October 16, 2017 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported initiation of a phase 1b/2 immuno-oncology trial to evaluate Genentech/Roche’s atezolizumab (TECENTRIQ) in combination with Inovio’s INO-5401, a T cell activating immunotherapy encoding multiple antigens, and INO-9012, an immune activator encoding IL-12 (Press release, Inovio, OCT 16, 2017, View Source [SID1234520944]).

The multi-center, open-label efficacy trial will be managed by Inovio, and Genentech will supply atezolizumab. The trial will evaluate the safety, immune response and clinical efficacy of the combination therapy in approximately 80 patients with advanced bladder cancer, specifically advanced unresectable or metastatic urothelial carcinoma (UC), the most common type of bladder cancer. The majority of the patients to be enrolled in the trial will have previously received and failed to demonstrate meaningful response to an anti-PD-1 or PD-L1 checkpoint inhibitor alone. Thus the study will evaluate potential benefit of a checkpoint inhibitor combined with a DNA-based immunotherapeutic and T cell activator within a bladder cancer patient population with very limited treatment options and poor outcomes. The immunologic analyses accompanying the study will provide further insight into mechanisms of checkpoint inhibition and T cell activation in bladder cancer.

Dr. Joaquim Bellmunt, MD, PhD, Director of Bladder Cancer Center, Dana-Farber Cancer Institute and Associate Professor, Harvard Medical School, said, “The unmet need for effective treatments for advanced UC patients remains very high even in the midst of approvals of multiple checkpoint inhibitors in this space — as only a small subset of patients respond to these therapies alone. Increasing evidence suggests that combinatorial approaches are needed to improve upon the initial success of checkpoint inhibitors; the benefit to this patient population may be significantly improved when combination therapies that also generate activated T cells are utilized. Furthermore, there is a very high need for effective treatment approaches in checkpoint-refractory patients.”

Dr. J. Joseph Kim, Inovio’s President and CEO, said, “Combining INO-5401 with TECENTRIQ may provide a synergistic therapeutic effect as a result of generating high levels of activated T cells and simultaneously inhibiting PD-L1. Bladder cancer has often been described as an immunogenic tumor, and here our approach is to augment the anti-PD-1/PD-L1 driven efficacy by further enhancing the T cells against the tumor in a cancer antigen-specific manner. We believe we can demonstrate the immense potential of INO-5401 as a universal cancer immunotherapy to treat patients with multiple cancers.”

Nearly 430,000 new cases of urinary bladder cancer are diagnosed each year worldwide; it accounts for about 165,000 deaths worldwide annually. Advanced unresectable or metastatic UC remains a high unmet medical need as survival remains poor for most patients who experience disease progression or intolerance to treatment during or after platinum-containing chemotherapy. The approval of several checkpoint inhibitors for advanced unresectable or metastatic UC has improved response and survival rates for some patients, however, the majority of patients do not experience meaningful clinical responses to checkpoint inhibitor monotherapy.

Inovio’s INO-5401, an immunotherapy encoding multiple cancer antigens (HTERT, PSMA, and WT1), is designed to generate and activate T cells to many cancer types including bladder cancer. INO-9012, a DNA-based immune activator encoding IL-12, is designed to amplify and accelerate T cell immune responses to INO-5401. Combining INO-5401/INO-9012 with atezolizumab may provide a synergistic therapeutic effect as a result of generating higher levels of activated T cells and simultaneously inhibiting PD-L1. Atezolizumab is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.

About Metastatic Urothelial Carcinoma (UC)

The prognosis for patients with advanced unresectable or metastatic UC is poor, with limited treatment options. It is a disease that has seen no major advances for more than 30 years until the approvals of checkpoint inhibitors. Expected survival is generally less than 12 months; in the U.S., five-year survival of patients with distant metastasis is 5%. In the US, an estimated 79,000 new cases of urinary bladder cancer are expected in 2017.

About INO-5401

INO-5401 includes Inovio’s SynCon antigens for WT1, hTERT and PSMA and has the potential to be a powerful cancer immunotherapy in combination with checkpoint inhibitors. The National Cancer Institute previously highlighted WT1, hTERT and PSMA among a list of attractive cancer antigens, designating them as high priorities for cancer immunotherapy development and placing WT1 at the top of the antigen list. The hTERT antigen is expressed in 85% of cancers; the WT1 and PSMA antigens are also widely prevalent in many cancers. In addition, INO-5401 is being evaluated for the treatment of GBM in combination with a checkpoint inhibitor.

On October 16, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has completed the safety review of its investigational new drug (IND) application for IMGN632 in patients with CD123-positive hematological malignancies, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Press release, ImmunoGen, OCT 16, 2017, View Source [SID1234520942]). Filed in mid-September, the IND is now in effect and ImmunoGen plans to open a Phase 1 study to enrollment before the end of the year.

“IMGN632 is the second ADC from our pipeline to use one of ImmunoGen’s indolino-benzodiazepine cancer-killing agents known as IGNs”
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“IMGN632 is the second ADC from our pipeline to use one of ImmunoGen’s indolino-benzodiazepine cancer-killing agents known as IGNs,” said Richard Gregory, Ph.D., Executive Vice President and Chief Scientific Officer of ImmunoGen. “Our IGN payloads were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that can enable continued patient treatment. Based on the encouraging preclinical findings, IMGN632 represents a potentially promising therapeutic approach for a range of hematological malignancies and we are working to transition this compound rapidly into clinical development before the end of the year.”

IMGN632 uses ImmunoGen’s novel DGN549 IGN payload, linker, and antibody technology and in preclinical models has demonstrated an impressive therapeutic window against CD123-positive malignancies. Preclinical findings reported at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting show that IMGN632, which alkylates DNA, had potent selective activity against AML cells with lower cytotoxicity to normal myeloid progenitor cells than an ADC designed to crosslink DNA activity. These data suggest IMGN632 has the potential to be a highly effective, yet tolerable ADC for AML patients. Supporting preclinical data for IMGN632 showed compelling activity in AML xenograft models.

About IMGN632
IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for AML, BPDCN, myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies. IMGN632 uses a novel IGN payload, linker and antibody technology and in AML xenograft models has demonstrated a large therapeutic index.1

About IGNs
Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.2,3 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing.

About Acute Myeloid Leukemia (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.

On October 16, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has completed the safety review of its investigational new drug (IND) application for IMGN632 in patients with CD123-positive hematological malignancies, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Press release, ImmunoGen, OCT 16, 2017, View Source [SID1234520942]). Filed in mid-September, the IND is now in effect and ImmunoGen plans to open a Phase 1 study to enrollment before the end of the year.

“IMGN632 is the second ADC from our pipeline to use one of ImmunoGen’s indolino-benzodiazepine cancer-killing agents known as IGNs”
Tweet this
“IMGN632 is the second ADC from our pipeline to use one of ImmunoGen’s indolino-benzodiazepine cancer-killing agents known as IGNs,” said Richard Gregory, Ph.D., Executive Vice President and Chief Scientific Officer of ImmunoGen. “Our IGN payloads were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that can enable continued patient treatment. Based on the encouraging preclinical findings, IMGN632 represents a potentially promising therapeutic approach for a range of hematological malignancies and we are working to transition this compound rapidly into clinical development before the end of the year.”

IMGN632 uses ImmunoGen’s novel DGN549 IGN payload, linker, and antibody technology and in preclinical models has demonstrated an impressive therapeutic window against CD123-positive malignancies. Preclinical findings reported at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting show that IMGN632, which alkylates DNA, had potent selective activity against AML cells with lower cytotoxicity to normal myeloid progenitor cells than an ADC designed to crosslink DNA activity. These data suggest IMGN632 has the potential to be a highly effective, yet tolerable ADC for AML patients. Supporting preclinical data for IMGN632 showed compelling activity in AML xenograft models.

About IMGN632
IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for AML, BPDCN, myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies. IMGN632 uses a novel IGN payload, linker and antibody technology and in AML xenograft models has demonstrated a large therapeutic index.1

About IGNs
Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.2,3 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing.

About Acute Myeloid Leukemia (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.

On October 16, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported initiation of a clinical trial evaluating its investigational new drug PEGPH20 with atezolizumab (TECENTRIQ), an anti-PDL1 cancer immunotherapy from Genentech, a member of the Roche Group, in patients with previously untreated, unresectable, locally advanced, or metastatic cholangiocarcinoma and gallbladder adenocarcinoma (Press release, Halozyme, OCT 16, 2017, View Source [SID1234520941]).

“Through the initiation of our HALO-110-101 study, we continue to explore the pan-tumor potential of PEGPH20 and seek new therapeutic options for patients with high unmet need cancers,” said Dr. Dimitrios Chondros, chief medical officer. “We are pleased to progress our clinical collaboration studies with Genentech to evaluate the potential for novel groundbreaking treatments for cancer patients.”

The Halozyme-sponsored Phase 1b/2, open-label, multicenter, randomized clinical trial is designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations compared with the standard chemotherapy regimens. The study will be conducted at more than 40 sites in three countries and is part of a clinical collaboration agreement announced last year to evaluate PEGPH20 and atezolizumab in up to eight tumor types.

Following a safety run-in portion to determine the tolerability of PEGPH20 in combination with atezolizumab, an expansion phase is planned to determine preliminary antitumor activity including overall response rate, duration of response and progression-free survival in patients with high levels of hyaluronan (HA). During the expansion portion, the study seeks to enroll approximately 50 unresectable, locally advanced, or metastatic cholangiocarcinoma (bile duct cancer) and gallbladder adenocarcinoma patients who have not previously been treated.

HA is a glycosaminoglycan, or chain of natural sugars in the body that can accumulate around cancer cells creating high pressure in a tumor, constricting blood flow and thereby reducing access of chemotherapy and immunotherapeutic agents. PEGPH20 is an enzyme that temporarily degrades HA, reducing tumor pressure and potentially increasing blood flow, allowing greater access for chemotherapies and immunotherapies to treat the tumor.

About PEGPH20 (pegvorhyaluronidase alfa)
PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan. PEGPH20 is an enzyme that temporarily degrades HA, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells, potentially constricting blood vessels and impeding the access of other therapies.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreas cancer and fast track designation for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreas cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreas cancer.