On October 18, 2017 Innovation Pharmaceuticals Inc. (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, reported that all patients participating in the Phase 2 trial of Brilacidin-OM for the prevention and treatment of Oral Mucositis (OM) in Head and Neck Cancer (HNC) patients have completed therapy and the last patient post-treatment follow-up examination is scheduled for next week (Press release, Innovation Pharmaceuticals, OCT 18, 2017, View Source [SID1234521019]).

Brilacidin oral rinse being developed as a preventative Oral Mucositis treatment

OM represents a large unmet medical need and sizable market opportunity

As announced on October 2, 2017, the last patient recently completed the therapeutic regimen in the double-blind study. After the final patient post-treatment follow-up is conducted next week, the Company will focus on the process of concluding the study, including closing clinical sites and aggregating and analyzing data. Innovation Pharmaceuticals anticipates reporting topline results later this quarter.

“There are no FDA-approved preventative or curative treatments for OM in patients with Head and Neck Cancer. As a result, a tremendous market opportunity exists in helping hundreds of thousands of patients worldwide who suffer from this painful and debilitating condition as a consequence of receiving cancer therapy,” commented Arthur P. Bertolino, MD, PhD, MBA, President and Chief Medical Officer at Innovation Pharmaceuticals. “We look forward to finishing the final follow-up visit, then unblinding and analyzing the full dataset from the study. Moreover, we remain optimistic that one day we will help address, in a substantial way, this area of considerable unmet medical need.”

On a related note, the Company recently published a blog post on its website further discussing the OM market opportunity. An excerpt from the blog post is as follows:

“Head and Neck Cancer (HNC) patients — comprising an estimated 65,000 newly diagnosed cases in the U.S. alone in 2017, and an estimated 700,000 worldwide (source: GLOBOCAN) — are at greatest risk of developing severe OM (a 90 to 100 percent rate of occurrence). By 2030, the global incidence of HNC cases is expected to exceed 1 million per year. Moreover, between 25 and 60 percent of cancer patients, regardless of cancer type, also will experience OM during the course of their chemo/radiotherapy.

Estimates vary as to the market size (in dollars) of an effective OM treatment, for HNC-only patients, across major markets (U.S., Europe and Japan), ranging between $500 million and $1.5 billion on an annual basis (sources: GlobalData; Redington Inc.). One company in the OM space projects the worldwide OM market opportunity to be as high as $2.6 billion annually.”

On October 18, 2017 Kite, a Gilead Company, (Nasdaq: GILD) reported that the U.S. Food and Drug Administration (FDA) has granted regular approval to Yescarta (axicabtagene ciloleucel), the first chimeric antigen receptor T cell (CAR T) therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL) (Press release, Gilead Sciences, OCT 18, 2017, View Source [SID1234521018]). Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

This press release features multimedia. View the full release here: View Source

CAR T therapy is a breakthrough in hematologic cancer treatment in which a patient’s own T cells are engineered to seek and destroy cancer cells. CAR T therapy is manufactured specifically for each individual patient.

“The FDA approval of Yescarta is a landmark for patients with relapsed or refractory large B-cell lymphoma. This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” said Arie Belldegrun, MD, FACS, Founder of Kite. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”

“Today is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” said John Milligan, PhD, President and Chief Executive Officer of Gilead Sciences. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”

Yescarta has a Boxed Warning in its product label regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities. A Risk Evaluation and Mitigation Strategy (REMS) has been approved by the FDA for Yescarta. The REMS program will inform and educate healthcare professionals about the risks associated with Yescarta therapy. Training and certification on the REMS program will be an integral part of the final authorization for centers offering Yescarta. Additional information about the REMS program can be found at www.yescartarems.com. Please see below for Important Safety Information.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for three out of every five cases. In the United States each year, there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy. Historically, when treated with the current standard of care, patients with refractory large B-cell lymphoma had a median overall survival of approximately six months, with only seven percent attaining a complete response. Currently, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes and greater unmet need, since nearly half of them either do not respond or relapse shortly after transplant.

“With CAR T therapy, we are reengineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Many of the patients that received CAR T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”

“This therapy is a new option for patients with relapsed or refractory large B-cell lymphoma who have run out of treatment options and face a dire prognosis,” said Louis J. DeGennaro, PhD, President and Chief Executive Officer of The Leukemia & Lymphoma Society (LLS). “Early on, LLS recognized the potential of CAR T therapy and we are proud to be part of making this historic approval possible.”

“Engineered cell therapies like Yescarta represent the potential for a changing treatment paradigm for cancer patients,” said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. “Together, Gilead and Kite will accelerate studies of CAR T therapy in multiple blood cancers and advance other cell therapy approaches for solid tumors, with the goal of helping patients with diverse cancers benefit from this new era of personalized cancer therapy.”

Yescarta will be manufactured in Kite’s state-of-the-art commercial manufacturing facility in El Segundo, California. In the ZUMA-1 pivotal trial, Kite demonstrated a 99 percent manufacturing success rate with a median manufacturing turnaround time of 17 days, which is important to patients given the potential for rapid disease progression in this population.

In 2017, Kite established a multi-disciplinary field team focused on providing education and logistics training for centers. Upon Yescarta’s approval, this team will provide final site certification to 16 centers, enabling them to make Yescarta available to appropriate patients. This support is designed to assure the safe and effective use of Yescarta for patients and physicians. Kite is actively working to train more than 30 additional centers with an eventual target of 70 to 90 centers across the United States. The latest information on Yescarta authorized centers is available at www.yescarta.com.

In support of Yescarta therapy, Kite has developed Kite Konnect, a program enabled by an integrated technology platform that focuses on providing information and assistance throughout the Yescarta therapy process, including courier tracking for shipments and manufacturing status updates. Kite Konnect also will provide information related to insurance benefits and third-party resources available for travel support. Healthcare providers and patients can reach Kite Konnect at www.KiteKonnect.com or 1-844-454-KITE (1-844-454-5483).

The list price of Yescarta in the United States is $373,000.

Yescarta has been granted Priority Medicines (PRIME) regulatory support for DLBCL in the European Union. A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA) and potential approval is expected in the first half of 2018.

Yescarta (axicabtagene ciloleucel) Pivotal Trial Results

The approval of Yescarta is supported by data from the ZUMA-1 pivotal trial. In this study, 72 percent of patients treated with a single infusion of Yescarta (n=101) responded to therapy (overall response rate) including 51 percent of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]).

In the study, 13 percent of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31 percent experienced neurologic toxicities. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA approved Yescarta with a Risk Evaluation and Mitigation Strategy.

Yescarta Indication

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with Yescarta. In Study 1, CRS occurred in 94% (101/108) of patients receiving Yescarta, including ≥ Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving Yescarta, four had ongoing CRS events at the time of death. The median time to onset was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities

Neurologic toxicities, that were fatal or life-threatening, occurred following treatment with Yescarta. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of Yescarta infusion, with a median time to onset of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients.

The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta.

Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

Yescarta REMS

Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are:

Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities.
Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483).

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of Yescarta. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

Serious Infections

Severe or life-threatening infections occurred in patients after Yescarta infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines.

Febrile neutropenia was observed in 36% of patients after Yescarta infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated.

Viral Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in (28%) of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Yescarta. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with Yescarta and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment with Yescarta.

Secondary Malignancies

Patients treated with YESCARTA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving Yescarta are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions

The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.

The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections.

On October 18, 2017 Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT, www.provectusbio.com), (“Provectus” or the “Company”), a clinical-stage biotechnology company leading the development of the first small molecule oncolytic immunotherapy, intralesional (“IL”) PV-10, as a single agent for locally advanced disease as well as in combination with another agent for widely metastatic disease, both for multiple cancer indications, reported that results from the Company’s ongoing Phase 1b/2 study of IL PV-10 in combination with KEYTRUDA (pembrolizumab), Merck’s systemic anti-PD-1 (programmed death receptor-1) antibody agent, were presented at the Society for Melanoma Research 2017 Congress, held in Brisbane, Australia from October 18-21 (Press release, Provectus Pharmaceuticals, OCT 18, 2017, View Source [SID1234521017]). IL injection of PV-10 induces immunogenic cell death that results in tumor-specific reactivity in circulating CD8+ T cells.

The Phase 1b portion of the study continues to enroll patients with metastatic melanoma at clinical sites in the U.S. and Australia (NCT02557321); Stage IV patients with at least one injectable lesion who are candidates for KEYTRUDA are eligible. A total of up to 24 patients would receive the combination of IL PV-10 and KEYTRUDA every three weeks for five cycles (i.e., for up to 12 weeks, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial is safety and tolerability; objective response rate and progression-free survival are key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

IL PV-10 Results from the Phase 1b Trial Presented at SMR:

Baseline characteristics (safety population, N=12): 92% men; median age of 71.5 years (range 28-81), 67% > 65 years; 67% Stage IV M1b/c.
Subject characteristics (safety population): 2.5 median number of cutaneous/subcutaneous lesions (range 1-40); patients had substantial non-injected systemic disease burden in addition to their injectable cutaneous and/or subcutaneous lesions; patients received a median of 5 cycles of PV-10 (mean 3.8, range 1-5); PV-10 was not administered after week 12.
Preliminary safety (safety population): adverse events were consistent with the established patterns for each drug; there were no unexpected toxicities or evidence of compounded toxicity.
Preliminary target lesion efficacy (efficacy evaluable population, N=10): 50% complete response; 80% objective response; maximum response.
Preliminary overall efficacy (efficacy evaluable population): 10% complete response; 50% objective response; 60% clinical benefit; highest responses observed in M1c patients; per RECIST 1.1.
Dominic Rodrigues, Chairman of the Company’s Board of Directors, said, “These preliminary results highlight the safety characteristics of the combination of intralesional PV-10 and checkpoint inhibition. The data confirm an almost complete absence of correlation of adverse events between the two drugs, which we refer to as ‘orthogonality.’ This outcome is very different from when oncolytic viruses or other biologics are used in combination with checkpoint inhibitors.”

Mr. Rodrigues added, “There also was promising clinical benefit after minimal PV-10 intervention, especially in those patients with Stage IV M1c disease. These data support the advancement of the combination of PV-10 and checkpoint inhibition in the clinical study of metastatic melanoma.”

A copy of the poster presentation is currently available on Provectus’ website at View Source