On April 20, 2020 Cue Biopharma, Inc. (NASDAQ: CUE), a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics to selectively engage and modulate targeted T cells within the body, reported it has entered into a clinical collaboration agreement with Merck (known as MSD outside the United States and Canada), through a subsidiary, to evaluate the combination of Cue Biopharma’s investigational product candidate CUE-101, a first-in-class biologic, with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in patients with advanced head and neck cancer (Press release, Cue Biopharma, APR 20, 2020, View Source [SID1234556500]).

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Collaboration with Merck
Under the terms of the agreement, Cue Biopharma will conduct a Phase 1 study, KEYNOTE-A78, evaluating CUE-101 in combination with KEYTRUDA in first-line HPV+ advanced head and neck cancer. KEYNOTE-A78 will be conducted in parallel with the ongoing Phase 1 monotherapy study of CUE-101 post first-line treatment. The early monotherapy PK data from the first two dosing cohorts demonstrates dose-related drug exposure consistent with preclinical modeling. Subsequent to the respective dose escalations, expansion cohorts evaluating CUE-101 as a monotherapy and in combination with KEYTRUDA will be conducted at optimized dosing regimens.

"We are very pleased to collaborate in this important study with Merck, an established leader in cancer immunotherapy, with our first clinical asset, CUE-101, which represents our IL-2 variant CUE-100 Series," said Daniel Passeri, chief executive officer of Cue Biopharma. "Through the monotherapy and combination studies, we believe we will be able to demonstrate the mechanistic advantages of our approach and platform for modulating disease-relevant T cells directly in the patient’s body to safely enhance efficacy over current standards of care."

"Immunotherapies have revolutionized the treatment of patients with certain types of cancers. However significant unmet need remains – particularly in those individuals who do not respond or develop resistance to checkpoint therapy," said Ken Pienta, M.D, acting chief medical officer of Cue Biopharma. "Based on a novel mechanism of action designed to induce and expand tumor-specific T cells in the patient’s body, we believe CUE-101 may lead to enhanced anti-tumor activity in combination with KEYTRUDA."

CUE-101 is a fusion protein comprised of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human interleukin-2 (IL-2) molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain. In preclinical studies, CUE-101 has demonstrated selective induction and expansion of HPV16 E7-specific cytotoxic T cells with both in vitro and in vivo evidence supporting its potential for clinical efficacy both as a monotherapy and in combination with anti-PD1 checkpoint blockade.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Phase 1 Trial Update
The Phase 1 CUE-101 monotherapy study is ongoing, with enrollment of patients at 13 leading centers in the United States for the treatment of post first-line metastatic and recurrent HPV+ advanced head and neck cancer. We have initiated the dosing of 3 patients in Cohort 3 and pending safety evaluation, we anticipate initiating the dosing of patients in Cohort 4 later this quarter. By design, CUE-101 includes 4 molecules of attenuated IL-2 and Cohort 2 patients were exposed to drug concentrations equivalent to those achieved with systemic IL-2 administration of aldesleukin (Proleukin) with no evidence of cytokine release syndrome. The Phase 1 monotherapy portion of the study is a standard dose escalation of CUE-101. After demonstration of safety at several dose levels, a parallel Phase 1 dose escalation of CUE-101 in combination with KEYTRUDA will be initiated in first-line patients. The primary endpoints of the dose escalation phase of the trials are to evaluate the safety, tolerability, and the pharmacokinetics/pharmacodynamics of the two regimens. Monitoring of disease-relevant T cells and additional biomarkers of anti-tumor immune response and exploration of response prediction markers employing multiple methodologies are included in the study design.

Preliminary data from early patient cohorts demonstrates tolerability and drug exposure, and provides confidence for drug activity consistent with projections based on preclinical data. Cue Biopharma expects to report initial pharmacodynamic data from the Phase 1 monotherapy portion of the study in the first half of 2020. Additional information about the trial can be found at clinicaltrials.gov (NCT03978689).

Clinical Cancer Research Publication
CUE-101 preclinical data were recently published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). (View Source)

The article titled, CUE-101, a Novel HPV16 E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies, includes CUE-101 data that demonstrate selective binding, activation and expansion of HPV16-specific, disease-relevant, T cells. A murine surrogate molecule (mCUE-101) administered to HPV16 E7 tumor bearing mice resulted in selective expansion of disease-relevant T cells, anti-cancer efficacy and immunologic memory. In addition, mCUE-101 administered as a combination therapy with anti-PD-1 checkpoint inhibition further enhanced anti-tumor efficacy.

About the CUE-100 Series
The CUE-100 series consists of Fc-fusion biologics that incorporate peptide-MHC (pMHC) molecules along with rationally engineered IL-2 molecules. This singular biologic is anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells directly in the patient. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.

About Immuno-STAT
Immuno-STAT biologics are designed for targeted modulation of disease-associated T cells in the areas of immuno-oncology and autoimmune disease. Each of our biologic drugs is designed using our proprietary scaffold comprising: 1) a peptide-MHC complex (pMHC) to provide selectivity through interaction with the T cell receptor (TCR), and 2) a unique co-stimulatory signaling molecule to modulate the activity of the target T cells.

The simultaneous engagement of co-regulatory molecules and pMHC binding mimics the signals delivered by antigen presenting cells (APCs) to T cells during a natural immune response. This design enables Immuno-STAT biologics to engage with the T cell population of interest, resulting in highly targeted T cell modulation. Because our drugs are delivered directly in the patient’s body (in vivo), they are fundamentally different from other T cell therapeutic approaches that require the patients’ T cells to be extracted, modified outside the body (ex vivo), and reinfused.

On April 20, 2020 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported that it has received a Notice of Allowance from the U.S. Patent and Trademark Office for a pending patent application which covers MN-166 (ibudilast) for the treatment of glioblastoma (Press release, MediciNova, APR 20, 2020, https://investors.medicinova.com/news-releases/news-release-details/medicinova-receives-notice-allowance-second-patent-covering-mn [SID1234556466]). This new patent has improved therapeutic claims compared to the first patent which covers MN-166 (ibudilast) for the treatment of glioblastoma, which was granted last year, and has a later expiration date than the first patent.

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Once issued, the patent maturing from this allowed patent application is expected to expire no earlier than February 2039. The allowed claims cover a method of treating a patient diagnosed with glioblastoma or recurrent glioblastoma, wherein the patient expresses methylated MGMT (O6-methylguanine-DNA methyltransferase), using MN-166 (ibudilast) in combination with one or more other therapeutic agents including temozolomide (TMZ), carmustine, bevacizumab, procarbazine, hydroxyurea, irinotecan, lomustine, nimotuzumab, sirolimus, mipsagargin, cabozantinib, onartuzumab, patupilone (epothilone B), and recombinant oncolytic poliovirus (PVS-RIPO). The allowed claims cover a wide range of doses of MN-166 (ibudilast) during an optionally repeating dosing cycle. The allowed claims also cover different types of glioblastoma including classical glioblastoma, proneural glioblastoma, mesenchymal glioblastoma, and neural glioblastoma.

Yuichi Iwaki, MD, PhD, President and Chief Executive Officer of MediciNova, Inc., commented, "We are very pleased to receive notice that this new patent will be granted as it offers better coverage than our first patent covering glioblastoma. We believe it could substantially increase the potential value of MN‑166 as we have an ongoing clinical trial of MN-166 in combination with temozolomide for the treatment of recurrent glioblastoma at the Dana-Farber Cancer Institute, Harvard Medical School. Results of the glioblastoma animal model study showed that median survival was longer in the group that received combination treatment with MN-166 plus temozolomide compared to the group that received the standard treatment of temozolomide alone, and this data was presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting. Encouragingly, the FDA granted orphan-drug designation to MN-166 as adjunctive therapy to temozolomide for the treatment of glioblastoma based on this data."

About Glioblastoma

According to the American Association of Neurological Surgeons, glioblastoma is an aggressive brain cancer that often results in death during the first 15 months after diagnosis. Glioblastoma develops from glial cells (astrocytes and oligodendrocytes), grows rapidly, and commonly spreads into nearby brain tissue. Glioblastoma is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that glioblastoma represents about 15% of all primary brain tumors and approximately 10,000 cases of glioblastoma are diagnosed each year in the U.S. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with glioblastoma. Median survival is about 11-15 months for adults with more aggressive glioblastoma (IDH-wildtype) who receive standard treatment of surgery, temozolomide, and radiation therapy.

About MN-166 (ibudilast)

MN-166 (ibudilast) is a first-in-class, orally bioavailable, small molecule macrophage migration inhibitory factor (MIF) inhibitor and phosphodiesterase (PDE) -4 and -10 inhibitor that suppresses pro-inflammatory cytokines and promotes neurotrophic factors. Our earlier human studies demonstrated significant reductions of serum MIF level after treatment with MN-166 (ibudilast). It also attenuates activated glial cells, which play a major role in certain neurological conditions. MN-166 (ibudilast)’s anti-neuroinflammatory and neuroprotective actions have been demonstrated in preclinical and clinical studies, which provide the rationale for treatment of amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis (MS) and other neurological diseases such as glioblastoma (GBM), and substance abuse/addiction. MediciNova is developing MN-166 for ALS, progressive MS and other neurological conditions such as degenerative cervical myelopathy (DCM), glioblastoma, substance abuse/addiction, and chemotherapy-induced peripheral neuropathy. MediciNova has a portfolio of patents which covers the use of MN-166 (ibudilast) to treat various diseases including ALS, progressive MS, and drug addiction.

On April 20, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted a supplemental new drug application (sNDA) of BeiGene’s anti-PD-1 antibody tislelizumab in combination with two chemotherapy regimens for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) (Press release, BeiGene, APR 20, 2020, View Source [SID1234556465]).

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"This sNDA filing is another important milestone in tislelizumab’s development program, coming on the heels of its recent approval in urothelial carcinoma in China – our first approval in solid tumors and the announcement of the positive outcome of our second study in first-line NSCLC, in patients with non-squamous histology. Our team was able to submit the regulatory application only 20 months after trial initiation, illustrating how efficiently we can move to serve those in need," commented Xiaobin Wu, Ph.D., General Manager of China and President of BeiGene. "We look forward to working closely with the CDE on this filing and hope to bring a new treatment option to the large population of patients with advanced squamous NSCLC in China who could benefit from immunotherapy."

This sNDA is supported by clinical results from a Phase 3 trial of tislelizumab combined with either paclitaxel and carboplatin or nab-paclitaxel (ABRAXANE) and carboplatin compared to paclitaxel and carboplatin alone in patients with untreated stage IIIB or IV squamous NSCLC from mainland China (NCT03594747). A total of 360 patients were randomized 1:1:1 to receive tislelizumab in combination with either chemotherapy regimen or chemotherapy alone. As announced in January 2020, the trial met the primary endpoint of statistically significant improvement in progression-free survival (PFS), as assessed by independent review committee (IRC), in the pre-planned interim analysis. The safety profile of tislelizumab in both combinations was consistent with the known risks of each study treatment, and no new safety signals were identified. Full results of the trial will be presented at an upcoming meeting.

About Non-Small Cell Lung Cancer

In contrast to most Western countries where lung cancer death rates are decreasing, lung cancer incidence rate is still increasing in China.1,2 There were approximately 770,000 new cases of lung cancer in China in 2018 and it is the leading cause of cancer-related death in both men and women, with approximately 690,500 deaths in China in 2018.3 Non-small cell lung cancer comprises the most common form of lung cancer in China.4

About Tislelizumab

Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Tislelizumab is approved by the China National Medical Products Administration as a treatment for patients with classical Hodgkin’s lymphoma who received at least two prior therapies and for patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Currently, 15 potentially registration-enabling clinical trials are being conducted in China and globally, including 11 Phase 3 trials and four pivotal Phase 2 trials.

Tislelizumab is not approved for use outside of China and is not approved to treat non-small cell lung cancer.

About Tislelizumab Clinical Program

Clinical trials of tislelizumab include:

Phase 3 trial in patients with locally advanced or metastatic urothelial carcinoma (NCT03967977);

Phase 3 trial comparing tislelizumab with docetaxel in the second- or third-line setting in patients with NSCLC (NCT03358875);

Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced squamous NSCLC (NCT03594747);

Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC (NCT03663205);

Phase 3 trial of tislelizumab combined with platinum and etoposide versus placebo combined with platinum and etoposide in patients with extensive-stage small cell lung cancer (NCT04005716);

Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with hepatocellular carcinoma (HCC; NCT03412773);

Phase 2 trial in patients with previously treated unresectable HCC (NCT03419897);

Phase 3 trial comparing tislelizumab with chemotherapy as second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC; NCT03430843);

Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC (NCT03783442);

Phase 3 trial of tislelizumab versus placebo in combination with chemoradiotherapy in patients with localized ESCC (NCT03957590);

Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer (NCT03777657);

Phase 2 trial in patients with MSI-H/dMMR solid tumors (NCT03736889); and

Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in patients with nasopharyngeal cancer (NCT03924986).

On April 20, 2020, Cumberland Pharmaceuticals, Inc. (the "Company"), reported that received the funding of a loan ("Loan") from Pinnacle Bank in the aggregate amount of $2,187,140 pursuant to the Paycheck Protection Program (the "PPP") under the Federal Coronavirus Aid, Relief, and Economic Security Act ("CARES Act"), which was enacted March 27, 2020 (Filing, 8-K, Cumberland Pharmaceuticals, APR 20, 2020, View Source [SID1234556459]). The PPP is administered by the U.S. Small Business Administration.

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The Loan, which was in the form of a Note dated April 14, 2020, maturing on April 14, 2022 and bearing interest at a rate of 1.0% per year, payable monthly commencing during November 2020. The Note may be prepaid by the Borrower at any time prior to maturity with no prepayment penalties. Funds from the Loan are to be used to maintain payroll, continue group health care benefits and pay for rent and utilities. Under the terms of the PPP, certain amounts of the Loan may be forgiven if they are used for qualifying expenses as described in the CARES Act. The Company intends to use the majority of the Loan amount for such qualifying expenses.

On April 20, 2020 Genome & Company (KONEX: 314130), a biotechnology company developing innovative therapeutics in immune-oncology, reported that the United States (US) Food and Drug Administration (FDA) has accepted the Investigational New Drug (IND) application for GEN-001 for combination treatment with avelumab (BAVENCIO) in patients with solid cancers (Press release, Genome & Company, APR 20, 2020, View Source;company-receives-fda-ind-clearance-for-gen-001-its-first-anti-cancer-microbiome-therapeutic-301043307.html [SID1234556445]). Avelumab is an anti-PD-L1 antibody co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc.

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With this clearance, Genome & Company will be the first Asian company to initiate a first-in-human trial of anti-cancer microbiome and anti-PD1/anti-PD-L1 combination treatment as a sole sponsor. The phase 1/1b clinical trial will be initiated at the US clinical sites and the first patient is expected to be enrolled within this year.

"IND clearance from FDA for our first anti-cancer microbiome therapeutic GEN-001 is a very significant milestone as it will transition Genome & Company into a clinical-stage biotechnology company. We hope to add meaningful value and advancement in the microbiome and immuno-oncology industry with our combinational approach to cancer patients who have progressed on prior anti-PD1/anti-PD-L1 therapy," said Dr. Hansoo Park, Chief Technical Officer of Genome & Company.

Dr. Jisoo Pae, CEO of Genome & Company further quoted, "This IND approval is a meaningful corporate milestone and a critical step forward to achieving new arrangements in strategic partnering. We are indeed looking forward to further investigate how our clinical data will be translated into our cancer patients. I thank all the members and partners of Genome & Company for dedicating themselves to accomplishing this milestone."

In January this year, Genome & Company had entered into a clinical trial collaboration and supply agreement with Merck KGaA, Darmstadt, Germany and Pfizer Inc. to evaluate the safety, tolerability, biological and clinical activities of GEN-001 therapy in combination with avelumab in multiple cancer indications. The combination trial is designed to be a first-in-human study including dose escalation and expansion cohorts to evaluate the safety and preliminary efficacy.

BAVENCIO is a trademark of Merck KGaA, Darmstadt, Germany.

About GEN-001

GEN-001 is an oral microbiome therapeutic candidate developed to have immune modulating activities, resulting in potential partnership with immune checkpoint inhibitors. GEN-001 consists a single strain bacteria isolated from gut of healthy human volunteers that has been shown to activate dendritic cells, macrophages and T cell response. In preclinical studies, GEN-001 has shown optimal safety margin and synergistic effects in combination with immune checkpoint inhibitors by enhancing the effect of suppressing the growth of both immune checkpoint inhibitor sensitive and resistant tumor models.