On June 30, 2020 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that the United States Food and Drug Administration (FDA) has granted the company orphan drug designations of cirmtuzumab for treatment of mantle cell lymphoma (MCL) and for treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (Press release, Oncternal Therapeutics, JUN 30, 2020, View Source [SID1234561583]). Cirmtuzumab is an investigational anti-ROR1 monoclonal antibody being evaluated in clinical trials in patients with MCL, CLL and HER2-negative breast cancer.

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Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs or biologics intended to treat rare diseases or conditions, which are defined as diseases or conditions that affect fewer than 200,000 people in the United States or that affect more than 200,000 people but where there is no reasonable expectation that the costs of developing and marketing the drug will be recovered through future sales of the drug in the United States. Orphan drug designation for cirmtuzumab qualifies Oncternal for certain benefits including tax credits for qualified clinical trials, exemption from certain FDA application fees, and the potential for market exclusivity upon regulatory approval, if received, for an orphan-designated indication.

"We are pleased to receive orphan drug designations for cirmtuzumab, our potentially first-in-class investigational ROR1 antibody," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "We are excited about cirmtuzumab’s potential for the treatment of patients with ROR1-expressing cancers, including MCL, CLL, HER2-negative breast cancer and other solid tumors, and look forward to further advancing its development to benefit patients with significant unmet medical needs."

MCL is an aggressive form of non-Hodgkin’s lymphoma. MCL prevalence is estimated to be approximately 13,000 to 21,000 patients in the United States. MCL is an aggressive cancer that carries a poor prognosis, with a median survival of about two to five years and a 10-year survival rate of approximately 5%-10%.

CLL is the most common form of leukemia in adults, accounting for 25-30% of all leukemias in the United States. CLL prevalence is estimated to be approximately 158,000 to 178,000 patients in the U.S. Despite various recently approved therapies, CLL generally remains incurable.

About Cirmtuzumab

Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of CLL or MCL, in a collaboration with the University of California San Diego School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, an investigator-initiated Phase 1 clinical trial of cirmtuzumab in combination with paclitaxel for women with HER2-negative metastatic breast cancer is being conducted at the UC San Diego School of Medicine.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and 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 targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab 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 cirmtuzumab for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.

On June 30, 2020 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported an updated clinical strategy for its investigational ROR1 monoclonal antibody, cirmtuzumab, that prioritizes development in mantle cell lymphoma (MCL), based on encouraging interim clinical results from the ongoing Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma (CIRLL) Phase 1/2 clinical trial that were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Annual Meeting (ASCO 2020) in May 2020 (Press release, Oncternal Therapeutics, JUN 30, 2020, View Source [SID1234561582]).

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The Company reported a 58% complete response (CR) rate, a 83% overall best objective response rate (ORR), and a progression free survival rate of 17.5 months with a median follow-up of 8.3 months, for patients with relapsed/refractory MCL in the ongoing Phase 1/2 CIRLL clinical trial of cirmtuzumab in combination with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, at ASCO (Free ASCO Whitepaper) 2020. These response rates in heavily pre-treated patients were higher than the historical published CR of 23% and ORR of 67% for single-agent ibrutinib for patients with MCL who had received more than one prior therapy (Rule 2019, Haematologica). Four of these patients with MCL had been previously treated with and responded to ibrutinib, prior to participating in the CIRLL study. All four of these patients responded to the combination of cirmtuzumab and ibrutinib, two achieving CRs and two achieving partial responses. The Company believes that the interim results presented at ASCO (Free ASCO Whitepaper) 2020 are clinically relevant given the unmet medical need for patients with MCL.

As a result, the Company is amending the CIRLL study to increase the number of patients with relapsed/refractory MCL to be enrolled in the Phase 2 Expansion Cohort to at least 20 patients and to allow enrollment of patients with a broader range of prior BTK inhibitor treatments.

The Company has also requested a meeting with the U.S. Food and Drug Administration (FDA) to discuss the results of the recent interim analysis of the CIRLL study and to seek guidance on a potential accelerated approval pathway for cirmtuzumab plus ibrutinib in patients with relapsed/refractory MCL.

At ASCO (Free ASCO Whitepaper) 2020, the Company also reported a 100% progression-free survival rate, 88% ORR and 3% CR rate, with a median follow-up of 12.8 months, for patients with chronic lymphocytic leukemia (CLL) treated with cirmtuzumab in combination with ibrutinib in the CIRLL study. These interim data did not satisfy the hypothesis that ibrutinib plus cirmtuzumab would produce a CR rate 25% greater than the historical response rate for ibrutinib alone. Based on these interim results, Oncternal will continue treatment and follow-up of the patients with CLL who are already enrolled in the CIRLL study for up to two years or until disease progression, but will limit total enrollment of patients in the randomized Phase 2 CLL cohort to approximately 35 patients, in order to focus resources on the MCL portion of the study. The Company believes that, while significant unmet medical need exists in both CLL and MCL, the MCL indication may offer a more rapid path to potential regulatory approval.

Additionally, Oncternal plans to further explore clinical combination strategies for cirmtuzumab for patients with hematologic malignancies. Accordingly, the Company is supporting a new, investigator-sponsored Phase 2 clinical trial of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL in collaboration with the University of California San Diego School of Medicine (UC San Diego). Preclinical studies performed in the laboratory of Dr. Thomas Kipps at UC San Diego reported synergy between cirmtuzumab and venetoclax, providing a rationale for this combination clinical trial (Rassenti 2017, PNAS).

"We are excited about the promising clinical data reported for cirmtuzumab in combination with ibrutinib for patients with relapsed/refractory MCL, for whom a significant unmet medical need exists for well-tolerated therapies that provide more complete and durable responses. We plan to prioritize the development of cirmtuzumab for patients with MCL and expect that the planned changes will accelerate the Company’s timetable for initiating a potential registrational study for cirmtuzumab, while having an overall favorable budget impact," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "Additionally, we are pleased to support a new, investigator-sponsored Phase 2 clinical trial of cirmtuzumab in combination with venetoclax for the treatment of patients with CLL, based on promising published preclinical data. Our collaborators at UC San Diego and the California Institute for Regenerative Medicine (CIRM) have indicated that they support our revised development strategy for cirmtuzumab."

About the CIRLL Clinical Trial

The CIRLL clinical trial (Cirmtuzumab and Ibrutinib for Relapsed Lymphoma and Leukemia, Study CIRM-0001) is a Phase 1/2 trial evaluating cirmtuzumab in combination with ibrutinib in separate groups of patients with MCL or CLL. Enrollment has been completed in the dose-finding cohorts in CLL and MCL, and the dose-expansion cohort in CLL. Based on the data from the dose-finding cohorts, the recommended dosing regimen was determined to be 600 mg of cirmtuzumab administered intravenously every two weeks for three doses, followed by dosing every four weeks, in combination with 560 mg of ibrutinib once daily for patients with MCL, or 420 mg of ibrutinib administered once daily for patients with CLL, which are the FDA-approved doses of ibrutinib in these indications.

About Cirmtuzumab

Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of CLL or MCL, in a collaboration with the University of California San Diego School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, an investigator-initiated Phase 1 clinical trial of cirmtuzumab in combination with paclitaxel for women with metastatic breast cancer is being conducted at the UC San Diego School of Medicine.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and 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 targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.

On June 30, 2020 BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, reported it has submitted a clinical trial application (CTA) to begin a Phase I/IIa, first-in-human study of BI-1808, a monoclonal antibody to tumor necrosis factor receptor 2 (TNFR2), as a single agent and in combination with KEYTRUDA (pembrolizumab) for the treatment of solid tumors and cutaneous T-cell lymphoma (CTCL) (Press release, BioInvent, JUN 30, 2020, View Source [SID1234561581]).

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The study will explore the safety, tolerability, and potential signs of efficacy of BI-1808 as a single agent and in combination with KEYTRUDA in patients with ovarian cancer, non-small cell lung cancer and cutaneous T cell lymphoma. It will also investigate the expression of potential immunological markers that might be associated with clinical responses. It will be conducted at several sites across Europe and the U.S. and is expected to enroll approximately 120 patients.

The Phase I stage is divided into two sections. Part A is a dose escalation of BI-1808 to assess safety, tolerability, and pharmacokinetics & pharmacodynamics, and to determine the recommended dose as a single agent for Phase II trials. It will be followed by part B, which will explore the safety, tolerability and recommended dose of BI-1808 in combination with KEYTRUDA. Phase IIa will consist of expansion cohorts to assess signs of efficacy of BI-1808 as single agent and in combination with KEYTRUDA in lung cancer and ovarian cancer patients. A separate cohort will explore the activity as single agent in CTCL (Sézary syndrome and mycosis fungoides).

Martin Welschof, CEO of BioInvent, says, "Targeting TNFR2 for cancer therapy is a very promising approach and BI-1808 is a further demonstration of the ability of our proprietary n-CoDeR and F.I.R.S.TTM platforms to generate antibodies with novel, first-in-class mechanisms of action. This Phase I/IIa study of BI-1808 marks the first anti-TNFR2 antibody to enter clinical evaluation. With CTAs filed in Europe, we expect to submit a U.S. IND in the coming months, and to enroll the first patient in Q4 2020."

On June 30, 2020 G1 Therapeutics, Inc. (Nasdaq: GTHX) and Boehringer Ingelheim reported that the companies have entered into a co-promotion agreement for trilaciclib in the United States and Puerto Rico (Press release, G1 Therapeutics, JUN 30, 2020, View Source [SID1234561575]). Under the terms of the three-year agreement, G1 and Boehringer Ingelheim will collaborate on the commercialization of trilaciclib for its first potential indication in small cell lung cancer (SCLC), with the Boehringer Ingelheim oncology commercial team, well-established in lung cancer, leading sales force engagement initiatives. Discovered and developed by G1, trilaciclib is a first-in-class investigational therapy designed to improve outcomes for people with cancer treated with chemotherapy.

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"We believe that trilaciclib has the potential to benefit patients with cancer being treated with chemotherapy across a broad range of solid tumors," said Mark Velleca, M.D., Ph.D., Chief Executive Officer of G1. "Our clinical trials of trilaciclib in small cell lung cancer have demonstrated significant myelopreservation benefits, and we are excited to collaborate with Boehringer Ingelheim’s experienced commercial oncology team to bring this innovative therapy to patients with SCLC. In addition, this capital efficient launch structure provides us with the ability to make investments in a robust development program to assess trilaciclib in other solid tumors, including colorectal cancer and breast cancer."

Under the terms of the agreement, G1 will book revenue in the United States and Puerto Rico and retain global development and commercialization rights to trilaciclib. In the U.S. and Puerto Rico, G1 will lead marketing, market access and medical engagement initiatives; Boehringer Ingelheim will lead sales force engagements. G1 will make initial payments to Boehringer Ingelheim to cover start-up expenses and pre-approval initiatives to support a successful commercial launch. G1 will pay a promotion fee of a mid-twenties percentage of net sales in the first year of commercialization, which decreases to a low double-digit/high single-digit percentage in the second and third years of commercialization, respectively (subject to certain adjustments for sales above pre-specified levels to reward out-performance). There are no payments due by either party beyond the expiration of the three-year term of the agreement. The agreement does not extend to additional indications that G1 may pursue for trilaciclib.

"Boehringer Ingelheim’s commitment to transform treatment expectations for the oncology community extends beyond research and drives us to explore innovative solutions for patients. We are pleased to be collaborating with G1 Therapeutics and applying our commercial strengths focused on lung cancer to support a new therapy for patients with clear synergies across customer audiences," said Kelli Moran, Senior Vice President, Specialty Care, Boehringer Ingelheim. "This strategic agreement builds on Boehringer Ingelheim’s achievements in oncology and contributes to our long-term vision to give patients new hope by taking cancer on."

G1 received Breakthrough Therapy Designation for trilaciclib from the U.S. Food and Drug Administration (FDA) in 2019 and submitted a New Drug Application (NDA) in June 2020. More than 25,000 people in the U.S. and Puerto Rico are diagnosed with SCLC each year. Approximately 90% of SCLC patients receive first-line chemotherapy treatment, and approximately 60% of those patients receive subsequent second-line chemotherapy treatment. Chemotherapy is an effective and important weapon against cancer. However, chemotherapy does not differentiate between healthy cells and cancer cells and kills both. One of the most common side effects of chemotherapy is myelosuppression – the result of damage to stem cells in the bone marrow that produce white blood cells, red blood cells and platelets. Myelosuppression often requires the administration of rescue interventions such as growth factors and blood or platelet transfusions, and may also result in chemotherapy dose delays and reductions. Immune cell damage may decrease the ability of the immune system to fight the cancer, as well as infection. Trilaciclib has the potential to be the first proactively administered myelopreservation therapy that can make chemotherapy safer and improve the patient experience.

Additional information regarding this agreement is disclosed in a Current Report on Form 8-K filed by G1 with the U.S. Securities and Exchange Commission (available here).

About Trilaciclib

Trilaciclib is a first-in-class investigational therapy designed to improve outcomes for people with cancer treated with chemotherapy. Trilaciclib has received Breakthrough Therapy Designation based on positive myelopreservation data from three randomized, double-blind, placebo-controlled clinical trials in which trilaciclib was administered prior to chemotherapy treatment in patients with small cell lung cancer (SCLC). In a randomized trial of women with metastatic triple-negative breast cancer, trilaciclib improved overall survival when administered prior to chemotherapy. In June 2020, G1 submitted a New Drug Application (NDA) for trilaciclib for myelopreservation in SCLC and began a study in neoadjuvant breast cancer as part of the I-SPY 2 TRIAL. The company expects to initiate a Phase 3 trial in colorectal cancer in the fourth quarter of 2020.

On June 30, 2020 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported that it will host a webcast and conference call to discuss progress on its corporate priorities and upcoming catalysts (Press release, Zymeworks, JUN 30, 2020, View Source [SID1234561574]).

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Webcast and Conference Call Details

Zymeworks will host a webcast and conference call on Wednesday, July 8, 2020 at 4:30pm ET (1:30pm PT).

Interested parties can access the live webcast via a link from Zymeworks’ website at View Source or join the live call and Q&A by dialing 1-800-319-4610 for North American callers, or 1-604-638-5340 for international callers. Callers should dial in five to 10 minutes prior to the scheduled start time and ask to join the "Zymeworks call".

A recorded replay will also be available on the website shortly after the call concludes.