On November 7, 2016 BioCryst Pharmaceuticals, Inc. (NASDAQ:BCRX) reported financial results for the third quarter ended September 30, 2016 (Press release, BioCryst Pharmaceuticalsa, NOV 7, 2016, View Source [SID1234516352]).

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"Our company’s primary focus is on the execution of the APeX-1 trial of BCX7353," said Jon P. Stonehouse, President & Chief Executive Officer. "The screening success rate in APeX-1 has been high, approximately 90%, similar to our previous studies in HAE. We are pleased that subject screening has gained momentum recently. As of last Friday, 19 subjects have been screened, of whom 16 have been randomized. Based on our current number of randomized patients, we are modifying our projection for reporting the results of part one to the first quarter of 2017."

Third Quarter Financial Results
For the three months ended September 30, 2016, revenues decreased to $7.8 million from $11.0 million in the third quarter of 2015, largely due to decreased RAPIVAB product sales associated with the transition of RAPIVAB commercialization to the Company’s partner, Seqirus UK Limited (Seqirus), as well as a decrease in collaborative revenue associated with galidesivir (formerly BCX4430) development, which is funded by U.S. Government contracts. This decrease was offset by a large increase in RAPIACTA royalties from government stockpiling sales by the Company’s commercial partner in Japan, Shionogi & Co. Ltd.

(Shionogi).
Research and Development (R&D) expenses for the third quarter of 2016 decreased to $14.1 million from $20.1 million in the third quarter of 2015. This decrease was related to the discontinuation of avoralstat development activities subsequent to OPuS-2 during the summer.
General and Administrative (G&A) expenses for the third quarter of 2016 were $2.8 million, and were consistent with $2.7 million for the third quarter of 2015.
Interest expense, which is currently and primarily related to the Company’s non-recourse notes payable, was $1.5 million in the third quarter of 2016 and $1.2 million in the third quarter of 2015. In addition, a $931,000 mark-to-market loss on the Company’s foreign currency hedge was recognized in the third quarter of 2016, as compared to a $460,000 mark-to-market loss in the third quarter of 2015. These losses resulted from periodic changes in the U.S. dollar/Japanese yen exchange rate and the related mark-to-market valuation of the Company’s underlying hedge arrangement. During the third quarter of 2015, the Company also realized a currency hedge gain of $108,000 from the exercise of a U.S. Dollar/Japanese yen currency option.
The net loss for the third quarter of 2016 was $11.5 million, or a $0.16 net loss per share as compared to a net loss of $14.6 million, or $0.20 net loss per share, for the third quarter 2015.
Cash, cash equivalents and investments decreased to $68.7 million at September 30, 2016, as compared to $100.9 million at December 31, 2015. Net operating cash use for the third quarter of 2016 was $15.0 million, as compared to $12.3 million for the third quarter of 2015. In September 2016, we closed a $23 million senior credit facility, which provided net proceeds to the Company that exceeded cash utilized for operations in the third quarter, thereby increasing the Company’s total cash and investments from June 30, 2016. The senior credit facility was fully funded at closing and bears a variable interest rate based upon LIBOR, currently at 8.5%; an interest-only payment period through fiscal 2017; and scheduled principal and interest payments starting in January 2018 and for the following 40 months. Proceeds from the facility are forecasted to extend the Company’s cash runway into the first quarter of 2018 based upon current operating plans. The Company has the option to repay the facility at any time prior to the scheduled principal repayment schedule.
Year to Date Financial Results
For the nine months ended September 30, 2016, total revenues decreased to $17.4 million, from $43.7 million in the first nine months of 2015. The decrease in revenue resulted from the recognition of approximately $21.7 million of collaborative revenue in the second quarter of 2015 associated with the RAPIVAB out-licensing transaction to Seqirus, no longer recording product sales in 2016 associated with the Seqirus transaction, as well as a decrease in collaborative revenue associated with galidesivir development.
R&D expenses decreased to $48.9 million in the nine months of 2016 from $53.7 million in the first nine months of 2015. The decrease in 2016 R&D expense, as compared to 2015, reflects the discontinuation of avoralstat development as well as reduced spending on the galidesivir program.
G&A expenses decreased to $8.7 million for the nine months ended September 30, 2016 from $10.3 million for the nine months ended September 30, 2015 due primarily to lower unrestricted grants awarded to HAE patient advocacy groups as well as a general reduction of administrative expenses.
In the nine months of 2016 and 2015, interest expense was $4.4 million and $3.9 million, respectively, and was primarily related to the Company’s non-recourse notes payable. A mark-to-market loss on the Company’s foreign currency hedge of $7.4 million was recognized in the first nine months of 2016, compared to a mark-to-market loss of $793,000 in the first nine months of 2015. These gains and losses result from periodic changes in the U.S. dollar/Japanese yen exchange rate and the related mark-to-market valuation of the Company’s underlying hedge arrangement. During the second quarters of 2016 and 2015, we also realized currency gains of $811,000 and $1.7 million, respectively, from the exercise of a U.S. Dollar/Japanese yen currency option within the Company’s foreign currency hedge.
The net loss for the nine months ended September 30, 2016 increased to $50.6 million, or $0.69 per share, from $24.9 million, or $0.34 per share for the same period last year.
Corporate Update & Outlook
In August, BioCryst announced that it dosed the first subject in the APeX-1 clinical trial of BCX7353 for the oral treatment of hereditary angioedema (HAE). The goal of the APeX-1 trial is to reduce or eliminate angioedema attacks in patients with HAE. Results from
APeX-1 are expected in the first quarter of 2017.

On September 7, BioCryst announced positive results from a proof-of-concept study of its broad spectrum antiviral, galidesivir, (formerly BCX4430), for the delayed treatment of Ebola virus infection in rhesus macaques.

On September 26, the Company announced that it closed a $23 million Senior Credit Facility with Midcap Financial.

On October 29, galidesivir nonclinical results from a Zika virus infection model were presented in a late-breaker scientific session at IDWeek by Dr. James B. Whitney, PhD, Assistant Professor of Medicine, Harvard Medical School, and Principal Investigator in the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. Galidesivir dosing in rhesus macaques was well-tolerated and offered significant protection against Zika virus infection.
Financial Outlook for 2016
Based upon development plans and the Company’s awarded government contracts, BioCryst continues to expect its 2016 net operating cash use to be in the range of $55 to $75 million, and has revised its 2016 operating expenses to be in the range of $68 to $80 million, which reflects a reduction from the previous forecasted range of $78 to $98 million. BioCryst’s operating expense range excludes equity-based compensation expense due to the difficulty in reliably projecting this expense, as it is impacted by the volatility and price of the Company’s stock, as well as the vesting of the Company’s outstanding performance-based stock options.

On November 7, 2016 Heat Biologics, Inc. (Nasdaq:HTBX), a leader in the development of gp96-based immunotherapies that activate a patient’s immune system to fight cancer, reported that it will present a poster on its ComPACT platform at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, in National Harbor, Maryland, on Friday, November 11th .

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The details are:

Title: Gp96-Ig/Costimulator (OX40L, ICOSL, or 4-IBBL) Combination Vaccine Improves T-cell Priming and Enhances Immunity, Memory and Tumor Elimination

Date and Time: November 11, 2016, 6:15-7:30 PM

Poster Number: 211

On November 7, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported the presentation of new data from clinical trials of cobimetinib in combination with other therapies to treat forms of advanced melanoma (Press release, Exelixis, NOV 7, 2016, View Source;p=RssLanding&cat=news&id=2219933 [SID1234516321]). Data from phase 1b trials of cobimetinib in combination with atezolizumab, and with atezolizumab and vemurafenib, respectively, form the basis for two Genentech-sponsored phase 3 pivotal trials anticipated to start in 2017. Additionally, data from a pooled analysis of the combination of cobimetinib and vemurafenib demonstrate the potential for the combination to deliver lasting clinical benefit.

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The data are being presented at the Society for Melanoma Research 2016 Congress, which is being held November 6-9 in Boston. Cobimetinib, a selective MEK inhibitor discovered by Exelixis and now the subject of a worldwide collaboration agreement with Genentech, a member of the Roche Group, is the subject of seven abstracts at the meeting.

"Since its initial regulatory approval last year, cobimetinib has continued to generate encouraging data with the potential to broaden its utility as a key component of combination regimens to treat serious forms of cancer," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "If confirmed in the pivotal trials planned to initiate next year, the cobimetinib/atezolizumab and triple-combination regimens described in data at this year’s Society for Melanoma Research Congress could become important new therapeutic options for clinicians treating multiple forms of advanced melanoma."

Pivotal Trial in BRAF Wild-Type Melanoma Planned Following Encouraging Phase 1b Data

In a plenary session at the SMR 2016 Congress today, Jeffrey R. Infante, M.D., Director of the Drug Development Program and Principal Investigator at Sarah Cannon Research Institute, Nashville, Tennessee will present results from the metastatic melanoma cohort of a phase 1b dose escalation trial of cobimetinib and atezolizumab, an anti-PDL1 antibody developed by Genentech, in patients with solid tumors. The primary objective of the trial is to determine the safety and clinical activity of the combination, and key eligibility criteria include ECOG Performance Status of 0 or 1, measurable disease per RECIST, and no prior anti-PD-1/PDL1 therapy.

As of the July 12, 2016 data cut-off, 22 patients with metastatic melanoma were evaluable for safety and efficacy, including 20 patients with non-ocular melanoma (10 each with BRAF wild type and BRAF V600-mutation positive disease) and two patients with ocular melanoma. Among the 20 non-ocular melanoma patients, the objective response rate (ORR) was 45 percent, with 9 partial responses, including 5 in BRAF wild-type patients. Median duration of response was 14.9 months (12.9, upper limit not yet reached) across 9 responders, and was not yet reached for the BRAF wild-type subgroup. Median progression-free survival (PFS) was 12 months across all non-ocular melanoma patients (15.7 months in BRAF wild-type and 11.9 months in BRAF mutation-positive patients). With a median follow-up of 18.9 months, median overall survival (OS) for the cohort had not been reached.

All patients in the cohort were evaluable for safety. In this phase 1b study, investigators reported the combination of cobimetinib and atezolizumab was generally well tolerated. Treatment-related Grade 3-4 adverse events (AEs) occurred in 59 percent of patients, and no treatment-related grade 5 AEs were reported.

Based on these results, Genentech plans to initiate a phase 3 pivotal trial of cobimetinib plus atezolizumab versus a PD-1 inhibitor in patients with previously untreated BRAF wild-type advanced melanoma next year. More information on the planned study will be posted to www.ClinicalTrials.gov when available.

Updated Results for Triple Combination of Cobimetinib, Vemurafenib and Atezolizumab Set Stage for TRILOGY Pivotal Trial

Also in a plenary session today, Ryan Sullivan, M.D., Instructor in Medicine at Harvard Medical School and Member of the Cancer Immunology and Melanoma Programs at Dana-Farber Cancer Institute will present results from the phase 1b trial of cobimetinib, vemurafenib and atezolizumab in patients with BRAF V600 mutation-positive metastatic melanoma. The primary objective of the trial is evaluation of the safety and tolerability of the triple combination, with secondary endpoints including PFS, OS, ORR, best overall response, and duration of response, among others.

Patients in the trial receive the triple combination of cobimetinib, vemurafenib and atezolizumab following a 28-day run-in cycle of cobimetinib plus vemurafenib. As of the June 15, 2016 data cut-off, 30 patients with previously untreated BRAF V600 mutation-positive advanced melanoma who received at least one dose of atezolizumab were evaluable for safety and efficacy. Responses were seen in 24 of 29 patients (83 percent) evaluable for efficacy, including three complete responses and 21 partial responses. Median duration of response and median PFS were not estimable due to limited follow-up time; the majority of patients continued to respond at time of data cut-off (median follow-up of 5.6 months).

Investigators reported the triple combination of cobimetinib, vemurafenib and atezolizumab was generally well tolerated in this investigational study. Median safety follow-up was 3.9 months (range 0.7-16.8 months). Grade 3-4 AEs were seen in 40 percent of patients that received the triple combination, and all AEs resolved after appropriate intervention. No unexpected AEs, grade 5 AEs or atezolizumab-related serious AEs occurred.

In early 2017, Genentech and Roche plan to initiate TRILOGY (NCT02908672), a pivotal placebo-controlled phase 3 trial evaluating the combination of cobimetinib, vemurafenib and atezolizumab compared to cobimetinib, vemurafenib and placebo. TRILOGY will enroll an estimated 500 patients with previously untreated BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of TRILOGY is PFS as determined by the investigator, and secondary endpoints include PFS by independent review committee, OS, ORR, duration of response, safety and pharmacokinetics. For more information, visit www.ClinicalTrials.gov.

Efficacy of Long-Term Cobimetinib and Vemurafenib Detailed in Poster Session

Also at the SMR 2016 Congress, Prof. Grant McArthur, Co-chair of the Melanoma and Skin Service at Peter MacCallum Cancer Centre (Melbourne, Victoria, Australia) and colleagues presented a poster demonstrating the continuing benefit across all patient subgroups of the combination therapy of cobimetinib and vemurafenib versus vemurafenib monotherapy as assessed in the coBRIM phase 3 pivotal trial that formed the basis for the combination’s regulatory approval to treat BRAF V600-mutation positive advanced melanoma. The percentage of patients alive at three years was 37.4 percent for cobimetinib and vemurafenib, as compared to 31.1 percent for patients treated with vemurafenib plus placebo. Median overall survival was 22.5 months for the combination versus 17.4 months for vemurafenib alone. The safety profile was similar to what was reported previously, and discontinuation rates due to AEs were below 20 percent.

About the Cobimetinib Development Collaboration

Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib.

Under the terms of the collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares U.S. commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and fields 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

Cobimetinib is now approved in multiple countries, including the United States, European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. The trade name for cobimetinib is COTELLIC. Further country approvals are anticipated in 2016 and beyond. Cobimetinib is also the subject of a clinical development program aimed at evaluating its potential in combination with a variety of investigational and approved therapies in disease settings including metastatic melanoma, triple-negative breast cancer and colorectal carcinoma.

About Advanced Melanoma

Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer. When melanoma is diagnosed early, it is generally a curable disease, but most people with advanced melanoma have a poor prognosis. The American Cancer Society estimates there will be nearly 74,000 new cases of melanoma and 10,000 melanoma deaths this year in the United States.

In recent years, there have been significant advances in treatment for advanced melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.

COTELLIC Indication

COTELLIC (cobimetinib) is a prescription medicine that is used with the medicine Zelboraf (vemurafenib), to treat a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene.

A patient’s healthcare provider will perform a test for the BRAF gene to make sure that COTELLIC is right for them. It is not known if COTELLIC is safe and effective in children under 18 years of age.

COTELLIC Important Safety Information

Patients should avoid sunlight during treatment with COTELLIC and Zelboraf. COTELLIC and Zelboraf can make a patient’s skin sensitive to sunlight. They may burn more easily and get severe sunburns. When a patient goes outside, they should wear clothes that protect their skin, including their head, face, hands, arms and legs. They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.

COTELLIC and Zelboraf may cause serious side effects, including risk of new skin cancers, risk of other cancers, bleeding problems, heart problems, allergic reactions, severe rash and other severe skin reactions, eye problems, changes in the electrical activity of the heart (QT prolongation), liver problems or liver injury, muscle problems (rhabdomyolysis), skin sensitivity to sunlight (photosensitivity), worsening side effects from radiation treatment, and kidney injury.

Patients should tell their doctor if they are pregnant or plan to become pregnant, as COTELLIC and Zelboraf can harm an unborn baby. Females who are able to become pregnant should use effective birth control during treatment with COTELLIC and Zelboraf and for two weeks after the final dose of COTELLIC or Zelboraf (whichever is taken later).

Patients should not breastfeed during treatment and for two weeks after the final dose of COTELLIC or Zelboraf (whichever is taken later). Patients should talk to their healthcare provider about the best way to feed their baby during this time.

Patients should tell their healthcare provider about all the medicines they take. Some types of medicines will affect the blood levels of COTELLIC.

Common side effects of COTELLIC in combination with Zelboraf include diarrhea, sunburn or sun sensitivity, nausea, fever and vomiting. COTELLIC and Zelboraf can also cause changes in blood test results.

Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away. These are not all the possible side effects of COTELLIC and Zelboraf.

Patients should call their doctor for medical advice about side effects. Patients may report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. Patients may also report side effects to Genentech at (888) 835-2555.

Please see both Full COTELLIC Prescribing Information and Patient Information and Full Zelboraf Prescribing Information and Medication Guide for additional Important Safety Information at www.cotellic.com and www.zelboraf.com.

On November 7, 2016 SignalRx Pharmaceuticals Inc., a clinical-stage company focused on developing more effective oncology drugs with designed multiple target-selected inhibition profiles, reported the publication of key research supporting the use of its clinical stage drug SF1126 alone and in combination with Sorafinib for the treatment of hepatocellular carcinoma (HCC) (Press release, SignalRx, NOV 7, 2016, http://www.ireachcontent.com/news-releases/signalrx-announces-publication-of-research-results-on-sf1126-as-a-first-in-class-dual-pi3kbrd4-inhibitor-for-treating-hcc-600328031.html [SID1234527326]). The research was published in the November issue of Molecular Cancer Therapeutics journal from the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Mol Cancer Ther November 1 2016 15 (11) 2553-2562; DOI:10.1158/1535-7163.MCT-15-0976).

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Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center, led by Dr. Donald Durden, Professor and Associate Director of Pediatric Oncology and senior scientific advisor for SignalRx, report results supporting the use of SF1126 as a novel therapeutic agent for the treatment of hepatocellular carcinoma (HCC), the most common kind of liver cancer and second most common cause of cancer death worldwide.

SF1126 is an anticancer agent shown to have an excellent therapeutic window with excellent tolerability and safety in Phase I clinical trials (Clinicaltrials.gov: NCT00907205). While most anti-cancer drugs only interact with a single cancer target, SF1126 inhibits two key cancer signaling molecules in liver cancer cells, phosphatidylinositol 3-kinase (PI3K) and bromodomain-containing 4 (BRD4). SF1126 represents a "first in class" approach to treat liver cancer by hitting two central signaling nodes of the liver cancer cell with only one therapeutic agent. The published work shows that this novel strategy kills liver cancer cells and prevents the growth of liver cancer tumors in mice.

Targeting two pathways with one drug can provide a significant therapeutic advantage since this approach also reduces the risk of severe "off-target" side effects resulting from the combination of side effects associated to each of the multiple drugs used. The treatment of HCC remains a challenge with Sorafenib as the only FDA-approved drug for liver cancer since it prolongs life for an average of only 2-3 months and can have significant side effects. Work from the Durden laboratory shows that using SF1126 with Sorafenib provides a dramatically improved anticancer effect by killing liver cancer cells in synergy.

In HCC, the deregulation of the PI3K/AKT/mTOR, Ras/Raf/MAPK and c-Myc signaling pathways are of prognostic significance. While Sorafenib blocks the Ras/Raf/MAPK pathway, it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. SF1126 controls c-Myc by inhibiting BRD4, which results in blockage of c-Myc production, and by inhibiting PI3K, which leads to enhanced c-Myc degradation. Hence, a combination of SF1126 with Sorafenib offers a new mechanism-driven mode of action to inhibit/treat HCC.

In particular, the research results published in Molecular Cancer Therapeutics demonstrate that:

SF1126 (pan PI3K/BRD4 inhibitor), as a single agent or in combination with Sorafenib, inhibits cancer cell proliferation (Hep 3B, Hep G2, SK-Hep1 and Huh7 HCC cell lines) by effectively inhibiting the PI3K/AKT/mTOR and Ras/Raf/MAPK pathways.
SF1126’s active moiety LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaces the BRD4 co-activator protein from the transcriptional start site of MYC in Huh7 and SK-Hep-1 HCC cell lines.
SF1126 blocks expression of c-Myc in HCC cells.
SF1126, either alone or in combination with Sorafenib, shows significant antitumor activity in vivo.
These published results establish SF1126 as a dual PI3K/BRD4 inhibitor and the first epigenetic/kinase inhibitor in the clinic. SF1126 has completed a Phase I clinical trial in humans with good safety profile, has received Orphan Drug Designation by the FDA, and is currently in a pediatric Phase I clinical trial in children with neuroblastoma.

Taken together, this published data strongly warrants additional clinical trials of SF1126 in advanced HCC as well as a combination Phase I trial with Sorafenib.

SignalRx is seeking partners for the clinical development of SF1126 as well as the acceleration of the company’s preclinical pipeline with novel and proprietary nM potent small molecules into first-in-man clinical trials.

SignalRx’s novel dual inhibitors have a unique competitive advantage over combining separate agents in cancers where lethality requires simultaneous target inhibition for maximal effect with minimal side-effects. Because it provides a single pharmacodynamics profile the dual inhibition in a single molecule approach provides the optimal way to effect simultaneous target inhibition with significantly less toxicity than combinations of inhibitors.