On December 12, 2022 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported an update for both Part A and Part B of the Company’s ongoing Phase 1 CARBON trial evaluating the safety and efficacy of CTX110, its wholly-owned allogeneic CAR T cell therapy targeting CD19+ B-cell malignancies (Press release, CRISPR Therapeutics, DEC 12, 2022, View Source [SID1234625100]). Part A data, presented at ASH (Free ASH Whitepaper), showed the potential for CTX110 to achieve long-term durable complete remissions (CRs) with a positively differentiated safety profile in heavily pre-treated patients, and emerging data from Part B showed an encouraging efficacy profile with several patients in ongoing CR beyond six months.

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"We are excited by these results in our CARBON trial, which demonstrate the potential of a single course of allogeneic CAR T treatment to produce long-lasting complete remissions in heavily pre-treated patients with LBCL," said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. "Furthermore, we are encouraged by the emerging data using consolidation dosing, which has the potential to further improve the efficacy profile while maintaining a positively differentiated safety profile. Based on these results, we have initiated a potentially registrational Phase 2 trial of CTX110 incorporating consolidation dosing with the hope of bringing this important therapy to patients in the near term."

CARBON Trial Overview
The Phase 1 CARBON trial is an open-label, multicenter clinical trial evaluating the safety and efficacy of CTX110 in adult patients with relapsed or refractory CD19+ B-cell malignancies who have received at least two prior lines of therapy. To date, enrollment has been focused on patients with the most aggressive disease presentations, including Diffuse Large B-cell Lymphoma (DLBCL) not otherwise specified (NOS), high-grade double- or triple-hit lymphomas, transformed follicular lymphoma, and grade 3B follicular lymphoma. In Part A of the trial, patients were infused with a single dose of CTX110 following three days of a standard lymphodepletion regimen consisting of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day). Patients received CTX110 at doses ranging from Dose Level (DL) 1 (30 million CAR+ T cells) to DL4 (600 million CAR+ T cells), with an option to re-dose CTX110 based on clinical benefit. In Part B of the trial, patients received CTX110 at DL4 following standard lymphodepletion, as well as a consolidation dose of CTX110 at the same dose level between four and eight weeks after the initial dose for patients that demonstrate clinical benefit. The primary endpoints include safety as measured by the incidence of dose limiting toxicities (DLTs) and overall response rate (ORR). Key secondary endpoints include complete response (CR) rate, duration of response (DOR) and overall survival (OS).

PART A

Data presented at ASH (Free ASH Whitepaper) (Poster #4629) show the potential for single infusions of CTX110 to achieve long-term durable complete remissions with a positively differentiated safety profile.

In a heavily pre-treated patient population with relapsed or refractory (R/R) LBCL (47% with ≥3 prior lines of therapy), CTX110 at DL≥3 (n=27) resulted in an ORR of 67% and CR rate of 41%.

Three patients remain in ongoing CR two years after treatment, and two additional patients remain in CR past one year.

No DLTs, no Graft versus Host Disease (GvHD) of any grade, and no Grade ≥3 cytokine release syndrome (CRS) events were observed.

These data formed the basis for Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA for CTX110, granted in November 2021.
PART B

Emerging data from Part B shows an encouraging efficacy profile with several patients in ongoing CR beyond six months.

Clear evidence of the benefits of consolidation dosing was observed, with deepening of CRs and conversions of stable disease and partial response to ongoing CRs after the second dose.

Safety profile remained consistent with Part A, confirming the tolerability of the consolidation regimen.

Peak expansion and overall pharmacokinetics of CTX110 were comparable between the initial and consolidation doses.

The Company plans to present additional Part B data at a future medical meeting.
Following discussions with regulatory agencies, the Company has initiated a single-arm, potentially registrational trial of CTX110, which incorporates consolidation dosing at DL4 and standard lymphodepletion. Dosing in this trial is expected to begin in early 2023 using drug product manufactured with a commercial-ready process and specifications.

About CTX110 and CARBON Trial

CTX110, a wholly owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting cluster of differentiation 19, or CD19. CTX110 is being investigated in the ongoing CARBON trial, a Phase 1 single-arm, multi-center, open label clinical trial, CARBON, is designed to assess the safety and efficacy of several dose levels of CTX110 for the treatment of relapsed or refractory B-cell malignancies. CTX110 has been granted RMAT designation by the FDA.

On December 12, 2022 Corvus Pharmaceuticals, Inc. (Corvus or the Company) (NASDAQ: CRVS), a clinical-stage biopharmaceutical company, reported updated results from its Phase 1/1b trial of CPI-818, the Company’s ITK inhibitor, which demonstrated its anti-tumor activity in patients with T cell lymphoma (TCL) and its therapeutic potential in Th2 and Th17-mediated autoimmune and allergic diseases (Press release, Corvus Pharmaceuticals, DEC 12, 2022, View Source [SID1234625099]). The data will be presented today in a poster at the 64TH American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, which is taking place in-person and virtually from December 10 to 13, 2022.

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"ITK inhibition with CPI-818 has demonstrated monotherapy anti-tumor activity in highly refractory T cell lymphoma patients, a population with limited and often ineffective treatment options," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "We have seen durable objective tumor responses in four of eleven evaluable patients. Based on the clinical results to-date, we plan to advance CPI-818 into a global Phase 2 clinical trial in T cell lymphoma in mid-2023. The study will be conducted in partnership with Angel Pharmaceuticals, which is responsible for the trial in China, where there is a higher incidence and prevalence of T cell lymphoma. The Phase 1 data also provided in vivo evidence of CPI-818’s ability to modulate immune functions of T cells by blocking both Th2 and Th17 T cells and skewing toward Th1 cells. The effects are important for cancer therapy – Th1 cells are essential for elimination of tumor cells – as well as in autoimmune and allergic diseases given that Th2 and Th17 cells are involved in many of these diseases. The clinical and preclinical findings reported at ASH (Free ASH Whitepaper) suggest that CPI-818 enhances anti-tumor immunity and represents a potential novel approach to immunotherapy. We are advancing CPI-818 across multiple therapeutic areas, starting with a Phase 1 clinical trial in atopic dermatitis, known to be a Th2 driven disease, planned for early 2023."

Dr. Miller concluded, "Overall, we believe the data presented at ASH (Free ASH Whitepaper) provides a strong foundation and rationale for ITK inhibition in lymphoma and certain immune diseases. CPI-818 is the most advanced ITK inhibitor we are aware of and has demonstrated high selectivity for ITK, which we believe has been crucial to achieving the immunomodulatory functions observed in our studies to date and represents a significant achievement of our research and development group. We look forward to providing updates on the development of CPI-818 and our other clinical programs – ciforadenant as a potential first line therapy for metastatic renal cell cancer and Angel Pharmaceutical’s study of mupadolimab in patients with relapsed refractory non-small cell lung cancer and head and neck squamous cell cancers – in the coming months and year."

CPI-818 Phase 1/1b Clinical Trial Key Results Presented at ASH (Free ASH Whitepaper) 2022
CPI-818 is being studied in a Phase 1/1b clinical trial as a single agent therapy in patients with relapsed TCL. As of September 2, 2022, 43 patients were enrolled in the trial across four escalating dosing cohorts: 100, 200, 400 and 600 mg, each being administered twice per day. The 200 mg dose was found to provide plasma drug concentrations that optimally affect T cell differentiation in vitro and correspondingly was found to lead to the most frequent and durable tumor responses in vivo. Accordingly, Corvus identified it as the optimal dose and additional patients are being enrolled in a 200 mg dose cohort of the clinical trial. The Phase 1/1b clinical trial endpoints are safety, pharmacokinetics (PK), immunologic effects and tumor response.

T Cell Lymphoma Interim Data Highlights

13 patients were enrolled in the 200 mg cohort and 11 were evaluable for response. Overall objective responses were seen in 4 of 11 patients. Enrolled patients were heavily pretreated receiving a median of 3 prior therapies. In this group, there was one complete response (CR) lasting 25 months in a patient with peripheral T cell lymphoma (PTCL); one nodal CR lasting 19 months in a patient with cutaneous T cell lymphoma; and two partial responses (PR) ongoing at six and eight months follow up, respectively, in patients with PTCL and anaplastic large cell lymphoma. An additional patient in the 600 mg cohort also had a PR.
No dose limiting toxicities were observed, and a maximally tolerated dose was not reached at doses as high as 600 mg twice per day.
All of the foregoing data was as of September 2, 2022.

Immunologic Effects Interim Data Highlights

As of September 2, 2022, the 200 mg optimal dose was shown to induce Th1 skewing and both Th2 and Th17 blockade based on peripheral blood samples from several patients:

In one patient that had a significant reduction of a large tumor on the abdominal wall, a blood sample analysis demonstrated an increase in blood Th1, a decrease in blood Th17, and a reduction of eosinophil count and IL-5 consistent with Th1 skewing and Th2 blockade. Tumor samples in this patient were also analyzed and showed an increase in terminally differentiated T effector memory cells (TEMRA cells), which are T cells that have responded to an antigen and are able to mediate effector functions, such as the destruction of tumor cells.
In four patients (two with PRs, one with stable disease (SD) and one with progressive disease (PD), the change in Th1 and CD8+ TEMRA cells was serially measured over time. The PR and SD patients showed an increase in both Th1 and CD8+ TEMRA cells. Of note, SD and PD patients were lymphopenic at baseline with absolute lymphocyte counts <1,000, highlighting the need for a minimal level of immune competence.

In vitro data demonstrated that CPI-818 induced Th1 skewing and Th2 blockade in a dose-dependent manner that supported the selection of the 200 mg dose. This includes an analysis of peripheral blood samples from 12 healthy volunteers that were stimulated in the presence of various concentrations of CPI-818 and other studies that showed that CPI-818 inhibited Th2 cytokine production from normal CD4+ and Sezary cells.
Other in vitro studies showed that CPI-818 inhibited the production of interleukin 4, 5 and 13 cytokines produced by Th2 cells.

In vivo preclinical studies in mice with transplanted T cell lymphoma showed that CPI-818 led to an increase in infiltration of normal CD8+ T cells in the tumor and inhibition of tumor growth.
The findings of the human and preclinical studies suggest that CPI-818 enhances anti-tumor immunity representing a potentially novel approach to immunotherapy.

Separate from the ASH (Free ASH Whitepaper) presentation, Corvus recently initiated a CPI-818 study in companion dogs with naturally occurring, refractory atopic dermatitis. Early results from this study demonstrated CPI-818’s potential activity in this disease with five out of five treated dogs responding to therapy within 14 days.
Conference Call, Webcast and Presentation Slides

Corvus will host a conference call and webcast today, Monday, December 12, 2022 from 4:30 – 5:30 pm ET to provide an overview of the CPI-818 data that presented at the ASH (Free ASH Whitepaper) meeting, along with providing an update on the Company’s development programs. The conference call can be accessed by dialing 1- 877-300-8521 (toll-free domestic) or 1- 412-317-6026 (international) and using the conference ID 10172958. The live webcast, which will include presentation slides, may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus’ website for 90 days.

On December 12, 2022 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that Roche issued a press release on data presentation regarding therapeutic antibodies created by Chugai, Hemlibra and crovalimab, at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Chugai, DEC 12, 2022, View Source [SID1234625097]).

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Please refer to the link below for details:

Interim data from phase III study presented at ASH (Free ASH Whitepaper) 2022 show Hemlibra achieved meaningful bleed control in infants from birth
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Roche’s subcutaneous crovalimab given every four weeks achieves disease control in people with PNH, a life-threatening blood condition
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On December 12, 2022 Caribou Biosciences, Inc. (Nasdaq: CRBU), a leading clinical-stage CRISPR genome-editing biopharmaceutical company, reported target selection for CB-020, an induced pluripotent stem cell (iPSC)-derived allogeneic anti-ROR 1 (receptor tyrosine kinase like orphan receptor 1) CAR-NK cell therapy (Press release, Caribou Biosciences, DEC 12, 2022, View Source [SID1234625093]). Preclinical data on the selection of the CB-020 CAR construct and armoring strategies for Caribou’s CAR-NK cell platform will be presented today at the 12th American Association for Cancer Research (AACR) (Free AACR Whitepaper) and Japanese Cancer Association (AACR-JCA) Joint Conference.

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"ROR1 has been selected as the target for CB-020, Caribou’s first off-the-shelf iPSC-derived CAR-NK cell therapy, and the preclinical data presented at AACR (Free AACR Whitepaper)-JCA shows that ROR1 may be a promising target for several solid tumor indications," said Steve Kanner, Ph.D., Caribou’s chief scientific officer. "We are leveraging our chRDNA genome-editing technology across our allogeneic CAR-T and CAR-NK cell programs to address disease-specific challenges. For solid tumors, we are exploring several armoring strategies for our allogeneic CAR-NK cell therapy platform, including a CBLB knockout, a B2M knockout with a B2M–HLA-E fusion protein insertion, and a membrane-bound IL-15 insertion/IL-15RA fusion protein to help overcome the complex tumor microenvironment that has challenged previous cell therapies."

iPSC-derived NK cells innately exhibit potent antitumor activity against solid tumors. CB-020 is being engineered using Caribou’s Cas12a chRDNA genome-editing technology to express a ROR1-specific CAR, which can enhance the innate NK cell antitumor activity by increasing specificity and function. ROR1 is a cell signaling receptor that is overexpressed on the surface of several solid tumor types and has been shown to drive tumor cell growth, survival, and metastasis. Preclinical data to be presented at AACR (Free AACR Whitepaper)-JCA show that a single dose of iPSC-derived anti-ROR1 CAR-NK cells, administered in a tumor xenograft model, significantly reduced tumor burden compared to iPSC-derived NK cells without an anti-ROR1 CAR.

Multiple armoring strategies are being developed for Caribou’s CAR-NK cell platform to enhance tumor targeting, allogeneic CAR-NK cell survival, and persistence of antitumor activity. Results from the company’s preclinical studies suggest iPSC-derived NK cells with a knockout of CBLB (Casitas B-Lineage lymphoma proto-oncogene-B), a ubiquitin ligase that negatively regulates NK cell function, results in reduced tumor burden and increased overall survival in an in vivo solid tumor xenograft model, compared to unedited iPSC-derived NK cells. Additionally, results show that iPSC-derived NK cells were not killed by donor-derived T cells and NK cells when harboring a knockout of B2M and an insertion of a BM2–HLA-E fusion protein. This strategy may induce more potent NK activity and help prevent CAR-NK cells from killing each other, which is a common problem with NK cell therapies. In addition, results from iPSC-derived NK cells with an insertion of membrane-bound IL-15/IL-15RA

fusion protein, which is shown to enhance NK cell antitumor activity, demonstrated high cytotoxicity against tumor cells compared to unedited iPSC-derived NK cells. Together, these preclinical data demonstrate Caribou’s genome-editing technology has the potential to be used to implement a variety of armoring strategies in iPSC-derived CAR-NK cells to address many of the challenges associated with treating solid tumors.

Details of the poster presentation at the AACR (Free AACR Whitepaper)-JCA Joint Conference are as follows:

Title: CB-020, an iPSC-derived allogeneic CAR-NK cell therapy
Speaker: Rudy Gonzalez, Ph.D., executive director of stem cell therapeutics, Caribou Biosciences, Berkeley, CA
Date and time: Monday, December 12 at 5:30 pm HST
Abstract number: B06
Location: Hyatt Regency Maui, Monarchy Ballroom

The full poster is available on Caribou’s Scientific Publications (www.cariboubio.com/technology/#pubs) webpage.

On December 12, 2022 PharmaMar (MSE:PHM) has reported receipt of a payment of $10 million from Janssen Products LP after reaching a commercial milestone for Yondelis (trabectedin) in the United States as defined in the licensing agreement (Press release, PharmaMar, DEC 12, 2022, View Source [SID1234625092]).

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In August 2019, PharmaMar entered into a new licensing agreement with Janssen, which replaced a 2001 licensing agreement, under which Janssen retained the right to sell and distribute, on an exclusive basis, Yondelis in the USA.

Today, Yondelis is approved in more than 70 countries for the treatment of soft tissue sarcoma and in some of these countries ovarian cancer as well.