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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

On January 9, 2023 Xilo therapeutics presented its corporate presentation (Presentation, Xilio Therapeutics, JAN 9, 2023, View Source [SID1234626119]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On January 9, 2023 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative disease through the inhibition of SEMA4D, reported that its licensee, Surface Oncology (NASDAQ: SURF, "Surface") dosed the first patient in its Phase 1/2 clinical study investigating SRF114, an antibody discovered using Vaccinex’s ActivMAb antibody discovery platform and licensed to Surface Oncology in 2021 (Press release, Vaccinex, JAN 9, 2023, View Source [SID1234626116]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are very pleased that Surface has progressed SRF114 into a Phase 1/2 clinical study. Advancing this promising drug candidate into the clinic provides positive validation of our proprietary ActivMAb antibody discovery platform," said Ernest Smith, PhD, Chief Scientific Officer of Vaccinex. "ActivMAb is particularly focused on antibody targets like CCR8, a complex GPCR protein. We are gratified that we were able to provide Surface Oncology with a potential best-in-class anti-CCR8 antibody and look forward to continued progress for the SRF114 program."

SRF114 is a potential best-in-class, fully human monoclonal antibody targeting, CCR8. SRF114 was designed to selectively deplete immuno-suppressive tumor T regulatory cells (Tregs) while sparing peripheral Tregs. The highly specific binding properties of the antibody are believed to position SRF114 as a potential best-in-class anti-CCR8 antibody as a monotherapy for the treatment of advanced solid tumors. Under the terms of the antibody discovery agreement, Vaccinex has the potential to receive progress-related clinical milestone payments and royalties on sales.

On January 9, 2023 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in advancing new standards of care for the frontline treatment of hematologic malignancies, reported an update on its clinical development programs and outlined its strategic priorities for 2023 (Press release, Syros Pharmaceuticals, JAN 9, 2023, View Source [SID1234626113]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are entering 2023 with a singular focus on developing and delivering new standards of care for the frontline treatment of hematologic malignancies," said Nancy Simonian, M.D., Chief Executive Officer of Syros Pharmaceuticals. "We recently shared encouraging data from the safety lead-in portion of SELECT-AML-1, demonstrating that tamibarotene can combine with existing treatments with the goal of delivering better outcomes to newly diagnosed unfit AML patients positive for RARA gene overexpression, including those with a disease phenotype that may be resistant to venetoclax. These results support our advancement into the randomized portion of SELECT-AML-1, which we expect to initiate in the first quarter of 2023, and give us growing confidence in the potential for tamibarotene to provide clinical benefit to AML and MDS patients with RARA overexpression. We are on track to report initial data from this study in the fourth quarter of 2023."

Dr. Simonian added, "In addition, we continue to open clinical sites and enroll newly diagnosed HR-MDS patients positive for RARA gene overexpression in our Phase 3 SELECT-MDS-1 trial. While we are encouraged by physician and patient enthusiasm at open clinical sites, we have experienced slower-than-anticipated site activations as we expanded the study global footprint and now expect data from the SELECT-MDS-1 trial in the third quarter of 2024."

Program Updates and Upcoming Milestones

Tamibarotene: Higher-Risk Myelodysplastic Syndrome (HR-MDS)

Syros is evaluating tamibarotene in combination with azacitidine in newly diagnosed HR-MDS patients with RARA overexpression in the ongoing SELECT MDS-1 Phase 3 trial, which the company believes is the only Phase 3 trial currently recruiting in frontline HR-MDS. This randomized, double-blind, placebo-controlled study is intended to enroll 190 patients. Syros currently has over 75 clinical sites open for recruitment in 12 countries. Syros expects to complete patient enrollment in SELECT-MDS-1 in the fourth quarter of 2023, with data to follow in the third quarter of 2024.

Tamibarotene: Acute Myeloid Leukemia (AML)

Syros is evaluating tamibarotene in combination with venetoclax and azacitidine in newly diagnosed unfit AML patients with RARA overexpression. At the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2022, Syros presented data from six response-evaluable patients from the safety lead-in portion of the ongoing SELECT-AML-1 Phase 2 trial, in which treatment with the triplet combination of tamibarotene, venetoclax and azacitidine demonstrated an 83 percent composite complete response rate and rapid onset of action, with no evidence of increased toxicity relative to historical data of the venetoclax and azacitidine doublet combination. Based on these data, Syros plans to initiate the randomized portion of the SELECT-AML-1 Phase 2 trial in the first quarter of 2023, directly comparing the triplet of tamibarotene, venetoclax and azacitidine to the doublet of venetoclax and azacitidine with initial randomized data expected in the fourth quarter of 2023 and additional data in 2024.

SY-2101: Acute Promyelocytic Leukemia (APL)

Syros is developing SY-2101, a novel oral form of arsenic trioxide (ATO) for the treatment of newly diagnosed APL patients. In August 2022, Syros reported promising preliminary data from its dose confirmation study of SY-2101, which showed that SY-2101 administered at 15 mg achieved comparable pharmacokinetic (AUC and Cmax) exposures to the approved intravenous (IV) dose of ATO administered at 0.15 mg/kg, with high oral bioavailability of approximately 80 percent and a favorable tolerability profile. Syros is encouraged by this initial data and, if additional data are supportive, intends to leverage these results to explore an alternative, more efficient registration strategy for SY-2101. Syros plans to provide an update on the dose confirmation study, as well as the development path and timing for further evaluation of SY-2101 in a registration enabling study in APL, in the second half of 2023.

CDK Inhibitor Portfolio and Discovery-Stage Oncology Programs

In November 2022, Syros announced initial data from the safety lead-in portion of its Phase 1 trial evaluating SY-5609 in combination with chemotherapy in patients with relapsed/refractory metastatic pancreatic cancer as well as an update from the single agent portion in advanced solid tumor patients. The data demonstrated encouraging safety and clinical activity in pancreatic cancer patients, including a partial response and an emerging exposure response relationship. Syros is continuing dose escalation of SY-5609 as a single agent and as a doublet with gemcitabine while seeking partnership opportunities for the program.

In addition, Roche continues to enroll patients in the arm of its ongoing Phase 1/1b INTRINSIC trial evaluating SY-5609 in combination with atezolizumab, its PD-L1 inhibitor, in BRAF-mutant colorectal cancer patients. Under the terms of the collaboration, Roche is the sponsor of the trial and Syros is supplying SY-5609.

As previously disclosed, Syros is also exploring partnership opportunities for its oncology discovery programs.

Financial Guidance

Based on its current operating plans, including the deferral of the SY-2101 registration enabling study, Syros expects that its existing cash, cash equivalents, and marketable securities will be sufficient to fund its anticipated operating expenses and capital expenditure requirements into the second quarter of 2025, beyond the Phase 3 data from the SELECT-MDS-1 trial and the initial data from the randomized portion of SELECT-AML-1 trial.

On January 9, 2023 Sutro Biopharma, Inc. (Sutro or the Company) (NASDAQ: STRO), a clinical-stage oncology company pioneering site-specific and novel-format antibody drug conjugates (ADCs), reported its results from a Phase 1 dose-expansion study of STRO-002 (luvelta), a novel Folate receptor alpha (FolRα)-targeting ADC and interim safety data from exploratory cohort C, a cohort of 15 patients with advanced ovarian cancer treated at the higher dose of luvelta, (5.2mg/kg), along with prophylactic pegfilgrastim. Additionally, the company provided details on the design of the registration-directed Phase 2/3 study, REFRaME, to start in the second quarter of 2023 (Press release, Sutro Biopharma, JAN 9, 2023, View Source [SID1234626112]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Results demonstrated that luvelta provided substantial clinical benefit in FolRα-selected patients, defined by Tumor Proportion Score (TPS) of >25%, with a 37.5% overall response rate (ORR), median duration of response (median DOR) of 5.5 months, and median progression free survival (median PFS) of 6.1 months, regardless of starting dose. Results also demonstrated the higher starting dose of 5.2 mg/kg providing greater patient benefit compared to the lower dose of 4.3mg/kg. FolRα-selected patients account for approximately 80% of the patient population in advanced ovarian cancer, as represented in the patient stratification in the Phase 1 study.

Consistent with prior luvelta data, the primary adverse event from the dose-expansion cohort was predominantly asymptomatic neutropenia, with no meaningful ocular toxicity signals or complications reported.

In cohort C, an additional 15 patients with advanced ovarian cancer were enrolled and treated with prophylactic pegfilgrastim on Day 8 after each 5.2 mg/kg administration of luvelta. Initial data on neutropenia and dose delays were available on the first 10 patients, which showed that patients in cohort C experienced substantial decreases in neutropenia and potential increases in dose intensity, due to decreased dose delays.

"Today, patients with this form of heavily pre-treated ovarian cancer have extremely limited treatment options available to them, and unfortunately, experience poor outcomes," said Dr. R. Wendel Naumann, Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, and a co-lead principal investigator in the STRO-002-GM1 studies. "To date, luvelta continues to demonstrate encouraging efficacy data, which was further supported by results from the dose-expansion cohort. The safety profile was shown to be manageable and notably devoid of ocular complications across a broad spectrum of patients with FolRα-selected ovarian cancer."

Commented Bill Newell, Chief Executive Officer of Sutro: "We are pleased with our Phase 1 dose-expansion efficacy data, which are generally consistent with previously reported results and demonstrate luvelta’s potential in a difficult-to-treat patient population. Through the addition of cohort C, we were able to evaluate patients at the higher dose of luvelta at 5.2mg/kg with the use of prophylactic pegfilgrastim and determined that the rates of asymptomatic neutropenia and dose delays could be diminished. Our meeting with the FDA in 2022 provided a framework for our path forward on the registration-directed Phase 2/3 trial for platinum resistant ovarian cancer patients, called REFRaME, which we plan to initiate in the second quarter of 2023."

Summary of Results from Phase 1 Dose-Expansion Study

Based on the results, luvelta has demonstrated the potential to provide meaningful clinical benefit to a substantially broader patient population than the on-label patient population of the approved FolRα-targeting agent

Patients who were FolRα-selected, defined by TPS>25%, regardless of starting dose, demonstrated an ORR of 37.5% (n=32) with a median DOR of 5.5 months (n=12) and a median PFS of 6.1 months (n=35)

Targeted luvelta patient population is approximately 80% of advanced ovarian cancer patients based on pooled Phase 1 biomarker data

Luvelta demonstrated a FolRα-dependent response, with patients who were unselected for FolRα (TPS≤25%) demonstrating an 11.1% ORR (n=9) with a median DOR of 2.9 months (n=1) and a median PFS of 3.8 months (n=9)

Luvelta, when given to patients at a starting dose of 5.2 mg/kg, provided greater patient benefit than a starting dose of 4.3 mg/kg

FolRα-selected patients given the higher dose of luvelta (5.2 mg/kg) demonstrated higher response rates

ORR of 43.8% (n=16)

Median DOR of 5.4 months (n=7)

Median PFS of 6.6 months (n=16)

FolRα-selected patients given the lower dose of luvelta (4.3 mg/kg) demonstrated

ORR of 31.3% (n=16)

Median DOR of 13 months (n=5)

Median PFS of 6.1 months (n=19)

Consistent with earlier reported data, the primary adverse event from the dose-expansion cohort was asymptomatic, transient neutropenia

Cohort C was initiated to explore the use of prophylactic pegfilgrastim for patients treated with the higher dose of luvelta (5.2mg/kg). Early results in the initial 10 patients in cohort C, when compared to patients who were not given prophylactic pegfilgrastim in the dose-expansion cohort at the higher dose (5.2mg/kg), showed substantial reductions in Grade 3+ neutropenia and in instances of dose delays

Grade 3+ neutropenia was reduced from 66.7% to 10.0%, resulting in an 85.0% decrease in Grade 3+ neutropenia rates at the first cycle of luvelta (p=0.006)

Instances of dose delays at the second cycle of luvelta were reduced by 60.6% (p=0.021)

Planned Phase 2/3 Study Details

As discussed with the U.S. Food and Drug Administration (FDA), the Phase 2/3 REFRaME study is planned to begin with a randomized, run-in dose confirmation phase. In this phase of the trial, 25 patients will be evaluated at the 5.2 mg/kg dose with pegfilgrastim delivered prophylactically for two cycles followed by a step-down dose to 4.3 mg/kg. The other 25 patients will be evaluated from the start at the 4.3 mg/kg dose without prophylactic pegfilgrastim. Following this 50-patient phase of the study, additional patients will be randomized between these two luvelta dose levels, and standard of care (chemotherapy). Upon agreement with FDA on the go-forward dose versus standard of care, the dose level of luvelta not chosen will be dropped. Upon having data on approximately 110 patients in the selected dose of luvelta arm, Sutro will look to apply for accelerated approval based on ORR as the primary endpoint. At the end of the Phase 3 portion of the trial, full approval can be sought based on PFS as the primary endpoint comparing the luvelta arm (n=160) and the standard of care arm (n=160).

Webcast Details

The data will be presented by members of the Sutro management team and Dr. R. Wendel Naumann, a co-lead principal investigator in the STRO-002-GM1 studies. Dr. Naumann is a Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina. Dr. Naumann is also a member of Sutro’s Clinical Advisory Board.

Monday, January 9, 2023 at 1:30 pm PT, or 4:30 pm ET

To access and register for the live audio webcast, please go to View Source

The webcast information will also be available through the News & Events section of the Investors portion of the Company’s website at www.sutrobio.com. An archived replay will be available for at least 30 days after the event.