On August 4, 2021 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, reported financial results and business highlights for the second quarter of 2021 (Press release, Sana Biotechnology, AUG 4, 2021, View Source [SID1234585842]).

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"We continue to be pleased with the progress across our in vivo and ex vivo technology platforms and programs as well as our progress in recruiting great people and building the infrastructure necessary to achieve our long-term vision of using engineered cells as medicines," said Steve Harr, Sana’s President and Chief Executive Officer. "In the second quarter, we presented data demonstrating the survival and immune evasion for transplanted hypoimmune cells into non-human primates without immunosuppression, an important step in enabling the use of engineered cells as medicines more broadly across multiple diseases. We also signed a long-term lease to enable the build out of a clinical trial and commercial manufacturing facility capable of supporting our broad pipeline. I would particularly like to thank the Sana team, who despite the ongoing complex operating environment of COVID continues to make progress in moving our product candidates forward, with a goal of beginning human studies for multiple medicines per year beginning as early as next year."

Recent Corporate Highlights

Presented data showing survival of transplanted stem cells in non-human primates without immunosuppression at a plenary session at the International Society for Stem Cell Research 2021 Virtual Annual Meeting. The transplanted cells incorporated Sana’s hypoimmune gene modifications that enable immune evasion, demonstrating a key step toward widespread treatment of disease using engineered cells.
Announced a lease agreement to develop a 163,000 square foot manufacturing facility in Fremont, California to support the manufacture of late-stage clinical development and early commercial product candidates across our technology platforms.
Second Quarter 2021 Financial Results

GAAP Results

Cash Position: Cash, cash equivalents, and marketable securities as of June 30, 2021 were $930.8 million compared to $412.0 million as of December 31, 2020, an increase of $518.8 million. Sana successfully completed its initial public offering in February 2021 and issued 27.0 million shares of common stock, including 3.5 million shares pursuant to the full exercise of the underwriters’ option to purchase additional shares, at a price of $25.00 per share, for net proceeds of $626.4 million.
Research and Development Expenses: For the three and six months ended June 30, 2021, research and development expense, inclusive of non-cash expenses, was $45.0 million and $86.9 million, respectively, compared to $30.0 million and $56.4 million for the same periods in 2020. The increases of $15.0 million and $30.5 million for the three and six months ended June 30, 2021, respectively, were due to an increase in personnel expenses related to increased headcount to expand Sana’s research and development capabilities, costs for preclinical studies, costs for laboratory supplies, and facility costs. Research and development expenses include non-cash stock-based compensation of $3.1 million and $5.8 million for the three and six months ended June 30, 2021, respectively, and $0.9 million and $1.6 million for the same periods in 2020.
Research and Development Related Success Payments and Contingent Consideration: For the three and six months ended June 30, 2021, we recognized a gain of $76.0 million and an expense of $51.0 million, respectively, in connection with the change in the estimated fair value of the success payment liabilities and contingent consideration, compared to $51.9 million and $52.8 million for the same periods in 2020. For the three and six months ended June 30, 2021, we recognized a gain of $83.2 million and an expense of $32.4 million, respectively, in connection with the change in the estimated fair value of the success payment liabilities, compared to expenses of $37.9 million and $38.5 million for the same periods in 2020. The decreases of $121.1 million and $6.1 million during the three and six months ended June 30, 2021, respectively, were due to changes in our market capitalization and stock price during the relative periods. For the three and six months ended June 30, 2021, we recognized expenses of $7.2 million and $18.6 million, respectively, in connection with the change in the estimated fair value of contingent consideration and $14.0 million and $14.3 million, respectively, for the same periods in 2020. The decrease of $6.8 million during the three months ended June 30, 2021 and the increase of $4.3 million during the six months ended June 30, 2021 were due to changes in the discount rate and scientific progress made toward the achievement of milestones during the relative periods.
General and Administrative Expenses: General and administrative expenses for the three and six months ended June 30, 2021, inclusive of non-cash expenses, were $12.5 million and $24.3 million, respectively, compared to $6.0 million and $12.0 million for the same periods in 2020. The increases of $6.5 million and $12.3 million in the three and six months ended June 30, 2021, respectively, were primarily due to increased personnel-related expenses attributable to an increase in headcount to build our infrastructure, legal fees to support our patent portfolio and license arrangements, insurance associated with being a public company, consulting fees, and facility costs. General and administrative expenses include stock-based compensation of $1.8 million and $3.3 million for the three and six months ended June 30, 2021, respectively, and $0.2 million and $0.3 million for the same periods in 2020.
Net Income (Loss): Net income for the three months ended June 30, 2021 was $18.7 million, or $0.10 per share, and net loss for the six months ended June 30, 2021 was $161.9 million, or $1.08 per share, compared to net losses of $87.8 million, or $7.18 per share, and $120.7 million, or $10.47 per share, for the same periods in 2020.
Non-GAAP Measures

Non-GAAP Operating Cash Burn: Non-GAAP operating cash burn for the six months ended June 30, 2021 was $89.8 million compared to $56.9 million for the six months June 30, 2020. Non-GAAP operating cash burn is the decrease in cash, cash equivalents, and marketable securities excluding cash inflows from financing activities, cash outflows from business development activities, and the purchase of property and equipment.
Non-GAAP Research and Development Expenses: Non-GAAP research and development expenses for the three and six months ended June 30, 2021 were $45.0 million and $86.9 million, respectively, compared to $28.9 million and $55.0 million for the same periods in 2020. Non-GAAP research and development expenses excludes one-time costs to acquire technology.
Non-GAAP Net Loss: Non-GAAP net loss for the three and six months ended June 30, 2021 was $57.3 million, or $0.32 per share, and $110.9 million, or $0.74 per share, compared to $34.8 million, or $2.85 per share, and $66.4 million, or $5.76 per share, for the same periods in 2020. Non-GAAP net loss excludes one-time costs to acquire technology and non-cash expenses related to the change in the estimated fair value of contingent consideration and success payment liabilities.
A discussion of non-GAAP measures, including a reconciliation of GAAP and non-GAAP measures, is presented below under "Non-GAAP Financial Measures."

On August 4, 2021 Select Health of South Carolina and Quest Diagnostics reported that they have entered into an agreement that expands Select Health’s laboratory network for its Medicaid and Medicare-Medicaid dual eligible enrollees (Press release, Quest Diagnostics, AUG 4, 2021, View Source [SID1234585841]).

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Select Health, the state’s oldest and largest Medicaid managed care organization, and a member of the AmeriHealth Caritas Family of Companies, offers the First Choice Medicaid health plan statewide and the First Choice VIP Care Plus Medicare-Medicaid plan (MMP) in 42 counties. Members of both health plans are now able to obtain in-network laboratory services from Quest’s 20 locations throughout the state.

In addition, Select Health, the AmeriHealth Caritas Family of Companies, and Quest are working together to enhance access to diagnostics information services for members, increase efficiency in the delivery of laboratory services, and improve the quality of care.

"Select Health is pleased to welcome Quest Diagnostics to our network of laboratory providers," said Market President Courtnay Thompson. "We look forward to working together to improve access to the highest quality, most effective care and services for South Carolina citizens, with the shared goal of helping them achieve the best health outcomes and overall quality of life."

"We are excited about our relationship with Select Health of South Carolina and working together to drive improvements in health care, especially in underserved communities where we know health care disparities exist," said David Pivinski, executive director, Medicare & Medicaid for Quest Diagnostics. "Quest offers convenience and access to high-quality diagnostic information services, and we look forward to empowering better health for First Choice by Select Health and First Choice VIP Care Plus plan members."

First Choice Medicaid health plan members can access a full list of providers and other tools at View Source First Choice VIP Care Plus MMP members can do likewise at View Source Members of both plans may also obtain assistance by calling Member Services at the phone number on the back of their member identification card.

On August 4, 2021 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported business highlights and financial results for the second quarter ended June 30, 2021 (Press release, Fate Therapeutics, AUG 4, 2021, View Source [SID1234585801]).

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"We are very pleased with the early clinical safety and activity we have observed with our off-the-shelf, iPSC-derived NK cell programs in relapsed / refractory lymphoma and acute myeloid leukemia, where interim Phase 1 data indicate FT516 and FT538 are well tolerated and can deliver complete responses for patients. We look forward to sharing additional clinical data from our FT516 and FT596 programs in B-cell lymphoma at our upcoming investor event," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Additionally, treatment of the first patient with FT819, the first-ever iPSC-derived T-cell therapy to undergo clinical investigation, is a landmark achievement and further demonstrates the Company’s leadership in off-the-shelf, iPSC-derived cell therapy and the versatility of its proprietary iPSC Product Platform."

B-cell Malignancy Disease Franchise

Positive Interim Phase 1 Clinical Data of FT516 Presented at ASCO (Free ASCO Whitepaper). At the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper) held in June, the Company highlighted interim clinical data from its dose-escalating Phase 1 study of FT516 in combination with rituximab for the treatment of relapsed / refractory B-cell lymphoma (BCL). As of the data cutoff date of March 11, 2021, eight of eleven patients (73%) in Dose Cohorts 2 and 3 (n=4 at 90 million cells / dose and n=7 at 300 million cells / dose, respectively) achieved an objective response, including six patients (55%) who achieved a complete response. Notably, two of four patients previously treated with autologous CD19 CAR-T cell therapy achieved a complete response. The FT516 treatment regimen was well tolerated, and no treatment-emergent adverse events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GVHD) were reported. Dose escalation is ongoing with enrollment in Dose Cohort 4 (900 million cells / dose).
FT596 Phase 1 Clinical Trial Enrolling in Dose Cohort 4. The dose-escalating Phase 1 study of FT596 for patients with relapsed / refractory BCL has successfully cleared dose-limiting toxicity in Dose Cohort 3 (single dose of 300 million cells) as monotherapy and in combination with rituximab. Dose escalation of the single-dose treatment schedule is ongoing in both regimens with enrollment in Dose Cohort 4 (900 million cells). The Company is also preparing to initiate enrollment of a multi-dose treatment schedule in both regimens, with FT596 administered on Day 1 and Day 15 at 300 million cells / dose with the potential to dose escalate to 900 million cells / dose.
First Patient Treated in Landmark Phase 1 Study of iPSC-derived T-cell Therapy. In July, the first patient was treated in the Company’s landmark Phase 1 clinical trial of FT819, the first-ever T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line to undergo clinical investigation. FT819 is an off-the-shelf, allogeneic CAR T-cell therapy targeting CD19, and is engineered with several first-of-kind features designed to improve the safety and efficacy of CAR T-cell therapy including a novel 1XX CAR signaling domain (1XX-CAR19) that extends T-cell effector function without eliciting exhaustion; integration of the CAR transgene directly into the T-cell receptor alpha constant (TRAC) locus, which promotes uniform CAR expression and enhances T-cell potency; and complete bi-allelic disruption of T-cell receptor expression to prevent GVHD. The first patient received a single FT819 dose of 90 million cells for the treatment of relapsed / refractory acute lymphoblastic leukemia (ALL).
AML Disease Franchise

Interim Phase 1 Clinical Data of FT516 Demonstrate Anti-leukemic Activity. At a virtual investor event in May, the Company highlighted interim clinical data from its dose-escalating Phase 1 study of FT516 as monotherapy for the treatment of relapsed / refractory acute myeloid leukemia (AML). As of the data cutoff date of April 16, 2021, of the nine patients treated in Dose Cohorts 1 and 2 (n=3 at 90 million cells / dose and n=6 at 300 million cells / dose, respectively), six patients showed anti-leukemic activity as evidenced by on-treatment reduction in bone marrow blasts, with four patients (44%) achieving an objective response with complete clearance of leukemic blasts in the bone marrow. Three of these four responders achieved a best overall response of complete remission with incomplete hematopoietic recovery (CRi) based on 2017 ELN response criteria, including two patients in Dose Cohort 2 with ongoing remission without further therapeutic intervention at six months’ follow-up. The FT516 treatment regimen was well tolerated, and no treatment-emergent adverse events of any grade of CRS, ICANS, or GVHD were reported. Dose escalation is ongoing with enrollment in Dose Cohort 3 (900 million cells / dose).
Anti-leukemic Activity Observed in Dose Cohort 1 of FT538 Phase 1 Study. The Company also highlighted initial clinical data from its dose-escalating Phase 1 Study of FT538 as monotherapy for the treatment of relapsed / refractory AML. As of the data cutoff date of May 6, 2021, two patients in Dose Cohort 1 (100 million cells / dose) were evaluable for safety and anti-leukemic activity, both of whom showed anti-leukemic activity as evidenced by on-treatment reduction in bone marrow blasts. One patient, who was refractory to their two most recent prior therapies, achieved a CRi based on 2017 ELN response criteria at the end of the first treatment cycle. The FT538 treatment regimen was well tolerated, and no treatment-emergent adverse events of any grade of CRS, ICANS, or GVHD were reported. No dose-limiting toxicities have been observed, and dose escalation is ongoing with enrollment in Dose Cohort 1. Upon clearance of Dose Cohort 1, enrollment is set to commence in an investigator-initiated Phase 1 clinical trial of FT538 in combination with the CD38-targeted monoclonal antibody daratumumab in patients with relapsed / refractory AML, a therapeutic strategy designed to exploit the product candidate’s proprietary high-affinity, non-cleavable (hnCD16) receptor and CD38 knock-out (CD38KO) to target and eliminate CD38+ leukemic blasts.
Adaptive Phenotype and Functionality of FT538 Featured at ASGCT (Free ASGCT Whitepaper) Symposium. At the 24th Annual American Society of Gene & Cell Therapy Meeting (ASGCT) (Free ASGCT Whitepaper) held virtually in May, Dr. Jeffrey S. Miller, Professor of Medicine, University of Minnesota and Deputy Director of the Masonic Cancer Center, presented preclinical data demonstrating that the metabolic, transcriptional and functional properties of FT538 are substantially similar to those of adaptive NK cells, a discrete subset of memory-like NK cells with superior effector function. The deletion of the CD38 gene (CD38KO) was shown to enhance metabolic fitness, resistance to oxidative stress, serial innate cytotoxicity, and antibody-dependent cellular cytotoxicity compared to peripheral blood NK cells.
Multiple Myeloma Franchise

Multiple Clinical Sites Activated for Phase 1 Study of FT538 in Combination with Daratumumab. The Phase 1 clinical trial is designed to assess three once-weekly doses of FT538 in combination with the CD38-targeted monoclonal antibody, daratumumab, for patients with relapsed / refractory multiple myeloma (NCT04614636). Multiple clinical sites have now been activated for study conduct, and the Company will initiate enrollment at 100 million cells per dose upon clearance of the first dose cohort in its Phase 1 study of FT538 in relapsed / refractory AML.
Initiated GMP Production of FT576 for Phase 1 Study. FT576 is derived from a clonal master iPSC line engineered with four functional components (CAR-BCMA + hnCD16 + IL-15RF + CD38KO) designed to enable multi-antigen targeting of myeloma cells, augment antibody-dependent cellular cytotoxicity (ADCC), promote NK cell activation without exogenous cytokine support, enhance NK cell persistence and prevent anti-CD38 monoclonal antibody-induced fratricide. GMP manufacture of FT576 is ongoing, and the Company is preparing to initiate a multi-center Phase 1 clinical trial to assess single-dose and multi-dose treatment regimens of FT576 as monotherapy and in combination with CD38-targeted monoclonal antibody therapy for the treatment of relapsed / refractory multiple myeloma.
Solid Tumor Franchise

Completed Qualification of FT536 Clonal Master Engineered iPSC Bank. The master cell bank, which was created from a single iPSC clone engineered with four functional elements including a novel CAR targeting the alpha-3 domain of the pan-tumor associated stress antigens MICA and MICB, has successfully been released for initiation of FT536 GMP manufacture. Pilot manufacturing runs in support of the Investigational New Drug (IND) application for FT536 are ongoing. The Company plans to submit an IND application to the U.S. Food and Drug Administration (FDA) in the second half of 2021 to initiate a Phase 1 clinical trial of FT536 for the treatment of solid tumors. In preclinical studies, FT536 has demonstrated superior recognition and killing against a broad array of cancer cell lines compared to expanded primary NK cells as well as anti-NKG2D CAR T cells.
Preclinical Milestone Reached for First Product Candidate under Janssen Collaboration. In June, the Company and Janssen elected to initiate IND-enabling activities for an iPSC-derived CAR NK cell product candidate incorporating a Janssen proprietary antigen binding domain that targets an antigen expressed on certain solid tumors, triggering the payment of a milestone fee to the Company from Janssen under the collaboration. Janssen maintains an option to develop and commercialize the iPSC-derived CAR NK cell product candidate in all territories of the world, with the Company retaining the option to co-commercialize the product candidate in the United States.
Other Corporate Highlights

Appointed Dr. Mark Plavsic as Chief Technical Officer. Dr. Plavsic brings to the Company over 20 years of broad technical excellence in global biopharmaceutical operations, having led teams in the commercial-scale cGMP manufacture and distribution, as well as the clinical-stage process, assay, and formulation development, of complex biologics. Mark will oversee the Company’s manufacturing, technical, and supply chain operations.
Appointed Dr. Yuan Xu to its Board of Directors. Dr. Xu has over 25 years of discovery, development, manufacturing, and commercial experience in the global biopharmaceuticals business, most recently serving as the Chief Executive Officer and Board Member of Legend Biotech Corporation, where she led the company’s efforts in advancing ciltacabtagene autoleucel (cilta-cel) from proof-of-concept in 2018 to BLA preparation in 2020.
Second Quarter 2021 Financial Results

Cash & Investment Position: Cash, cash equivalents and investments as of June 30, 2021 were $845.1 million.
Total Revenue: Revenue was $13.4 million for the second quarter of 2021, which was derived from the Company’s collaborations with Janssen and Ono Pharmaceutical.
R&D Expenses: Research and development expenses were $48.0 million for the second quarter of 2021, which includes $8.6 million of non-cash stock-based compensation expense.
G&A Expenses: General and administrative expenses were $12.2 million for the second quarter of 2021, which includes $4.6 million of non-cash stock-based compensation expense.
Shares Outstanding: Common shares outstanding were 94.3 million, and preferred shares outstanding were 2.8 million, as of June 30, 2021. Each preferred share is convertible into five common shares.
Today’s Conference Call and Webcast
The Company will conduct a conference call today, Wednesday, August 4, 2021 at 5:00 p.m. ET to review financial and operating results for the quarter ended June 30, 2021. In order to participate in the conference call, please dial please dial 800-773-2954 (toll free) or 847-413-3731 (toll) and refer to conference ID 50196101. The live webcast can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.fatetherapeutics.com. The archived webcast will be available on the Company’s website beginning approximately two hours after the event.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT516
FT516 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies. CD16 mediates antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. ADCC is dependent on NK cells maintaining stable and effective expression of CD16, which has been shown to undergo considerable down-regulation in cancer patients. In addition, CD16 occurs in two variants, 158V or 158F, that elicit high or low binding affinity, respectively, to the Fc domain of IgG1 antibodies. Numerous clinical studies with FDA-approved tumor-targeting antibodies, including rituximab, trastuzumab and cetuximab, have demonstrated that patients homozygous for the 158V variant, which is present in only about 15% of patients, have improved clinical outcomes. FT516 is being investigated in a multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for the treatment of advanced B-cell lymphoma (NCT04023071). Additionally, FT516 is being investigated in a multi-dose Phase 1 clinical trial in combination with avelumab for the treatment of advanced solid tumor resistant to anti-PDL1 checkpoint inhibitor therapy (NCT04551885).

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

About FT538
FT538 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three functional components: a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; an IL-15 receptor fusion (IL-15RF) that augments NK cell activity; and the deletion of the CD38 gene (CD38KO), which promotes persistence and function in high oxidative stress environments. FT538 is designed to enhance innate immunity in cancer patients, where endogenous NK cells are typically diminished in both number and function due to prior treatment regimens and tumor suppressive mechanisms. In preclinical studies, FT538 has shown superior NK cell effector function, as compared to peripheral blood NK cells, with the potential to confer significant anti-tumor activity to patients through multiple mechanisms of action. FT538 is being investigated in a multi-dose Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and in combination with daratumumab, a CD38-targeted monoclonal antibody therapy, for the treatment of multiple myeloma (NCT04614636).

About FT819
FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease (GvHD). FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Valamehr et al. 2020). FT819 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).

On August 4, 2021 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational conditionally activated therapeutics based on its Probody technology platform, reported the publication of three articles in peer-reviewed journals on pacmilimab (CX-072), the Company’s wholly-owned conditionally activated antibody directed against PD-L1 currently being developed in combination with praluzatamab ravtansine (CX-2009) for the treatment of triple-negative breast cancer (TNBC) (Press release, CytomX Therapeutics, AUG 4, 2021, View Source [SID1234585799]).

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"My colleagues and I are delighted to see our ground-breaking work on the CytomX Probody therapeutic platform being published in high quality journals as we continue to lead this emerging and important field," said Sean McCarthy, D.Phil., president, chief executive officer and chairman of CytomX Therapeutics. "These comprehensive first-in-human results with the first ever Probody therapeutic candidate evaluated in clinical studies provide robust evidence that Probodies function as designed, eliciting potent anti-tumor activity in the context of enhanced systemic tolerability. Our technology is enabling a wide range of potentially first-in-class therapies against previously undruggable targets and also new combination therapies, opening up different ways of thinking about cancer treatment."

Constructed using CytomX’s industry-leading conditional activation Probody platform, each Probody therapeutic has a unique built-in mask that limits target binding in healthy tissues, while localizing its activation in the tumor microenvironment. This conditional activation is achieved by enabling mask removal by specific enzymes called proteases, which are activated in the tumor microenvironment, but tightly controlled in healthy tissues. Upon removal of the mask in the tumor microenvironment, Probody therapeutics engage their targets and destroy the cancer cells they were ultimately activated by.

While immune checkpoint inhibitor (ICI) therapies have transformed the landscape of cancer treatment, the limited response rates observed for cancer patients treated with single-agent PD-1/PD-L1 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibodies leave significant room for improvement. Conventional anti-PD-1/PD-L1 therapies can be impaired by immune-related adverse events (irAEs), which have been reported in as many as 30% of patients in Phase 3 studies, and particulary in combination settings.1

Pacmilimab (CX-072) is a Probody therapeutic directed against PD-L1 designed and developed by CytomX. Pacmilimab is engineered to be conditionally activated in the tumor microenvironment by tumor-associated proteases and to remain predominantly masked in the circulation. In preclinical studies, pacmilimab induced anti-tumor responses comparable to those of the parental anti-PD-L1 antibody and demonstrated reduced toxicity. Pacmilimab is wholly owned by CytomX.

First-in-human PET Imaging Study of Pacmilimab Biodistribution Published in Clinical Cancer Research

To evaluate the effect of Probody modifications on biodistribution and pharmacokinetics, we, in collaboration with Elisabeth G.E. de Vries, MD, PhD., Professor of Medical Oncology at the University Medical Centre Groningen, Groningen, the Netherlands, studied the biodistribution of pacmilimab labeled with the positron emission tomography (PET) isotope, zirconium-89 (89Zr), in patients with locally advanced or metastatic malignancies.

89Zr-labeled pacmilimab was found to be intact in the blood for up to 7 days and predominantly in its masked form in circulation, consistent with Probody design. All patients showed uptake of radioactivity into tumor lesions. Tumor-to-blood ratio of radioactivity increased over time, indicating that tumor uptake of pacmilimab is specific and retained in the tumor.

"This is the first human imaging report of a Probody therapeutic candidate that is conditionally activated in the tumor microenvironment," stated Marcia P. Belvin, Ph.D., senior vice president and head of research of CytomX Therapeutics. "The findings of intact pacmilimab in the circulation, modest uptake in normal lymphoid organs, and accumulation in the tumor, all support mechanistic performance of the Probody therapeutic platform, with target engagement in the tumor and reduced target engagement in normal tissues."

First-in-human Study of Pacmilimab in Patients with Advanced Solid Tumors Published in the Journal for ImmunoTherapy of Cancer

Patients with advanced solid tumors who were naïve to ICI therapies were eligible for this Phase 1/2 multicenter study. After the dose escalation (n=53) was complete and a recommended dose for future study defined, an additional 98 patients were enrolled into the dose expansion phase of the study, with pacmilimab administered intravenously at 10 mg/kg, the recommended Phase 2 dose (RP2D), every two weeks until confirmed disease progression or unacceptable toxicity. The tumor types evaluated included TNBC, anal squamous cell carcinoma (aSCC), cutaneous SCC (cSCC), undifferentiated pleomorphic sarcoma (UPS), small bowel adenocarcinoma (SBA), thymic epithelial tumor (TET), and high tumor mutational burden tumor (hTMB).

Combining all patients treated at 10 mg/kg, the overall objective response rate (ORR) in 114 evaluable patients who had at least one post-baseline disease assessment was 12 percent, with a disease control rate of 42 percent. Best responses per RECIST 1.1 in each tumor type are summarized in the table below:

TNBC
(n=15) aSCC (n=15) cSCC
(n=14) UPS
(n=20) SBA
(n=14) TET
(n=10) hTMB
(n=14) Others (n=12) Total (N=114)
ORR, % 7 13 36 5 0 0 29 8 12
CR, n (%) 0 0 1 (7) 0 0 0 1 (7) 0 2 (2)
PR, n (%) 1 (7) 2 (13) 4 (29) 1 (5) 0 0 3 (21) 1 (8) 12 (11)
SD, n (%) 7 (47) 6 (40) 5 (36) 4 (20) 2 (14) 5 (50) 2 (14) 3 (25) 34 (30)
DCR, n (%) 8 (53) 8 (53) 10 (71) 5 (25) 2 (14) 5 (50) 6 (43) 4 (33) 48 (42)
ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate (defined as CR, PR or SD of at least 8 weeks duration)

"These early results are very encouraging when compared with historical data from conventional ICIs," remarked Amy C. Peterson, M.D., executive vice president and chief development officer of CytomX Therapeutics. "The activities in TNBC and aSCC are particularly noteworthy given that single-agent atezolizumab had a 6% ORR in second or higher-line metastatic TNBC and the ORR for single-agent pembrolizumab in recurrent, PD-L1-positive aSCC was 17%, both of which are similar to our findings with pacmilimab in patients with more advanced disease," added Dr. Peterson.

At the RP2D of 10 mg/kg, pacmilimab displayed a favorable tolerability profile. Grade 3 or higher treatment-related adverse events (TRAEs) were reported in 10 patients (9%) and serious TRAEs in six patients (5%). The discontinuation rate due to TRAEs was a low 2%. Grade 3 or higher irAEs occurred in two patients, one each for rash and myocarditis. Additionally, pneumonitis and colitis, irAEs commonly seen in patients receiving conventional anti-PD-1/PD-L1 agents (2.2% and 0.7%, respectively),2 were reported only once for pneumonitis (0.7%) and there were no reports of colitis (0%). Collectively, these adverse event data indicate that pacmilimab is an attractive candidate for combination therapy.

First-in-human Study of Pacmilimab in Combination with Ipilimumab in Advanced Solid Tumors Published in the Journal for ImmunoTherapy of Cancer

To maximize the benefits of immunotherapy for patients, the field has moved aggressively toward combination therapy. While many of these combinations have been shown to elicit improved response rates compared with monotherapy, their adverse event profiles are often worse. A notable example is the combination of nivolumab (anti-PD-1) at a dose of 1 mg per kilogram of body weight and 3 mg per kilogram of ipilimumab (anti-CTLA-4) every three weeks, which produced a 58% ORR in a cohort of 314 patients with previously untreated advanced melanoma. However, this improved efficacy came at the cost of safety and tolerability, with grade 3 or 4 TRAEs occurring in 59% of patients.3

The goal of this first-in-human dose-finding study was to evaluate the tolerability and preliminary antitumor activity of pacmilimab combined with ipilimumab in patients with advanced, unresectable solid tumors. Twenty-seven patients who had not been previously treated with an ICI were enrolled. Dose-escalation followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy.

The ORR was 19%, including one patient with anal squamous cell carcinoma having a complete response and four partial responses in patients with leiomyosarcoma, mesothelioma, testicular cancer, and cancer of unknown primary. Moreover, these responses appeared durable, with four of five responses lasting for more than 1 year as of data cutoff on August 28, 2020, including the patient with a complete response maintaining for more than 24 months. Pacmilimab-related grade 3-4 AEs and grade 3-4 irAEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment due to AEs. There were no treatment-related deaths and no new safety signals were identified. Based on these findings, the MTD and recommended Phase 2 dose was pacmilimab 10 mg/kg in combination with ipilimumab 3 mg/kg administered every 3 weeks.

Pacmilimab is currently being evaluated in combination with praluzatamab ravtansine (CX-2009), the Company’s wholly-owned conditionally activated antibody-drug conjugate targeting CD166, in a Phase 2 study in patients with TNBC. To learn more about this study, please go to www.ClinicalTrials.gov using the identifier: NCT04596150.

On August 4, 2021 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of small molecule, MasterKey therapies, reported that its President and Chief Executive Officer, David M. Epstein, Ph.D., will present an update about the Company’s progress at the following upcoming investor conferences (Press release, Black Diamond Therapeutics, AUG 4, 2021, View Source [SID1234585796]):

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The 2021 Wedbush PacGrow Healthcare Conference. Dr. Epstein will be featured in a Targeted Oncology panel on Wednesday, August 11, 2021 at 10:20 AM ET. The session will be available via live webcast to conference attendees.
The Canaccord Genuity 41st Annual Growth Conference. The presentation will take place on Thursday, August 12, 2021 at 1:00 PM ET.
A live webcast of the Canaccord Genuity presentation can be accessed by visiting the investor relations section of the Company’s website, www.blackdiamondtherapeutics.com. A replay of the presentation will also be available and archived on the site for three weeks.