On December 11, 2021 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported new results for higher dose level cohorts of its investigational REGN5458 (BCMAxCD3) bispecific antibody, which were presented in an oral session at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, GA (Press release, Regeneron, DEC 11, 2021, View Source [SID1234596810]). The new results from the Phase 1 portion of the Phase 1/2 trial in patients with relapsed/refractory multiple myeloma found a 51% overall response rate (ORR) across all dose groups, rising to 75% in patients who received higher doses of REGN5458 (200-800 mg).

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"Patients with multiple myeloma often face a long and challenging journey, with most becoming refractory to multiple lines of therapy over time," said Jeffrey Zonder, M.D., Professor of Oncology at the Karmanos Cancer Institute, MI, and a trial investigator. "Today’s REGN5458 data show promising response rates, particularly at the higher dose levels, in patients with a high disease burden and highly refractory disease who otherwise would have very limited options available."

REGN5458 is a bispecific antibody designed to bind to BCMA on multiple myeloma cells and the CD3 receptor on T-cells in order to bridge them together and activate T-cells to kill the cancer cells. It is currently being assessed in the potentially registrational Phase 2 portion of the trial, which is expected to complete recruitment in 2022.

In results presented at ASH (Free ASH Whitepaper) today, 73 patients were treated with REGN5458 doses ranging from 3-800 mg for up to 21 months at the time of data cutoff. Patients had received a median of 5 prior lines of therapy, with 38% (n=28) being penta-refractory and 90% (n=66) being refractory to the last line of therapy.

The ORR was 75% at the highest dose levels (200-800 mg, n=18/24), and 51% among all enrolled patients (n=37/73). Most responses occurred within the first month of treatment and deepened over time. Among responders across all dose groups:

86% (n=32/37) achieved a very good partial response (VGPR) or better.
43% (n=16/37) achieved a complete response (CR), with 40% of evaluable CR patients (n=4/10) being minimal residual disease (MRD) negative.
8 months from the time of response, there was a 90% probability of being event-free (95% CI: 73%, 97%), defined by the absence of disease progression or death. The estimated median duration of response had not yet been reached at the time of data cutoff.
Responses occurred rapidly, usually within the first month of treatment, and continue to deepen with longer treatment; the higher dose groups currently have substantially shorter follow up.
The safety profile was generally consistent across all dose levels. Cytokine release syndrome (CRS) was reported in 38% of patients (n=28), the majority of which were Grade 1 (n=25), with no cases >Grade 3. The other most common treatment-emergent adverse events (TEAEs) were fatigue (n=33), pyrexia (n=26), nausea (n=24) and anemia (n=23). The most common >Grade 3 TEAEs were anemia (n=17), neutropenia (n=16), lymphopenia (n=14), thrombocytopenia (n=10) and pneumonia (n=9). There were 5 deaths in the trial, all due to infection; none were considered related to the underlying disease by investigators.

"In multiple myeloma, the highest treatment response rates are typically seen earlier in the course of the disease, using multi-drug regimens. It is very encouraging that we observed a 75% response rate with higher doses of REGN5458 monotherapy in patients with more advanced disease," said L. Andres Sirulnik, M.D., Ph.D., Senior Vice President, Clinical Development, Hematology at Regeneron. "This adds to the growing body of encouraging data across our investigational CD3 bispecifics, supporting the continued development of this class across a diverse range of blood cancers."

REGN5458 is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

Investor Webcast Information
Regeneron will host a conference call and simultaneous webcast to share updates on the company’s hematology portfolio on Monday, December 13 at 4:30 PM ET. To access this call, dial (888) 660-6127 (U.S.) or (973) 890-8355 (International); conference ID 2668896. A link to the webcast may be accessed from the ‘Investors and Media’ page of Regeneron’s website at View Source A replay of the conference call and webcast will be archived on the company’s website for at least 30 days.

About the Dose-escalation Trial
The open-label Phase 1/2 dose-escalation trial is investigating REGN5458 (BCMAxCD3) in patients with relapsed/refractory multiple myeloma who had received at least three prior lines of therapy or were double refractory. All patients had received prior treatment with proteasome inhibitors, immunomodulatory drugs and CD38 antibody treatments.

The Phase 1 portion of the trial is primarily assessing safety, tolerability and dose-limiting toxicities of REGN5458, with efficacy as secondary endpoints. The Phase 2 portion will further assess REGN5458 anti-tumor activity and safety. If you are interested in learning more about this trial, please contact us ([email protected], +1 844 734 6643), or visit our clinical trial website.

About Multiple Myeloma
Multiple myeloma is the second most common blood cancer with approximately 30,192 and 168,765 new diagnoses in the U.S. and the world, respectively, in 2020. It is characterized by the proliferation of cancerous plasma cells (multiple myeloma cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Multiple myeloma is not curable despite treatment advances, and while current treatments are able to slow the progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies. In addition, patients are at increased risk of frequent infections, bone problems, reduced kidney function and anemia.

About Regeneron in Hematology
At Regeneron, we’re translating more than 3 decades of biology expertise with our proprietary VelociSuite technologies to develop potentially paradigm-changing medicines for patients with diverse blood cancers and rare blood disorders.

Our blood cancer research is focused on bispecific antibodies that are being assessed both as monotherapies and in combination with each other and emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop customized and potentially synergistic cancer treatments.

Our research and collaborations to develop potential treatments for rare blood disorders include explorations in antibody medicine, gene editing using CRISPR and gene-knockout technologies, as well as investigational RNA-approaches that are being investigated for their ability to deplete abnormal proteins or block disease-causing cellular signaling.

For more information, visit View Source

About Regeneron’s VelocImmune Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved or authorized fully human monoclonal antibodies currently available. This includes Dupixent (dupilumab), REGEN-COV (casirivimab and imdevimab), Libtayo (cemiplimab-rwlc), Praluent (alirocumab), Kevzara (sarilumab), Evkeeza (evinacumab-dgnb) and Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn).

On December 11, 2021 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biotechnology company employing its pioneering TALEN gene-editing platform to develop innovative therapeutics for the treatment of serious diseases, reorted that preliminary results from the BALLI-01 Phase 1 study of UCART22, its allogeneic CAR-T cell therapy candidate targeting CD22, in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), and preclinical data on TALGlobin01, its autologous cell therapy product candidate for homozygous SCD patients (HbSS) at the 63rd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Cellectis, DEC 11, 2021, View Source [SID1234596809]).

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"We are excited by the encouraging preliminary results obtained from patients administered UCART22 after fludarabine, cyclophosphamide and alemtuzumab (FCA) lymphodepletion in the BALLI-01 study. The addition of alemtuzumab to fludarabine and cyclophosphamide (FC) was demonstrated to be safe, improve host-lymphocyte suppression, and promote UCART22 expansion, which was associated with anti-leukemic activity," said Carrie Brownstein, MD, Chief Medical Officer. "We believe these initial data support our mission to develop UCART22 for patients with r/r B-ALL, who remain in dire need of additional treatment options, particularly those who have failed CD19 therapy."

BALLI-01 investigating UCART22 product candidate in R/R B-ALL

BALLI-01, a phase 1 open-label dose-escalation study, is designed to assess the safety, maximum tolerated dose (MTD), and preliminary anti-leukemia activity of UCART22 in patients with r/r B-ALL. Additional endpoints include characterization of the expansion, trafficking, and persistence of UCART22 cells.

The poster presentation includes preliminary data from patients who received UCART22 at dose level 2 (DL2) and intermediate dose level 2 (DL2i) after lymphodepletion with FCA. Alemtuzumab was added to FC to deepen and sustain host lymphocyte suppression and thereby promote UCART22 expansion and persistence.

As of the clinical cut-off date of October 1, 2021, 12 patients received lymphodepletion; 11 were administered UCART22, of which 6 received UCART22 and FCA. Enrolled patients were predominantly male [n=7], young (median age 30 [range 20-61]), and most had recurrent genetic abnormalities including the CRFL2 (cytokine receptor-like factor 2) rearrangement. Additionally, enrolled patients were heavily pretreated with a median of 3 prior lines of therapy [range 2-6]. Three-fourths of patients had received prior blinatumomab, approximately half had received prior inotuzumab, and 3 had received prior CD19 autologous CAR-T therapy.

Safety Data
The FCA lymphodepletion regimen was well tolerated, and most treatment-emergent adverse events (TEAEs) were mild to moderate in intensity and manageable. Importantly, no patients experienced protocol-defined dose limiting toxicities (DLTs), immune effector cell-associated neurotoxicity syndrome (ICANS), nor UCART22-related severe (grade ≥3) TEAEs. Three patients experienced mild to moderate cytokine release syndrome (CRS), and one patient reported grade II GvHD with skin involvement only, that required hospitalization.

Activity Data
Encouraging anti-leukemic activity was observed in two (2/6) patients in the FCA cohorts. Both patients, one at DL2 and one at DL2i, achieved blast reductions to < 5% (0.4% and 0%, respectively) by day 28, accompanied by measurable UCART22 expansion and changes in relevant inflammatory cytokines.

Overall, UCART22 after FCA lymphodepletion regimen demonstrated promising signs of anti-leukemic activity at DL2 and DL2i, without unexpected or significant treatment-related toxicity. The addition of alemtuzumab to the FC lymphodepletion regimen was safe and promoted sustained host T-cell suppression and expansion of UCART22. These data are encouraging and support the further development of UCART22 for patients with r/r B- ALL. BALLI-01 is currently enrolling patients at dose level 3 with FCA lymphodepletion.

TALGlobin01; an autologous ex vivo TALEN-edited hematopoietic stem and progenitor cell gene therapy for the treatment of Sickle Cell Disease

Initial pre-clinical data from Cellectis’ .HEAL platform’s product candidate, TALGlobin01 demonstrates that TALEN is specific and efficient in correcting the mutated beta-globin gene, the underlying cause of sickle cell disease.

The data, presented in a poster, demonstrate that TALEN-based engineering could be used to correct the beta-globin gene mutation in HbSS patient-derived hematopoietic stem and progenitor cells. The data show up to 70% of HBB allelic correction, with only 9% of HBB biallelic inactivation and a low level of TALEN off-target cleavage. Genetic correction of HBB translates into high level of hemoglobin A expression (up to 47% HbA detected among total hemoglobin) and reversion of the sickling phenotype in differentiated red blood cells. Preclinical data show the capacity of TALGlobin01 edited cells to engraft in vivo using an NSG mouse model.

Collectively, the preclinical data demonstrate high efficiency and safety of TALEN treatment in HbSS patient-derived hematopoietic stem and progenitor cells.

A copy of each poster presentation is available on Cellectis’ website, linked here.

About UCART22

UCART22 is an allogeneic T-cell product manufactured from healthy donor cells. T-cells are transduced using a lentiviral vector to express the anti-CD22 chimeric antigen receptor (CAR) and are genetically modified using TALEN gene-editing technology to disrupt the T-cell receptor alpha constant (TRAC) gene to minimize risk of graft-vs-host disease (GvHD) and the CD52 gene to eliminate sensitivity to anti-CD52–directed agents used in lymphodepletion regimens. UCART22 is being developed for the treatment of R/R B-cell ALL.

About TALGlobin01

TALGlobin01, is an autologous ex vivo TALEN-edited CD34+ HSC gene therapy for the treatment of SCD. TALGlobin01 is developed using both TALEN technology to induce a double strand DNA break in the SCD-causing hemoglobin subunit beta (HBB) gene and adeno-associated virus (AAV) particles containing a DNA repair template designed to correct the faulty HBB gene via endogenous homology directed repair.

On December 11, 2021 Ichnos Sciences Inc., a global biotechnology company developing innovative biologics in oncology, reported that preclinical data that support the potential for ISB 1442, a first-in-class 2+1 biparatopic bispecific antibody that targets both CD38 and CD47, as a treatment for relapsed/refractory multiple myeloma and other CD38+ hematological malignancies (Press release, Ichnos Sciences, DEC 11, 2021, View Source [SID1234596808]). The data were presented today by Stefano Sammicheli, Ph.D., Director of Innate Cell Engagers, during an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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ISB 1442 includes three arms in a 2+1 biparatopic BEAT 2.0 bispecific[1] format:

Two proprietary high-affinity anti-CD38 binding arms, each targeting different CD38 epitopes, neither of which competes functionally with daratumumab, drive the binding of this molecule to CD38 expressing tumor cells.
A third, lower affinity arm masks CD47 and disrupts binding to SIRPα on macrophages, blocking the "do not eat me signal."
Engineering of the fragment crystallizable (Fc) region enhances antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
Ichnos’ proprietary BEAT 2.0 platform is among the most innovative multispecific platforms: it mimics the natural full length antibody format, the BEAT interface enables high yield for heavy chain pairing, and light chains are assembled via common light chain Fab technique.
The data presented today demonstrate the potency and anti-tumor activity of ISB 1442 in multiple in vitro and in vivo tumor models relative to daratumumab and magrolimab. Specifically, the results show that:

ISB 1442 induces comparable blockade of CD47/SIRPα interactions to the clinical benchmark magrolimab, an antibody that targets CD47.
ISB 1442 enables a significant increase in phagocytosis in CD38 low tumor cells relative to that of daratumumab, an antibody that targets CD38.
ISB 1442 shows higher ADCC relative to daratumumab.
ISB 1442 improved tumor growth inhibition in an in vivo preclinical model compared to daratumumab.
"We are excited to present data on Ichnos’ first-in-class biparatopic CD38 x CD47 bispecific antibody at ASH (Free ASH Whitepaper)," said Mario Perro, Ph.D., Vice President Oncology, Interim Head of Discovery at Ichnos. "ISB 1442 has demonstrated high potency in multiple in vitro tumor models, including one that assessed multiple antibody-dependent mechanisms of actions simultaneously, and higher tumor growth inhibition in vivo. We believe that this asset has the potential to effectively treat patients with multiple myeloma who have relapsed or are refractory to daratumumab as well as other CD38 expressing hematological malignancies."

"Today’s presentation represents another step forward as Ichnos works to bring this novel multispecific approach that co-targets CD38 and CD47 to patients with hematologic malignancies," said Cyril Konto, M.D., President and Chief Executive Officer of Ichnos. "With its unique design and mechanisms of action, data suggest that ISB 1442 may enhance anti-tumor activity relative to approved anti-CD38 targeted therapies by overcoming primary and acquired tumor mechanisms of resistance. We look forward to submitting the IND to FDA in early 2022 and initiating our first-in-human clinical study in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia and T-cell acute lymphoblastic leukemia in the middle of 2022."

The video presentation is available to registered meeting attendees on the ASH (Free ASH Whitepaper) platform. Additional details are also included in the abstract.

Ichnos continues to advance its pipeline of agents based on the proprietary BEAT technology platform. Using this platform, Ichnos is exploring the full design space for treating cancer and engineering multispecific antibodies capable of simultaneously engaging tumor and immune cells.

On December 11, 2021 Incyte (Nasdaq:INCY) reported data from three ongoing Phase 2 studies evaluating parsaclisib, an investigational novel potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), for the treatment of patients with relapsed or refractory follicular lymphoma (FL) (CITADEL-203), marginal zone lymphoma (MZL) (CITADEL-204) and mantle cell lymphoma (MCL) (CITADEL-205) (Press release, Incyte, DEC 11, 2021, View Source [SID1234596807]). These data were accepted as oral presentations at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2021), held December 11–14, 2021 in Atlanta, Georgia and virtually.

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The primary endpoint for the CITADEL-203, -204 and -205 studies is objective response rate (ORR). Key secondary endpoints include complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and tolerability. All radiology-based endpoints are based on independent review committee (IRC) assessment.

Building on previous findings presented at ASH (Free ASH Whitepaper) 2020, these updated data from the primary analysis continue to show treatment with parsaclisib resulted in a rapid and durable response with an acceptable safety profile, and supported the New Drug Application (NDA) for parsaclisib, recently accepted by the U.S. Food and Drug Administration (FDA).

Key results from the CITADEL studies include:

ORR (95% CI), %

CRR (95% CI), months

mDOR (95% CI), months

mPFS (95% CI), months

mOS (95% CI), months

CITADEL-203: R/R Follicular Lymphoma

DG (N=103)

77.7 (68.4–85.3)

19.4 (12.3-28.4)

14.7 (10.4-NE)

15.8 (11.0-NE)

NR (NE-NE)

All (N=126)

75.4 (66.9-82.6)

18.3 (11.9-26.1)

14.7 (12.0-20.3)

14.0 (11.3-19.6)

NR (NE-NE)

CITADEL-204: R/R Marginal Zone Lymphoma

DG (N=72)

58.3 (46.1-69.8)

4.2 (0.9-11.7)

12.2 (8.1-17.5)

16.5 (11.5-20.6)

NR (NE-NE)

All (N=100)

58.0 (47.7-67.8)

6.0 (2.2-12.6)

12.2 (8.1-17.5)

16.5 (13.5-19.6)

NR (NE-NE)

CITADEL-205: R/R Mantle Cell Lymphoma (BTK Inhibitor Treatment Naive)

DG (N=77)

70.1 (58.6-80.0)

15.6 (8.3-25.6)

12.1 (9.0-NE)

13.6 (10.0-16.9)

NR (NE-NE)

All (N=108)

68.5 (58.9-77.1)

17.6 (10.9-26.1)

13.7 (9.0-19.9)

11.99 (8.3-16.9)

NR (NE-NE)

R/R: relapsed or refractory; ORR: objective response rate; CRR: complete response rate; mDOR: median duration of response (reported for responders); mPFS: median progression-free survival; mOS: median overall survival; DG: daily dosing group; NE: not estimable; NR: not reached.

Parsaclisib was generally well tolerated in all studies with a manageable safety profile.

"We are pleased to share these updated results from the CITADEL studies with the oncology community," said Peter Langmuir, M.D., Group Vice President, Oncology Targeted Therapies, Incyte. "The promising data add to the body of evidence that support parsaclisib, which has the potential to become a meaningful treatment for patients with relapsed or refractory follicular, marginal zone or mantle cell lymphomas, and we look forward to working with the FDA as we strive to bring this therapy to patients."

"Non-Hodgkin lymphoma is composed of varying subtypes and is one of the most common cancers in the United States. Given the fact that a significant subset of those afflicted will not be cured with current options, we need new treatment options," said Tycel Phillips, M.D., Primary Investigator, CITADEL-204 and Associate Professor, Division of Hematology and Oncology, Rogel Cancer Center, University of Michigan. "I am encouraged to see parsaclisib result in rapid and durable responses with a manageable safety profile in patients with a variety of non-Hodgkin lymphomas. The results observed across several key endpoints of the CITADEL studies suggest that parsaclisib may be a favorable treatment option for patients."

Presentations can be accessed via the ASH (Free ASH Whitepaper) website at View Source; #813 (Oral presentation, CITADEL-203), #44 (Oral presentation, CITADEL-204), #382 (Oral presentation, CITADEL-205).

About Follicular, Marginal Zone and Mantle Cell Lymphomas
Non-Hodgkin lymphoma (NHL) is a type of cancer that starts in the lymphocytes, a type of white blood cell. Follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL) are forms of B-Cell NHLs. FL and MZL are indolent or slow growing lymphomas; MCL is an aggressive or rapidly developing form. There is an unmet medical need for treatment options for patients who are relapsed or refractory to initial therapies.

About CITADEL
The CITADEL (Clinical Investigation of TArgeted PI3K-DELta Inhibition in Lymphomas) clinical trial program is evaluating parsaclisib in several ongoing studies as a treatment for adult patients with lymphomas, including:

CITADEL-203 (NCT03126019) is evaluating patients with relapsed or refractory follicular lymphoma (FL) Grade 1, 2 or 3a who received at least two prior systemic therapies, had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and were ineligible for hematopoietic stem cell transplantation (HSCT).
CITADEL-204 (NCT03144674) is evaluating patients with relapsed or refractory marginal zone lymphoma (MZL) who received at least one prior systemic therapy and were Bruton’s tyrosine kinase (BTK) inhibitor treatment naive. Patients with prior ibrutinib treatment were initially allowed to enroll; however, the cohort was terminated due to slow enrollment. Eligible patients had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an ECOG PS ≤2.
CITADEL-205 (NCT03235544) is evaluating patients with relapsed or refractory mantle cell lymphoma (MCL), who received one to three prior systemic therapies and were either naive to or were previously treated with a BTK inhibitor. Eligible patients had an ECOG PS ≤2, and radiologically measurable lymphadenopathy or extranodal lymphoid malignancy.
Patients eligible for each trial were allocated to receive parsaclisib 20 mg once daily for eight weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg once daily (daily-dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and the WG patients were allowed to switch to DG. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required.

About Parsaclisib
Parsaclisib is a potent, highly selective, next-generation investigational novel oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ). It is currently under evaluation as a monotherapy in several ongoing Phase 2 trials as a treatment for non-Hodgkin lymphomas (follicular, marginal zone and mantle cell); and autoimmune hemolytic anemia. Pivotal trials of parsaclisib in combination with ruxolitinib for the treatment of patients with myelofibrosis are underway; and there are plans to initiate trials to evaluate parsaclisib in combination with tafasitamab, including a pivotal trial in B-cell malignancies.

In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates, including parsaclisib. Under the terms of the agreement, Innovent has received the rights to develop and commercialize parsaclisib and two other assets in Mainland China, Hong Kong, Macau and Taiwan.

On December 11, 2021 Sanofi reported that Sarclisa (isatuximab) trial is first Phase 3 study to meet primary endpoint of minimal residual disease negativity in transplant-eligible patients with newly diagnosed multiple myeloma (Press release, Sanofi, DEC 11, 2021, View Source [SID1234596806])

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Sarclisa combination therapy is first to demonstrate superiority to standard of care lenalidomide, bortezomib and dexamethasone (RVd) in a Phase 3 trial
50.1% of patients achieved undetectable levels of disease after 18 weeks of induction treatment with Sarclisa-RVd
GMMG will share the results as an oral presentation, and as part of the press program, at ASH (Free ASH Whitepaper) 2021

December 11, 2021

The Phase 3 HD7 trial, conducted by the German-Speaking Myeloma Multicenter Group (GMMG), met the primary endpoint, the rate of minimal residual disease (MRD) negativity after induction therapy and before transplant in patients with newly diagnosed multiple myeloma (MM) treated with Sarclisa (isatuximab) in combination with lenalidomide, bortezomib and dexamethasone (RVd). This is the first Phase 3 trial to evaluate MRD negativity at the end of induction as a primary endpoint, and to demonstrate statistically significant improvement in rates of MRD negativity in this patient population by adding an anti-CD38 monoclonal antibody to RVd. MRD negativity is an important clinical endpoint associated with better patient outcomes, which is meaningful for MM where most patients relapse.1

"It is unprecedented for half of patients to achieve MRD negativity this early in treatment with this regimen," said Hartmut Goldschmidt, M.D., President of GMMG, Professor of Medicine at the Heidelberg University Hospital (UKHD), Germany and principal investigator of the study. "We know that achieving deeper responses earlier in treatment may translate to longer periods of progression free survival and are excited about these results."

After an induction phase of 18 weeks, the rate of MRD negativity for patients receiving Sarclisa combination therapy (n=331) was 50.1% versus 35.6% for those who received RVd (n=329) (odds ratio [OR]=1.83; 95% confidence interval [CI]: 1.34-2.51; p<0.001). The safety and tolerability of Sarclisa observed in this trial was consistent with the observed safety profile of Sarclisa in other clinical trials, with no new safety signals observed. Rates of all adverse events observed were 63.6% for the Sarclisa combination versus 61.3% for RVd and serious adverse effects and discontinuations were similar in both study arms (34.8% versus 36.3%, respectively). However, the number of deaths were higher in the RVd arm (1.2% versus 2.4%) during the induction period. The trial is ongoing, following the second randomization to evaluate progression free survival (PFS) for Sarclisa and lenalidomide combination as maintenance therapy.

"The results of this trial reinforce our belief in Sarclisa’s potential to become the anti-CD38 of choice," said Peter C. Adamson, Global Development Head, Oncology at Sanofi. "To observe such a high proportion of patients who have MRD negative disease following a relatively brief induction period is highly encouraging. We look forward to our continued collaborative efforts with GMMG to deliver a potential treatment option to transplant-eligible patients with newly diagnosed multiple myeloma."

MRD negativity is defined as the absence of myeloma cells in the bone marrow after treatment, as measured by diagnostic techniques that must have a sensitivity of at least 1 in 100,000 cells.2 This assessment is the most sensitive tool to measure the depth of response to treatment in patients with MM.3

This GMMG initiated clinical trial was conducted in close collaboration with Sanofi based on jointly defined research. Sanofi provided financial support to GMMG for this study.

The use of Sarclisa in combination with RVd is investigational and has not been evaluated by any regulatory authority.

About the trial

The pivotal, randomized, open-label, multicenter, Phase 3 GMMG-HD7 trial is a two-part study that enrolled 662 patients with newly diagnosed, transplant-eligible MM across 67 sites in Germany. In the first part of the study, all participants were equally randomized to receive three 42-day cycles of RVd in both arms of the trial, while Sarclisa was added to only one trial arm. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks of cycle one, then every other week for the rest of the induction period.

MRD negativity was assessed by next-generation flow cytometry (cut off 1×10-5) after induction. An odds ratio was used to measure this endpoint to determine the association between adding Sarclisa to standard of care and participants achieving MRD negativity.

The primary endpoints are MRD negativity after induction treatment for the first part of the study, and PFS following the second randomization after transplant for part two of the study, in which Sarclisa is added to lenalidomide maintenance. Secondary endpoints include rates of complete response after induction, overall survival after maintenance therapy and safety.

About Sarclisa

Sarclisa is a monoclonal antibody that targets a specific epitope on the CD38 receptor on MM cells. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.

Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase 3 IKEMA study, Sarclisa is also approved in combination with carfilzomib and dexamethasone in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).

Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies and solid tumors. The safety and efficacy of these additional uses have not been reviewed by any regulatory authority worldwide.

For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.

About multiple myeloma

MM is the second most common hematologic malignancy,4 with more than 130,000 new diagnoses of MM worldwide yearly.5 Despite available treatments, MM remains an incurable malignancy and is associated with significant patient burden. Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.

About the German-Speaking Myeloma Multicenter Group (GMMG)

GMMG is the largest study group focusing on MM in Germany, with headquarters based in Heidelberg. Within the last 20 years, the GMMG study group has performed numerous trials including five randomized, multicenter Phase 3 clinical trials with 4,000 patients enrolled from about 90 participating and co-treating centers throughout Germany. The overall goal of GMMG is to generate improved therapies for myeloma patients through the development and testing of novel and personalized, genome- and signaling-driven treatment strategies.