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8-K – Current report

On March 30, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "The Company"), reported its financial results for the fourth quarter and year ended December 31, 2015 (Filing, Q4/Annual, Provectus Pharmaceuticals, 2015, MAR 30, 2016, View Source [SID:1234510223]).

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Provectus is holding its previously announced conference call at 4 p.m. (EDT) today to discuss the Company’s 2015 financial results and answer questions from investors.

Those who wish to participate in the conference call may telephone 877-407-4019 from the U.S. International callers may telephone 201-689-8337 approximately fifteen minutes before the call. A webcast will also be available at www.pvct.com. A digital replay will be available by telephone approximately two hours after the completion of the call until June 30, 2016 and may be accessed by dialing 877-660-6853 from the U.S. or 201-612-7415 for international callers, and using the Conference ID #13633721.

Fourth Quarter and Year End Results and Balance Sheet Highlights

At December 31, 2015, cash and cash equivalents were $14,178,902 compared to $17,391,601 at December 31, 2014. The decrease of approximately $3.2 million was due primarily to operating activities.

Our ability to continue as a going concern is reasonably assured due to our financing completed during 2015 and thus far in 2016 from our Warrant Exchange Transaction. Given our current rate of expenditures and our ability to curtail or defer certain controllable expenditures, we do not anticipate the need to raise additional capital to further develop PV-10 on our own to treat melanoma, HCC and cancers of the liver, recurrent breast carcinoma, and other indications. Moreover, we plan to license PH-10 for psoriasis and other related indications described as inflammatory dermatoses, and strategically monetize PV-10, although there can be no assurance that any such transactions will occur. Additionally, our existing funds are sufficient to meet minimal necessary expenses until 2017.

Shareholders’ equity at December 31, 2015 was $16,316,941. This compares to shareholders’ equity at December 31, 2014 of $25,189,876.

For additional information regarding Provectus’s results of operations and financial condition for the fourth quarter and year ended December 31, 2015, please see Provectus’s Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 30, 2016.

First Phase 3 Trial of Daratumumab in Combination with Standard Therapy in Relapsed/Refractory Multiple Myeloma Meets Primary Endpoint in Planned Interim Analysis

On March 30, 2016 Janssen Research & Development, LLC reported positive results of a pre-planned interim analysis of the Phase 3 MMY3004 (CASTOR) trial evaluating the efficacy and safety of daratumumab, a CD38-directed monoclonal antibody (mAb), in combination with bortezomib and dexamethasone, compared to bortezomib and dexamethasone alone, in patients with relapsed or refractory multiple myeloma (Press release, Johnson & Johnson, MAR 30, 2016, View Source [SID:1234510220]). The interim analysis, conducted by an Independent Data Monitoring Committee (IDMC), found that the daratumumab combination treatment regimen improved progression-free survival (PFS) compared with bortezomib and dexamethasone alone, achieving the primary study endpoint (p < 0.0001). Based on the recommendation of the IDMC, the study will be stopped early. Study patients originally assigned to the standard treatment group (bortezomib plus dexamethasone) will be offered the option of receiving daratumumab following confirmed disease progression. All patients continue to be followed for long-term safety and overall survival.

"These results suggest daratumumab could potentially be used in combination with standard therapy in patients with relapsed or refractory multiple myeloma," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development. "We are especially proud that Janssen was involved in the development of two of the medicines in this trial, daratumumab and bortezomib." Janssen licensed daratumumab from Genmab A/S and is responsible for development and marketing. Janssen co-developed bortezomib with Takeda Pharmaceutical Company Limited through its wholly owned subsidiary Millennium Pharmaceuticals Inc. and commercializes the treatment outside of the U.S.

MMY3004 is a Phase 3, multinational, open-label, randomized, multicenter, active-controlled study in approximately 490 patients with relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with subcutaneous bortezomib (a proteasome inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. Participants were treated until disease progression, unacceptable toxicity, or if they had other reasons to discontinue the study. The primary endpoint of the study is PFS.1

These results are planned to be submitted for presentation at an upcoming medical congress, as well as for publication in a peer-reviewed journal. A full study report is being prepared for submission and will be shared with health authorities. Janssen will initiate discussions about the potential for a regulatory submission for this indication. For additional study information, visit ClinicalTrials.gov.

In November 2015, daratumumab (DARZALEX) was approved by the U.S. Food and Drug Administration 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. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.3,4 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, the disease progresses within 60 days of their last therapy.5,6 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.5 Accounting for approximately one percent of all cancers and 15 percent to 20 percent of haematologic malignancies worldwide, multiple myeloma is designated as an orphan disease in both the U.S. and Europe.7 Globally, it is estimated that 124,225 people were diagnosed, and 87,084 died from the disease in 2015.8,9 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.10 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.4

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed monoclonal antibody (mAb) approved anywhere in the world.2 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.11 Daratumumab is believed to induce tumor cell death through apoptosis, in which a series of molecular steps in a cell lead to its death2,12 as well as immunomodulatory effects and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).2,13,14 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. 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 and non-Hodgkin’s lymphoma. DARZALEX is the first mAb to receive regulatory approval to treat relapsed or refractory multiple myeloma.2

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX. DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc.15

DARZALEX (daratumumab) Important Safety Information – Professional

CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence =20%) were: fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection.

Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS – No drug interaction studies have been performed.

ImmunoCellular Therapeutics Announces 2015 Financial Results

On March 30, 2016 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported financial results for 2015 (Press release, ImmunoCellular Therapeutics, MAR 30, 2016, View Source [SID:1234510218]).

Andrew Gengos, ImmunoCellular Chief Executive Officer, commented: "We made important progress in advancing the company in 2015. In particular, we designed and began executing what we believe is the best possible phase 3 registration trial for ICT-107 in patients with newly diagnosed glioblastoma. We took full advantage of about five years of placebo-controlled survival data and immune monitoring results from the phase 2 trial, conversations with key opinion leaders in the field of glioblastoma and discussions with major regulatory bodies in designing this trial. The process of bringing clinical sites online and screening patients in the US is accelerating, and we anticipate that all sites in the US, Canada and Europe will be activated by the end of 2016. In addition, our research relationships and collaborations with prestigious academic institutions, including the University of Texas MD Anderson Cancer Center, Stanford University and the University of Maryland, are progressing well, and represent value-enhancing opportunities for our Company. We are proud of the progress we made in 2015, and are looking forward to delivering another year of growth and achievement in 2016."

For the year ended December 31, 2015, ImmunoCellular incurred a net loss of $12.8 million, or $0.15 per basic and diluted share, compared to a net loss of $9.4 million, or $0.16 per basic and diluted share, for the year ended December 31, 2014. During 2015 the Company incurred $10.9 million of research and development expenses compared to $6.0 million in 2014. The $4.9 million increase primarily reflects the additional expenses associated with the phase 3 trial of ICT-107. General and administrative expenses increased in 2015 to $4.6 million from $3.9 million in 2014, primarily due to additional professional fees and payroll-related expenses. During 2015, the Company recorded a credit to other income of $2.9 million to reflect a write-down in the Company’s warrant liability compared to a credit to other income of $530,000 in 2014. For the quarter ended December 31, 2015, the Company recorded a net loss of $4.8 million, or $0.05 per basic and diluted share, compared to $2.1 million, or $0.03 per basic and diluted share, during the same period in 2014. The increase in the net loss between periods reflects the additional costs of the phase 3 trial of ICT-107.

The Company also reported that cash used in operations in 2015 was $19.0 million compared to $9.9 million in 2014. In addition to the incremental expenses associated with starting the phase 3 trial of ICT-107, the Company also purchased $2.2 million in supplies and made additional vendor deposits of $3.7 million related to the trial. These items will benefit future periods and are reflected on the Company’s balance sheet at December 31, 2015.

During 2015, the Company raised $14.6 million net of offering costs from the issuance of 26,650,000 shares of common stock and warrants to purchase 18,655,000 shares. The warrants have a term of five years and an exercise price of $0.66. During the third quarter of 2015, the Company was awarded $19.9 million from the California Institute of Regenerative Medicine (CIRM) that the Company will be entitled to receive as patients are enrolled in the phase 3 trial of ICT-107, and during the fourth quarter of 2015, the Company received $4.0 million in its first award payment from CIRM. The next award payment is anticipated to be $3.0 million when the next enrollment milestone is achieved. As of December 31, 2015, the Company had $22.6 million in cash.

The Company has agreed in principle with the staff of the SEC on a proposed settlement framework to an investigation related principally to its former Chief Executive Officer involving conduct between November 2011 and August 2012. If the settlement is approved, the Company would consent to the entry of an administrative order requiring that we cease and desist from any future violations of Sections 5, 17(a), and 17(b) of the Securities Act of 1933, as amended, and Section 10(b) of the Securities Exchange Act of 1934, as amended, without admitting or denying any allegations. The proposed settlement also involves the adoption of certain corporate governance amendments to the Company’s policies and practices, in particular as it relates to the retention of investor relations and public relations firms. The proposed settlement is contingent upon execution of a formal offer of settlement and approval by the Commissioners of the SEC, neither of which can be assured. Based upon the settlement framework with the staff of the SEC, the Company has not accrued and does not currently expect to accrue a liability related to this matter. However, any final settlement must be approved by the Commissioners. If the Commissioners do not approve the settlement, the Company may need to enter into further discussions with the SEC to resolve the investigated matters on different terms and conditions. As a result, there can be no assurance as to the final terms of any settlement including its financial impact or any future adjustment to the financial statements.

Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway.

The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). The specific binding of β-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD.
Based on the specific binding of β-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of β-arrestin2 to its target domain in JNK3 in vitro and in vivo.
The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between β-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity.
JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway.

Evidence that histone H1 is dispensable for proper meiotic recombination in budding yeast.

Histone H1, referred to as the linker histone, associates with the nucleosome core particle. While there is indication that the budding yeast version of histone H1 (Hho1) contributes to regulation of chromatin structure and certain chromatin-related processes, such as DNA double-strand break repair, cells lacking Hho1 are healthy and display subtle phenotypes. A recent report has revealed that Hho1 is required for optimal sporulation. The studies described here were conducted to determine whether Hho1 influences meiotic recombination, an event that occurs during sporulation, involves generation and repair of DNA double-strand breaks, and is critical for spore viability.
Through tetrad analysis, cells with or without Hho1 were compared for meiotic reciprocal recombination events within several chromosome XV intervals. Parameters investigated included crossover frequency (genetic map distance) and crossover interference. No significant differences were detected between the two cell types. In agreement with earlier studies, spore viability was not affected by Hho1 absence.
These data suggest that complete absence of Hho1 from chromatin does not affect reciprocal recombination between homologous chromosomes during meiosis. Therefore, the basal level of Hho1 that remains after its reported depletion early in meiosis is unlikely to be important for regulating recombination. Furthermore, the subsequent accumulation of Hho1 as the haploid products mature does not appear to be crucial for spore viability.