On January 8, 2019 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that gonadotrophin-releasing hormone (GnRH) receptor antagonist, Gonax received approval for partial changes for the additional dosage and administration of Gonax for the treatment of prostate cancer at 12-week intervals, and obtained manufacturing and marketing authorization for Gonax 240 mg in Japan (Press release, Astellas, JAN 8, 2019, View Source [SID1234534620]).

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Gonax is a GnRH receptor antagonist with a subcutaneously injectable formulation. Astellas acquired exclusive development and commercialization rights of Gonax for the use of prostate cancer treatment in Japan from Ferring Pharmaceuticals in January 2006, and launched Gonax for the indication of prostate cancer in Japan in October 2012.

GnRH is a hormone synthesized and released from the hypothalamus in the brain and is involved in the production of the male hormone testosterone thorough binding to the GnRH receptors in the pituitary gland. Although testosterone is an important hormone that plays a central role in the maintenance of male function, it also stimulates prostate cancer to grow and to spread out and in result, often aggravates symptoms in prostate cancer patients. Gonax competitively inhibits the binding of GnRH to the GnRH receptors and controls the growth of prostate cancer by suppressing the testosterone.

Astellas believes that adding the maintenance dose of Gonax 480 mg at 12-week intervals to the maintenance dose of Gonax 80 mg at 4-week intervals will improve convenience for patients and reduce the burden on patients and further contribute to the treatment of prostate cancer.

Astellas reflected the impact from this approval in its financial forecasts of the current fiscal year ending March 31, 2019.

On January 8, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, requesting conditional approval for the treatment of patients with relapsed or refractory multiple myeloma (MM) who have received at least three prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody (mAb), and to their most recent treatment regimen (penta-refractory MM) (Press release, Karyopharm, JAN 8, 2019, View Source [SID1234532591]). Karyopharm also announced that the selinexor MAA has been granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use (CHMP).

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"The MAA submission for selinexor is an important milestone for Karyopharm and the CHMP’s granting of accelerated assessment further underscores the urgent need to improve outcomes for patients with highly refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "The results from the pivotal Phase 2b STORM study provide compelling evidence that selinexor in combination with low-dose dexamethasone has the potential to be an effective new treatment option for patients with this difficult to treat disease. With the filing of the MAA and an accelerated assessment designation from the EMA, we hope to make oral selinexor available as quickly as possible to patients throughout Europe."

An accelerated assessment is granted to products deemed by the CHMP to be of major interest for public health and represent therapeutic innovation. Accelerated assessments can reduce the active review time of an MAA from the standard 210 days down to 150 days once it has been validated by the EMA. Selinexor has also previously received orphan designation in multiple myeloma from the EMA.

A New Drug Application (NDA) seeking accelerated approval for oral selinexor with low dose dexamethasone as a treatment for patients with penta-refractory multiple myeloma is under Priority Review by the U.S. Food and Drug Administration (FDA) with an action date of April 6, 2019, under the Prescription Drug User-Fee Act (PDUFA).

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with penta-refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

On January 8, 2019 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of precisely targeted oncology therapies, reported that it has initiated patient enrollment in the second arm of its ongoing Phase 1/1b dose-escalation study (Press release, Corvus Pharmaceuticals, JAN 8, 2019, View Source [SID1234532576]). This arm is evaluating CPI-006, a humanized monoclonal antibody directed against CD73, in combination with CPI-444, a selective and potent inhibitor of the adenosine A2A receptor.

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The Phase 1/1b study is currently enrolling patients with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and other cancers who have failed standard therapies. The first arm of the study is evaluating CPI-006 as a single agent and has dosed patients in several cohorts of escalating doses. A third arm is planned to evaluate CPI-006 in combination with pembrolizumab, an anti-PD-1 antibody.

"Enrollment in our CPI-006 Phase 1/1b trial is progressing well," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "With this combination of drugs from our two lead programs, we believe we have initiated the first trial targeting two points in the adenosine pathway: blocking CD73 to reduce adenosine production with CPI-006, and inhibiting the binding of adenosine to its receptor with CPI-444. We believe this approach represents a unique mechanism of action that may result in a more complete adenosine blockade and immune cell activation."

Corvus previously reported initial data from the single-agent arm of the Phase 1/1b study demonstrating that CPI-006 blocked production of adenosine by inhibiting the enzymatic active site of CD73, activated peripheral blood B cells, and affected B lymphocyte trafficking. To date, CPI-006 has been well tolerated at the doses evaluated, with no dose-limiting toxicities. Dr. Miller added, "We have reported encouraging results from our ongoing Phase 1/1b and 1b/2 studies of CPI-444, including the recently described adenosine biomarker signature. We plan to initiate clinical studies for our third pipeline program, a covalent inhibitor of ITK, CPI-818, in the first quarter of 2019, demonstrating the depth of our pipeline and strong overall momentum for our precisely-targeted development programs."

About the Phase 1/1b Trial Design
The Phase 1/1b trial is designed to select the dose and evaluate the safety, pharmacokinetics, immune biomarkers and efficacy of CPI-006 as a single agent, in combination with CPI-444, and in combination with pembrolizumab. Patients with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and other cancers who have failed standard therapies are eligible. The efficacy endpoints are complete response (CR), partial response (PR), disease control rate, duration of response, progression-free survival and overall survival.

In the dose-selection part of the trial, doses of CPI-006 will be escalated in the single-agent arm and in the two combination arms to determine the maximally tolerated dose or the dose that saturates the CD73 enzyme. Fixed doses of CPI-444 will be used. Once an optimum dose of CPI-006 is determined, the second part of the trial is planned to enroll patients in nine cohorts: three will receive CPI-006 alone, three will receive CPI-006 in combination with CPI-444, and three will receive CPI-006 with pembrolizumab. Patients with NSCLC, RCC and the group of other cancers will be enrolled into each of the three disease-specific arms. Each of the nine cohorts may initially enroll up to 11 patients. However, if there are one or more objective responses (CR or PR) in the 11 patients, the cohort may be expanded to 28 patients. The trial may enroll up to 350 patients in total.

About CD73 and Adenosine
CD73 is a cell surface enzyme whose function is to convert adenosine monophosphate (AMP) to adenosine by removing phosphate from AMP. CD73 is expressed on cells of the immune system, including T-cells and B-cells. CD73 is also present on many tumors, including lung, renal, melanoma, colon, prostate, breast and others. In the tumor microenvironment, CD73 produces adenosine, which binds to the adenosine A2A receptor on immune cells and inhibits various immune responses including those directed against the tumor. Tumors utilize this immunosuppressive mechanism to escape attack by the immune system.

About CPI-006
CPI-006 is a potent humanized monoclonal antibody that reacts with the active site of CD73, blocking the conversion of AMP to adenosine. In vitro studies of CPI-006 have shown it is capable of substantially inhibiting the production of adenosine by blocking the CD73 enzyme and leads to activation of peripheral blood B cells.

About CPI-444
CPI-444 is a small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. CD39 and CD73 are enzymes on the surface of tumor cells and immune cells. These enzymes work in concert to convert ATP to adenosine. In vitro and preclinical studies have shown that dual blockade of CD73 and the A2A receptor may be synergistic.

On January 8, 2019 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 the first glioblastoma patient has enrolled in the clinical trial of MN-166 (ibudilast) in combination with temozolomide (TMZ, Temodar‑) for the treatment of recurrent glioblastoma (GBM) (Press release, MediciNova, JAN 8, 2019, View Source;p=RssLanding&cat=news&id=2382746 [SID1234532592]). The principal investigators are Patrick Y. Wen, M.D., Professor of Neurology, Harvard Medical School and Director, Neuro-Oncology Division at the Dana-Farber Cancer Institute (DFCI) in Boston, and Kerrie McDonald, Ph.D., Associate Professor and Head of Biomarkers and Translational Research at the Lowy Cancer Research Centre, University of New South Wales, Australia.

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The scientific rationale for this clinical trial is based on positive results from preclinical studies conducted by Dr. McDonald and her team. MN-166 (Ibudilast) and temozolomide (TMZ) combination treatment significantly increased GBM cell apoptosis and cell cycle arrest in an in-vitro study. Combination treatment of MN-166 (ibudilast) with TMZ resulted in significantly extended survival times compared to TMZ monotherapy in a GBM animal model study with complete tumor regression observed in two out of 16 mice. This is the first clinical trial to evaluate the safety, tolerability and preliminary efficacy of MN-166 (ibudilast) in combination with temozolomide for the treatment of recurrent GBM.

Patrick Y. Wen, M.D., principal investigator, commented, "We are very excited to study ibudilast with TMZ combination treatment as we believe ibudilast’s mechanisms of action and good penetration of the blood-brain barrier could benefit patients with recurrent GBM."

Kerrie McDonald, Ph.D., Associate Professor, University of New South Wales, Australia, commented, "Earlier studies indicate that macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE)-4 may factor in proliferation of GBM tumors. MIF was found to be highly expressed within GBM cells, and especially around necrotic areas and in close proximity to blood vessels. Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis, and longer survival in vivo."

Yuichi Iwaki, MD, PhD, President and Chief Executive Officer of MediciNova, Inc., commented, "We are very pleased that enrollment has commenced for this trial at Dana-Farber Cancer Institute, one of the most highly rated cancer treatment institutions in the U.S. We believe MN-166 offers a novel approach to treating GBM, a highly lethal form of cancer that develops from glial cells."

About the Clinical Trial

This Phase 1/2 clinical trial is divided into a dose-escalation phase (Part 1) followed by a fixed-dose phase (Part 2). A total of 15-18 adult subjects are planned to be enrolled in Part 1 and approximately 32 subjects are planned to be enrolled in Part 2. Part 1 will evaluate the safety and tolerability of MN-166 (ibudilast) when given in combination with TMZ, and determine the dose of MN-166 (ibudilast) to be used in Part 2 of the study. Part 2 will evaluate the efficacy of MN-166 (ibudilast) and temozolomide combination treatment in patients with recurrent GBM as measured by the proportion of patients who are progression-free at 6 months. Other outcome measures include the evaluation of overall survival, response rate, and median six-month progression-free survival.

About Glioblastoma

According to the American Association of Neurological Surgeons, GBM is a devastating brain cancer that typically results in death in the first 15 months after diagnosis. GBM develops from glial cells (astrocytes and oligodendrocytes) and rapidly grows and commonly spreads into nearby brain tissue. GBM 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 GBM represents 15% of all brain tumors and 56% of all gliomas and has the highest number of cases of all malignant tumors, with an estimated 12,760 new cases predicted for 2018. 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 GBM. Median survival is 14.6 months and two-year survival is 30%. Approximately 5% of GBM patients survive longer than 36 months.

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. It 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 progressive multiple sclerosis (MS) and other neurological diseases such as amyotrophic lateral sclerosis (ALS), substance abuse/addiction and glioblastoma (GBM). MediciNova is developing MN-166 for progressive MS and other neurological conditions such as ALS, substance abuse/addiction, chemotherapy-induced neuropathy, and glioblastoma. MediciNova has a portfolio of patents which cover the use of MN-166 (ibudilast) to treat various diseases including progressive MS, ALS, and drug addiction.

On January 8, 2019 Genmab A/S (Nasdaq Copenhagen: GEN) reported that it has achieved a USD 75 million sales volume milestone in its DARZALEX (daratumumab) collaboration with Janssen Biotech, Inc (Press release, Genmab, JAN 8, 2019, View Source [SID1234532577]). The milestone was triggered by confirmation by Janssen that sales of DARZALEX reached USD 2 billion in the calendar year of 2018. In August 2012, Genmab granted Janssen an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.

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"We are very pleased that as the launch continues, DARZALEX has become available to so many more multiple myeloma patients in need, which is reflected in the achievement of this sales milestone. With the potential for further indications to be approved in the future, we look forward to even greater growth in the coming years," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The milestone payment was included in the financial guidance issued by Genmab originally on February 21, 2018 and then reiterated in subsequent quarterly financial reports, most recently on November 14, 2018, and as such there is no change to the company’s financial guidance for 2018.