On October 7, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported 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 lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, OCT 7, 2016, View Source [SID:SID1234515656]). The sBLA was submitted by Genmab’s licensing partner, Janssen Biotech, Inc. in August 2016. 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 February 17, 2017 to take a decision on daratumumab in this indication. In addition, the FDA has granted a Standard Review period for the use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, with a proteasome inhibitor and an immunomodulatory agent.

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The PDUFA date for the combination of daratumumab with pomalidomide/dexamethasone is June 17, 2017.
The FDA granted a Breakthrough Therapy Designation for daratumumab 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 July 2016.

"People suffering from multiple myeloma always ultimately relapse after receiving treatment with the therapies available today. The application for daratumumab in combination with current backbone therapies for patients who have already received at least one type of treatment is a key step towards trying to bring new treatment options to patients with multiple myeloma," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The sBLA submission included data from two Phase III studies: the CASTOR study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma. The submission also included data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma.

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 are expected to be diagnosed with multiple myeloma and approximately 12,650 people are 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 for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 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 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. 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. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor.

On October 7, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) and Agensys, an affiliate of Astellas, reported updated clinical data for enfortumab vedotin (ASG-22ME) and ASG-15ME at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress being held October 7-11, 2016 in Copenhagen, Denmark (Press release, Seattle Genetics, OCT 7, 2016, View Source [SID:SID1234515651]). Enfortumab vedotin and ASG-15ME are investigational antibody-drug conjugates (ADCs) that target the cell surface proteins Nectin-4 and SLITRK6, respectively. The clinical data for both agents continue to demonstrate overall response rates in patients with previously treated metastatic urothelial cancer, including those with prior checkpoint inhibitors. Safety and recommended phase II doses were also presented for both programs. While both phase I studies will continue to enroll patients, the companies plan to advance enfortumab vedotin and discuss next steps with regulatory agencies. Evaluation of next developmental steps for ASG-15ME is ongoing.

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"We are pleased to advance the enfortumab vedotin development program for patients with metastatic urothelial cancer. These patients are in dire need of new treatment options as their prognosis is grim, with a five-year survival rate of about 15 percent," said Jonathan Drachman, M.D., chief medical officer and executive vice president, Research and Development at Seattle Genetics. "The antitumor activity and safety profile of enfortumab vedotin in heavily pretreated metastatic patients is encouraging, particularly in those patients who have failed both platinum-based chemotherapy and checkpoint inhibitors. We look forward to discussions with regulatory agencies."

"Both enfortumab vedotin and ASG-15ME hold potential promise for metastatic urothelial cancer patients," said Steven Benner, M.D., senior vice president, therapeutic area head for oncology development, Astellas. "As we consider our next steps in these two development programs, we also pause to thank the patients, caregivers and clinical investigators who participate in these clinical trials for the important role they play in advancing the science of cancer care."

Interim data from two phase I dose-escalation studies of enfortumab vedotin and ASG-15ME monotherapy in patients with metastatic urothelial cancer will be presented at the ESMO (Free ESMO Whitepaper) Congress during poster sessions on Sunday, October 9, 2016. The respective clinical trial data showed that each agent had antitumor activity in patients previously treated with platinum-based chemotherapy, checkpoint inhibitors, taxanes and those with liver metastases. Enfortumab vedotin and ASG-15ME were generally well-tolerated, and phase 1 enrollment is ongoing with both agents, with an increased focus on checkpoint-inhibitor treated patients to further understand safety and activity in this population. Detailed findings are summarized below:

Interim Analysis of a Phase 1 Dose Escalation Trial of ASG-22CE (ASG-22ME; enfortumab vedotin), an Antibody-Drug Conjugate (ADC) in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #788P, poster presentation on Sunday, October 9, 2016)

Data were reported from 58 patients with metastatic urothelial cancer having a median age of 67 years. Of these patients, 56 patients (97 percent) had undergone treatment with a platinum-based chemotherapy regimen and 20 patients (35 percent) had progressed on or after treatment with checkpoint inhibitors. Thirty-six patients (62 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate pharmacokinetics and safety of enfortumab vedotin as a monotherapy at escalating doses of 0.5 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

Of the 49 patients evaluable for response, 18 patients (37 percent) had an objective response, including one patient (two percent) who achieved a complete response and 17 patients (35 percent) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.6 weeks.
The recommended phase 2 dose is 1.25 mg/kg. In 17 patients treated at the 1.25 mg/kg dose level, 10 patients (59 percent) had a partial response. Disease control was achieved for 14 patients (82 percent), defined as achieving complete response, partial response or stable disease.
In the 16 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (38 percent) achieved a partial response. At the recommended phase 2 dose, four out of seven patients (57 percent) previously treated with checkpoint inhibitors achieved a partial response.
In the 12 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, five patients (42 percent) achieved an objective response. Of 20 patients previously treated with taxanes, eight (40 percent) achieved an objective response.
The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were pruritis (31 percent), fatigue (30 percent), diarrhea (29 percent), nausea (28 percent), rash (26 percent) and alopecia (21 percent).
Eight of 19 patients (42 percent) experienced a rash at the recommended phase 2 dose and none of these patients required dose modification or discontinued therapy as a result.
Enrollment is ongoing at 1.25 mg/kg and the study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population.
Interim Analysis of a Phase 1 Dose Escalation Trial of the Antibody-Drug Conjugate (ADC) AGS15E (ASG-15ME) in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #780PD, poster presentation with discussion on Sunday, October 9, 2016)

Data were reported from 54 patients with metastatic urothelial cancer having a median age of 64 years. Of these patients, 52 patients (96 percent) had previously undergone treatment with a platinum-based chemotherapy regimen and 17 patients (32 percent) had progressed on or after treatment with checkpoint inhibitors. Thirty patients (56 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate the pharmacokinetics and safety of ASG-15ME as a monotherapy at escalating doses of 0.1 to 1.25 mg/kg weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

Of the 48 patients evaluable for response, 18 patients (38 percent) had an objective response, including one patient (two percent) who achieved a complete response and 17 patients (35 percent) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.1 weeks.
The recommended phase 2 dose is 1.0 mg/kg. In 20 patients treated at the 1.0 mg/kg dose level, 10 patients (50 percent) had an objective response, including one patient (five percent) who achieved a complete response and nine patients (45 percent) who achieved a partial response. Disease control was achieved for 14 patients (70 percent), defined as achieving complete response, partial response or stable disease.
Of the 14 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (43 percent) achieved a partial response. At the recommended phase 2 dose, three out of seven patients (43 percent) previously treated with checkpoint inhibitors achieved a partial response.
In the 13 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, six patients (46 percent) achieved an objective response. Of 22 patients previously treated with taxanes, nine (41 percent) achieved an objective response.
The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were fatigue (44 percent), nausea (22 percent) and decreased appetite (20 percent).
Fourteen patients (26 percent) experienced ocular adverse events and six patients (11 percent) developed ocular symptoms with corneal abnormalities at the recommended phase 2 dose. All events resolved with appropriate management.
Enrollment is ongoing at 1.0 mg/kg and the study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population.
More information about these clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

About Urothelial Cancer

Urothelial cancers include carcinomas of the bladder, ureter, and renal pelvis, which occur at a ratio of 50:3:1, respectively. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial cancer begins when urothelial cells in the urinary bladder, ureter, or renal pelvis start to grow uncontrollably.

While patients with early stage urothelial cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15 percent. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

About Enfortumab Vedotin and ASG-15ME

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics proprietary, industry-leading linker technology. Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys (now Astellas), which is expressed on many solid tumors. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.

ASG-15ME is an investigational antibody-drug conjugate (ADC) composed of an anti-SLITRK6 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics proprietary, industry-leading linker technology. ASG-15ME is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity.

Nectin-4 and SLITRK6 are highly expressed in urothelial cancers, particularly bladder cancer. Enfortumab vedotin and ASG-15ME consist of monoclonal antibodies which selectively target and kill tumor cells with microtubule-disrupting agents. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

On October 7, 2016 Incyte Corporation (Nasdaq:INCY) reported that updated data from the Phase I portion of the ECHO-202 trial evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with pembrolizumab (Keytruda)*, Merck’s anti-PD-1 therapy, have been published as a poster at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2016 in Copenhagen, Denmark (Press release, Incyte, OCT 7, 2016, View Source [SID:SID1234515643]).

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Further to the previously published abstract, today’s updated data show that among patients with treatment-naïve advanced melanoma (n=19), the combination of epacadostat plus pembrolizumab resulted in progression-free survival (PFS) rates of 74 percent and 57 percent at 6 months and 12 months, respectively. Median PFS has not been reached. The updated data also show an increase in the complete response (CR) rate to 26 percent. The objective response rate (ORR) and disease control rate (DCR) remained consistent with the previously published abstract data, at 58 percent and 74 percent, respectively. All responses are confirmed and ongoing (median follow-up among responders 56 plus [range of 46 to 90 plus] weeks).

"We are excited to share further data with additional follow-up from the Phase 1 portion of the ECHO-202 study," said Steven Stein, M.D., Incyte’s Chief Medical Officer. "The durable responses seen in patients with treatment-naïve advanced or metastatic melanoma reaffirm the activity of this immunotherapy combination, and we look forward to the read-out of ECHO-301, the ongoing, pivotal Phase 3 trial."

Epacadostat in combination with pembrolizumab was well tolerated in the Phase 1 population (n=62). The most common (≥15%) all grade treatment-related AEs (TRAEs) were fatigue, rash, pruritus, arthralgia, diarrhea and nausea. Grade ≥3 TRAEs were observed in 19 percent of patients; the most common were rash (8%) and increased lipase (5%). Five patients (8%) discontinued treatment due to TRAEs.

The ECHO-202 poster was made available to attendees at the ESMO (Free ESMO Whitepaper) Congress today, Friday, 7 October, and will be made available via the Events and Presentations tab of the Investor section of www.incyte.com. Incyte will host an investor conference call and webcast at 14:00 CET (8:00 a.m. ET) today, 7 October 2016, which can also be accessed via the Events and Presentations tab of the Investor section of www.incyte.com

About ECHO-202 (KEYNOTE-037)
The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 inhibitor, in combination with pembrolizumab. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + pembrolizumab 2 mg/kg IV Q3W and epacadostat 300 mg BID + pembrolizumab 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + pembrolizumab 200 mg IV Q3W) portions of the trial. Enrollment in Phase 2, tumor-specific, cohorts is ongoing.

About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study evaluating pembrolizumab in combination with epacadostat or placebo for the first-line treatment of patients with advanced or metastatic melanoma, is also underway. ECHO-301 was initiated in June 2016 and initial data from this study are expected to be available in 2018.

About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor pembrolizumab improved response rates compared with studies of the immune checkpoint inhibitors alone.