On December 14, 2021 Magenta Therapeutics (Nasdaq: MGTA), a clinical-stage biotechnology company developing novel medicines designed to bring the curative power of stem cell transplants to more patients, reported that three presentations made at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Magenta Therapeutics, DEC 14, 2021, View Source [SID1234597064]).

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Stem Cell Mobilization: ASH (Free ASH Whitepaper) Presentation and Clinical Development Plans

The data from an investigator-initiated Phase 2 clinical trial in multiple myeloma, presented on December 13, 2021, at the ASH (Free ASH Whitepaper) Annual Meeting and previously reported in a Magenta press release on November 4, 2021, confirmed that MGTA-145 plus plerixafor (i) achieved the primary endpoint for collection of hematopoietic stem cells (HSCs), (ii) was well-tolerated and (iii) mobilized HSCs which were able to successfully engraft with positive 100-day outcomes. The data continue to support MGTA-145 plus plerixafor as a potentially compelling combination with complementary mechanisms of action.

Building upon the encouraging cell collection data from the Phase 2 investigator-initiated trial, Magenta plans to pursue a company-sponsored Phase 2 clinical trial in healthy subjects to further increase cell collection yield through adjustments of the dosing and administration regimen. This is a capital-efficient approach designed to enable expedited enrollment, flexibility in execution and reduced patient variability which will inform planned clinical trial evaluations in multiple myeloma patients and allogeneic stem cell transplant. Magenta will close its current allogeneic clinical trial while continuing to advance its MGTA-145 clinical trial in sickle cell disease in partnership with bluebird bio due to the predicted pharmacology of MGTA-145 and plerixafor in the sickle cell patient setting for HSC gene therapy.

"We believe the current profile of MGTA-145 plus plerixafor, with enhanced cell collection yield, could provide significant clinical benefit to patients and favorably position the product commercially," said Jeff Humphrey, M.D., Chief Medical Officer, Magenta Therapeutics. "We believe there are dosing and administration adjustments that could further improve cell collection and also expect that this proposed clinical trial will answer key clinical questions which could, ultimately, be major differentiators for the program moving forward."

Targeted Conditioning: ASH (Free ASH Whitepaper) Presentations and Phase 1/2 Clinical Trial

Two presentations relating to Magenta’s MGTA-117 targeted conditioning program were made on December 11-12, 2021, at the ASH (Free ASH Whitepaper) Annual Meeting. The first was an oral presentation of non-human primate data supporting the use of a CD117-targeted ADC to condition for HSC gene therapy. The second was a poster presentation of preclinical mouse data that supports the use of a CD117-targeted ADC in combination with lymphodepletion to condition prior to allogeneic HSC transplant. The results from these two presentations were previously disclosed in a press release by Magenta on November 4, 2021.

Gene Therapy. In support of using a CD117-targeted conditioning ADC in gene therapy, Dr. Naoya Uchida, staff scientist at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), presented preclinical data generated using a tool CD117-targeted ADC in a clinically relevant and fully immune-competent primate gene therapy model for sickle cell disease. The data was generated as part of an NIH-funded (Grant No. HL006008), joint-research collaboration between Magenta and the NIH. The tool CD117-ADC uses the same antibody and engineering as MGTA-117, and although it utilizes a different payload, the results validate CD117 as a target for ADC-based conditioning because of (i) the value of the ADC’s selectivity to the CD117-expressing hematopoietic stem cells and (ii) the effective cell depletion following delivery of an on-target, cell-killing payload. In primates, a single dose of CD117-ADC led to >99% depletion of stem cells, a reduction previously only achieved by four daily doses of busulfan chemotherapy. The data also showed successful engraftment of gene-modified cells with robust and durable fetal hemoglobin levels.

Magenta’s MGTA-117 clinical candidate uses an amanitin payload which has been shown preclinically to be a potent agent for stem cell depletion. Potent stem cell depletion is critical to making room in the bone marrow for engraftment of the modified cells used in gene therapy (and non-modified stem cells used in transplantation). Importantly, depleting CD117-expressing hematopoietic stem cells in a gene therapy setting may allow for the elimination of busulfan, other chemotherapies and irradiation and their known off-target and damaging adverse effects.

"The results suggest that a single dose of a CD117-targeted ADC can enable comparable levels of gene-therapy cell engraftment to multi-dose busulfan while avoiding many of busulfan’s common toxicities," said Dr. John Tisdale, Chief of Cellular and Molecular Therapeutics, NHLBI, NIH. "If successfully translated to the clinic, a single dose of a CD117-targeted ADC may improve the risk/benefit profile for patients with hemoglobinopathies who are considering HSC gene-therapy."

Allogeneic HSC Transplant. In support of using a CD117-targeted conditioning ADC in allogeneic HSC transplant, Magenta presented a poster demonstrating successful use of a tool CD117-ADC in combination with lymphodepleting antibodies that enabled allogeneic transplant in immune-competent murine models. These studies support the therapeutic potential of CD117-targeted ADCs, without the use of toxic chemotherapy, for conditioning in allogeneic HSC transplantation.

Phase 1/2 Clinical Trial. Magenta is on track to open a Phase 1/2 clinical trial this month to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MGTA-117, a CD117-targeted ADC. Preclinical efficacy and GLP toxicology studies with MGTA-117: (i) enabled selection of the starting dose in this dose-escalating Phase 1/2 clinical trial, (ii) demonstrated that MGTA-117 efficiently depleted stem cells, (iii) showed that MGTA-117 was efficiently cleared from the body in the preclinical models which is especially important for autologous gene therapy or allogeneic stem cell transplants, and (iv) showed that MGTA-117 was well-tolerated. MGTA-117, as a targeted conditioning therapy, is designed to substantially improve against the known safety and tolerability concerns of current non-specific conditioning agents which include busulfan, other chemotherapies, and irradiation. Magenta expects to provide the details of the MGTA-117 clinical trial design at its company presentation at the 2022 JP Morgan Healthcare Conference on January 13, 2022.

On December 14, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from the phase III POLARIX study showing that treatment with Polivy (polatuzumab vedotin) in combination with MabThera/Rituxan (rituximab) plus cyclophosphamide, doxorubicin and prednisone (R-CHP) significantly reduced the risk of disease progression, relapse or death (progression-free survival; PFS) by 27% compared with the current standard-of-care, MabThera/Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), in people with previously untreated diffuse large B-cell lymphoma (DLBCL) (Press release, Hoffmann-La Roche, DEC 14, 2021, View Source [SID1234597063]). Safety outcomes were consistent with those seen in previous trials and the safety profile was comparable for Polivy plus R-CHP versus R-CHOP.1,2 Results were presented as a late-breaking abstract and during a press briefing at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Tuesday, December 14, 2021. Data from POLARIX were simultaneously published in the New England Journal of Medicine (NEJM). The study is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC).

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"As many as 40% of people with this aggressive lymphoma experience a return of their cancer after initial therapy, at which point they face a poor prognosis and limited treatment options," said Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development. "This Polivy-based regimen may conceivably change the disease course for many people with DLBCL, so we are working with health authorities around the world to make this important, potential new treatment option available as soon as possible."

"DLBCL is an aggressive disease and, despite continuous research efforts, there have been limited treatment advances in the frontline setting in the past 20 years," said Professor Hervé Tilly, POLARIX Principal Investigator and Professor of Haematology at the University of Rouen. "Results from the POLARIX trial represent an important advancement, bringing hope to people with this disease."

First efficacy and safety data from the pivotal phase III POLARIX study showed a significant improvement in PFS with Polivy plus R-CHP versus R-CHOP in patients with previously untreated DLBCL after a median follow-up of 28.2 months (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57–0.95; P<0.02).1,2 PFS is a clinically meaningful disease-related outcome for patients with previously untreated DLBCL as it represents the goals of first-line therapy: avoiding disease relapse, disease progression, and death. The safety profile was comparable for Polivy plus R-CHP versus R-CHOP, including rates of grade 3-4 adverse events (AEs; 57.7% versus 57.5%), serious AEs (34.0% versus 30.6%), grade 5 AEs (3.0% versus 2.3%), and AEs leading to dose reduction (9.2% versus 13.0%), respectively.1,2 The POLARIX data form the basis of ongoing marketing applications to global health authorities.

Currently Polivy is used as an off-the-shelf, fixed-duration treatment option in the relapsed or refractory (R/R) DLBCL setting and is approved in combination with bendamustine and MabThera/Rituxan for the treatment of R/R DLBCL in more than 70 countries worldwide, including in the EU and in the United States. Roche continues to explore areas of unmet need where Polivy has the potential to deliver benefit, with ongoing studies investigating combinations of Polivy with the CD20xCD3 T-cell engaging bispecific antibodies mosunetuzumab and glofitamab, with Venclexta/Venclyxto (venetoclax), which is being developed by AbbVie and Roche, and with MabThera/Rituxan in combination with gemcitabine and oxaliplatin in the phase III POLARGO study.

Follow Roche on Twitter via @Roche and keep up to date with ASH (Free ASH Whitepaper) 2021 news and updates by using the hashtag #ASH21.

About the POLARIX study
POLARIX [NCT03274492] is an international phase III, randomised, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Polivy (polatuzumab vedotin) plus MabThera/Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) versus MabThera/Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in people with previously untreated diffuse large B-cell lymphoma. Eight-hundred and seventy-nine patients were randomised 1:1 to receive either Polivy plus R-CHP plus a vincristine placebo for six cycles, followed by MabThera/Rituxan for two cycles; or R-CHOP plus a Polivy placebo for six cycles, followed by two cycles of MabThera/Rituxan. The primary outcome measure is progression-free survival as assessed by the investigator using the Lugano Response Criteria for malignant lymphoma. POLARIX is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC).

About the LYSA and the LYSARC
The Lymphoma Study Association, or LYSA, is the internationally leading cooperative group for lymphoma research in Europe, conducting clinical studies ranging from the first tests of new medicines in humans to the establishment of reference therapeutic strategies. LYSA includes in its network more than 120 care centres distributed throughout three countries (France, Belgium, Portugal), and collaborates with many scientific teams at the international level.

The Lymphoma Academic Research Organisation, or LYSARC, is the LYSA operational structure that conducts clinical research projects on lymphomas at the international level.

About Polivy (polatuzumab vedotin)
Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B-cells, an immune cell impacted in some types of non-Hodgkin lymphoma, making it a promising target for the development of new therapies.3,4 Polivy binds to cancer cells such as CD79b and kills these B-cells through the delivery of an anti-cancer agent, which is thought to minimise the effects on normal cells.5,6 Polivy is being developed by Roche using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL. Polivy is marketed in the US by Genentech as Polivy (polatuzumab vedotin-piiq), with piiq as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration.

About diffuse large B-cell lymphoma (DLBCL)
DLBCL is the most common form of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL.7 DLBCL is an aggressive (fast-growing) type of NHL.8 While it is generally responsive to treatment in the frontline, as many as 40% of patients will relapse or have refractory disease, at which time salvage therapy options are limited and survival is short.8 Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.9

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes T-cell engaging bispecific antibodies, glofitamab and mosunetuzumab, targeting both CD20 and CD3, and cevostamab, targeting both FcRH5 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On December 14, 2021 Phosplatin Therapeutics Inc., a clinical stage pharmaceutical company focused on oncology therapeutics, reported that it has completed a $37 million Series A financing (Press release, Phosplatin, DEC 14, 2021, View Source [SID1234597062]). The round was led by Adinvest AG and included participation from existing investors, including the conversion of previously issued convertible notes.

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Robert Fallon, President and Chief Executive Officer of Phosplatin Therapeutics, commented, "This is a major milestone for Phosplatin that adds the capital and resources needed to advance the clinical development of PT-112 for cancer patients who lack treatment options. We are particularly pleased with the investment support for our clinical and translational research plan."

PT-112 is the first pyrophosphate-platinum conjugate with a unique mechanism of action that induces immunogenic cell death, leading to the recruitment of tumor-infiltrating lymphocytes, and associates with bone (osteotropism), due to its pyrophosphate moiety. Two trials are underway with PT-112: a monotherapy Phase 2 clinical trial in metastatic castration-resistant prostate cancer (mCRPC) patients; and the Phase 2a dose confirmation portion of an ongoing Phase 1b/2a clinical trial in combination with PD-L1 immune checkpoint inhibition in non-small cell lung cancer (NSCLC) patients.

Dr. Neil Sunderland, Adinvest AG Chairman and lead investor, stated, "Phosplatin is advancing PT-112 based on compelling scientific validation, with top-tier collaborations. We see a range of promising opportunities ahead and are excited by the Company’s prospects."

Dr. Sunderland serves as a Director of Phosplatin Therapeutics. He has invested in life science companies for many years and was a founding Partner of Montreux Growth Partners in San Francisco, a biotech and medtech growth capital firm.

Phosplatin has raised $74 million in equity capital since inception, and receives milestone fees from its sub-licensee for Greater China.

About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 may represent the best-in-class inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and the PD-L1 combination study is ongoing in a dose confirmation cohort of NSCLC patients.

On December 14, 2021 HiberCell, a clinical-stage biotechnology company developing therapeutics to address therapeutic resistance, cancer relapse and metastasis, reported a clinical trial collaboration with Merck, known as MSD outside of the United States and Canada (Press release, HiberCell, DEC 14, 2021, View Source;utm_medium=rss&utm_campaign=hibercell-to-collaborate-with-merck-on-phase-2-clinical-trial-of-odetiglucan-in-combination-with-keytruda-pembrolizumab-in-patients-with-metastatic-breast-cancer [SID1234597060]). This metastatic breast cancer clinical trial evaluates KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with HiberCell’s odetiglucan (Imprime PGG), a Dectin-1, pattern recognition receptor agonist.

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Odetiglucan, a novel intravenously-administered innate immune activator, has been previously investigated in combination with pembrolizumab in immune checkpoint inhibitor-naive TNBC, as well as non-small cell lung carcinoma in combination with other immune checkpoint inhibitors, anti-angiogenic antibodies, and tumor-targeting antibodies. Under this collaboration with Merck, the phase 2 single arm, open-label clinical trial is anticipated to enroll up to 50 patients with metastatic breast cancer who have progressed through prior hormone therapy with at least one CDK4/6 inhibitor in sites across the United States. Merck will provide KEYTRUDA for the planned clinical trials.

"We are pleased to continue the important work that we began five years ago, with a focus on improving outcomes for cancer patients who suffer from treatment-mediated resistance," said Alan Rigby, Ph.D., chief executive officer at HiberCell. "This clinical trial is expected to build upon encouraging clinical and translational data from our prior collaborative studies with the team at Merck, which investigated odetiglucan in combination with pembrolizumab in metastatic TNBC. The data-driven decision to establish a new clinical trial represents an expansion of our odetiglucan clinical development program and highlights our continued priority of combining odetiglucan with other therapies in an effort to develop new treatment options."

For more information about HiberCell’s odetiglucan, visit the company’s website at View Source

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About Odetiglucan
Odetiglucan is a Dectin-1, pattern recognition receptor agonist that drives a coordinated innate and adaptive anti-cancer immune cell response in metastatic cancers including TNBC, melanoma, and non-small cell lung carcinoma. Phase 2 clinical studies of odetiglucan in combination with immune checkpoint inhibitors have demonstrated mechanistic proof-of-concept data including the activation of innate and adaptive immunity that has resulted in clinical benefit for patients.

On December 14, 2021 Biomea Fusion, Inc. ("Biomea") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel irreversible small molecules to treat and improve the lives of patients with genetically defined cancers, reported that the company has been selected for addition to the NASDAQ Biotechnology Index (Nasdaq: NBI), effective prior to market open on Monday, December 20, 2021 (Press release, Biomea Fusion, DEC 14, 2021, View Source [SID1234597059]).

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The NASDAQ Biotechnology Index contains securities of NASDAQ-listed companies classified according to the Industry Classification Benchmark as either Biotechnology or Pharmaceuticals which also meet other eligibility criteria. The NASDAQ Biotechnology Index is calculated under a modified capitalization-weighted methodology. Nasdaq selects constituents once annually in December. For more information about the NASDAQ Biotechnology Index, please visit View Source