8-K – Current report

On July 21, 2014, Advaxis, Inc. ("Advaxis") and MedImmune, LLC ("MedImmune"), the global biologics research and development arm of AstraZeneca, entered into a Clinical Trial Collaboration Agreement (the "Agreement") pursuant to which the parties intend to initiate Phase I and Phase II clinical trials in the United States to evaluate the safety and efficacy of MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with Advaxis’s investigational Lm-LLO cancer immunotherapy, ADXS-HPV, as a combination treatment for patients with advanced, recurrent or refractory human papillomavirus (HPV) associated cervical cancer and HPV-associated head and neck cancer (Filing 8-K , Advaxis, JUL 24, 2014, View Source [SID:1234500643]). A joint steering committee, to be composed of equal numbers of Advaxis and MedImmune representatives, will be responsible for various matters associated with the clinical trials, including approving protocols for the trials, as well as reviewing and monitoring the progress of the trials.

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MedImmune will be responsible for providing MEDI4736 for the clinical trials at no cost. Advaxis will be the sponsor of the clinical trials and be responsible for the submission of all regulatory filings to support the trials, the negotiation and execution of the clinical trial agreements associated with each study site, and the packaging and labelling of the Advaxis and MedImmune product candidates to be used in the clinical trials and the costs associated therewith.

For a period beginning upon the completion of the clinical trials and the receipt by MedImmune of the last final report for the trials and ending one hundred twenty (120) days thereafter (unless extended), MedImmune will be granted first right to negotiate in good faith in an attempt to enter into an agreement with Advaxis with respect to the development, regulatory approval and commercialization of ADXS-HPV and MEDI4736 to be used in combination with each other for the treatment or prevention of cancer. Neither party is obligated to enter into such an agreement. In the event the parties do not enter an agreement and Advaxis obtains regulatory approval for ADXS-HPV in combination with any PD-1 antibody or PD-L1 antibody, Advaxis shall pay MedImmune a royalty obligation and one-time payment.

All intellectual property rights made, conceived or generated through the clinical trials that relate solely to a MedImmune development product shall be owned solely by MedImmune. All intellectual property rights made, conceived or generated through the clinical trials that relate solely to an Advaxis development product shall be owned solely by Advaxis. All intellectual property rights made, conceived or generated through the clinical trials that relate to the combination of one or more MedImmune development product and one or more Advaxis development product shall be jointly owned by MedImmune and Advaxis; provided, however that in the event the parties do not enter into a clinical development and commercialization agreement, Advaxis will not exploit, commercialize or license the joint inventions, except for the performance of its obligations under the Agreement. MedImmune has the sole right to prosecute and enforce all patents and other intellectual property rights covering all joint inventions and all associated costs will be shared by the parties.

The Agreement shall remain in effect until the earlier of (i) permitted termination, (ii) the parties entering into a clinical development and commercialization agreement or expiration of the negotiation period (unless extended), except with respect to rights that survive termination. Either party may terminate the Agreement upon thirty (30) days written notice upon material breach of the other party, unless the breach is cured in such period or reasonable actions to cure the breach are initiated and pursued (if the breach is not capable of being cured during the 30-day notice period). In addition, either party may terminate the Agreement immediately if the party determines in good faith that the trials may unreasonably affect the safety of trial subjects.

Bristol-Myers Squibb Reports Second Quarter 2014 Financial Results

On July 24, 2014 Bristol-Myers Squibb Company (NYSE:BMY) reported financial results for the second quarter of 2014, which was highlighted by strong global sales for the company’s key brands; the achievement of important regulatory milestones for key brands in Japan, Europe and the U.S.; a new strategic immuno-oncology collaboration agreement with Ono Pharmaceutical Co., Ltd.; and the initiation of several research collaborations that will strengthen the company’s leadership position in immuno-oncology. In addition, the company adjusted 2014 GAAP guidance and confirmed 2014 non-GAAP guidance.

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"During the second quarter we delivered strong financial and operating results, invested in key business development opportunities, and achieved important regulatory milestones for products in HCV and immuno-oncology," said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb. "These results reflect the promise of our late-stage pipeline, the strong performance of our in-line products and the continued success of our strategy in driving growth for the company."

Second Quarter
$ amounts in millions, except per share amounts
2014 2013 Change
Total Revenues $3,889 $4,048 (4)%
GAAP Diluted EPS 0.20 0.32 (38)%
Non-GAAP Diluted EPS 0.48 0.44 9%

SECOND QUARTER FINANCIAL RESULTS

Bristol-Myers Squibb posted second quarter 2014 revenues of $3.9 billion, a decrease of 4% compared to the same period a year ago. Excluding the divested Diabetes Alliance, global revenues increased 7%.
U.S. revenues decreased 7% to $1.9 billion in the quarter compared to the same period a year ago. International revenues decreased 1% to $2.0 billion.
Gross margin as a percentage of revenues was 74.5% in the quarter compared to 72.6% in the same period a year ago.
Marketing, selling and administrative expenses decreased 9% to $951 million in the quarter.
Advertising and product promotion spending decreased 14% to $187 million in the quarter.
Research and development expenses increased 49% to $1.4 billion in the quarter and included impairment and acquisition-related charges of $458 million.
The effective tax rate on earnings before income taxes was 25.4% in the quarter, compared to 0% in the second quarter last year. Income taxes in the second quarter last year reflect a more favorable earnings mix between high and low tax jurisdictions, primarily driven by specified items.
The company reported net earnings attributable to Bristol-Myers Squibb of $333 million, or $0.20 per share, in the quarter compared to $536 million, or $0.32 per share, a year ago.
The company reported non-GAAP net earnings attributable to Bristol-Myers Squibb of $798 million, or $0.48 per share, in the second quarter, compared to $730 million, or $0.44 per share, for the same period in 2013. An overview of specified items is discussed under the "Use of Non-GAAP Financial Information" section.
Cash, cash equivalents and marketable securities were $11.1 billion, with a net cash position of $3.3 billion, as of June 30, 2014.
SECOND QUARTER PRODUCT AND PIPELINE UPDATE

Bristol-Myers Squibb’s global sales in the second quarter included Eliquis, which grew by $159 million, Yervoy, which grew 38%, Sprycel, which grew 18%, and Orencia, which grew 14%.

Daklinza+Sunvepra

In July, the company announced that the Japanese Ministry of Health, Labor and Welfare has approved Daklinza (daclatasvir), the company’s potent, pan-genotypic NS5A replication complex inhibitor (in vitro), and Sunvepra (asunaprevir), the company’s NS3/4A protease inhibitor. The approvals are Japan’s first for an all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic hepatitis C virus infection, particularly those with compensated cirrhosis. The Daklinza+Sunvepra Dual Regimen provides a new treatment alternative that can lead to cure for many patients in Japan who currently have no treatment options. Daklinza and Sunvepra are expected to be commercially available in Japan in early September.
In June, the company announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion recommending that Daklinza be granted approval for use in combination with other medicinal products for the treatment of chronic hepatitis C virus infection in adults. This is the first positive opinion given by the CHMP for an NS5A inhibitor. It will now be reviewed by the European Commission (EC), which has the authority to approve medicines for all European Union (EU) member states plus Iceland and Norway.
In April, the company announced the submission of New Drug Applications (NDAs) for Daklinza and Sunvepra to the U.S. Food and Drug Administration (FDA). The data submitted in the NDAs support use of the Daklinza+Sunvepra Dual Regimen in patients with genotype 1b hepatitis C. The Daklinza NDA also seeks approval for use of this compound in combination with other agents for multiple genotypes. The FDA accepted the submissions for filing and assigned both submissions priority review with a user fee goal date of November 30, 2014.
Opdivo

In July, the company announced that, following discussions with the FDA, the company is planning a third quarter submission of a Biologics License Application (BLA) for Opdivo (nivolumab) for previously treated advanced melanoma. This will mark the second tumor type for which Bristol-Myers Squibb has a regulatory submission under way for Opdivo in the U.S. In April, the company initiated a rolling BLA submission for Opdivo in third-line squamous cell non-small cell lung cancer (NSCLC). The company expects to complete the first submission by the end of the year.
In June, the company announced that a randomized, blinded comparative Phase III study evaluating Opdivo versus dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma (CheckMate -066) was stopped early because an analysis conducted by the independent Data Monitoring Committee showed evidence of superior overall survival in patients receiving Opdivo compared to the control arm.
Also in June, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in Chicago, the company announced results from several clinical trials for Opdivo, both as monotherapy and in combination with Yervoy, in advanced cancers of the lungs, skin and kidneys. Bristol-Myers Squibb is at the forefront of research and discovery in the field of immuno-oncology and these data add to the growing body of research from its leading immuno-oncology pipeline, further supporting the scientific rationale for the potential of these checkpoint inhibitors as single agents or as part of a combination regimen.
In May, the FDA granted Opdivo Breakthrough Therapy Designation for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. The designation is based on data from a cohort of patients with Hodgkin lymphoma in the company’s ongoing Phase Ib study of relapsed and refractory hematological malignancies.
Eliquis

In July, the company and its partner, Pfizer, announced that the first patient has enrolled in a Phase IV clinical trial assessing the effectiveness and safety of Eliquis in patients with nonvalvular atrial fibrillation undergoing cardioversion.
In June, the company and its partner, Pfizer, announced that CHMP has adopted a positive opinion recommending that Eliquis be granted marketing authorization for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE, in adults. The CHMP’s positive opinion will now be reviewed by the EC, which has the authority to approve medicines for all EU member states plus Iceland and Norway.
Elotuzumab

In May, the company and its partner, AbbVie, announced that the FDA has granted elotuzumab, an investigational humanized monoclonal antibody, Breakthrough Therapy Designation for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one or more prior therapies. The designation is based on findings from a randomized Phase II, open-label study that evaluated two dose levels of elotuzumab in combination with lenalidomide and low-dose dexamethasone in previously-treated patients, including the 10 mg/kg dose that is being studied in Phase III trials.
Yervoy

In June, at the ASCO (Free ASCO Whitepaper) meeting in Chicago, the company announced results from a Phase III randomized, double-blind study demonstrating that Yervoy 10 mg/kg (n=475) significantly improved recurrence-free survival (RFS, the length of time before recurrence or death) vs. placebo (n=476) for patients with Stage 3 melanoma who are at high risk of recurrence following complete surgical resection, an adjuvant setting. A 25% reduction in the risk of recurrence or death was observed. At three years, an estimated 46.5% of patients treated with Yervoy were free of disease recurrence compared to an estimated 34.8% of patients on placebo. The median RFS was 26.1 months for Yervoy vs. 17.1 months for placebo, with a median follow-up of 2.7 years.
Orencia

In June, at the European League Against Rheumatism meeting in Paris, the company presented data from the Phase IIIb AVERT trial showing that treatment with Orencia, a T-cell co-stimulation modulator, in combination with methotrexate (MTX) achieved significantly higher rates of DAS-defined (DAS28 CRP <2.6) remission at 12 months than treatment with standard of care agent MTX (60.9% vs. 45.2%, respectively), in biologic and MTX-naïve patients with early active rheumatoid arthritis (RA). A small but statistically significantly higher number of patients treated with Orencia plus MTX, versus MTX alone, for 12 months maintained remission 6 months after all RA treatment, including Orencia, MTX or steroids, was withdrawn.
Baraclude

In June, the U.S. Court of Appeals for the Federal Circuit denied the company’s appeal of a February 2013 ruling by the U.S. District Court for the District of Delaware that found invalid the patent covering Baraclude (U.S. patent 5,206,244). In July, the company filed a petition for an en banc rehearing of the case by the full U.S. Court of Appeals.
SECOND QUARTER BUSINESS DEVELOPMENT UPDATE

In July, the company and Ono Pharmaceutical Co., Ltd., signed a collaboration agreement to jointly develop and commercialize Opdivo, Yervoy and three immunotherapy agents in early clinical development as single agents and combination regimens in Japan, South Korea and Taiwan. Also in July, Ono announced that Opdivo received manufacturing and marketing approval in Japan for the treatment of unresectable melanoma. Opdivo is the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world.
In June, the company and Syngene International announced a five-year extension of their drug discovery and development collaboration at the Biocon Bristol-Myers Squibb Research Center in Bangalore, India.
In May, the company announced a clinical trial collaboration with Incyte Corporation to evaluate the safety, tolerability and preliminary efficacy of a combination regimen of Opdivo and INCB24360, Incyte’s oral indoleamine dioxygenase-1 inhibitor, in a Phase I/II study.
In May, the company also announced a clinical trial collaboration with Celldex Therapeutics to evaluate the safety, tolerability and preliminary efficacy of Opdivo and varlilumab, Celldex’s CD27 targeting investigational antibody, in a Phase I/II study. Multiple tumor types will be explored in the study, which could potentially include NSCLC, metastatic melanoma, ovarian, colorectal and squamous cell head and neck cancers.
In May, the company and CytomX Therapeutics announced a worldwide research collaboration and license agreement to discover, develop and commercialize novel therapies against multiple immuno-oncology targets using CytomX’s proprietary Probody Platform.
SECOND QUARTER RESEARCH & DEVELOPMENT UPDATE

In June, the company announced a collaboration with Duke University, through its Duke Clinical Research Institute (DCRI), that will focus on clinical trial transparency. The company will expand access to a broader set of clinical trial information from in-scope company-sponsored studies and enable an independent scientific review through DCRI of requests from researchers that meet pre-specified requirements.
2014 FINANCIAL GUIDANCE

Bristol-Myers Squibb is adjusting its 2014 GAAP EPS guidance range from $1.70-$1.80 to $1.50-$1.60 as a result of impairment and expected additional restructuring charges. The company is also confirming its non-GAAP EPS guidance range of $1.70-$1.80. Both GAAP and non-GAAP guidance assume current exchange rates and that we retain exclusivity on Baraclude sales in the U.S. at least through the end of 2014. Key 2014 non-GAAP line-item guidance assumptions remain unchanged.

The financial guidance for 2014 does not include the impact of any potential strategic acquisition and divestitures, or any specified items that have not yet been identified and quantified. The non-GAAP 2014 guidance also excludes specified items as discussed under "Use of Non-GAAP Financial Information." Details reconciling adjusted non-GAAP amounts with the amounts reflecting specified items are provided in supplemental materials available on the company’s website.

Celgene Reports Second Quarter 2014 Operating and Financial Results

Submitted REVLIMID for newly diagnosed multiple myeloma (NDMM) in the U.S. and Europe. FDA assigned a U.S. Prescription Drug User Fee Act (PDUFA) goal date of February 22, 2015 for REVLIMID in NDMM (Press release Celgene, JUL 24, 2014, View Source [SID:1234500647]).

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ZIOPHARM Announces Expansion of Ground-Breaking Synthetic Immuno-Oncology Programs With Intrexon and Clinical Program Update

On July 22, 2014 ZIOPHARM Oncology reported the expansion of synthetic immuno-oncology programs in conjunction with Intrexon Corporation (NYSE:XON) to include chimeric antigen receptor T-cell (CAR-T) therapy (Press release Ziopharm, JUL 22, 2014, View Source [SID:1234501132]). Additionally the Company has provided an update on its development efforts with the proprietary RheoSwitch Therapeutic System (RTS) platform, an inducible regulator for expression of therapeutic molecules through administration of an oral activator ligand, as well as its clinical program with Ad-RTS-IL-12, a novel DNA-based therapeutic candidate for the controlled expression of IL-12.

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CAR-T cells represent an emerging, high value immunological therapy that can target and destroy cancer cells displaying "personalized" fingerprints, yet current approaches feature challenges associated with toxicity, off-target effects, and uneconomical manufacturing. Intrexon possesses the integrated technology platforms, molecular engineering, systems biology, and cell engineering capabilities required to overcome these challenges and fully realize the potential of CAR-T cell therapies. Most significantly, utilization of the RTS platform will facilitate exquisite regulation of one or more bioeffectors in CAR-T cells enabling physicians to control systemic effects of cell therapies with an appropriate dosing regimen of the oral activator ligand (veledimex), and eventually bring about improved safety and efficacy of these and related therapeutic strategies. Further preclinical work is underway in this promising area of study, and ZIOPHARM and Intrexon expect to provide a progress update in the second half of 2014.

Samuel Broder, M.D., EVP of Scientific and Public Affairs at Intrexon, said, "As a leader in the second generation of biotechnology, Intrexon is applying industrial engineering principles to synthetic immunology to potentiate important biotechnology platforms enabling end-to-end solutions for complex biologic challenges. In particular, the utilization of our proprietary RheoSwitch platform may be especially advantageous in CAR-T treatments."

To date, the RheoSwitch platform has been shown to function as a regulatable switch in an array of cell types for multiple proteins, and RTS expansion into CAR-T therapy is further demonstration of the breadth of Intrexon’s single and multi-genic expression and control technologies. According to data from ClinicalTrials.gov, more than 1,000 clinical trials utilizing gene therapy are currently underway, with the majority in either Phase I or Phase II. Intrexon’s proprietary switch system is uniquely positioned as the first clinically-evaluated gene switch with in vivo data showing the ability to control gene expression with a broad dynamic range. The RTS platform provides a mechanism for titrating therapeutic effects on a patient-specific and predictable basis, as well as a safety switch to rapidly turn off gene-expression. The ability to administer or withdraw the veledimex pill to sustain continued treatment cycles is a key benefit exclusive to RTS technology.

"We are excited by the prospects of applying our advanced synthetic immuno-oncology toolkit towards targeted immunotherapies like CAR-T," said Jonathan Lewis, M.D., Ph.D., CEO of ZIOPHARM. "We also look forward to expanding RTS applications in novel therapeutic strategies for cancer where the ability to control gene expression is essential."

With respect to the Ad-RTS-IL-12 clinical programs, ZIOPHARM continues to conduct Phase II studies in melanoma and breast cancer using Ad-RTS-IL-12 as a monotherapy. Additionally, the Company is evaluating future trials with IL-12 in potential combination therapies with other immune-targeting agents in various cancers including melanoma and breast. ZIOPHARM also plans to initiate a Phase I trial to evaluate Ad-RTS-IL-12 as a single agent in the treatment of patients with Glioblastoma Multiforme in the second half of 2014.

"The development of potent yet tightly controlled cancer depleting therapies such as CAR-T and other targeted cellular products through the molecular rewiring of immunologic gene programs adds to the foundation of our multifaceted strategy in synthetic immuno-oncology," remarked Gregory Frost, Ph.D., SVP of Intrexon’s Health Sector.

ZIOPHARM Announces Expansion of Ground-Breaking Synthetic Immuno-Oncology Programs With Intrexon and Clinical Program Update

On July 22, 2014 ZIOPHARM Oncology reported the expansion of synthetic immuno-oncology programs in conjunction with Intrexon to include chimeric antigen receptor T-cell (CAR-T) therapy (Press release Intrexon, JUL 22, 2014, View Source;p=RssLanding&cat=news&id=1949640 [SID:1234500637]). Additionally the Company has provided an update on its development efforts with the proprietary RheoSwitch Therapeutic System (RTS) platform, an inducible regulator for expression of therapeutic molecules through administration of an oral activator ligand, as well as its clinical program with Ad-RTS-IL-12, a novel DNA-based therapeutic candidate for the controlled expression of IL-12.

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CAR-T cells represent an emerging, high value immunological therapy that can target and destroy cancer cells displaying "personalized" fingerprints, yet current approaches feature challenges associated with toxicity, off-target effects, and uneconomical manufacturing. Intrexon possesses the integrated technology platforms, molecular engineering, systems biology, and cell engineering capabilities required to overcome these challenges and fully realize the potential of CAR‐T cell therapies. Most significantly, utilization of the RTS platform will facilitate exquisite regulation of one or more bioeffectors in CAR-T cells enabling physicians to control systemic effects of cell therapies with an appropriate dosing regimen of the oral activator ligand (veledimex), and eventually bring about improved safety and efficacy of these and related therapeutic strategies. Further preclinical work is underway in this promising area of study, and ZIOPHARM and Intrexon expect to provide a progress update in the second half of 2014.

Samuel Broder, M.D., EVP of Scientific and Public Affairs at Intrexon, said, "As a leader in the second generation of biotechnology, Intrexon is applying industrial engineering principles to synthetic immunology to potentiate important biotechnology platforms enabling end-to-end solutions for complex biologic challenges. In particular, the utilization of our proprietary RheoSwitch platform may be especially advantageous in CAR-T treatments."

To date, the RheoSwitch platform has been shown to function as a regulatable switch in an array of cell types for multiple proteins, and RTS expansion into CAR-T therapy is further demonstration of the breadth of Intrexon’s single and multi-genic expression and control technologies. According to data from ClinicalTrials.gov, more than 1,000 clinical trials utilizing gene therapy are currently underway, with the majority in either Phase I or Phase II. Intrexon’s proprietary switch system is uniquely positioned as the first clinically-evaluated gene switch with in vivo data showing the ability to control gene expression with a broad dynamic range. The RTS platform provides a mechanism for titrating therapeutic effects on a patient-specific and predictable basis, as well as a safety switch to rapidly turn off gene-expression. The ability to administer or withdraw the veledimex pill to sustain continued treatment cycles is a key benefit exclusive to RTS technology.

"We are excited by the prospects of applying our advanced synthetic immuno-oncology toolkit towards targeted immunotherapies like CAR-T," said Jonathan Lewis, M.D., Ph.D., CEO of ZIOPHARM. "We also look forward to expanding RTS applications in novel therapeutic strategies for cancer where the ability to control gene expression is essential."

With respect to the Ad-RTS-IL-12 clinical programs, ZIOPHARM continues to conduct Phase II studies in melanoma and breast cancer using Ad-RTS-IL-12 as a monotherapy. Additionally, the Company is evaluating future trials with IL-12 in potential combination therapies with other immune-targeting agents in various cancers including melanoma and breast. ZIOPHARM also plans to initiate a Phase I trial to evaluate Ad-RTS-IL-12 as a single agent in the treatment of patients with Glioblastoma Multiforme in the second half of 2014.

"The development of potent yet tightly controlled cancer depleting therapies such as CAR-T and other targeted cellular products through the molecular rewiring of immunologic gene programs adds to the foundation of our multifaceted strategy in synthetic immuno-oncology," remarked Gregory Frost, Ph.D., SVP of Intrexon’s Health Sector.