On December 19, 2022 Mustang Bio, Inc. ("Mustang") (Nasdaq: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, reported recent CAR T cell therapy portfolio updates and provided anticipated milestones for 2023 (Press release, Mustang Bio, DEC 19, 2022, View Source [SID1234625420]).

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Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "In 2022, Mustang successfully advanced our CAR T cell therapy portfolio which has laid the foundation for us to achieve multiple milestones in the coming year. Our lead clinical candidate, MB-106, a first-in-class CD20-targeted, autologous CAR T cell therapy for the treatment of relapsed or refractory B-cell non-Hodgkin lymphomas ("B-NHL") and chronic lymphocytic leukemia ("CLL"), continues to progress in our multicenter Phase 1/2 clinical trial. We’re pleased to report that Mustang has met its accrual target for the year for that trial and has manufactured product for all enrolled patients. We look forward to providing first safety and efficacy data in 2023. Additionally, data from the initial ongoing Phase 1/2 clinical trial taking place at Fred Hutchinson Cancer Center ("Fred Hutch") continue to exhibit high efficacy and a favorable safety profile compared to currently approved autologous CAR Ts. In particular, while other cell therapies in development have struggled to show durability of response, we reported in October that twelve of 28 patients enrolled had experienced complete remission (CR) for more than 12 months (10 ongoing), four patients had experienced CR for more than 2 years (all ongoing), and the first patient enrolled was in sustained CR at 33 months."

"In 2023, we anticipate filing an Investigational New Drug application ("IND") for our combination therapy MB-109 to treat glioblastoma ("GBM"). Additionally, we continue to collaborate with the Mayo Clinic to progress our exclusively licensed novel in vivo CAR T technology platform and anticipate the publication of proof-of-concept research in a murine tumor model. We’re looking forward to another productive year across our CAR T therapy programs, as we continue working with our world-class partners to advance therapies for difficult-to-treat cancers and rare diseases," said Dr. Litchman.

CAR T Candidate Portfolio Highlights:

MB-106 (first-in-class CD20-targeted, autologous CAR T cell therapy)
To date, six patients have been enrolled in Mustang’s multicenter Phase 1/2 clinical trial and five patients have been infused at the starting dose levels of their respective protocol arms. Mustang has successfully manufactured product for all enrolled patients at its facility in Worcester, MA. In 2023, the Company anticipates dose escalation and reporting response data at a major medical meeting.

As previously reported, MB-106 continues to demonstrate high efficacy and a favorable safety profile across patients with a wide range of hematologic malignancies in a Phase 1 investigator-sponsored trial at Fred Hutch, including a 100% overall response rate in patients with Waldenstrom macroglobulinemia ("WM"), a rare form of blood cancer. Given this, Mustang plans to treat patients with WM in the Phase 1 portion of its multicenter clinical trial to support a fast-to-market Phase 2 strategy for this indication. Data from the Fred Hutch clinical trial also support the potential of MB-106 to be administered as outpatient therapy and provide a best-in-class immunotherapy option for patients treated previously with CD19-directed CAR T cell therapy. In 2023, Mustang anticipates the U.S. Food and Drug Administration granting Orphan Drug Designation in at least one additional CD20 positive malignancy.

MB-109 (MB-101 (IL-13Rα2 targeted CAR T cell therapy) + MB-108 oncolytic virus)
Preclinical data presented at American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 ("AACR") supported this combination therapy to optimize results to treat recurrent GBM. The combination leverages MB-108 to make cold tumors "hot," thereby improving the efficacy of MB-101 CAR T cell therapy. Data presented separately on MB-101 and MB-108 showed infusions were well tolerated in highly refractory GBM patients. Two patients treated solely with MB-101 who had high levels of intratumoral CD3+ T cells pre-therapy (i.e., "hot" tumors) achieved complete responses lasting 7.5 and 31+ months, respectively. Phase 1 clinical trials of MB-101 at City of Hope and of MB-108 at the University of Alabama at Birmingham continue to enroll patients. Additionally, Mustang will advance the preclinical investigation of MB-109 and plans to file an IND for this treatment in 2023.

MB-102 (CD123-targeted CAR T cell therapy)
The Safety Review Team ("SRT") composed of Investigators and Mustang representatives recently met to assess the progress and safety data from the ongoing Mustang-sponsored, open label, multicenter Phase 1/2 clinical trial to evaluate the safety and efficacy of MB-102 in patients with relapsed or refractory blastic plasmacytoid dendritic cell neoplasm ("BPDCN"), a rare form of leukemia. After thoroughly reviewing the safety data from Dose Level 1 (100 x 106 CAR T cells), the SRT unanimously recommended dose escalation to Dose Level 2 (300 x 106 CAR T cells). There are currently no curative treatments for BPDCN. The trial continues to enroll and study sites include City of Hope, where the CAR T cell therapy was initially developed, Dana-Farber Cancer Institute, Duke University and The University of Texas MD Anderson Cancer Center. The MB-102 clinical trial is the first under Mustang’s IND in which a patient was dosed with cells processed in its own manufacturing facility. In 2023, Mustang expects to provide information about Dose Level 2 after that level is fully enrolled and the SRT has reviewed the data.

In vivo CAR-T platform technology
Mustang executed an exclusive license agreement with Mayo Clinic for this novel technology that may transform the administration of CAR T therapies. The Mayo approach involves activating immune cells in vivo using natural methods employed by the body to deal with infection, thus having the potential to reduce toxicities associated with traditional CAR T therapy. Successful implementation of this technology could lead to an off-the-shelf product with no need to isolate and expand patient T cells ex vivo in a manufacturing facility. Published proof-of-concept data from murine tumor model studies are anticipated in 2023. Additionally, Mustang plans to file an IND application for a multicenter Phase 1 clinical trial once a lead CAR construct has been identified.

On December 19, 2022 Biogen Inc. (Nasdaq: BIIB) reported that it has reached an agreement with Genentech, a member of the Roche Group, related to the commercialization and sharing of economics for glofitamab (Press release, Biogen, DEC 19, 2022, View Source [SID1234625417]). Under the terms of the agreement, Biogen will have no payment obligations and will receive tiered royalties on potential net sales of glofitamab within the United States as part of the companies long-standing collaboration on antibodies targeting CD20.

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Glofitamab is an investigational CD20xCD3 T-cell engaging bispecific antibody being developed by Roche for the treatment of B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other blood cancers1. Glofitamab is based on a novel structural format called ‘2:1’, which is engineered to have two ‘Fab’ regions that bind to CD20 and one ‘Fab’ region which binds to CD3. This dual targeting activates and redirects a patient’s own T-cells to engage and eliminate cancer B cells.

Data from the Phase II NP30179 study investigating glofitamab in patients with relapsed/refractory (R/R) DLBCL have been submitted for review to the European Medicines Agency (EMA), and submissions to additional health authorities worldwide, including the U.S. Food and Drug Administration, are ongoing. If approved, glofitamab has the potential to be a first-in-class fixed-duration CD20xCD3 T-cell engaging bispecific antibody in DLBCL.

Genentech will have sole decision-making rights on the commercialization of glofitamab within the United States and, in the event of approval, Biogen is eligible to receive tiered royalties in the mid-single digits range on potential net sales of glofitamab within the United States.

Glofitamab, together with mosunetuzumab, is part of the Roche and Genentech CD20xCD3 antibody portfolio that seeks to address the unmet needs of people living with blood cancers. In January 2022, Biogen exercised the option to have joint decision-making rights related to the development and potential commercialization of mosunetuzumab, and Genentech will continue to lead the strategy and implementation of the program. The companies have had a collaboration on antibodies targeting CD20 since 1995.

On December 19, 2022 Atara Biotherapeutics, Inc. (Nasdaq: ATRA) and Pierre Fabre reported that the European Commission (EC) has granted marketing authorization for Ebvallo (tabelecleucel) as a monotherapy for the treatment of adult and pediatric patients two years of age and older with relapsed or refractory Epstein‑Barr virus positive post‑transplant lymphoproliferative disease (EBV+ PTLD) who have received at least one prior therapy (Press release, Atara Biotherapeutics, DEC 19, 2022, View Source [SID1234625415]). For solid organ transplant patients, prior therapy includes chemotherapy unless chemotherapy is inappropriate.

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The approval follows a positive opinion in October by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and is applicable to all 27 European Union member states plus Iceland, Norway, and Liechtenstein. The CHMP positive opinion is based on results from the pivotal Phase 3 ALLELE study.1 In this study, EbvalloTM demonstrated a favorable risk-benefit profile.

"The approval of EbvalloTM in Europe is a medical breakthrough for patients with significant unmet need," said Pascal Touchon, President and Chief Executive Officer of Atara. "As the first allogeneic, or donor-derived, T-cell immunotherapy to receive approval from any regulatory agency in the world, this marks a historic moment for Atara, our European partner, Pierre Fabre, and for the broader cell therapy field."

EBV+ PTLD is a rare, acute, and potentially deadly hematologic malignancy that occurs after transplantation when a patient’s T-cell immune response is compromised by immunosuppression. It can impact patients who have undergone solid organ transplant (SOT) or allogeneic hematopoietic cell transplant (HCT). Poor median survival of 0.7 months and 4.1 months for HCT and SOT, respectively, is reported in EBV+ PTLD patients for whom standard of care failed, underscoring the significant need for new therapeutic options.

Under a previously announced License Agreement with Atara, Pierre Fabre will lead all commercialization and distribution activities in Europe and select other markets, in addition to medical and regulatory activities following the transfer of the EbvalloTM Marketing Authorization Application (MAA) from Atara to Pierre Fabre.

"Ebvallo represents a significant moment in the cell therapy space and a breakthrough for European patients with EBV+ PTLD," said Eric Ducournau, CEO of Pierre Fabre, Atara’s commercialization partner in Europe. "We are proud and excited to bring this innovative therapy to the marketplace, which will reinforce Pierre Fabre’s portfolio in oncology, hematology, and rare diseases."

EbvalloTM has orphan designation in Europe. Orphan designation is reserved for medicines treating life-threatening or chronically debilitating diseases that are rare (affecting not more than five in 10,000 people in the EU). Authorized orphan medicines benefit from ten years of market exclusivity, protecting them from competition with similar medicines with the same therapeutic indication, which cannot be marketed during the exclusivity period.

On December 19, 2022 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported that the Phase 3 ENVISION study of investigational agent UGN-102 (mitomycin) for intravesical solution in development for the treatment of LG-IR-NMIBC is fully enrolled. The ENVISION study targeted enrollment of 220 patients across 90 sites and, assuming positive findings, UroGen anticipates submitting a New Drug Application (NDA) for UGN-102 in 2024 (Press release, UroGen Pharma, DEC 19, 2022, View Source [SID1234625414]).

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"Completing enrollment for the ENVISION trial is a major milestone that brings us one step closer to validating chemoablation for the treatment of LG-IR-NMIBC," said Sandip Prasad, M.D., M.Phil., Director of Genitourinary Surgical Oncology, Morristown Medical Center, Atlantic Health System, NJ, and lead study investigator for the ENVISION trial. "These patients are burdened with disease recurrences and repeat surgeries that take a toll on an elderly population who often have co-morbidities that increase the risks associated with surgery. If successful ENVISION has the potential to fundamentally change the way we treat these patients."

ENVISION is a Phase 3, single-arm, multinational, multicenter study evaluating the efficacy and safety of UGN-102 as primary chemoablative therapy, in 220 patients with LG-IR-NMIBC from 90 sites. The design for the Phase 3 ENVISION trial is similar to the Phase 2b OPTIMA II trial in that the patient population will have similar clinical characteristics, receive the same treatment regimen and undergo the same efficacy and safety assessments and qualitative follow-up. Patients enrolled in ENVISION will receive six once-weekly intravesical instillations of UGN-102. The primary endpoint is the complete response rate at PDE (primary disease evaluation) which will typically occur within three months from the first instillation, and the key secondary endpoint will be durability of response in patients who achieve complete response.

"We are optimistic about the clinical potential of UGN-102 because ENVISION shares a similar approach to the successful OPTIMA II Phase 2b study," said Mark Schoenberg, Chief Medical Officer, UroGen. "Also, our chemoablative treatment for low-grade upper tract urothelial cancer and UGN-102 uses our proprietary RTGel technology, and the urothelial lining in the bladder and upper tract is similar. If approved UGN-102 may offer additional advantages because it is instilled into the bladder via urethral catheter in an outpatient setting – a common procedure in most urologists’ offices."

If approved UGN-102 has the potential to offer a simpler, minimally invasive, and non-surgical option to transurethral resection of bladder tumor (TURBT), as UGN-102 can be administered without the use of anesthesia or special equipment. UroGen’s first product and UGN-102 utilize mitomycin as their active pharmaceutical ingredient, although in a different ratio and both allow for local delivery and sustained exposure to mitomycin for up to six hours.

About LG-IR-NMIBC

Approximately 800,000 people are living with bladder cancer in the U.S., of that 80,000 suffer from LG-IR-NMIBC. Patients with LG-IR-NMIBC face a future of recurrence and additional surgeries. Currently, the only primary treatment available is a surgical procedure known as TURBT, which requires anesthesia. Every time TURBT is performed it may impose more burden and serious risks on patients, including pain, bleeding, infection and injury (including perforation).

About UGN-102

UGN-102 (mitomycin) for intravesical solution is an investigational drug formulation of mitomycin in Phase 3 development for the treatment of LG-IR-NMIBC. Utilizing UroGen’s proprietary RTGel technology, a sustained release, hydrogel-based formulation, UGN-102 is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using a standard urinary catheter in an outpatient setting. Assuming positive findings from the ENVISION Phase 3 study, UroGen anticipates submitting a New Drug Application (NDA) for UGN-102 in 2024. If approved, UGN-102 would be the first non-surgical primary therapeutic to treat a subset of bladder cancer characterized by high recurrence rates and multiple surgeries.

On December 19, 2022 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported publication of a manuscript in the Journal of Medicinal Chemistry that details the discovery efforts leading to RMC-5552, the company’s first-in-class, bi-steric mTORC1-selective inhibitor (Press release, Revolution Medicines, DEC 19, 2022, View Source [SID1234625413]). The manuscript describes the unprecedented compound profile that includes 40-fold selectivity for mTORC1 over mTORC2 and greater than 53-fold selectivity over other lipid kinases. The paper also shows that selective mTORC1 inhibition using the company’s related preclinical tool compound (RMC-6272) in combination with a covalent KRASG12C inhibitor induced tumor regressions in a preclinical model of KRASG12C mutant non-small cell lung cancer (NSCLC) that exhibits resistance to KRASG12C inhibitor monotherapy.

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RMC-5552 is designed to suppress phosphorylation and inactivation of 4EBP1, a key translational regulator of oncogene expression, in cancers with hyperactive mTORC1 signaling. This bi-steric compound is designed to bind simultaneously to two different sites on mTORC1 to drive deep inhibition of mTORC1 while maintaining selectivity for mTORC1 over mTORC2, a unique profile compared to prior generations of mTOR inhibitors. Revolution Medicines is currently evaluating RMC-5552 as monotherapy in a Phase 1/1b clinical trial in patients with refractory solid tumors (NCT04774952), and initial antitumor activity has been reported. The company plans to evaluate RMC-5552 in combination with RAS(ON) inhibitors in patients with cancers harboring mutations in both RAS and the mTOR pathways.

"The Journal of Medicinal Chemistry manuscript details the sophisticated structure-based chemical design and synthesis employed by our drug discovery team that produced RMC-5552," said Steve Kelsey, M.D., president, research and development at Revolution Medicines. "The differentiated antitumor and tolerability profile of RMC-5552 in the preclinical setting compared to earlier mTORC inhibitors provides a strong rationale for evaluating it in patients with tumors that have abnormally high mTORC1 growth signaling, including in combination with our RAS(ON) Inhibitors in patients with tumors that have both RAS and mTORC1 pathway co-mutations."

The manuscript published in the Journal of Medicinal Chemistry is titled, "Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-activated Tumors," and can be accessed at: View Source

About mTORC1

The mTOR Complex 1 (mTORC1) is a central node within the mTOR signaling pathway and a critical regulator of metabolism, growth, and proliferation in cancer cells. Oncogenic mutations of genes encoding proteins that lie upstream of mTOR, including PI3K, PTEN, and STK11, can drive abnormal activation of mTORC1 and subsequent inactivation of the tumor suppressor 4EBP1. Selective inhibition of mTORC1 to reactivate 4EBP1 is a potential therapeutic strategy for patients with tumors bearing such mutations. These mutations are often co-occurring with RAS mutations in RAS-addicted tumors and combinations of mTORC1- and RAS-targeted inhibitors may be of particular benefit in this context.