairment, was highlighted in a poster presentation (Abstract #1646).5 Research shows that approximately 20 to 50 percent of patients with multiple myeloma have baseline renal impairment that can impact their choice of treatment and efficacy.5 The exploratory analyses presented at ASH (Free ASH Whitepaper) showed that PFS and overall survival (OS) benefits were observed in these patients who were treated with daratumumab-Rd compared to Rd alone, regardless of the lenalidomide starting dose.5 OS data from the MAIA study were recently published in The Lancet Oncology.

"The clinical data presented at ASH (Free ASH Whitepaper) support daratumumab as a foundational therapy for patients with newly diagnosed multiple myeloma in transplant-ineligible populations," said Imran Khan, M.D., Ph.D., U.S. Vice President, Medical Affairs, Hematology, Janssen Scientific Affairs, LLC. "Real-world evidence about efficacy, safety and adherence is becoming increasingly important for clinicians in optimising treatment approaches for patients with multiple myeloma. We will continue to advance research that can provide important insights about daratumumab as part of a standard of care regimen in the frontline setting."

#ENDS#

About the GRIFFIN Study1,6

The Phase 2 GRIFFIN (NCT02874742) study evaluated the investigational regimen of daratumumab in combination with VRd and enrolled and treated more than 200 adults aged 18–70 years with newly diagnosed multiple myeloma (NDMM) and who were eligible for high-dose therapy/autologous stem cell therapy (ASCT).6

In the safety run-in cohort, patients received 25 mg of lenalidomide orally on Days 1–14; 1.3 mg/m2 of bortezomib subcutaneously on Days 1, 4, 8 and 11; and 20 mg of dexamethasone on Days 1, 2, 8, 9, 15 and 16, every 21 days during the induction and consolidation phases (Cycles 1–6).1 Daratumumab 16 mg/kg IV was given on days 1, 8 and 15 of Cycles 1–4 and on day 1 of Cycles 5–6.1

During the maintenance phase (Cycles 7–32), patients received 10 mg daily of lenalidomide (15 mg beginning at Cycle 10 if tolerated) on days 1–21 every 28 days and daratumumab 16 mg/kg IV every 56 days; this was amended to every 28 days based upon emerging clinical pharmacokinetic data demonstrating improved target saturation with every four-week maintenance dosing.1 Maintenance therapy with lenalidomide may be continued beyond Cycle 32 in both arms, per local standard of care.1

In the subsequent randomised Phase 2 portion of the study, 207 patients were randomised and received treatment with VRd induction and consolidation, ASCT, and maintenance therapy with lenalidomide; or daratumumab and VRd, ASCT, and maintenance therapy with daratumumab and lenalidomide.1

About the MAIA Study7

The randomised, open-label, multicentre Phase 3 MAIA study (NCT02252172) included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and ASCT, aged 45–90 years (median age of 73).7 Patients were randomised to receive either daratumumab-Rd or Rd alone in 28-day cycles. In the daratumumab-Rd arm, patients received daratumumab 16 mg/kg IV weekly for Cycles 1–2, every two weeks for Cycles 3–6 and every four weeks for Cycle 7 and thereafter.7 Patients in both treatment arms received 25 mg of lenalidomide on Days 1–21 of each 28-day cycle, and dexamethasone at 40 mg once a week.7 Patients in both treatment arms continued until disease progression or unacceptable toxicity.7

Earlier results from the MAIA study supported the European Commission (EC) approval of daratumumab in combination with Rd, marking the first approval of a CD38 monoclonal antibody for patients with transplant-ineligible NDMM. These data were also published in The New England Journal of Medicine in 2019.

Modelling and Real-World Data Limitations

Modelling and real-world data have the potential to supplement randomised controlled trial data by providing additional information about how a medicine performs across all available Phase 2 and 3 clinical trials and in routine clinical practice. There are limitations, however, and these data cannot be used as stand-alone evidence to validate the efficacy or safety of a treatment.

*The Flatiron Health database is a longitudinal database comprising de-identified, patient-level structured and unstructured data curated via technology-enabled abstraction.

About daratumumab

Janssen is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. Daratumumab has been approved in eight indications for multiple myeloma, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.8

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 227,000 patients worldwide.9 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab subcutaneous (SC) formulation is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.10

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.8 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death.8 Daratumumab may also have an effect on normal cells.8 Data across eight Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in PFS and/or OS.11,12,13,14,15,16,17,18

For further information on daratumumab, please see the Summary of Product Characteristics at: View Source

About Multiple Myeloma

Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.19 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.20 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.20 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.21

On December 11, 2021 Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for cancer and other serious diseases, reported that clinical updates on omidubicel in two presentations on the first day of the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in Atlanta, Georgia and virtually December 11-14, 2021 (Press release, Gamida Cell, DEC 11, 2021, View Source [SID1234596849]).

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In an oral presentation titled "Hematopoietic Stem Cell Transplantation (HSCT) with Omidubicel is Associated with Robust Immune Reconstitution and Lower Rates of Severe Infection Compared to Standard Umbilical Cord Blood Transplantation," Gamida Cell shared data from an analysis of a subset of 37 patients from the Phase 3 randomized trial of omidubicel. The analysis was aimed at investigating the reduced infection rates observed in the study and showed that the omidubicel-treated patients had more rapid recovery of a wide variety of immune cells including CD4+ T cells, B cells, NK cells and dendritic cell subtypes. The robust recovery of the immune system provides rationale for fewer severe bacterial, fungal and viral infections in patients treated with omidubicel. Further analyses are ongoing to further characterize the immune recovery following omidubicel transplantation.

"These results demonstrating rapid and functional reconstitution of the immune cells – particularly the T cell recovery which is known to lag in cord blood transplants – provides mechanistic support for the lower rates of severe infection observed in the omidubicel-treated patients," said Paul Szabolcs, M.D., Division of Blood and Marrow Transplantation and Cellular Therapy, UPMC Children’s Hospital of Pittsburgh. "These data provide encouraging support for patients suffering from blood cancers who are particularly vulnerable to devastating infections following transplant."

An additional poster presentation unveiled today, "Allogeneic Stem Cell Transplantation with Omidubicel: Long-Term Follow-up from a Single Center," includes outcomes of 22 patients in the Phase 1 and 2 studies of omidubicel at Duke University over a 10-year period and shows long-term sustained bone marrow function and immune recovery. With a median follow-up of 2.3 years the estimated 10-year overall survival (OS) is 48.5% and disease-free survival (DFS) is 43.6%, with no major and or unexpected long-term complications. Durable hematopoiesis was observed at up to 10 years with one case of secondary graft failure and no secondary malignancies.

"Following our positive Phase 3 study results that showed enhanced hematopoietic recovery with omidubicel, it is extremely encouraging to see these additional data that demonstrate the durability of the graft, providing long-term recovery of the hematopoietic system," said Ronit Simantov, M.D., Chief Medical Officer of Gamida Cell. "The analyses presented at ASH (Free ASH Whitepaper) build on our understanding of the clinical benefits of omidubicel and provide compelling evidence of its potential to change the outlook for a patient population in dire need of enhanced treatment options."

Gamida Cell will present additional clinical updates at ASH (Free ASH Whitepaper) including two-year survival data for GDA-201, the company’s lead NAM-enabled NK cell therapy, and an analysis of hospital and healthcare resource use for patients treated with omidubicel compared to cord blood transplantation. Both poster presentations will be publicly available on Monday, Dec. 13.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant solution for patients with blood cancers. Omidubicel is the first bone marrow transplant graft to receive Breakthrough Therapy Designation from the U.S. FDA and has also received Orphan Drug Designation in the U.S. and EU. For more information about omidubicel, please visit View Source

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the FDA or any other health authority.