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Novel cancer vaccine in combination with check point blockades holds promise

On February 5, 2016 Elios Therapeutics begins enrollment of phase I/IIa melanoma trial (NCT02678741) combining approved check point inhibitors with the Elios personalized cancer vaccine (Press release, Elios Therapeutics, FEB 5, 2016, View Source [SID:SID1234515509]).

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The trial attempts to address the unmet need of metastatic melanoma patients who fail to respond to checkpoint inhibitors(CPIs) alone
The trial will underscore the natural synergies between vaccines and CPIs
The trial will use Elios’ autologous tumor lysate (TL), particle loaded (PL), dendritic cell (DC) vaccine (TLPLDC) currently in a randomized phase IIb adjuvant trial

Elios Therapeutics, LLC, has received FDA approval to proceed with a 45-patient study that will combine the company’s novel autologous vaccine technology (TLPLDC) with standard-of-care "check point inhibitors" in metastatic melanoma patients with stable or slowly progressing disease. The study will be conducted at leading clinical research sites in the U.S. and be led by Steven O’Day, MD, Professor of Medical Oncology, Director of Immuno-Oncology, Director of Clinical Research, The John Wayne Cancer Institute, Providence Saint John’s Medical Center, Santa Monica, California.

Checkpoint inhibitors such as Yervoy, Keytruda, and Opdivo are approved for use in patients with metastatic melanoma. A small subset of patients treated with such ‘checkpoint inhibitors’ will achieve a clinical complete response; however, the majority of patients will not. "While some patients may experience partial responses or stable disease, most will see their disease progress," commented Tom Wagner, PhD, the TLPLDC vaccine inventor: "Checkpoint inhibitors work on a patient’s existing T Cell population. In order for checkpoint inhibitors to be effective, the patient must have corresponding T Cells that can recognize and attack their specific disease. It is likely that patients who do not respond or partially respond to this therapy do not have any or enough specifically-corresponding T Cells to overcome their disease. The way you create those T Cells is through autologous vaccination. Our vaccine creates a specific immune response without toxicity in a production environment that does not carry the financial burden of other therapies – possibly a perfect combination."

In early clinical studies, the TLPLDC vaccine has shown effectiveness in both the adjuvant and metastatic settings. Elios is also currently enrolling a phase II(b) 120-patient adjuvant trial in stage III and IV (resected) melanoma patients (NCT#02301611). "The unique way that the TLPLDC vaccine presents antigen to the immune system with or without other therapeutic agents and the logistical ease with which the vaccine is produced makes it easily deployed in clinical settings," said George Peoples, MD, FACS, Chief Medical Officer at Elios. "We are excited about our progress in the ongoing adjuvant trial and encouraged that adding the autologous TLPLDC vaccine to existing check point inhibitor therapy will significantly improve patient outcomes in the metastatic setting."

"Immune Checkpoint Inhibitors have revolutionized the treatment of melanoma and other cancers," said Steven O’Day, MD. "Despite durable responses and prolonged survival in many patients the majority of patients do not respond to single agent checkpoint blockade. Novel combinations of checkpoint inhibitors with other immune modulators will be critical as we build on our new found success. Novel Vaccines offer a potential additive or synergistic role in combination with PD1 inhibitors with a favorable toxicity profile."

Initial readouts for (i) the 45 patient phase I/II(a) trial of the TLPLDC vaccine in combination with checkpoint inhibitors in metastatic melanoma patients, and (ii) the 120 patient phase II(b) adjuvant trial in stage III and IV (resected) patients to prevent recurrence are both expected in December 2016.

8-K – Current report

On February 5, 2015 Biota Pharmaceuticals, Inc. (NASDAQ: BOTA) reported its financial results for the three month period ended December 31, 2015, which is the second quarter of the Company’s 2016 fiscal year, and also provided an update on recent corporate developments (Filing, 8-K, Nabi Biopharmaceuticals, FEB 5, 2016, View Source [SID:1234508985]).

"I am very pleased today to report that significant progress is being made with our antiviral pipeline for respiratory indications and we remain on track to have Phase 2 data readouts in the second half of the year from both the HRV and RSV programs. Our oral RSV fusion inhibitor, BTA585, successfully completed a robust Phase 1 single ascending dose study showing a favorable safety and pharmacokinetic profile. We are nearing completion of the Phase 1 multiple ascending dose study and plan to initiate the Phase 2 RSV challenge study next quarter. Additionally we are progressing with enrollment in the Phase 2b SPIRITUS trial of vapendavir and anticipate top-line data in the second half of this year. Not only is this our lead program but it is the most advanced direct-acting antiviral in the field targeting HRV and has the potential to treat problematic upper respiratory infections in the almost 11 million moderate-to-severe asthmatics in the U.S.," stated Joseph M. Patti, PhD, president and chief executive officer at Biota Pharmaceuticals.

"I am glad to report that we have begun screening patients for the Phase 2 study of BTA074, our first-in-class direct-acting antiviral for the treatment of condyloma caused by HPV types 6 & 11, which is the most common manifestation of HPV infection and also the most common sexually-transmitted viral disease worldwide. Current topical treatments do not act on the virus directly so there is a need for a therapy with improved efficacy and reduced local skin reactions to address this contagious infection."

Recent Highlights
Announced positive Phase 1 data for BTA585. The top-line results were from a blinded, placebo-controlled single ascending dose study, which tested doses of up to 800 mg of BTA585, an oral fusion inhibitor in development for the treatment and prevention of respiratory syncytial virus (RSV) infections. Findings included:

● No serious or severe adverse events

● Low incidence of adverse events

● Pharmacokinetic (PK) data demonstrated that all doses of 100 mg or greater achieved BTA585 plasma levels that exceeded the mean EC50 of RSV clinical isolates for 24 hours. The EC50 represents the concentration of drug that is required for 50% inhibition of viral replication in vitro

● BTA585 plasma Cmax was rapidly achieved at approximately one hour following oral dosing and the half-life (T1/2) was approximately five to six hours across the dose range

● Dosing of BTA585 with a high fat meal did not adversely affect the PK

Commenced dosing in Phase 1 multiple ascending dose (MAD) study of BTA585. This study will evaluate the safety and PK of BTA585 in healthy volunteers following seven days of oral dosing. Top-line data is anticipated to be available in the first quarter of 2016.

Enrollment on track for Phase 2b SPIRITUS trial for vapendavir. Top-line data are expected in the second half of 2016 from the multi-center, randomized, double-blind, placebo-controlled dose-ranging study in moderate-to-severe adult asthmatics with symptomatic human rhinovirus (HRV) and a history of asthma exacerbation from colds.

Corporate Updates

Appointed Mark P. Colonnese as Executive Vice President and Chief Financial Officer on November 2, 2015. The Company announced the appointment of Mark Colonnese as Executive Vice President and Chief Financial Officer. Mr. Colonnese has held a number of senior executive positions in the pharmaceutical industry and, most recently, was Chief Financial Officer of Stealth BioTherapeutics, Inc.

Financial Results for the Three Month Period Ended December 31, 2015

The Company reported a net loss of $6.5 million for the three month period ended December 31, 2015, as compared to net income of $6.5 million in the same quarter of the prior fiscal year. Basic and diluted net loss per share was $0.17 for the three month period ended December 31, 2015, as compared to a basic and diluted net income per share of $0.19 in the same period of 2014.

Revenue decreased to $1.7 million for the three month period ended December 31, 2015 from $13.9 million in the same period in 2014 due to a $4.8 million decrease in royalty revenues, related to a larger Relenza government stockpile order received in the prior year, as well as lower seasonal sales of Relenza and Inavir reflecting an earlier than normal flu season in 2014, and $7.4 million decrease in revenue from services as a result of the termination of the Company’s contract with BARDA in 2014.

Cost of revenue decreased to zero for the three month period ended December 31, 2015 from $1.6 million in the same period last year due to the termination of the Company’s contract with BARDA in 2014.

Research and development expense increased to $6.3 million for the three month period ended December 31, 2015 from $4.8 million in the same period in 2014. The $1.5 million increase was the result of a $2.8 million increase in clinical costs related to the ongoing Phase 2b SPIRITUS trial for vapendavir; the Phase 1 SAD and MAD trials for BTA585; and startup expenses for the Phase 2 trial for BTA074. These costs were offset in part by a $0.8 million decrease in compensation expenses and a decrease of $0.5 million in depreciation and facility related expenses associated with the closure of the Company’s early-stage research facility in March 2015.

General and administrative expense decreased to $2.1 million for the three month period ended December 31, 2015 from $2.6 million in the same period in 2014, due largely to lower compensation expenses as a result of administrative staff reductions related to the facility closure in March 2015.

The Company held $57.2 million in cash, cash equivalents, and short and long-term investments as of December 31, 2015.

U.S. FOOD AND DRUG ADMINISTRATION (FDA) GRANTS BREAKTHROUGH THERAPY DESIGNATION TO IMMUNOMEDICS FOR SACITUZUMAB GOVITECAN FOR THE TREATMENT OF PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER

On February 5, 2016 Immunomedics reported that its lead investigational antibody-drug conjugate, sacituzumab govitecan, or IMMU-132, has received Breakthrough Therapy Designation from the FDA for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease (Press release, Immunomedics, FEB 5, 2016, View Source [SID:1234508982]).

The Breakthrough Therapy Designation was supported by a Phase 2 study in patients with metastatic TNBC who had received a median of 5 prior therapies (range, 2 – 12).

"We believe Breakthrough Therapy Designation for IMMU-132 further validates this potential therapeutic for patients with TNBC, and we are delighted to receive this important recognition," commented Cynthia L. Sullivan, President and Chief Executive Officer. "We continue to assess partnering opportunities while completing the scale-up manufacturing and regulatory activities for an international, randomized, controlled, registration trial in TNBC, based on the Special Protocol Assessment agreement that was already granted by the FDA," she added.

Ms. Sullivan further stated: "IMMU-132 is also in Phase 2 trials in patients with advanced, heavily-pretreated, non-small-cell lung cancer, small-cell lung cancer, and urothelial cancers, where encouraging results have been observed. The Trop-2 receptor targeted by this antibodydrug conjugate has increased expression in a large number of solid cancers. To date, we have enrolled about 300 patients with diverse cancer types."

10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, ImmunoGen, FEB 4, 2016, View Source [SID:1234508974])

Lrg-1 antagonists: Direct effect upon cancer cells

Summary
The formation of new blood vessels by angiogenesis is a key feature of number of diseases including Age-related Macular Degeneration (AMD), Proliferative Diabetic Retinopathy (PDR), atherosclerosis, rheumatoid arthritis and cancer (Press release, UCLB, FEB 4, 2016, View Source [SID:1234508995]). Vascular Endothelial Growth Factors (VEGFs) and their receptors have been previously identified as targets for therapy of these diseases but their success in human therapy is limited with adverse side effects upon long term use.
Researchers at UCL Institute of Ophthalmology have now identified a novel protein Lrg1 which acts in the pathogenic angiogenesis pathway. An antibody therapy has been developed against Lrg1 and is currently in pre-clinical development.

The Technology and its Advantages
Researchers at UCL Institute of Ophthalmology have identified Lrg1 (leucine-rich alpha-2-glycoprotein-1) as a player in angiogenesis, tumour development, migration and aberrant scaring. Lrg1 is a secreted glycoprotein that stimulates angiogenesis by modulating the activity of TGFß. UCL researchers showed that antibodies against Lrg1 block lesion formation in the mouse model of laser-induced choroidal neovascularisation (CNV) (Wang et al., 2013, Nature, 499(7458):306-11). Significantly, in the mouse model of oxygen-induced retinopathy they observed that Lrg1 is involved specifically in the development of pathological vascular tufts, but not the normal vessel growth that occurs during the revascularisation phase. Collectively, these data revealed that Lrg1 is required for pathological angiogenesis, identifying Lrg1 as a therapeutic target for diseases such as wet AMD and cancer, in which aberrant blood vessel growth occurs.

The team developed a series of monoclonal antibodies against Lrg1. The lead candidate has been humanised and de-immunised and funding has been secured to develop the CMC process to GMP standards, perform pre-clinical toxicology studies and Phase IIa trial.

Targeting Lrg1 offers an alternative over currently used anti-VEGFs. These compounds have efficacy in wet AMD, diabetic retinopathy and cancer, but there is a significant fraction of patients who either fail to respond to VEGF blockade or who become refractory. The currently used VEGF blockers are known to have adverse effects in ocular indications, most likely because VEGF has a homeostatic role in neuronal cells, and this may limit long-term drug administration. In cancer, systemic administration of Avastin is associated with an increased risk of cardiovascular events, haemorrhage and stroke.

Market Opportunity
Currently the anti-angiogenic therapeutic market is dominated by the anti-VEGFs, in particular Avastin, Lucentis and Eylea.
Although Wet AMD, which results from the abnormal growth of blood vessels accounts for only 10-15% of all AMD cases, it is responsible for more than 80% of AMD-related vision loss. Datamonitor Healthcare estimates that sales of drugs for wet AMD across the US and five major EU markets (France, Germany, Italy, Spain, and the UK) will reach almost $5.8bn by 2023.
Diabetic retinopathy is the leading cause of blindness in adults of working age affecting 11.5M people in the seven major markets in 2010. According to Grand View Research Inc, global DR market is expected to reach $10.11bn by 2022.
Global cancer prevalence is driven by the aging population and even though cancer is not a single, homogenous disease, TGFß has been implicated in many cancer types – making this therapeutic approach suitable for many cancer indications. The global market for cancer is expected to reach $147bn by 2018, according to a report by the IMS Institute for Healthcare Informatics.
Collectively these three main indications for which Lrg1 antagonists could be used can be estimated to achieve ca. $160bn market potential.