On June 10, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that preclinical data from its ROR1-targeting cell therapy programs will be highlighted in a poster presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress (Press release, Oncternal Therapeutics, JUN 10, 2022, View Source [SID1234615875]). Oncternal’s collaborators from the Karolinska Institutet in Stockholm, Sweden, have conducted a series of preclinical studies evaluating T cells as well as Natural Killer cells expressing Oncternal’s ROR1 CAR containing the antigen binding region of zilovertamab. The ROR1 CAR mediated target recognition and cell activation when expressed in either T cells or NK cells. Also, ROR1 CAR-T cells demonstrated dose-dependent anti-tumor activity in a mantle cell lymphoma mouse model.

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Poster Title: Preclinical Evaluation of Zilovertamab-Based Anti-ROR1 Chimeric Antigen Receptors in NK and T Cells
Abstract Number: P1435
Session Title: Gene therapy, cellular immunotherapy and vaccination – Biology & Translational Research
Session Date and Time: June 11, 2022 from 9:00am CEST
"Despite recent significant advances in treating hematological malignancies with current CAR-based cell therapies, certain limitations remain, such as treatment failures due to tumor antigen escape, and toxicities including induction of immunodeficiencies like B-cell aplasia. Patients are in need of more effective treatment options" said Evren Alici, M.D., Ph.D., Associate Professor and group leader of the Cell and Gene Therapy Group, HERM, Department of Medicine, Karolinska Institutet. "The ROR1-targeting cell therapies have shown strong activity in our lymphoma models. We are now working with our Oncternal colleagues to evaluate the therapies in models of other tumor indications. With our strong focus on NK cells, we are excited to further study ROR1 CAR-NK cells within our NextGenNK competence center."

"Based on the wide expression of ROR1 across tumor indications and its underlying importance in cancer biology as well as the safety and efficacy shown by zilovertamab in our clinical studies, we believe that targeting ROR1 using zilovertamab-based CAR cell therapy might offer a potentially effective treatment option for patients suffering from unmet medical needs, including heme malignancies and solid tumors" said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "In preclinical research, our zilovertamab-derived ROR1 cell therapies have demonstrated anti-tumor activity in a series of studies, including these presented here by our colleagues from the Karolinska Institutet. We are working closely with Professor Evren Alici and his team to evaluate our ROR1 cell therapies using T cells and NK cells, thus potentially laying the foundation for an off-the-shelf cell therapy program. Oncternal is proud to be an industry partner of the NextGenNK competence center located at the Karolinska Institutet. Near-term, we are looking forward to dosing the first patient with our autologous ROR1 CAR-T cell therapy, ONCT-808, in the coming months."

ONCT-808 is the Company’s lead autologous ROR1-targeted CAR-T cell therapy program candidate. The program is advancing towards an Investigational New Drug (IND) application submission expected in mid-2022.

On June 10, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that the rationale and plans for its upcoming Phase 3 ZILO-301 (zilovertamab plus ibrutinib targeting ROR1 for patients with Mantle Cell Lymphoma) clinical trial will be highlighted in a poster presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress (Press release, Oncternal Therapeutics, JUN 10, 2022, View Source [SID1234615874]). ZILO-301 is designed to evaluate the efficacy and safety of zilovertamab, an investigational anti-ROR1 monoclonal antibody, plus ibrutinib compared to ibrutinib monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma (R/R MCL).

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Poster Title: Study ZILO-301: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Zilovertamab Plus Ibrutinib vs. Ibrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma
Abstract Number: P1154
Session Title: Indolent and mantle-cell non-Hodgkin lymphoma – Clinical
Session Date and Time: June 10, 2022 at 16:30 CEST
"The recently announced updated interim data from our Phase 1/2 study presented at ASCO (Free ASCO Whitepaper) 2022, provides ample support for the rationale of the design of our global registration Phase 3 study, ZILO-301, evaluating the combination of zilovertamab and ibrutinib in patients with MCL," noted Salim Yazji, M.D., Oncternal’s Chief Medical Officer. "We are excited to pursue a registrational pathway for zilovertamab based on an innovative enrichment study design that we believe can provide both an accelerated approval and regular approval in a single study. We expect to initiate ZILO-301 in the third quarter of 2022."

Zilovertamab is being evaluated in combination with ibrutinib in patients with R/R MCL and chronic lymphocytic leukemia (CLL) in the Phase 1/2 study, CIRM-0001. The most recent interim data update showed an Objective Response Rate (ORR) of 85% and a Complete Response (CR) rate of 41% in 27 evaluable patients with mantle cell lymphoma, both of which compare favorably to the historical ORR of 66% and CR rate of 20% for ibrutinib monotherapy.

The phase 3 study, ZILO-301, will evaluate the potential benefit for patients who achieve either a partial response (PR) or stable disease (SD) during a lead-in with ibrutinib monotherapy. Initially, patients enrolled in ZILO-301 will receive single agent ibrutinib (560 mg daily) for 4 months. Patients with an inadequate response (PR or SD) will be randomized (1:1) to receive zilovertamab or placebo while continuing to receive ibrutinib. The study aims to randomize approximately 250 patients.

Key Inclusion criteria:
Adults with histologically confirmed MCL
Relapsed or refractory with at least 1 prior therapy
Primary Objective
Progression-free survival (PFS) among subjects who had a PR or SD after open-label ibrutinib monotherapy phase and were randomized to receive zilovertamab + ibrutinib or ibrutinib + placebo
Secondary Objectives
Objective Response Rate (ORR) and Duration of Response (DoR)
Complete Response Rate (CR Rate)
Overall Survival (OS)
Proportion of subjects experiencing grade 3 or 4 neutrophil count decrease and overall safety profile
About Zilovertamab

Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or MZL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

On June 10, 2022 NuCana plc (NASDAQ: NCNA) reported that data to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress highlighting the activity of NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA), in a broad range of Acute Myeloid Leukemia (AML) cell lines. NUC-7738 has already shown promise as monotherapy in patients with solid tumors in a Phase 1/2 study (NuTide:701) and will also be combined with a PD-1 checkpoint inhibitor (Press release, Nucana BioPharmaceuticals, JUN 10, 2022, View Source [SID1234615873]).

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The data at EHA (Free EHA Whitepaper) 2022 show that NUC-7738 can suppress the expansion and survival of AML cells by reducing β-catenin signaling, a key pathway in AML. NUC-7738’s effect was observed in multiple different AML cell lines suggesting broad therapeutic potential. Furthermore, it was observed that NUC-7738 resulted in a reduction of the cells that are resistant to standard chemotherapy drugs and thought to be responsible for disease relapse.

These findings, combined with the anti-cancer activity and favorable safety profile of NUC-7738 observed in the NuTide:701 study provide a strong rationale for the evaluation of NUC-7738 in patients with leukemia.

The details of NuCana’s poster presentation at EHA (Free EHA Whitepaper) are as follows:

Title: NUC-7738 regulates β-catenin signaling resulting in reduced proliferation and self-renewal of AML cells
Abstract Number: P459
Presentation Date & Time: Friday June 10, 2022 from 16:30-17:45 CEST (e-poster online at 9:00 CEST)
Presenting Author: Akbar M. Shahid

Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "NUC-7738 has entered Phase 2 development in patients with solid tumors and we have been encouraged by the clinical activity and favorable safety profile we have observed. The data presented at EHA (Free EHA Whitepaper) indicate that NUC-7738 may have applications beyond solid tumors and we are currently evaluating the optimal pathway for NUC-7738’s development for the treatment of hematologic malignancies."

About NUC-7738
NUC-7738 is a ProTide transformation of 3′-deoxyadenosine (3′-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as an anti-cancer agent due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cancer cells, thus overcoming 3’-dA’s key limitations of breakdown, transportation and activation. The cytotoxic effect of NUC-7738 is largely attributed to the generation of the main active anti-cancer metabolite, 3′-dATP. Primarily, 3′-dATP interferes with RNA polyadenylation, causing changes in the expression of genes involved in metabolism, differentiation, and apoptosis, ultimately leading to metabolic stress, cessation of cancer-cell growth and cell death.

On June 10, 2022 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported that data from multiple analyses of the ongoing MANIFEST study, an open-label Phase 2 clinical trial of pelabresib, an investigational BET inhibitor, in patients with myelofibrosis, a rare bone marrow cancer for which only limited treatment options are available (Press release, MorphoSys, JUN 10, 2022, View Source [SID1234615872]). The latest findings suggest pelabresib may have disease-modifying properties and confirm previous data supporting the potential of pelabresib as a treatment for patients with myelofibrosis. The data are being presented during oral and poster sessions at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 (EHA 2022) Hybrid Congress being held in Vienna.
"The standard for evaluating disease response in myelofibrosis focuses on symptom relief rather than true disease modification, which remains an unmet need for these patients," said John Mascarenhas, M.D., Director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai, New York. "The body of data being presented at EHA (Free EHA Whitepaper) 2022 – including new findings that pelabresib may address cellular defects seen in myelofibrosis, thereby getting at the root cause of the disease – with correlated clinical improvements, suggests pelabresib may have the potential to enhance the current standard of care in the first-line treatment of myelofibrosis."

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A study that will be presented in an oral session on June 11 analyzed cells derived from blood of patients who enrolled in the MANIFEST trial and from healthy volunteers. The findings indicate that pelabresib alone or in combination with the JAK inhibitor ruxolitinib may have the potential to improve the typical imbalance in the two white blood cell populations, the myeloid and lymphoid cells, and help restore normal blood cell development. These improvements also correlated with decreases in spleen volume, a key clinical measure of treatment success. Additionally, pelabresib alone or in combination decreased pro-inflammatory and pro-fibrotic signaling in monocytes, suggesting a potential attenuation of disease processes.
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"The latest findings from the MANIFEST trial at EHA (Free EHA Whitepaper) 2022 highlight the potential of pelabresib to offer patients and their physicians benefits over monotherapy with JAK inhibitors, if approved," said Malte Peters, M.D., MorphoSys Chief Research and Development Officer. "The full complement of MANIFEST data being presented this week suggests pelabresib may help improve outcomes for patients with myelofibrosis and reaffirms our confidence in the Phase 3 MANIFEST-2 study. We are committed to these patients, who need better options in first-line treatment and beyond."
A second oral presentation on June 11 highlights positive interim data from the MANIFEST trial on the safety and efficacy of pelabresib in combination with ruxolitinib in patients who were not previously treated with a JAK inhibitor and in those with suboptimal response to ruxolitinib. The findings show that the combination was generally well tolerated and offered reductions in spleen volume and symptom burden, with disease-modifying activity as measured by reduced levels of pro-inflammatory cytokines and improved bone marrow morphology. Over two-thirds (68%; n=57) of JAK inhibitor-naïve patients treated with the combination achieved at least a 35% reduction in spleen volume (SVR35) from baseline at week 24. Notably, 80% of patients achieved SVR35 at any time on study. Most patients also saw their symptoms reduced, with 56% (n=46) achieving at least a 50% reduction in total symptom score (TSS50) from baseline at week 24. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (12%, grade 3/4) and anemia (34%, grade 3/4). Non-hematological events included dyspnea (5%, grade 3) and respiratory tract infections (8%, grade 3/4).
In a poster presentation at EHA (Free EHA Whitepaper) 2022, matching-adjusted indirect comparisons were used to compare findings for the combination of pelabresib plus ruxolitinib in treatment-naïve patients with intermediate- or high-risk disease in one arm of the MANIFEST trial with findings from historical clinical trials examining the use of JAK inhibitor monotherapy in myelofibrosis. Adjusting for cross-trial differences, the estimated response rate ratios favored the pelabresib combination over ruxolitinib, fedratinib or momelotinib monotherapy for SVR35 and for TSS50, suggesting improved efficacy versus the JAK inhibitors alone.
A second poster presentation includes trial design information for the Phase 3 MANIFEST-2 study. MANIFEST-2, which is currently enrolling, will compare pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in approximately 400 patients with myelofibrosis who are naïve to JAK inhibitor therapy. MorphoSys is expected to report topline data from the MANIFEST-2 trial in the first half of 2024.
About Pelabresib
Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About Myelofibrosis
Myelofibrosis is a type of chronic leukemia that causes extensive scarring in the bone marrow, which disrupts the body’s normal production of healthy blood cells. The result is a reduction in red blood cells, which can cause weakness and fatigue, and in platelets, which increases the risk of bleeding due to deficient clotting. Myelofibrosis
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often causes an enlarged spleen. It is most often diagnosed in people older than 50 and can occur on its own (called primary myelofibrosis) or because of another bone marrow disorder.

About MANIFEST
MANIFEST (NCT02158858) is an open-label Phase 2 clinical trial of pelabresib in patients with myelofibrosis.

The MANIFEST trial is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve myelofibrosis patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. The trial is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or myelofibrosis progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST trial sponsor.

About MANIFEST-2
MANIFEST-2 (NCT04603495) is a global, double-blind, randomized Phase 3 clinical trial with pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. The primary endpoint of the study is a 35% or greater reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is a 50% or greater improvement in total symptom score (TSS50) from baseline at 24 weeks.

Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST-2 trial sponsor.

On June 10, 2022 Massive Bio Co-Founder and Chief Medical Officer Dr. Arturo Loaiza-Bonilla, MD, MSEd, reported that it will be featured in the BIO International Convention, presented by Biotechnology Innovation Organization (BIO) (Press release, Massive Bio, JUN 10, 2022, View Source [SID1234615871]). The BIO International Convention is the world’s largest gathering of leaders in the biotechnology and life sciences industries, bringing together thousands of biotechnology and pharmaceutical executives.

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This event takes place in-person at the San Diego Convention Center in San Diego, California from June 13th to June 16th. Keynote speakers of the convention include Venus Williams and Erin Andrews.

Dr. Bonilla is a speaker in the discussion titled "The Roles of AI and Big Data in Precision Healthcare: Perspectives from the Drug Development Pathway and the Patient Journey" and takes place on June 15th at 2:00 pm ET. During this conference, panelists will discuss the role of Big Data and AI at each stage of the drug development pathway as concurrently intertwined with the patient’s journey as part of the developing precision healthcare field.

BIO is committed to speaking up for the millions of families around the globe who depend upon our success. Their goal is to drive a revolution that aims to cure patients, protect our climate, and nourish humanity.

In addition to being a Co-Founder of Massive Bio, Dr. Bonilla is a renowned medical oncologist and has a distinguished clinical career in precision medicine oncology, immunotherapy, clinical trial design, digital health, and patient advocacy. Visit the event’s full agenda.

Register to attend the in-person event on BIO’s website. Tag @MassiveBio and use #BIO2022 to connect on Twitter and other social media websites during the BIO International Convention from June 13th to June 16th.