On December 9, 2019 Celularity, Inc. ("Celularity"), a clinical-stage cell therapeutics company focused on the development of innovative allogeneic cellular therapies derived from post partum human placentas, reported data introducing an extensive platform in genetically-modified NK- and T cell-based programs, and highlighting long-term safety and efficacy results from the Phase 1 study of PNK-007 in patients with multiple myeloma (MM) (Press release, Celularity, DEC 9, 2019, View Source [SID1234552141]). These data were announced at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, F.L.

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In pre-clinical studies, Celularity’s allogeneic, placental-derived CD19 CAR T cell-based product candidate demonstrated in vivo anti-tumor efficacy in a lymphoma tumor model. Additionally, the Company’s CD38 CAR NK cell-based product candidate showed in vitro and in vivo anti-tumor activity against CD38+ lymphoma and multiple myeloma cell lines without any on-target, off-tumor effect. Moreover, the Company’s allogeneic, placental CD34+ cell-derived NK product candidate overexpressing a CD16 variant demonstrated its versatile combination potential with monoclonal antibodies to elicit in vitro and in vivo enhanced antibody-dependent cell mediated cytotoxicity (ADCC) function against lymphoma cell lines.

Results from a Phase 1 clinical study evaluating PNK-007 in patients with multiple myeloma demonstrated a single infusion of PNK-007 was well tolerated after autologous stem cell transplant (ASCT) for up to one year. PNK-007 is a first-generation investigational allogeneic off-the-shelf NK cell therapy. No serious adverse events (AEs) were attributable to PNK‐007, and no dose-limiting toxicity, graft-verse-host disease (GvHD), cytokine release syndrome (CRS), graft failure or graft rejection was observed.

"We are excited about the pre-clinical and clinical findings presented at ASH (Free ASH Whitepaper) this year which adds to a growing body of evidence about the range and versatility of our allogeneic, off-the-shelf, placental-derived cell therapy platform, and its potential uses against a range of devastating cancers which today have limited treatment options," said Robert Hariri, M.D., Ph.D., Founder, Chairman and CEO at Celularity. "At Celularity we believe the next evolution in immunotherapy for cancer demands scalable, high quality and economical solutions which provide fully allogeneic, off-the-shelf products. The Celularity technology platform can provide that solution. We look forward to rapidly advancing multiple placental-derived NK- and T cell-based product candidates with potential as more tolerable, more accessible immunotherapies."

About PNK-007

PNK‐007 is the only allogeneic, off-the-shelf NK cell therapy being developed from placental hematopoietic stem cells as a potential treatment option for various hematologic cancers and solid tumors. NK cells are a unique class of immune cells, innately capable of targeting cancer cells and interacting with adaptive immunity. When derived from the placenta, these cells offer intrinsic safety and versatility, allowing potential use across a range of organs and tissues. PNK cells are currently being investigated as a treatment for acute myeloid leukemia (AML) and multiple myeloma (MM).

On December 9, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) and Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) reported additional analyses of results from the ECHELON-1 and ECHELON-2 frontline phase 3 trials of ADCETRIS (brentuximab vedotin) (Press release, Seattle Genetics, DEC 9, 2019, View Source [SID1234552140]). These analyses were presented at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 7-10, 2019 in Orlando, Fla. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma and expressed on the surface of several types of peripheral T-cell lymphomas (PTCL).

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The ECHELON-1 analysis highlighted a four-year update of the phase 3 clinical trial in a poster presentation. ECHELON-1 is evaluating ADCETRIS in combination with AVD (Adriamycin [doxorubicin], vinblastine and dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine) in patients with Stage III or IV frontline classical Hodgkin lymphoma.

The ECHELON-2 phase 3 clinical trial data were presented in an oral session at ASH (Free ASH Whitepaper) and focused on the outcomes of the subset of patients who underwent consolidative stem cell transplant. ECHELON-2 is evaluating ADCETRIS in combination with CHP (cyclophosphamide, doxorubicin, prednisone) compared to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in frontline CD30-expressing PTCL.

"For decades, the standard of care for the treatment of frontline Hodgkin lymphoma has been combination chemotherapy, called ABVD. Unfortunately, approximately 30 percent of patients with advanced stage Hodgkin lymphoma do not respond or relapse following treatment with this therapy," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "The four-year update from the ECHELON-1 trial continues to support the robust and durable frontline treatment benefit of ADCETRIS plus AVD, including in both Stage III and IV disease settings, compared to ABVD across subgroups, regardless of PET2 status. These data reinforce ADCETRIS plus AVD as a treatment option that should be offered to all newly diagnosed advanced stage patients with Hodgkin lymphoma."

"Updated data from the ECHELON-1 trial and further insights from ECHELON-2 build upon our continued understanding of the potential ADCETRIS offers patients with CD30-positive lymphomas," said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "We’re especially encouraged by the promising four-year follow-up ECHELON-1 results being presented at ASH (Free ASH Whitepaper), as approximately one in three patients with advanced Hodgkin lymphoma do not achieve long-term remission after standard frontline therapy."

Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma (cHL): 4-Year Update of the ECHELON-1 Study (Abstract #4026, poster presentation on Monday, December 9, 2019)

As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of ADCETRIS plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) compared to the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio (HR), 0.77; p=0.035). A four-year post-hoc exploratory analysis was conducted to examine PFS outcomes per investigator assessment in the intent-to-treat population of 1,334 patients, including results by PET2 status, age, stage and prognostic risk scores. Results include:

The four-year PFS rate for patients in the ADCETRIS plus AVD arm was 81.7 percent compared to 75.1 percent in the ABVD arm, a difference of 6.6 percent (HR, 0.69 [95% CI: 0.542, 0.881]). This represents a 31 percent reduction in the risk of progression or death. Median follow-up time was 48.4 months.
A PFS benefit at four-years for ADCETRIS plus AVD was observed for all patients independent of PET2 status, including in patients who are less than 60 years old.
PET2-negative result was 86.2 percent in the ADCETRIS plus AVD arm compared to 81.0 percent in the ABVD arm (HR, 0.69), a difference of 5.2 percent.
PET2-positive result was 62.1 percent in the ADCETRIS plus AVD arm compared to 47.7 percent in the ABVD arm (HR, 0.65), a difference of 14.4 percent.
Consistent improvement in PFS was observed among patients treated with ADCETRIS plus AVD compared with ABVD across the majority of pre-specified subgroups, including disease stage, age and prognostic score.
Notably, improvements compared to ABVD were observed in patients with Stage III (HR, 0.595; [95% CI: 0.386, 0.917]) and Stage IV (HR, 0.745; [95% CI: 0.555, 1.001]) disease.
As previously reported for the primary analysis, on the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent in the ABVD arm. The four-year update shows that among patients with peripheral neuropathy, 83 percent in the ADCETRIS plus AVD arm and 84 percent in the ABVD arm reported complete resolution or improvement at last follow-up.
More than 45 countries and regions have approved ADCETRIS in combination with AVD for the treatment of patients with previously untreated Stage III or IV Hodgkin lymphoma. The U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with AVD for the treatment of adult patients with previously untreated stage III or IV classical Hodgkin lymphoma in March 2018, based on the results of the ECHELON-1 phase 3 clinical trial in which the primary endpoint was modified PFS. In February 2019, the European Commission (EC) approved ADCETRIS for the treatment of adult patients with previously untreated CD30+ Stage IV Hodgkin lymphoma in combination with AVD.

An Exploratory Analysis of Brentuximab Vedotin plus CHP (A+CHP) in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant (Abstract #464, oral presentation on Sunday, December 8, 2019)

As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of ADCETRIS plus CHP resulting in a statistically significant improvement in PFS versus the control arm of CHOP per blinded independent central review (HR, 0.71; p=0.0110). In addition, the overall survival benefit in the ADCETRIS plus CHP arm was statistically significant compared to CHOP (HR, 0.66; p=0.0244). A post-hoc exploratory analysis evaluated the impact of consolidative stem cell transplant in the ECHELON-2 study for the patients who achieved CR treated with ADCETRIS plus CHP. In the ADCETRIS plus CHP arm, this included 38 patients in CR who received a stem cell transplant and 76 patients in CR who did not. Key findings of this analysis include:

The PFS estimate favored the use of stem cell transplant (HR, 0.38; [95% CI: 0.18, 0.82]). After a median follow-up time of 35.9 months, the three-year PFS rate for the 38 patients who received a stem cell transplant was 76.1 percent. After a median follow-up time of 41.6 months, the three-year PFS rate for the 76 patients who did not receive a stem cell transplant was 53.3 percent.
As previously reported, the safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,110 cases of Hodgkin lymphoma will be diagnosed in the United States during 2019 and 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About T-Cell Lymphomas

There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). PTCL accounts for approximately 10 percent of non-Hodgkin lymphoma cases in the U.S. and Europe and may be as high as 24 percent in parts of Asia.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three completed phase 3 trials: ECHELON-2 trial in frontline peripheral T-cell lymphomas, ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions in 2013 for patients with (1) HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and (2) sALCL after failure of at least one multi-agent chemotherapy regimen. Non-conditional approval was granted for (3) post-ASCT consolidation treatment of patients with HL at increased risk of relapse or progression in 2017, (4) adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy in 2018, (5) for previously untreated patients with Stage IV HL in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and (6) for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) for the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy and (5) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD (Adriamycin, vinblastine and dacarbazine).

ADCETRIS has received marketing authorization by regulatory authorities in 73 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 9, 2019 Lantheus Holdings, Inc. (the "Company") (NASDAQ: LNTH), parent company of Lantheus Medical Imaging, Inc. ("LMI"), a global leader in the development, manufacture and commercialization of innovative diagnostic imaging agents and products, reported it has entered into a strategic commercial supply agreement with CarThera for the use of Lantheus’ microbubbles in combination with SonoCloud, a proprietary implantable device in development for the treatment of recurrent glioblastoma (rGBM) (Press release, Lantheus Medical Imaging, DEC 9, 2019, View Source [SID1234552139]). Gliobastoma is a lethal and devastating form of brain cancer with median survival of 15 months after diagnosis1. The collaboration directly aligns with key Lantheus growth strategies of pursuing new applications for its microbubble franchise and expansion into oncology.

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Under the commercial supply agreement, Lantheus’ microbubbles will be used as a component in CarThera’s SonoCloud System, which uses low-intensity pulsed ultrasound (LIPU) specifically designed to open the blood-brain barrier to facilitate more effective delivery of chemotherapy to tumors. As part of the agreement, CarThera will be responsible for regulatory filings and approvals in the U.S., Europe and rest of world as well as commercialization of SonoCloud. Lantheus will supply its microbubble vials (the ultrasound resonator) and activation devices at a predetermined transfer price. Additionally, Lantheus will receive royalties on the SonoCloud kit product sales upon regulatory approval.

"We are excited to collaborate with CarThera to extend our microbubble franchise into the oncology field to target glioblastoma, an aggressive type of brain cancer with significant unmet medical need," said Mary Anne Heino, President and Chief Executive Officer of Lantheus. "Our collaboration leverages both companies’ strengths to bring novel solutions to the healthcare community. As the use of microbubbles in diagnostic and therapeutic applications gains more interest around the world, our collaboration with CarThera demonstrates our commitment to drive Lantheus’ microbubble into new disease areas with great potential for significant improvement in patient outcomes."

"We are delighted to enter into this collaboration with Lantheus for the development of our SonoCloud ultrasound-based medical device," said Frederic Sottilini, Chief Executive Officer of CarThera. "With Lantheus’ expertise in the field of microbubbles combined with CarThera’s novel and proprietary ultrasound technology, we see the potential for a long-term, highly successful collaboration. We are excited to work with Lantheus to advance our promising SonoCloud technology with the goal of improving treatment and prognosis of patients with glioblastoma, a debilitating, and all too often, fatal disease."

CarThera’s SonoCloud-9 System is currently being evaluated in a Phase IIa clinical trial with a Phase IIb/III pivotal clinical trial to follow. The objective of this trial to evaluate the safety and efficacy of repeated opening of the blood brain barrier using the SonoCloud-9, its next-generation implantable ultrasound device designed to cover the entire tumor and surrounding infiltrative areas. Twenty-one patients will undergo repeated blood brain barrier opening with the SonoCloud-9 prior to infusion of carboplatin at clinical sites in France (Paris, Lyon, Marseille, Angers) and the United-States (MD Anderson Cancer Center in Houston, Northwestern Memorial Hospital in Chicago).

About Glioblastoma

Roughly 12,000 people are diagnosed per year with glioblastoma in the U.S.4, and incidence is growing more than 1% per year5. Worldwide, annual incidence is as high as 5 in 100,000 people, and roughly 225,000 people die from the disease each year.6

The first line treatment for most glioblastoma patients is surgical resection of the tumor. After a healing period from surgery, patients will then typically undergo radiation and chemotherapy treatment cycles.2 The main goal of surgery is to remove as much GBM tumor as possible without impacting surrounding normal brain tissue that is critical for normal neurological function (such as motor skills, speaking and walking ability, etc.). However, GBMs are commonly surrounded by a reservoir of migrating, infiltrating tumor cells that invade surrounding tissue, making it virtually impossible to remove the cancer entirely. Surgery does help to reduce the amount of solid tumor tissue within the brain and thus can reduce intracranial pressure. The surgical debulking of tumor can prolong life and improve the quality of life for patients.2 The treatment of this region surrounding the tumor using chemotherapy is challenging due to the limited penetration of agents into the brain owing to the highly protective blood-brain barrier, a layer of specialized endothelial cells. Research has shown the blood-brain barrier can be accessed using ultrasound in combination with systemic injection of an ultrasonically resonated microbubble.

About the SonoCloud System

Earlier this year, CarThera published results from a Phase I/IIa clinical trial using SonoCloud-1 ultrasound implantable device to open the blood-brain barrier prior to carboplatin chemotherapy in patients with rGBM. Those results from 19 patients, published in the March 19, 2019 edition of journal Clinical Cancer Research, revealed a good safety profile and demonstrated the feasibility and promising potential of the SonoCloud approach. Notably, the 11 rGBM patients who received optimal pressure levels of ultrasound showed a median progression-free survival (PFS) of 4.11 months and a median overall survival (OS) of 12.94 months as compared to those patients who received a suboptimal dosage, in whom median PFS and OS were 2.73 months and 8.64 months, respectively.3

On December 9, 2019 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of updated interim clinical data from the ongoing Phase 1/2 CIRLL (Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma) clinical trial, in which cirmtuzumab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) (Press release, Oncternal Therapeutics, DEC 9, 2019, View Source [SID1234552138]). The results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando. A copy of the poster presentation is available online at www.oncternal.com.

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Thirty-four patients with CLL who had never been treated with a BTK inhibitor were enrolled in the dose-finding and dose-confirming cohorts of this clinical trial, including 12 treatment-naïve and 22 relapsed/refractory patients, and all 34 were evaluable for efficacy. As of the data cut-off in early November 2019,

Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR, bone marrow biopsy not performed but pending.
Five patients had stable disease.
The total clinical benefit rate was 100%.
None of the patients progressed or died, for a progression-free survival (PFS) of 100% with a median follow-up of 7.4 months.
Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on combination therapy.
The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib monotherapy was blunted with the cirmtuzumab plus ibrutinib combination, and leukemic cell counts returned toward baseline and normal levels rapidly.
Twelve patients with relapsed/refractory MCL, eight of whom were evaluable for efficacy, were enrolled in the dose-finding cohort of this trial. As of the data cut-off, five of the eight evaluable patients had achieved a clinical response, for an overall best objective response rate of 63% at a median follow-up of six months. Two patients with aggressive or bulky and heavily pre-treated MCL achieved CR, the longest of which is continuing with the patient on study for over 17 months. In addition, three patients had stable disease, for a total clinical benefit rate of 100%.

Cirmtuzumab as a single agent has been very well tolerated in this study. The combination of cirmtuzumab plus ibrutinib has also been well tolerated, with adverse events consistent with those reported for ibrutinib alone. There have been no dose limiting toxicities and no serious adverse events attributed to cirmtuzumab alone.

Genetic analysis of CLL cells from three patients showed pre-treatment transcriptome profiles associated with a stemness signature and NF-kB-driven inflammation. Both genetic signatures were reversed in these patients following cirmtuzumab treatment.

"It is exciting to see that cirmtuzumab in combination with ibrutinib continues to be well tolerated and has demonstrated 100% progression-free survival in patients with CLL, as well as encouraging early signals of efficacy in patients with MCL," said Michael Choi, M.D., Associate Clinical Professor of Medicine in the Division of Hematology-Oncology at University of California San Diego School of Medicine, who is the lead investigator for the CIRLL clinical trial.

The CIRLL clinical trial is supported by a grant from the California Institute for Regenerative Medicine (CIRM) and is being conducted in collaboration with the UC San Diego School of Medicine.

"We are encouraged by the evidence of clinical activity and the safety data demonstrated by cirmtuzumab in the ongoing CIRLL clinical trial. We continue to be excited about its potential for the treatment of patients with ROR1-expressing cancers, including CLL, MCL, Her2-negative breast cancer and other solid tumors," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

About the CIRLL Clinical Trial

The CIRLL clinical trial (CIRM-0001) is a Phase 1/2 trial evaluating cirmtuzumab in combination with ibrutinib in separate groups of patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). Part 1 of the clinical trial was a Phase 1 dose-finding cohort designed to determine the Phase 2 dose, or recommended dosing regimen (RDR). Part 2 is a Phase 1b expansion cohort to confirm the RDR. Part 3 of the study, which is now open for enrollment, is a Phase 2 study in which approximately 90 patients with CLL will be randomized to receive either ibrutinib alone or ibrutinib plus cirmtuzumab, with a primary endpoint of complete response rate. Additional information about the CIRM-0001 clinical trial and other clinical trials of cirmtuzumab may be accessed at ClinicalTrials.gov.

About Cirmtuzumab

Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of CLL and MCL, in a collaboration with the University of California San Diego School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, an investigator-initiated Phase 1 clinical trial of cirmtuzumab in combination with paclitaxel for women with metastatic breast cancer is being conducted at the UC San Diego School of Medicine. CIRM has also provided funding to support development programs for cirmtuzumab and a CAR-T therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors.

ROR1 is a potentially attractive target for cancer therapy because it is an oncofetal antigen – a protein that confers a survival and fitness advantage when reactivated and expressed by tumor cells. When expressed by hematologic malignancies such as CLL and MCL, ROR1 acts as a receptor for the tumor growth factor Wnt5a. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to inhibiting Wnt5a activation, specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. Cirmtuzumab is in clinical development and has not been approved by the U.S. Food and Drug Administration for any indication.

On December 9, 2019 Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of immune reset to more patients, reported that new results from its CD117-ADC patient preparation program were presented at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Magenta Therapeutics, DEC 9, 2019, View Source [SID1234552136]). These results, which were highlighted in an oral presentation at ASH (Free ASH Whitepaper) by John Tisdale, M.D., Director, Molecular and Clinical Hematology Section, National Institutes of Health, showed the first-ever successful transplant of gene-modified cells in non-human primates using a targeted, single-agent antibody-drug conjugate (ADC), without the use of chemotherapy or radiation.

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"Today’s conditioning regimens involve high doses of chemotherapy, often paired with radiation, to remove the disease-causing cells. As a result, patients undergoing gene therapy or stem cell transplant are all faced with a difficult choice: whether to endure severe toxicity and risk infertility and cancer for the chance for a cure. Magenta’s portfolio of targeted ADCs represents an extremely promising new option to prepare patients for gene therapy or transplant with no need for toxic chemotherapy or radiation," said Dr. Tisdale. "The results presented today show that a single dose of single agent CD117-ADC achieves the same level of depletion as four doses of busulfan chemotherapy to enable successful engraftment and persistence of stem cells modified with the β-globin gene, the gene that causes sickle cell disease and β-thalassemia when mutated. Importantly, the animals undergoing preparation with CD117-ADC showed none of the damaging toxicities associated with busulfan conditioning."

"Magenta is the only company with the people, platforms and a product engine committed to comprehensively transforming immune and blood system reset, which includes revolutionizing the toxic methods that are used to prepare patients for gene therapy and transplant today." said Jason Gardner, D.Phil., Chief Executive Officer and President, Magenta Therapeutics. "The gene therapy field has learned that higher levels of stem cell depletion, which meant higher doses of busulfan, were needed to ensure long-term engraftment of the gene-modified cells and persistence of gene therapy. Across all the modalities we have tested, we have seen that ADCs are most effective at achieving these high levels of stem cell depletion without chemotherapy to enable engraftment and long-term durability of the transplant. Today’s impressive results provide important validation of the ADC approach as well as the CD117 target for patient preparation and underscore Magenta’s leadership in the field of conditioning."

Results from the CD117-ADC Patient Preparation Program

Title: A Single Dose of CD117 Antibody Drug Conjugate Enables Autologous Gene-Modified Hematopoietic Stem Cell Transplant (Gene Therapy) in Nonhuman Primates (Abstract #610)
Presenter: John Tisdale, M.D., Director, Molecular and Clinical Hematology Section, National Institutes of Health, Bethesda, Md.

Magenta’s most advanced patient preparation program, CD117-ADC, targets CD117, a protein expressed on hematopoietic stem cells. CD117-ADC is designed to remove the genetically mutated cells in the bone marrow that cause certain genetic diseases, such as sickle cell disease, enabling curative stem cell transplant or gene therapy.

Results presented by Dr. Tisdale showed:

A single dose of a tool CD117-ADC fully depleted human hematopoietic stem cells in humanized mouse models.
A single dose of CD117-ADC selectively depleted hematopoietic stem cells in non-human primates, while sparing immune cells, which are important for recovery following transplant.
CD117-ADC was engineered to have a fast half-life to clear the body quickly and enabled transplant of the gene-modified cells within days of dosing in non-human primates.
A single dose of CD117-ADC in non-human primates enabled successful transplant and engraftment of hematopoietic stem cells modified with a lentiviral vector encoding the β-globin gene, the gene that causes sickle cell disease and β-thalassemia.
Vector copy number was stable beyond three months, the longest time point in the study, suggesting that the gene-modified cells persisted in the body. This was comparable to historical data with multiple doses of busulfan conditioning.
CD117-ADC was well tolerated in non-human primates with no evidence of the often severe side effects seen with busulfan conditioning, including veno-occlusive disease, weight loss, diarrhea, mucositis, vomiting, pulmonary fibrosis or seizures.
No ADC-related blood chemistry changes outside normal range were observed.
These proof-of-concept studies validate the use of CD117-ADC for targeted stem cell depletion prior to transplant and support its use as a new conditioning agent for gene therapy and stem cell transplant without toxic chemotherapy or radiation.