On November 10, 2017 Amgen (NASDAQ:AMGN) and Allergan plc. (NYSE:AGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the Marketing Authorization of ABP 215, a biosimilar to Avastin (bevacizumab) (Press release, Amgen, NOV 10, 2017, View Source;p=RssLanding&cat=news&id=2316169 [SID1234521930]). ABP 215 has been recommended for approval for the treatment of certain types of cancer, including in combination with fluoropyrimidine-based chemotherapy for metastatic carcinoma of the colon or rectum; in combination with paclitaxel for metastatic breast cancer; in combination with platinum-based chemotherapy for unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC); in combination with erlotinib for unresectable advanced, metastatic or recurrent non-squamous NSCLC; in combination with interferon alfa-2a for advanced and/or metastatic renal cell cancer; in combination with carboplatin and paclitaxel, carboplatin and gemcitabine, and paclitaxel, topotecan, or pegylated liposomal doxorubicin for advanced, platinum-sensitive, or platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; and in combination with paclitaxel and cisplatin, or alternatively, paclitaxel and topotecan for persistent, recurrent, or metastatic carcinoma of the cervix.

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"ABP 215 has the potential to provide healthcare professionals and appropriate patients across Europe access to high-quality, targeted cancer therapy," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The positive CHMP opinion for ABP 215 marks the first time a bevacizumab biosimilar has been recommended for approval in the European Union, which is an exciting milestone for Amgen."

Amgen and Allergan are committed to developing high-quality biosimilars with a robust analytic and clinical package. The Marketing Authorization Application for ABP 215 was based on a comprehensive data package that demonstrated ABP 215 and bevacizumab are highly similar, with no clinically meaningful differences in terms of the efficacy, safety and immunogenicity between the products. Clinical studies included results from a Phase 3 trial in patients with non-squamous NSCLC.

"This positive opinion underscores our commitment with Amgen to bringing biosimilars to market to help patients with difficult-to-treat cancers," said David Nicholson, chief research and development officer at Allergan. "We are encouraged by the progress Amgen and Allergan have made in developing biosimilars in critical disease areas and look forward to providing important medicines to patients in the future."

The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). If approved, a centralized marketing authorization will be granted that will be valid in the 28 countries that are members of the EU. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the EC.

In September 2017, ABP 215 became the first anti-cancer biosimilar, as well as the first bevacizumab biosimilar, to be approved by the U.S. Food and Drug Administration (FDA). It is approved in the U.S. with the brand name MVASI (bevacizumab-awwb). Amgen and Allergan are collaborating on the development and commercialization of four oncology biosimilars. Amgen has a total of 10 biosimilars in its portfolio, one of which has been approved by the EC.

About ABP 215 in the European Union
ABP 215 is being developed as a biosimilar to bevacizumab. Once approved in the EU, ABP 215 will be indicated in combination with fluoropyrimidine-based chemotherapy for metastatic carcinoma of the colon or rectum; in combination with paclitaxel for metastatic breast cancer; in combination with platinum-based chemotherapy for unresectable advanced, metastatic or recurrent NSCLC; in combination with erlotinib for unresectable advanced, metastatic or recurrent non-squamous NSCLC; in combination with interferon alfa-2a for advanced and/or metastatic renal cell cancer; in combination with carboplatin and paclitaxel, carboplatin and gemcitabine, and paclitaxel, topotecan, or pegylated liposomal doxorubicin for advanced, platinum-sensitive, or platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; and in combination with paclitaxel and cisplatin, or alternatively, paclitaxel and topotecan for persistent, recurrent, or metastatic carcinoma of the cervix. Indications in the U.S., EU and other regions vary due to regional differences.

About MVASI (bevacizumab-awwb) in the U.S.
MVASI is a biosimilar to bevacizumab, a recombinant immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2, thus inhibiting establishment of new blood vessels necessary for the maintenance and growth of solid tumors.

MVASI is indicated for the treatment of metastatic colorectal cancer (mCRC), with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment.

MVASI is indicated for the treatment of mCRC, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen. MVASI is not indicated for adjuvant treatment of colon cancer.

MVASI is indicated for the treatment of non-squamous NSCLC, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

MVASI is indicated for the treatment of glioblastoma, as a single agent for adult patients with progressive disease following prior therapy.

The effectiveness of bevacizumab products in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab products.

MVASI is indicated for the treatment of metastatic renal cell carcinoma with interferon alfa.

MVASI is indicated for the treatment of cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease.

MVASI is currently not available commercially. This is not an offer for sale. The following information is derived from the approved label in the U.S.

MVASI U.S. Important Safety Information

Boxed WARNINGS

Gastrointestinal (GI) Perforations
The incidence of gastrointestinal perforation, some fatal, in bevacizumab product-treated patients ranges from 0.3-3.2%. Fatal outcome was reported in <1% of bevacizumab-treated patients. Discontinue MVASI in patients with gastrointestinal perforation.

Surgery and Wound Healing Complications
The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab product-treated patients. Discontinue MVASI in patients with wound dehiscence. The appropriate interval between termination of bevacizumab products and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days after surgery and until the surgical wound is fully healed.

Hemorrhage
Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 6.9%. Do not administer MVASI to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue MVASI in patients with serious hemorrhage (ie, requiring medical intervention).

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI fistulae (up to 2% in metastatic colorectal cancer)
Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial)
Arterial thromboembolic events (grade ≥3, 2.6%)
Proteinuria (nephrotic syndrome, <1%)
Additional serious adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
Venous thromboembolism (grade 3-4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with chemotherapy and bevacizumab product
Hypertension (grade 3-4, 5%-18%)
Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
Infusion reactions with the first dose of bevacizumab product-treated patients were uncommon (<3%), and severe reactions occurred in 0.2% of patients
Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with MVASI
Pregnancy warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that MVASI may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose of MVASI
Advise nursing women that breastfeeding is not recommended during treatment with MVASI
MVASI may impair fertility
Most Common Adverse Events

Across indications, the most common adverse reactions observed in bevacizumab product-treated patients at a rate of >10% and at least twice the control arm rate were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab product was discontinued in 8.4% to 21% of patients because of adverse reactions.
Please see full Prescribing Information, including Boxed WARNINGS, at www.Amgen.com.

On November 10, 2017 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported that two of its cancer immunotherapies demonstrated antigen-specific T-cell stimulation in phase 1 studies. INO-3112 (now called MEDI0457), an investigational T-cell activation immunotherapy that targets cancers caused by human papillomavirus (HPV) types 16 and 18 and licensed to MedImmune, the global Research and Development arm of AstraZeneca, also led to a head and neck cancer patient’s complete response when matched with a PD-1 checkpoint inhibitor (Press release, Inovio, NOV 10, 2017, View Source [SID1234521931]). In addition, INO-1400, Inovio’s investigational cancer immunotherapy targeting hTERT, which is over-expressed in a majority of cancers, generated hTERT-specific IFN-γ secreting T cells, suggesting an ability to break immune tolerance. These results were revealed at poster presentations at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 32nd Annual Meeting starting today at National Harbor, Md.

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Dr. J. Joseph Kim, Inovio’s President and CEO, said, "This study of MEDI0457 shows efficacy signals that Inovio’s activation immunotherapy coupled with checkpoint inhibitor could have meaningful therapeutic impact, given an unusual complete response in one patient. Separately, we are evaluating our hTERT therapy, INO-1400, in nine different solid tumors including breast, lung and pancreatic cancers in a clinical study. Any success we see in our hTERT therapy gives us added confidence in our recently initiated efficacy studies combining PD-1/PD-L1 inhibitors and INO-5401, which includes three of Inovio’s top SynCon cancer antigens – hTERT, WT1, and PSMA, which are over-expressed in multiple tumor types. We look forward to sharing further data on our immunotherapies as studies progress."

In a phase 1 study of MEDI0457 in 22 HPV-positive patients with squamous cell carcinoma of the head and neck, Inovio has previously demonstrated that this cancer immunotherapy generated robust antigen-specific CD8+ killer T cell responses in both tumor tissue and peripheral blood. One patient which initially displayed a slight increase in T cell immune responses developed progressive disease at 11 months into the study and received nivolumab, a PD-1 checkpoint inhibitor. Subsequently, the patient had a sustained complete response after only four doses, and continues on therapy with no evidence of disease, 16 months after initiation of nivolumab.

Detailed immune analyses found that MEDI0457 had activated HPV16-specific CD8+ T cells in the patient and the subsequent treatment with nivolumab helped to unleash the expansion of these killer T cells, which is contributing to the sustained complete response observed in this patient. Medimmune is conducting a separate phase 1/2 trial combining its PD-L1 inhibitor (durvalumab) with MEDI0457 in HPV-associated head and neck cancer patients to evaluate the clinical efficacy of the combination treatment.

Dr. Charu Aggarwal, MD, MPH, medical oncologist and assistant professor of medicine at the hospital of the University of Pennsylvania and the principal investigator of this study, said "This observation suggests that treatment with MEDI0457 prior to PD-1 inhibition can be synergistic, and increase efficacy of checkpoint inhibitors."

In Inovio’s phase 1 dose-escalation study of its synthetic optimized DNA plasmids that target hTERT, the immunotherapies were administered via Inovio’s CELLECTRA delivery device to assess the safety, tolerability, and immune effects of INO-1400 or INO-1401 (two different versions of HTERT constructs), alone or co-administered with a plasmid encoding for IL-12 (INO-9012), in 90 patients with 9 different solid tumors. Interim results presented at the conference show positive safety and tolerability data as well as the generation of hTERT-specific IFN-γ secreting T cells, suggestive of an ability to break immune tolerance.

Dr. Robert Vonderheide, MD, DPhil, Director of the Abramson Cancer Center of the University of Pennsylvania and a principal investigator for the study, said: "If successful, this vaccine platform could represent not only a novel type of immune therapy for cancer patients, but also one day offer an opportunity for immune prevention of cancer."

High levels of human telomerase reverse transcriptase (hTERT) have been reported in many tumor types such as breast, lung, and pancreas. Inovio’s hTERT therapy may prove to be a promising immuno-oncology target for the treatment of these cancers. In 2017, over 530,000 new cases of breast, lung, or pancreatic cancers were reported in the United States and over 240,000 people died from these cancers. Despite available treatments, mortality rates remain unacceptably high in these tumor types. In addition, many existing treatment modalities are associated with significant adverse events.

On November 10, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported that its corporate presentation will be webcast at the upcoming Jefferies 2017 London Healthcare Conference in London on Wednesday, November 15, 2017 at 10:00 a.m. GMT (Press release, Nektar Therapeutics, NOV 10, 2017, View Source [SID1234521926]).

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The presentation will be accessible via a Webcast through a link posted on the Investors, Events Calendar section of the Nektar website: View Source This Webcast will be available for replay until December 11, 2017.

On November 10, 2017 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for autoimmune/inflammatory diseases and cancer, reported immuno-oncology preclinical data characterizing the functional activity of molecules Alpine successfully generated from its variant immunoglobulin domain (vIgD) platform (Press release, Alpine Immune Sciences, NOV 10, 2017, View Source [SID1234521920]). Several novel immuno-oncology molecules were functionally active via multiple mechanisms of action, including the demonstration of tumor suppression in an animal model. The findings will be presented on Friday, November 10, in a poster session titled "Immune Modulation, Cytokines, and Antibodies" [#P343] at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 32nd Annual Meeting in National Harbor, MD.

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"Our unique vIgD platform is capable of producing first-in-class immuno-oncology biologics with potentially unique mechanisms of action," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "This promising data highlights the versatility of the platform, showing vIgDs may be implemented in multiple therapeutic formats and may be tailored to modulate multiple molecular pathways according to the desired therapeutic application."

Preclinical Study Design and Results

Alpine scientists used the vIgD directed evolution platform to engineer a number of vIgDs with unique binding profiles to proteins relevant to the immune synapse, including PD-1, PD-L1, CTLA-4, TIGIT, CD155, CD28, and/or ICOS. The poster describes the vIgD domains in multiple therapeutic formats, including tumor-localized Fc fusion proteins, multi-checkpoint inhibitors, and vIgDs fused with tumor-specific monoclonal antibodies (V-mAbs). Various in vitro and in vivo tests characterized the functional activity of these potentially novel therapeutics. Data include:

Tri-specific vIgDs for treating cancer with a single domain capable of interacting with three different B7 family members. Depending on formatting, tri-specific vIgDs are potentially capable of agonizing CD28, blocking PD-L1, blocking CTLA-4, and/or depleting tumor cells and/or regulatory T cells. Initial formats investigated in an animal model of cancer demonstrated activity with tumor growth suppression.
A dual ICOS/CD28 costimulatory vIgD fused with the HER2-targeting monoclonal antibody trastuzumab to provide immune stimulation in the tumor microenvironment. These V-mAbs demonstrated in vitro proof of principle for immune cell stimulation and proliferation in response to HER2-positive tumor cells.
Multiple vIgD Fc fusions capable of targeting TIGIT and PD-1 while sparing CD226. These multi-checkpoint inhibitory molecules blocked checkpoint activity and improved IFN-γ production by "exhausted" T cells.
"The SITC (Free SITC Whitepaper) data suggest the versatile vIgD platform has the potential to contribute to the next generation of immuno-oncology therapeutics. Based on these and other encouraging preclinical data, we are continuing to identify and develop appropriate candidates from our vIgD platform for clinical trials for both oncology and inflammation," said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine.

On November 10, 2017 BioSpecifics Technologies Corp. (NASDAQ: BSTC), a biopharmaceutical company that originated and continues to develop collagenase based-therapies with a first in class collagenase-based product marketed as XIAFLEX in the U.S. and Xiapex in Europe, reported its financial results for the third quarter ended September 30, 2017 and provided a corporate update (Press release, BioSpecifics Technologies, NOV 10, 2017, View Source [SID1234521921]).

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"BioSpecifics continues to make important progress as we remain focused on further developing XIAFLEX for the treatment of serious medical conditions. We are excited about the potential of our ongoing Phase 1 trial of XIAFLEX for the treatment of uterine fibroids and look forward to reporting data in 2018," said Thomas L. Wegman, President of BioSpecifics. "Additionally, we look forward to our partner Endo initiating Phase 3 trials of XIAFLEX for the treatment of cellulite in the coming months."

Third Quarter 2017 Financial Results

BioSpecifics reported net income of $2.7 million for the third quarter ended September 30, 2017, or $0.38 per basic share and $0.37 per share on a fully diluted basis, compared to net income of $3.1 million, or $0.43 per basic share and $0.42 per share on a fully diluted basis, for the same period in 2016.

Total revenue for the third quarter ended September 30, 2017 was $6.5 million, compared to $6.9 million for the same period in 2016. Royalty revenue increased by $0.4 million for the 2017 quarter as compared to the 2016 quarter primarily due to increased sales of XIAFLEX for the treatment of Peyronie’s disease and Dupuytren’s contracture, whereas total revenue was lower due to the exercise of an opt-in right by Endo for the human lipoma indication of $750,000 in the 2016 period.

Research and development expenses for the third quarter ended September 30, 2017 were $0.4 million compared to $0.3 million for the same period in 2016.

General and administrative expenses for the third quarter ended September 30, 2017 were $2.2 million compared to $1.8 million for the same period in 2016.

Provision for income taxes for the third quarter ended September 30, 2017 were $1.5 million, compared to $1.8 million for the same period in 2016.

As of September 30, 2017, BioSpecifics had cash and cash equivalents and investments of $61.3 million, compared to $52.8 million as of December 31, 2016.

XIAFLEX Commercial Highlights

On November 9, 2017, Endo reported commercial highlights for XIAFLEX for the third quarter of 2017 (Endo’s third quarter 2017 financials are reported in BioSpecifics’ fourth quarter 2017 financials). For the third quarter of 2017, total revenues were $52.5 million compared to $47.7 million in the third quarter of 2016, an 10 percent growth. Endo continues to expect high-single to low-double digit revenue growth for sales of XIAFLEX in 2017.

Endo announced a partnership with Tim Herron, a four-time PGA Tour winner, and Damon Adamany, MD, of the CORE Institute, launched Facts on Hand, an unbranded campaign to raise awareness of Dupuytren’s Contracture, a progressive, potentially disfiguring hand condition. Endo also recently launched several direct-to-consumer initiatives intended to increase patient awareness of XIAFLEX as a possible treatment option for Dupuytren’s Contracture and Peyronie’s Disease.

XIAFLEX Pipeline Updates and Anticipated Upcoming Milestones

BioSpecifics manages the development of XIAFLEX for the treatment of uterine fibroids. The Phase 1 clinical trial is currently enrolling. BioSpecifics has the right to initiate the development of any new potential indication not licensed by Endo. Endo’s licensed indications include Dupuytren’s Contracture and Peyronie’s Disease, both approved and marketed; in addition to cellulite, adhesive capsulitis, human and canine lipoma, lateral hip fat and plantar fibromatosis.

The Phase 1 clinical trial of XIAFLEX for the treatment of uterine fibroids is ongoing and BioSpecifics plans to announce results in 2018. The study, being conducted at the Department of Gynecology & Obstetrics at Johns Hopkins University, is designed to enroll 15 subjects administered XIAFLEX prior to hysterectomy. The primary endpoint of the study will assess the safety and tolerability of a single injection of XIAFLEX directly into the uterine fibroid under transvaginal ultrasound guidance. The secondary endpoints will assess symptoms of pain and bleeding, quality of life throughout the study as well as size, collagen content and rate of apoptosis of XIAFLEX treated fibroids.
Endo plans to initiate Phase 3 clinical trials of XIAFLEX for the treatment of cellulite in the coming months following discussions with the U.S. Food and Drug Administration.
Endo continues its commercial review of additional indications.