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U.S. FDA Grants Priority Review for Daratumumab in Front Line Multiple Myeloma

On January 19, 2018 Genmab A/S (Nasdaq Copenhagen: GEN) announced today that the U.S. Food and Drug Administration (FDA) has granted Priority Review to the supplemental Biologics License Application (sBLA) for the use of daratumumab (DARZALEX) in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) (Press release, Genmab, JAN 19, 2018, View Source [SID1234523369]). The sBLA was submitted by Genmab’s licensing partner, Janssen Biotech, Inc., in November 2017. Priority Review is an FDA designation for drugs that treat a serious condition and may provide a significant improvement in safety or efficacy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target date of May 21, 2018 to take a decision on daratumumab in this indication. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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"The granting of priority review to the submission of daratumumab in front line multiple myeloma is an important step forward towards potentially bringing this product to an even larger number of patients in need," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The sBLA submission was based on data from the Phase III ALCYONE study of daratumumab in combination with bortezomib, melphalan and prednisone in front line multiple myeloma. This data was presented as a Late-Breaking Abstract at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and published in The New England Journal of Medicine in December, 2017.

About the ALCYONE study
This Phase III study (NCT02195479) is a randomized, open-label, multicenter study and includes 706 newly diagnosed patients with multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT). Patients were randomized to receive 9 cycles of either VMP [bortezomib (a proteasome inhibitor), melphalan (an alkylating chemotherapeutic agent) and prednisone (a corticosteroid)] combined with daratumumab, or VMP alone. In the daratumumab treatment arm, patients received 16 mg/kg of daratumumab once weekly for six weeks (cycle 1; 1 cycle = 42 days), followed by once every three weeks (cycles 2-9). Following the 9 cycles, patients in the daratumumab treatment arm continued to receive 16 mg/kg of daratumumab once every four weeks until disease progression. The primary endpoint of the study is progression free survival (PFS).

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients were expected to be diagnosed with multiple myeloma and approximately 12,650 people were expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.6 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. In Japan, DARZALEX is approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for treatment of adults with relapsed or refractory multiple myeloma. DARZALEX is the first human CD38 monoclonal antibody to reach the market. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).7,8,9,10,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies, in relapsed and frontline multiple myeloma settings and in amyloidosis. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, NKT-cell lymphoma, myelodysplastic syndromes and solid tumors. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.

AVEO Oncology Announces Presentation of Data from Phase 1b/2 Study of Tivozanib in Patients with Advanced Hepatocellular Carcinoma

On January 19, 2018 AVEO Oncology (NASDAQ:AVEO) reported the presentation of data from a multicenter, Phase 1b/2 study of FOTIVDA (tivozanib), a potent, selective, long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors, in patients with advanced, unresectable hepatocellular carcinoma (HCC) (Press release, AVEO, JAN 19, 2018, View Source;p=RssLanding&cat=news&id=2327533 [SID1234523364]). The data were presented during a poster session titled, "Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma" (Abstract #364) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium held January 18-20, 2018 in San Francisco. A copy of the presentation is available at www.aveooncology.com.

"Advanced HCC represents an area of high unmet need, with the limited number of currently available therapies often associated with increased levels of hepatotoxicity, further complicating effective treatment," said Michael Needle, MD, chief medical officer of AVEO. "Findings from this study suggest that low doses of tivozanib may yield comparable PFS and a favorable response rate to current first line standards of care for HCC patients, with a favorable safety profile which may enable therapeutic combinations with immunotherapy. We expect the clinical investigation of the combination of VEGF and checkpoint inhibition to be the next critical step forward for the treatment of HCC. We look forward to reporting preliminary Phase 2 data from the TiNivo combination trial of tivozanib and nivolumab in the lead indication of renal cell cancer at the upcoming ASCO (Free ASCO Whitepaper) GU conference, and to exploring options for pursuing similar combinations in HCC."

The study, designed to evaluate the safety and efficacy of tivozanib in advanced HCC, enrolled a total of 21 patients at three study sites. In the Phase 1b portion of the trial, which used a modified 3+3 dose escalation design, 8 patients were dosed with tivozanib starting at 1.0 mg daily for 21 days followed by 7 days off drug, with inter-patient escalation to 1.5 mg daily or de-escalation to 0.5 mg daily based on cumulative dose-limiting toxicities (DLT). Upon escalation to 1.5 mg, two patients had on target dose limiting toxicities (grade 3 mucositis and hypertension), which were likely due to the high potency of tivozanib, and came off study without completing the DLT period. Tivozanib at 1.0 mg daily was selected for the Phase 2 expansion portion and was well tolerated.

Of 19 evaluable patients, at a median follow up of 16.9 months, the study’s primary endpoint of median progression-free survival (PFS) and PFS at week 24 were 5.5 months and 47%, respectively. A partial response (PR) was seen in 4/19 patients (21%) and stable disease (SD) in 8/19 patients (42%), for a disease control rate (DCR) of 63%. Overall survival (OS) at 6 and 12 months was 58% and 25%, respectively, with a median OS of 7.5 months. Notably, 4 patients have maintained SD for over two years. There were no significant changes in HBV or HCV viral load during study treatment. Tivozanib was generally well tolerated at 1.0 mg daily, with adverse events consistent with those observed in previous tivozanib trials.

The Phase 1b/2 study was one of several studies funded by a grant provided to the National Comprehensive Cancer Network from AVEO.

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.

First patient enrolled into phase I/II clinical trial of NY-ESO-1?siTCR?gene therapy against synovial sarcoma in Japan

On January 19, 2018 Takara Bio Inc. (Takara Bio), reported that the first patient with synovial sarcoma has been enrolled into NY-ESO-1・siTCR gene therapy (TBI-1301) phase I/II clinical trial in Japan on January 15-16, 2018.

In the clinical trial, the gene of TCR which recognizes NY-ESO-1 antigen, a tumor antigen, is transferred ex-vivo to lymphocytes of patients, and the gene-modified lymphocytes are infused back to the patients. The patients will be monitored for safety and efficacy. The Takara Bio’s method for gene transduction, T-cell expansion methods using RetroNectin, and Takara Bio’s original retroviral vectors for siTCR transduction will be used during the cell processing for the clinical trial. NY-ESO-1・siTCR gene transduced lymphocytes manufactured at Center for Gene and Cell Therapy (Kusatsu, Shiga), Takara Bio’s facility, will be used.

Takara Bio attempts to achieve the early-approval utilizing the conditional and term-limited approval system for regenerative medicine under The Law on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical devices. Takara Bio aims to commercialize the NY-ESO-1・siTCR gene therapy in the fiscal year 2020.

Reference
"Announcement on submission of the Clinical Trial Plan Notification for phase I/II clinical trial of NY-ESO-1・siTCR gene therapy in Japan"
– Our news release January 24, 2017 View Source

Lynparza receives approval in Japan for the treatment of advanced ovarian cancer

On January 19, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US (known as MSD outside the US and Canada) reported that the Japanese Ministry of Health, Labour and Welfare has approved Lynparza (olaparib) tablets (300mg twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, regardless of their BRCA mutation status, who responded to their last platinum-based chemotherapy (Press release, AstraZeneca, JAN 19, 2018, View Source [SID1234523304]). Lynparza is the first poly ADP-ribose polymerase (PARP) inhibitor to be approved in Japan.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: "We are proud to bring this important first-in-class treatment to women with platinum-sensitive relapsed ovarian cancer in Japan who currently have very few treatment options. The trials show that with Lynparza maintenance therapy, women with ovarian cancer can live longer without their disease worsening and Lynparza is well tolerated."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Today’s decision is significant for Lynparza and, more importantly, for Japanese patients living with advanced ovarian cancer. Our global collaboration with AstraZeneca reinforces how our joint efforts can advance science for patients, and we look forward to working together to explore the potential of Lynparza across multiple tumour types."

The approval was granted on the basis of two randomised trials of Lynparza maintenance therapy for platinum-sensitive relapsed ovarian cancer, SOLO-2 and Study 19.

Table 1. Summary of key efficacy results from randomised trials:

Analysis

Reduction in the risk of disease progression or death (PFS)

Reduction in the risk of death (OS)

SOLO-2

[gBRCAm]

n=295

Lynparza

70% (HR 0.30 [95% CI, 0.22-0.41], P<0.0001; median 19.1 vs 5.5 months by investigator-assessed analysis)

Data not yet mature

Placebo

Study 19

[PSR OC*]

n=265

Lynparza

65% (HR 0.35 [95% CI, 0.25-0.49], P<0.0001;

median 8.4 vs 4.8 months)

27% (HR 0.73 [95% CI, 0.55-0.95];

median 29.8 vs 27.8 months)

Placebo

*PSR = Platinum-sensitive recurrent ovarian cancer

In SOLO-2, the most common adverse drug reactions (≥20%) of any grade reported in patients in the Lynparza arm were nausea (66.7%), anaemia (39.0%), fatigue (29.7%), vomiting (25.6%), asthenia (24.1%) and dysgeusia (23.1%).

In Study 19, the most common adverse drug reactions (≥20%) of any grade reported in patients in the Lynparza arm were nausea (64.0%), fatigue (43.4%) and vomiting (21.3%).

Lynparza is also currently under review for use in unresectable or recurrent BRCA-mutated, HER2-negative breast cancer in Japan, with a decision expected in the second half of 2018 based upon a priority review.

NOTES TO EDITORS
About Ovarian Cancer in Japan

Worldwide, ovarian cancer is the seventh most-commonly diagnosed cancer and the eighth most-common cause of cancer deaths in women. In Japan, more than 9,000 women are diagnosed with ovarian cancer every year and the five-year survival rate is 58%, the lowest among all gynaecological cancers. In 2012, 4,758 women with ovarian cancer died, which represents one out of every two patients. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improving or maintaining a patient’s quality of life.

About SOLO-2

SOLO-2 was a Phase III, randomised, double-blinded, multicentre trial designed to determine the efficacy of Lynparza tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive, relapsed or recurrent gBRCA-mutated ovarian, fallopian tube and primary peritoneal cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomised 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response. Eligible patients were randomised to receive 300mg Lynparza tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a Phase II, randomised, double-blinded, placebo-controlled, multicentre trial, which evaluated the efficacy and safety of Lynparza compared with placebo in relapsed, high-grade serous ovarian cancer patients. The trial randomised 265 patients regardless of BRCA mutation status and who had completed at least two courses of platinum-based chemotherapy and their most recent treatment regimen. Eligible patients were randomised to receive Lynparza maintenance monotherapy at a dose of 400mg per day or matching placebo.

About Lynparza (olaparib)

Lynparza is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit tumour DNA damage response (DDR)-pathway deficiencies to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza is being investigated in a range of DDR-deficient tumour types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for a range of tumour types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody-Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

Bavarian Nordic Announces Initiation of Clinical Trial with Novel Cancer Immunotherapy Targeting Brachyury in Cancer Metastasis

On January 19, 2018 Bavarian Nordic A/S (OMX: BAVA, OTC: BVNRY) reported the initiation of a clinical trial of BN-Brachyury, a novel cancer immunotherapy candidate designed to target brachyury, a key driver of cancer metastasis in several tumor types (Press release, Bavarian Nordic, JAN 19, 2018, View Source [SID1234523299]). The open-label Phase 1 trial will evaluate the safety and tolerability of the MVA‑BN Brachyury vaccine, followed by a Brachyury encoded fowlpox (FPV) booster in patients.

The trial will enroll up to 10 patients with metastatic or unresectable, locally advanced malignant solid tumors. Patients will receive two prime doses of MVA-BN Brachyury, followed by multiple booster doses with FPV-Brachyury. The primary endpoint of the study is safety and tolerability, and secondary endpoints include immunologic responses as measured by an increase in brachyury-specific T-cells and other tumor-associated antigens, as well as evidence of clinical benefit such as progression-free survival (PFS) and objective response (OR). The priming vaccine alone, MVA-BN Brachyury, was previously investigated in a Phase 1 study in 38 patients with chordoma or metastatic solid cancers, and was shown to be well-tolerated and to induce brachyury-specific T-cell immune responses in the vast majority of patients.

"The brachyury target represents an exciting new approach to attacking multiple cancers and deadly metastasis," commented Paul Chaplin, President and Chief Executive Officer of Bavarian Nordic. "Based on clinical results to date, we believe that BN-Brachyury may be a viable treatment option for patients with various forms of cancer. We look forward to further expanding the program with a Phase 2 study later this year in patients with chordoma – a rare tumor of the spine known to overexpress brachyury, for which there are currently no systemic treatments of proven efficacy available."

About BN-Brachyury
BN-Brachyury is a novel prime-boost cancer immunotherapy candidate, developed in collaboration with the National Cancer Institute (NCI). The product candidate consists of a prime (MVA-BN) and a booster dose (fowlpox or FPV), which have been modified to express brachyury and to encode three costimulatory molecules, known as TRICOM. Brachyury is a tumor-associated antigen that is overexpressed in major solid tumor indications, as well as several rare, ultra-orphan cancer indications, and is reported to play a key role in the metastasis and progression of tumors. Tumors that overexpress brachyury are believed to be highly resistant to standard therapies, including radiation and chemotherapy, and are associated with decreased survival rates.