On December 5, 2020 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported updated data for REGN5458, a BCMAxCD3 bispecific antibody, from the Phase 1 portion of a Phase 1/2 trial in patients with relapsed or refractory (R/R) multiple myeloma. The results were shared in an oral presentation at the virtual 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. BCMA (B-cell maturation antigen) is a protein that is typically over-expressed on multiple myeloma cells. REGN5458 is 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.

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"REGN5458 continues to show early, deep and durable anti-tumor responses in patients with relapsed and refractory multiple myeloma across all dose levels. This is particularly encouraging given that a majority of patients were heavily pretreated and had few options remaining. All patients were triple-refractory, with 57% being penta-refractory," said Deepu Madduri, M.D., Assistant Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York and a trial investigator. "As these data continue to mature, we look forward to assessing whether responses will further deepen and remain durable with ongoing REGN5458 treatment."

In the trial, the 49 patients evaluated had a median of five prior lines of therapy (range: 2-17) with 100% being triple-refractory and 57% being penta-refractory; all patients were refractory to anti-CD38 therapy. With a median follow up of 2.6 months (range: 1-13), responses generally occurred by week 4 and deepened over time. Exploratory analyses suggest that patient-reported global health status/quality of life (per EORTC QLQ-C30) also improved meaningfully at week 4 and was maintained through week 24, with assessment ongoing.

*As of data cut-off, dose level 6 patients had been followed for a median of 2 months, and responses may deepen over time.

Among all patients who responded to treatment (n=19) as of data cut-off:

95% (n=18) achieved a VGPR or better
42% (n=8) had a CR or sCR
57% of evaluable patients (4 of 7 patients) were minimal residual disease (MRD) negative
Tumor response was not correlated with BCMA expression as assessed by immunohistochemistry
In assessing durability among patients who responded to treatment and with data continuing to mature at the time of analysis:

Among responding patients with ≥6 months of follow-up, 83% (10 of 12 patients) have ongoing responses for up to 13 months at the time of analysis
74% of responders (n=14) remain on treatment
The observed median duration of response was 6 months (range: 1-13)
The most common adverse events (AEs) were cytokine release syndrome (CRS; 39%; n=19), anemia (37%; n=18), fatigue (35%; n=17), nausea (31%; n=15), pyrexia (31%; n=15) and back pain (27%; n=13). Grade ≥3 AEs occurred in 69% (n=34) of patients with the most common being anemia (22%; n=11), neutropenia (14%; n=7) and lymphopenia (12%; n=6). There were no reports of Grade ≥3 CRS or neurotoxicity. Dose-limiting toxicity was reported in 2 patients with 1 patient experiencing acute kidney injury and 1 patient experiencing elevated alanine aminotransferase (ALT)/raised aspartate aminotransferase (AST). Both cases were resolved with supportive care, and the patient that experienced elevated ALT/AST remains on REGN5458 and has since achieved a VGPR.

"REGN5458 is the second CD3 bispecific in our oncology portfolio to show clinically meaningful results. Alongside our CD20xCD3 bispecific odronextamab, REGN5458 offers additional evidence to support the potential of our bispecific platform to transform the treatment of diverse blood cancers for patients," said L. Andres Sirulnik, M.D., Ph.D., Senior Vice President, Translational & Clinical Sciences, Hematology at Regeneron. "Regeneron continues to drive increasing momentum across our oncology and non-oncology hematology programs. We are currently enrolling patients in a potentially registrational Phase 2 portion of this REGN5458 trial. We are also expanding our odronextamab program with multiple pivotal trials in 2021."

In addition to the REGN5458 data, updated results from the Phase 1 odronextamab trial in R/R follicular lymphoma, diffuse large B-cell lymphoma and other B-cell non-Hodgkin lymphomas will also be shared in an oral presentation (Abstract 400) at ASH (Free ASH Whitepaper) and will include patient follow-up data of up to 3 years.

REGN5458 and odronextamab were invented using Regeneron’s proprietary VelocImmune technology and created using the company’s Veloci-Bi platform. These allow for the creation of bispecific antibodies that closely resemble natural human antibodies with no linkers or artificial sequences. Additionally, Regeneron bispecifics are manufactured using similar approaches used for human monoclonal antibody medicines, yielding similar properties and pharmacokinetics.

REGN5458 and odronextamab are currently under clinical development, and their safety and efficacy have not been evaluated by any regulatory authority.

About the Phase 1/2 Dose-escalation Trial
REGN5458 monotherapy is being investigated in an open-label, Phase 1/2 dose-escalation trial in patients with R/R multiple myeloma who are at least triple refractory to existing therapeutic options, including 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 is currently enrolling patients and will further assess REGN5458 anti-tumor activity and safety.

Among the patients being enrolled are those with heavily pre-treated, triple refractory and penta-exposed multiple myeloma, including those with extra-medullary (outside of the bone marrow) and non-secretory (do not secrete detectable myeloma proteins) disease.

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. While current treatments are able to slow progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies.

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On December 4, 2020 Magenta Therapeutics (NASDAQ: MGTA) and bluebird bio, Inc. (NASDAQ: BLUE) reported an exclusive clinical trial collaboration to evaluate the utility of MGTA-145, in combination with plerixafor, for mobilization and collection of stem cells in adults and adolescents with sickle cell disease (SCD) (Press release, Magenta Therapeutics, DEC 4, 2020, View Source [SID1234639033]). The data from this clinical trial could provide proof-of-concept for MGTA-145, in combination with plerixafor, as the preferred mobilization regimen for patients with SCD. bluebird bio’s experience with plerixafor as a mobilization agent in sickle cell disease aligns with Magenta’s combination therapy approach, utilizing MGTA-145 plus plerixafor with potential to achieve safe, rapid and reliable mobilization of sufficient quantities of high-quality stem cells to improve outcomes associated with stem cell transplantation. Under the collaboration, the stem cells will be fully characterized, and Magenta will undertake preclinical studies to evaluate the ability of these cells to be gene corrected and engrafted in mouse models. The companies will co-fund the clinical trial and Magenta will retain all rights to its product candidate.

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This press release features multimedia. View the full release here: View Source

"We are excited to build upon our leading position in the field of ex-vivo gene therapy and the promising clinical data with LentiGlobin in SCD with a collaboration focused on achieving improved stem cell mobilization," said Dave Davidson, M.D., chief medical officer, bluebird bio. "In this initial study, we hope to establish whether the combination of plerixafor with MGTA-145 can generate appropriate CD34+ stem cells with a single round of mobilization. If successful, we hope to evaluate this novel mobilization regimen with LentiGlobin to make another step forward in the treatment of patients with SCD."

"Achieving reliable and rapid stem cell mobilization and a simplified collection process can ensure the entire patient experience is optimal with respect to therapeutic outcome. The incorporation of bluebird bio’s experience in this area of treatment will be immensely valuable in further developing MGTA-145 plus plerixafor to address the remaining unmet needs in gene therapy approaches for diseases like sickle cell disease," said John Davis Jr., M.D., M.P.H., M.S., Head of Research & Development and Chief Medical Officer, Magenta Therapeutics. "We look forward to collaborating with bluebird bio to evaluate MGTA-145 as the preferred mobilization option for people with sickle cell disease."

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin (HbS), causing red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive events (VOEs). For adults and children living with SCD, this means unpredictable episodes of excruciating pain due to vaso-occlusion as well as other acute complications—such as acute chest syndrome (ACS), stroke, and infections, which can contribute to early mortality in these patients.

Currently available mobilization drugs, including granulocyte-colony stimulating factor (G-CSF), a commonly used mobilization agent administered over the course of five to seven days in other transplant settings, is not used in sickle cell disease because it can trigger vaso-occlusive crises and even death in adults and adolescents. Plerixafor is used to mobilize a patient’s stem cells for collection prior to transplant and while an available treatment option, multiple cycles of apheresis and collection may sometimes be required to generate sufficient stem cells for gene therapy. Magenta is developing MGTA-145, in combination with plerixafor, to be the preferred mobilization regimen for rapid and reliable mobilization and collection of hematopoietic stem cells (HSCs) to improve stem cell transplantation outcomes in multiple disease areas, including genetic diseases such as sickle cell disease, as well as blood cancers and autoimmune diseases.

About Magenta Therapeutic’s MGTA-145

MGTA-145, in combination with plerixafor, has demonstrated, in a recently completed Phase 1 study in healthy volunteers, it can rapidly and reliably mobilize high numbers of functional stem cells in a single day, without the need for G-CSF. MGTA-145 works in combination with plerixafor to harness a physiological mechanism of stem cell mobilization to rapidly and reliably mobilize HSCs for collection and transplant across multiple indications.

Additionally, as shown in preclinical studies, stem cells mobilized with MGTA-145 can be efficiently gene-modified and are able to engraft, potentially allowing for safer and more efficient mobilization for gene therapy approaches to treat sickle cell disease and other genetic diseases.

Magenta completed its Phase 1 trial of MGTA-145 in healthy volunteers, demonstrating MGTA-145 was well tolerated and enables same-day dosing, mobilization and simplified collection of sufficient stem cells for transplant, meeting all primary and secondary endpoints.

On December 4, 2020, Atara Biotherapeutics, Inc. (the "Company" or "Atara") reported that it entered into a Research, Development and License Agreement (the "License Agreement") with Bayer AG ("Bayer") (Filing, 8-K, Atara Biotherapeutics, DEC 4, 2020, View Source [SID1234572309]). Pursuant to the License Agreement, the Company grants to Bayer an exclusive, field-limited license under the applicable patents and know-how owned or controlled by the Company and its affiliates covering or related to ATA2271 and ATA3271, the Company’s next-generation CAR T immunotherapy programs targeting mesothelin, of which the Company is currently developing ATA2271 in collaboration with Memorial Sloan Kettering Cancer Center ("MSK"), to develop, manufacture and commercialize products comprising ATA2271 and ATA3271 and certain derivatives thereof ("Licensed Products"), in each case targeting mesothelin.

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Under the terms of the License Agreement, the Company will be responsible at its cost for all mutually agreed pre-clinical and clinical activities for ATA2271 through the first in human Phase 1 clinical study, following which Bayer will be responsible for the further development of ATA2271 at its cost. Bayer will be responsible for the development of ATA3271, except for certain mutually agreed pre-clinical, translational, manufacturing and supply chain activities to be performed by the Company relating to ATA3271, in each case at Bayer’s cost. Bayer will also be solely responsible for commercializing the Licensed Products at its cost. The Company will own any intellectual property rights developed solely by the Company under the collaboration, and Bayer will own any intellectual property rights developed solely by Bayer or jointly by the parties under the collaboration. Such Bayer-developed or jointly-developed intellectual property rights are subject to the Company’s rights to certain manufacturing and process development-related intellectual property. The Company has agreed to not develop or commercialize (or assist any third party to develop or commercialize) any cell therapy targeting mesothelin outside of the collaboration with Bayer for a period of three years from the first commercial sale of a Licensed Product.

Bayer will pay the Company an upfront cash payment of $45.0 million for the exclusive license grant, and will make an additional $15.0 million reimbursement payment to the Company for certain research and process development activities to be performed by the Company under the License Agreement. The Company is also entitled to receive (i) up to an additional $5.0 million for additional, specified pre-clinical and translational activities under the License Agreement, (ii) an aggregate of up to $610.0 million in milestone payments upon achieving certain development, regulatory and commercial milestones relating to Licensed Products and (iii) additional amounts for manufacturing services and product supply. In addition, the Company is eligible to receive tiered royalties at percentages up to low double digits on worldwide net product sales of Licensed Products on a country-by-country and product-by-product basis until the later of 12 years after the first commercial sale in such country or the expiration of specified patent rights in such country, subject to certain reductions and aggregate minimum floors. The License Agreement includes (i) various representations, warranties, covenants, indemnities, and other customary provisions and (ii) contains customary provisions for termination by Bayer for convenience, by the Company upon a challenge of the Company’s licensed patents, and by either party, including in the event of breach of the License Agreement (subject to cure), subject, in each case, to certain reversion rights, or upon the other party’s bankruptcy.

Pursuant to the License Agreement, for a limited period of time and only if the Company pursues a potential out-license of an additional Atara CAR T product candidate, the Company also grants Bayer a non-exclusive right to negotiate a license of such additional Atara CAR T product candidate on mutually agreed terms. The foregoing right granted to Bayer will expire upon certain change of control events of the Company.

The foregoing summary is qualified in its entirety by reference to the License Agreement. The License Agreement will be filed as an exhibit to the Company’s Annual Report on Form 10-K for the year ended December 31, 2020.

On December 4, 2020 AB Science SA (Euronext-FR0010557264-AB) reported that its Phase 3 study (AB12005-NCT03766295) met its primary objective to demonstrate increase in survival in pancreatic cancer with pain (Press release, AB Science, DEC 4, 2020, View Source [SID1234572271]).

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Study AB12005 evaluated masitinib 6.0 mg/kg/day in combination with gemcitabine in first-line treatment of unresectable locally advanced or metastatic pancreatic cancer patients with pain. The study was successful if its primary objective to test a significant increase in overall survival was reached at a 2.5% level of statistical significance in either the overall population with pain or in the population with unresectable locally advanced tumors with pain.

In the population with unresectable locally advanced tumors with pain, the masitinib treatment-arm showed a significant improvement in overall survival (OS) relative to the control arm. The between group difference in median OS was 1.8 months (p=0.007) in favor of masitinib (13.0 months in masitinib arm versus 11.2 months in control group), with a 0.46 hazard ratio (HR) of death, which represents a reduction in risk of death of 54% for masitinib-treated patients relative to control. Results on the primary endpoint were consistent with secondary analysis in progression free survival (PFS), which measures the time to tumor progression or death (whichever occurs first) from the start of treatment. The between group difference in median PFS was 1.8 months (p=0.039) in favor of masitinib (7.4 months in masitinib arm versus 5.6 months in control group), with a 0.47 hazard ratio representing a reduction in risk of having a progression or death of 53%.

Masitinib also reduced pain relative to the control arm in patients with unresectable locally advanced tumors, as demonstrated by a between group difference that reached statistical significance or approached significance at each timepoint. In pancreatic cancer, there is evidence that pain is a clinical predictor of poor prognosis [1]. Study AB12005 demonstrated that mast cells are associated with pain and that blocking mast cells, as masitinib does, is able to reverse the poor prognosis of patients with unresectable locally advanced tumors with pain.

In the overall population including both locally advanced and metastatic pancreatic cancer patients with pain, no survival benefit was detected, suggesting that masitinib treatment should be initiated early in the course of the disease, prior to metastasis.

From the first Phase 3 study AB07012 [2] and literature [3], around 50% of patients with pancreatic cancer had pain intensity (VAS > 20) and 25% to 50% of pancreatic cancer patients are patients with unresectable locally advanced tumors.

The safety of masitinib 6.0 mg/kg/day in combination with gemcitabine compared favorably to that of gemcitabine as a single agent, with fewer adverse event and severe adverse events reported in the masitinib arm as compared with the control arm:
-96.3% of patients had at least one adverse event in masitinib arm versus 99.3% in the control arm
-18.7% of patients had one fatal adverse event in masitinib arm versus 19.1% in the control arm
-19.1% of patients had at least one serious adverse event (non-fatal) in masitinib arm versus 21.3% in the control arm
-74.8% of patients had at least one adverse event with Grade 3 or 4 in masitinib arm versus 83.1% in the control arm Page 2/5 Study AB12005 was a confirmatory Phase 3 study.

The first Phase 3 study (AB07012) was a hypothesis generating study and identified that patients with pain had a median OS increased by 2.6 months (p=0.012) with masitinib as compared to control. Study AB12005 demonstrated that there is a benefit generated by masitinib for pancreatic cancer patients with pain, provided that treatment is initiated prior to metastasis.

Dr. Joël Ezenfis, MD, principal coordinating investigator of the study, said: "We are very pleased that this study is successful. The increase of 1.8 months in median overall survival for masitinib-treated patients is clinically relevant as this population of patients suffers from a condition with very limited treatment options and survival rate has remained stubbornly poor despite decades of clinical studies."

Julien Taieb, MD, PhD, Head of the Gastroenterology and Gastrointestinal Oncology Department at the Georges Pompidou European Hospital said: "Masitinib is not a cytotoxic agent but a targeted drug blocking two cells of the innate immune system, mast cells and macrophages. Study AB12005 demonstrated for the first time that this targeted approach is beneficial in a targeted population, made of patients with unresectable locally advanced tumors with pain".

Prof. Olivier Hermine, president of the Scientific Committee of AB Science and member of the Académie des Sciences in France, said: "This study is particularly important as it confirms the relevance of targeting mast cells and macrophages in oncology. We had previously observed the benefit of masitinib targeting mast cells and macrophages in cancer through in vitro and in animal assays in my laboratory. This study validates the benefit of masitinib in humans in the most difficult-to-treat cancer. We can now state that masitinib is an anti-metastatic drug that could be useful in patients at high risk of developing metastases. In addition, it validates the role of mast cells in pain and the acceptable safety profile of masitinib even in combination with chemotherapy."

Alain Moussy, co-founder and CEO of AB Science said: "This is a major achievement for masitinib in oncology. The next step is to discuss with the Health Authorities a potential filing for marketing authorization application of masitinib in the first line treatment of unresectable locally advanced pancreatic cancer associated with pain". AB Science plans to present complete study results at an upcoming medical meeting.

AB12005 Study Design Study AB12005 was a randomized, placebo-controlled, phase 3 study of masitinib in first-line treatment of unresectable locally advanced or metastatic pancreatic cancer patients with pain at baseline or taking opioids. The pre-specified primary endpoint was overall survival.

The primary analysis was pre-specified both in the overall population and also in patients with unresectable locally advanced tumors, with a 5% alpha spending split, which corresponds to the chance factor threshold below which the statistical test is considered significant by regulatory authorities, of 2.5% for the overall population and 2.5% for the locally advanced subgroup.

The distinction between unresectable locally advanced or metastatic disease status was a stratification factor, thereby ensuring that treatment-arms were unbiased for this known prognostic factor. Secondary endpoints included progression free survival according to central RECIST criteria and change in pain from baseline. The study enrolled 383 patients (randomization 2:1 between masitinib and placebo) with i) histologically or cytologically confirmed adenocarcinoma of the pancreas, unresectable locally advanced or metastatic stage, ii) pain related to the disease (Visual Analogue Scale > 20 mm or opioid analgesics at a dose ≥ 1 mg/kg/day), and iii) chemotherapy naïve for the advanced/metastatic disease. 92 patients had unresectable locally advanced with pain criteria. Page 3/5 Efficacy analysis was performed in the modified intent-to-treat (mITT) population, which included all randomized patients who took at least one dose of study treatment (masitinib/placebo) and with pain criteria (VAS > 20 and/or patients treated with opioid analgesics dose ≥ 1 mg/kg/day at baseline).

There was a difference of 4 patients between the ITT population and the mITT population, with 1 patient receiving no study treatment and 3 patients without pain criteria. Rationale for developing masitinib in patients with pancreatic cancer with pain A first phase 2/3 study (AB07012) enabled the identification of a subgroup based on the level of pain at baseline where survival was statistically increased (+2.6 months, p=0.012, Hazard Ratio=0.62). Pain intensity was assessed via a visual analog scale (VAS) at baseline. This linear scale provides a visual representation of pain as perceived by the patient. Pain intensity was represented by a 100 mm long, continuous line free of any internal reference marks. One extremity indicated an absence of pain (0-value) and the other extremity indicated very severe pain (100-value).

The VAS threshold for the ‘pain’ subgroup was set to VAS ≥20 mm, which is consistent with established precedent from the scientific literature [3-6]. There is evidence from the scientific literature in support of biological plausibility for the observed masitinib treatment-effect in patients with baseline pain (VAS ≥ 20). The presence of pain in pancreatic cancer is thought to flag an increased mast cell activity within the tumor microenvironment, which promotes disease progression. Masitinib’s highly selective inhibition of mast cell activation is expected to be of therapeutic benefit by modulating mast cell related remodeling of the tumor microenvironment.

About pancreatic cancer
The estimated prevalence of people living with pancreatic cancer is 21 per 100,000 [7]. At the time of diagnosis, most patients with pancreatic ductal adenocarcinoma present with locally advanced or metastatic disease and only 10-20% of cases are candidates for curative surgery. Median overall survival is between 6 to 7 months and 1-year survival rates range between 17 to 25% [8;9]. As such, population with unresectable pancreatic cancer in first line is around 100,000 in the EU and 60,000 in the USA. From the first Phase 3 study AB07012 [2] and literature [3], around 50% of patients with pancreatic cancer had pain intensity (VAS > 20) and 25% to 50% of pancreatic cancer patients are patients with unresectable locally advanced tumors

Reference
[1] Okusaka T, et al. Abdominal pain in patients with resectable pancreatic cancer with reference to clinicopathologic findings. Pancreas. 2001;22(3):279-284.
[2] Deplanque 2015, Ann Oncol. doi: 10.1093/annonc/mdv133. View Source
[3] Balaban EP, et al. Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Clinical Practice Guideline Summary. J Oncol Pract. 2017 Apr;13(4):265-269. doi: 10.1200/JOP.2016.017376. [3] Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. Mar 2011;30(1):45-60. [4] Theoharides TC. Mast cells and pancreatic cancer. N Engl J Med. Apr 24 2008;358(17):1860-1861.
[5] Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immunemodulation. Biochim Biophys Acta. Aug 2009;1796(1):19-26.
[6] Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol. Sep 1 2007;179(5):2673-2679
[7] National Cancer Institute, Pancreatic Cancer statistics, 2015
[8] Heinemann V, et al. BMC Cancer. 2008;8:82.
[9] Von Hoff DD, et al. N Engl J Med. Oct 31 2013;369(18):1691-1703. Page 4/5

About masitinib
Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and microglia and consequently the inhibition of the activation of the inflammatory process, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.