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FDA Does Not Grant Seven Year Orphan Drug Exclusivity for BENDEKA (bendamustine hydrochloride injection)

On March 28, 2016 Eagle Pharmaceuticals, Inc. (Nasdaq:EGRX) ("Eagle" or the "Company") reported that the U.S. Food and Drug Administration (FDA) has denied Eagle’s request for seven years of orphan drug exclusivity in the U.S., for BENDEKA (bendamustine hydrochloride injection, or bendamustine HCI), a liquid, low-volume (50 mL) and short-time 10-minute infusion formulation of bendamustine hydrochloride (Press release, Eagle Pharmaceuticals, MAR 28, 2016, View Source [SID:1234510046]).

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BENDEKA was approved in December 2015 for the treatment of patients with chronic lymphocytic leukemia (CLL) and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Efficacy in CLL relative to first-line therapies other than chlorambucil has not been established.

Eagle believes that the FDA’s decision is incorrect, and that BENDEKA was automatically entitled to orphan drug exclusivity for CLL and indolent B-cell NHL upon the drug’s December 2015 approval. The FDA previously granted orphan drug designation for BENDEKA for both indications. Eagle is evaluating all options to challenge the FDA’s decision.

Orphan drug designation is granted by the FDA Office of Orphan Products Development to novel drugs or biologics that treat rare diseases or conditions affecting fewer than 200,000 patients in the U.S. The designation typically provides the drug developer with a seven-year period of U.S. marketing exclusivity upon approval, as well as certain financial incentives that can help support its development.

The FDA currently requires sponsors of certain orphan designated drugs to make a "clinical superiority" demonstration as a condition to obtaining the seven-year exclusivity period upon approval. The FDA applies this requirement whenever the FDA has previously approved another drug of the same active moiety for the same indication.

In September 2014, DepoMed, Inc. (DepoMed) prevailed in litigation in federal district court in the District of Columbia, challenging the FDA’s application of this clinical superiority demonstration requirement to its orphan-designated drug product, GRALISETM. DepoMed argued that the requirement violates the Orphan Drug Act, which automatically confers seven years of marketing exclusivity on orphan designated products upon approval. District Judge Ketanji Brown Jackson agreed with DepoMed’s position, and ordered the FDA to recognize orphan drug exclusivity for GRALISE without requiring proof of "clinical superiority." While the FDA granted orphan drug exclusivity for GRALISE without a clinical superiority demonstration, it has continued to require the clinical superiority demonstration for other orphan designated drugs, such as BENDEKA.

Eagle believes that the FDA’s rejection of orphan drug exclusivity for BENDEKA closely mirrors the decision that Judge Jackson overturned in the DepoMed litigation, and Eagle is evaluating all options to obtain a reversal of the FDA’s BENDEKA decision at this time.

"We are disappointed with the agency’s decision regarding orphan drug exclusivity for BENDEKA, which we believe to be incorrect," said Scott Tarriff, President and Chief Executive Officer. "With six Orange Book listed patents extending from 2026 through 2033, and additional pending patent applications, the market protection for BENDEKA is likely to be intact for many years. These patents will continue to be in effect beyond the seven years of exclusivity that would have been provided had the orphan drug exclusivity been granted. We believe the FDA’s decision will have little to no impact on our bendamustine HCI business in the near term," concluded Tariff.

The following table lists the patents for liquid bendamustine hydrochloride (HCl) formulations:

U.S. Patent No. Patent Expiration
8,609,707 8/11/2031
8,791,270*PED (Owned by Teva Pharmaceutical Industries, Ltd.) 7/12/2026
9,000,021 3/15/2033
9,034,908 3/15/2033
9,144,568 3/15/2033
9,265,831

1/28/2031
Under a February 2015 exclusive license agreement for BENDEKA, a subsidiary of Teva Pharmaceutical Industries, Ltd. is responsible for all U.S. commercial activities for the product including promotion and distribution. BENDEKA was launched by Teva in late January 2016. As previously announced, Eagle receives a 20% royalty on Teva’s sales of BENDEKA.

Indications

BENDEKA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

BENDEKA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information

Contraindication: BENDEKA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol.

Myelosuppression: Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. Monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred. Patients with myelosuppression following treatment with BENDEKA are more susceptible to infections. Patients treated with Bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate monitoring, prophylaxis, and treatment measures.

Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine hydrochloride has occurred. The onset tends to be within the first treatment cycle with –bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with bendamustine hydrochloride treatment including rash, toxic skin reactions, and bullous exanthema. In a study of bendamustine hydrochloride (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when bendamustine hydrochloride was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue BENDEKA.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with BENDEKA therapy has not been determined.

Extravasation Injury: Extravasations resulting in hospitalizations from erythema, marked swelling, and pain have been reported with bendamustine hydrochloride. Assure good venous access prior to starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BENDEKA.

Embryo-fetal Toxicity: Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using BENDEKA.

Most Common Adverse Reactions:

• Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue.

• Most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting.

• Most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.

• Most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.

For BENDEKA Full Prescribing Information, please visit: View Source

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease.

T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed thatTigitexpression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.
Copyright © 2016 by The American Association of Immunologists, Inc.

Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.

High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome.
Copyright © 2015. Published by Elsevier B.V.

Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.

Patient-reported outcomes have been associated with survival in numerous studies across cancer types, including breast cancer. However, the Brief Pain Inventory-Short Form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) have rarely been investigated in this regard in breast cancer.
Here we describe a post hoc analysis of the prognostic effect of baseline scores of these instruments on survival in a phase III trial of patients with advanced breast cancer who received gemcitabine plus paclitaxel or paclitaxel alone after anthracycline-based adjuvant or neoadjuvant therapy. The variables for this analysis were baseline BPI-SF &quot;worst pain&quot; and BPI-SF &quot;pain interference&quot; scores, and four RSCL subscales (each transformed to 0-100). Univariate and multivariate Cox models were used, the latter in the presence of 11 demographic/clinical variables. Kaplan-Meier curves and log-rank tests were used to compare survival for patients by BPI-SF or RSCL scores.
Of 529 randomized patients, 286 provided BPI-SF data and 336 provided RSCL data at baseline. Univariate analyses identified BPI-SF worst pain and pain interference (both hazard ratios [HR], 1.07 for a 1-point increase; both p ≤ 0.0061) and three of four RSCL subscales [activity level, physical distress, and health-related quality of life (HRQOL) (HR, 0.86-0.91 for 10-point increase all p ≤ 0.0104)], to have significant prognostic effect for survival. BPI-SF worst pain (p = 0.0342) and RSCL activity level (p = 0.0004) were prognostic in the multivariate analysis. Median survival for patients categorized by BPI-SF worst pain score was 23.8 (n = 91), 17.9 (n = 94) and 14.6 (n = 94) months for scores 0, 1-4, and 5-10, respectively (log-rank p = 0.0065). Median survival was 23.8 and 14.6 months for patients (n = 330) with above- and below-median RSCL activity level scores respectively (log-rank p &lt; 0.0001).
Pretreatment BPI-SF worst pain and RSCL activity scores provide distinct prognostic information for survival in patients receiving paclitaxel or gemcitabine plus paclitaxel for advanced breast cancer even after controlling for multiple demographic and clinical factors.
Clinicaltrials.gov, NCT00006459 .

[Perceptual gap between oncologists/oncology nurses and patients in the management and impact of chemotherapy/radiotherapy-induced nausea and vomiting: French results of the GAP survey].

Despite progress in the treatment of chemotherapy/radiotherapy-induced nausea and vomiting (CINV/RINV), their management remains insufficient.
In order to evaluate the incidence and impact of CINV/RINV on the quality of life perceived by patients and estimated by clinicians, a declarative, cross-sectional survey was conducted in France through an online questionnaire.
This survey included 187 participants: 75 oncologists, 35 oncology nurses and 77 patients. Clinicians over-estimated the incidence of CINV/RINV, but underestimated their impact on the quality of life of patients. The sub-optimal prescription of anti-emetic treatments was more prominent when the therapy administered had low or medium emetogenic potential. Only 30% of patients rated their nausea and vomiting as controlled from the start. A major proportion of patients (68%) declared poor compliance with their anti-emetic regimen. The acceptance of CINV/RINV as normal side effects of the chemotherapy/radiotherapy (51%) led the patients not to report them, thus limiting their active management. The number of drugs to absorb, and the fear that the action of swallowing the pill would induce nausea or vomiting were also quoted by the patients as compliance-limiting factors.
The perceptual gap between clinicians and patients regarding the incidence and impact of CINV/RINV contributes to a sub-optimal level of anti-emetic cover and control. The anti-emetic regimen needs to be regularly assessed and adapted to the patient in order to improve CINV/RINV management.
Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.