On January 9, 2023 – Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported its 2023 corporate priorities and provided multiple clinical development updates (Press release, Xencor, JAN 9, 2023, View Source [SID1234626118]).
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Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor, said:
"The plug-and-play nature of Xencor’s XmAb Fc domains and our protein engineering expertise have enabled a broad portfolio of bispecific antibody and engineered cytokine drug candidates in oncology and autoimmune disease, as well as a multitude of partnerships that continue to generate milestone payments and ongoing royalties. We seek to address challenging areas of biology with our drug candidates, testing them in early-phase clinical trials to rapidly determine which we advance internally, partner or terminate. In 2022 we advanced this strategy, presenting encouraging clinical data from multiple programs, stopping internal development of two programs, and expanding our clinical-stage portfolio with two novel format bispecific antibodies.
"We are building on this momentum in 2023, progressing our clinical portfolio internally and with our co-development partners, including four bispecific antibody programs targeting solid tumors. Later this year, we will add a third engineered cytokine program to the clinic, following recent Phase 1 data for XmAb564, our regulatory T-cell targeting IL-2-Fc for autoimmune disease. We plan to present emerging clinical data as our programs advance and look forward to important updates and milestones from several partner programs throughout the year."
Execute on development plans for XmAb bispecific antibody and cytokine programs in oncology
Plamotamab (CD20 x CD3), for B-cell malignancies
Xencor is co-developing plamotamab with Janssen Biotech, Inc. Xencor presented updated Phase 1 expansion cohort data for intravenously administered plamotamab in December 2022. In the fourth quarter of 2022, Xencor began dosing patients with subcutaneously administered plamotamab. Separately, the Company is winding down and ending enrollment in the Phase 2 study evaluating intravenous plamotamab in combination with tafasitamab and lenalidomide, in patients with relapsed or refractory diffuse large B-cell lymphoma, due to challenges with patient accrual in lymphoma. Xencor plans to:
Advance chemotherapy-free treatment options for patients with lymphoma, and in collaboration with Janssen scientists, Xencor is developing B-cell targeted, co-stimulatory CD28 bispecific antibodies to selectively enhance T-cell cytotoxic activity in combination with plamotamab.
Continue enrolling patients into the Phase 1 subcutaneous dose escalation study.
Vudalimab (PD-1 x CTLA-4), designed to activate intra-tumoral T cells
Xencor is advancing vudalimab, a selective dual checkpoint inhibitor, in multiple Phase 2 clinical studies. Initial Phase 2 combination data in patients with metastatic castration-resistant prostate cancer (mCRPC) were presented in November 2022. Xencor is also conducting a Phase 2 monotherapy study in patients with advanced gynecologic tumors and clinically defined high-risk mCRPC. Xencor plans to:
Continue enrolling patients into the two Phase 2 clinical studies of vudalimab.
XmAb306, potency-reduced IL15/IL15Rα-Fc fusion protein
Xencor is co-developing XmAb306 in collaboration with Genentech, a member of the Roche Group. Genentech is conducting a Phase 1 study of XmAb306 as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Genentech is also conducting two additional Phase 1 studies, evaluating XmAb306 in patients with relapsed/refractory multiple myeloma, either in combination with daratumumab (anti-CD38 antibody) or in combination with cevostamab (FcRH5 x CD3 bispecific antibody). Xencor plans to:
Support enrollment into clinical studies in combination with other agents.
XmAb104 (PD-1 x ICOS), designed to activate intra-tumoral T cells
A Phase 1 study is evaluating XmAb104 with or without the anti-CTLA4 antibody ipilimumab, as CTLA-4 blockade has been found to increase the frequency of ICOS-expressing T cells in multiple solid tumors. Initial data reported in 2022 indicated XmAb104 was well tolerated and exhibited a distinct safety profile compared to other clinical-stage ICOS programs. Xencor plans to:
Continue enrolling patients into the expansion portion of the Phase 1 clinical study.
XmAb819 (ENPP3 x CD3), XmAb 2+1 bispecific antibody for renal cell carcinoma (RCC)
XmAb819 uses Xencor’s XmAb 2+1 bispecific antibody format for greater selectivity of ENPP3-expressing tumor cells compared to normal cells, which express lower levels of ENPP3. Xencor plans to:
Continue enrolling patients into the Phase 1 dose-escalation study in patients with RCC.
XmAb808 (B7-H3 x CD28), tumor-selective, co-stimulatory CD28 bispecific antibody
CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are usually not expressed on tumor cells. Targeted CD28 bispecific antibodies may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies. XmAb808 targets the broadly expressed tumor antigen B7-H3. Xencor plans to:
Continue enrolling patients into the Phase 1 dose-escalation study in patients with advanced solid tumors. The first patient was dosed in the fourth quarter of 2022.
XmAb662, potency-reduced IL12-Fc fusion protein designed to increase tumor immunogenicity
IL-12 is a potent pro-inflammatory cytokine that promotes high levels of interferon gamma secretion from T-cells and NK cells, increasing their cytotoxicity and the immunogenicity of the tumor microenvironment by making tumor antigens more visible to the immune system. Xencor plans to:
Initiate a Phase 1 study in patients with advanced solid tumors in mid-2023.
XmAb541 (Claudin-6 x CD3), XmAb 2+1 bispecific antibody for ovarian cancer
Claudin-6 (CLDN6) is a tumor-associated antigen overexpressed in ovarian cancer and other solid tumors, and its differential expression in cancerous tissue makes CLDN6 an intriguing target for CD3 bispecific antibodies. Many members of the claudin family, which are small transmembrane proteins, have high sequence identity, complicating the design of antibodies selective among claudins. XmAb541 was engineered with the XmAb 2+1 bispecific antibody format, and the tumor binding domain was further engineered for improved selectivity of CLDN6 over similar claudin family members, such as CLDN9. Xencor plans to:
Submit an investigational new drug application (IND) in 2023.
Explore the clinical potential of XmAb564, a wholly owned IL2-Fc cytokine fusion targeting regulatory T cells in autoimmune disease
XmAb564 is a potency-reduced, monovalent interleukin-2 Fc (IL-2-Fc) fusion protein, designed to selectively activate and expand regulatory T cells (Tregs) for the potential treatment of patients with autoimmune diseases. In November 2022, Xencor presented data from a Phase 1a single-ascending dose study in healthy volunteers, demonstrating that a single dose was well tolerated and generates durable, dose-dependent and selective expansion of Tregs. Xencor plans to:
Continue enrolling patients into the Phase 1b, multiple-ascending dose study in patients with atopic dermatitis and psoriasis.
Cash Position and Financial Guidance
Xencor’s broad development portfolio is supported by a strong financial position. Xencor ended the fourth quarter of 2022 with unaudited cash, cash equivalents, receivables and marketable debt securities totaling approximately $610 million. Based on current operating plans, Xencor expects to have sufficient cash resources to fund research and development programs and operations through the end of 2025.