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Sandoz proposed biosimilar rituximab accepted for review by the FDA

On September 12, 2017 Sandoz, a Novartis Division, and the pioneer and global leader in biosimilars, reported that the US Food and Drug Administration (FDA) has accepted its Biologics License Application (BLA) under the 351 (k) pathway for a proposed biosimilar to the reference medicine, Rituxan** (rituximab) (Press release, Novartis, SEP 12, 2017, View Source [SID1234520494]).

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Rituxan** is used to treat blood cancers including non-Hodgkin’s lymphoma (follicular lymphoma and diffuse large B-cell lymphoma) and chronic lymphocytic leukemia, as well as immunological diseases such as rheumatoid arthritis.

"The cost of treating cancer in the US is a major concern for many patients and their families as well as for the healthcare system[3]" said Mark Levick, MD PhD, Global Head of Development, Biopharmaceuticals. "With the FDA acceptance of our regulatory submission for proposed biosimilar rituximab, we plan to deliver patients a high-quality Sandoz biosimilar that, following approval, could help drive healthcare savings and increase competition, while freeing up resources for and supporting patient access in other areas of cancer care including innovative therapies."

The BLA consists of a comprehensive data package that includes analytical, preclinical and clinical data. Clinical studies included a pharmacokinetic/pharmacodynamic (PK/PD) trial in rheumatoid arthritis (ASSIST-RA)[4], and a Phase III confirmatory safety and efficacy study in follicular lymphoma (ASSIST-FL)[5]. Sandoz believes these data provide confirmation that the proposed biosimilar matches the reference medicine in terms of safety, efficacy and quality.

Sandoz is committed to increasing patient access to high-quality biosimilars. As the pioneer and global leader in biosimilars, Sandoz has five biosimilars marketed worldwide, as well as a leading global pipeline. We plan to launch a total of five major oncology and immunology biosimilars between 2017 and 2020. This includes biosimilar rituximab, which was approved by the European Commission for use in Europe in June 2017 (marketed as Rixathon).

Sandoz is well positioned to continue leading the biosimilars industry based on its experience and capabilities in development, manufacturing and commercialization. As a division of Novartis, the first global healthcare company to establish a leading position in both innovative and off-patent medicines, Sandoz benefits strongly from this unique blend of experience and expertise in many different market environments.

Sandoz also continues to champion policy and legislation that enables patients and the healthcare system to benefit from biosimilars. This was demonstrated by the recent US Supreme Court unanimous positive decision related to the Notice of Commercial Marketing (NCM). The Supreme Court ruled that NCM can be provided before FDA approval, accelerating patient access to future US biosimilars by 180 days. The Court also provided additional clarity on how the "patent dance," the process by which biosimilar manufacturers may provide confidential and proprietary information to the manufacturer of the reference medicine in the patent exchange process, will function.

ATARA BIOTHERAPEUTICS RECEIVES POSITIVE HEALTH CANADA REGULATORY FEEDBACK FOR ATA129

On September 11, 2017 Atara Biotherapeutics, Inc. (Nasdaq:ATRA), a leading "off-the-shelf" T-cell immunotherapy company developing novel treatments for patients with cancer and autoimmune diseases, reported receipt of positive regulatory feedback from Health Canada for ATA129, the Company’s most advanced T-cell immunotherapy in development for the treatment of cancer patients with rituximab-refractory Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (EBV-PTLD) following a hematopoietic cell transplant (HCT) or solid organ transplant (SOT).

Based on feedback from a meeting with Health Canada’s Biologics and Genetic Therapies Directorate (BGTD), Atara plans to request advance consideration under the Notice of Compliance with Conditions (NOC/c) policy for ATA129 in the treatment of patients with rituximab-refractory EBV-PTLD after HCT. A Notice of Compliance issued under the NOC/c policy is an authorization to market a drug in Canada with the condition that the sponsor undertake additional studies to verify the clinical benefit, and is analogous to a conditional marketing authorization in the EU.

Consistent with Atara’s previously communicated regulatory plan in Europe, the Canadian filing is expected to be based on results from the Phase 1 and 2 clinical studies conducted at Memorial Sloan Kettering Cancer Center (MSK) and supported by available data from the Company’s planned MATCH and ALLELE Phase 3 studies, which are anticipated to be ongoing at the time of the NDS filing.

"Health Canada represents the second major regulatory body to provide feedback supporting the submission of ATA129 for an expedited approval pathway based on the compelling results of the prior Phase 1 and 2 studies," said Isaac Ciechanover, M.D., Chief Executive Officer and President of Atara Biotherapeutics. "We look forward to working closely with Health Canada and other global health authorities to make ATA129 available to patients as expeditiously as possible."

Following completion of the Phase 3 studies, Atara also expects to file a ATA129 supplemental NDS for the treatment of cancer patients with rituximab-refractory EBV-PTLD after SOT, as well as request to remove the conditions of the NOC/c for the HCT indication.

About EBV-PTLD
Since its discovery as the first human oncovirus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders, including lymphomas and other cancers. EBV is widespread in all human populations and persists as a lifelong, asymptomatic infection. In immunocompromised patients, such as those undergoing hematopoietic cell transplants (HCT) or solid organ transplants (SOT), EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD), represents a life-threatening condition. Median overall survival in EBV-PTLD patients after HCT who have failed rituximab-based first line therapy is 16-56 days. In EBV-PTLD following SOT, patients failing rituximab experience increased chemotherapy-induced treatment-related mortality compared to other lymphoma patients. One and two-year survival in high-risk EBV-PTLD patients after SOT is 36% and 0%, respectively.

About ATA129
Atara’s most advanced T-cell immunotherapy in development, ATA129, is a potential treatment for cancer patients with rituximab-refractory EBV-PTLD as well as other EBV positive hematologic and solid tumors including nasopharyngeal carcinoma (NPC). In February 2015, FDA granted ATA129 Breakthrough Therapy Designation for EBV-PTLD following allogeneic hematopoietic cell transplant (HCT) and in October 2016, ATA129 was accepted into the EMA Priority Medicines (PRIME) regulatory pathway for the same indication, providing enhanced regulatory support. In addition, ATA129 also has orphan status in the U.S. and EU. Phase 3 studies of ATA129 in EBV-PTLD after HCT (MATCH study) or solid organ transplant (ALLELE study) are expected to start in 2017, and a Phase 1/2 study in NPC is planned for 2018. ATA129 is also available to eligible patients with EBV-positive tumors through an ongoing multicenter expanded access protocol (EAP) clinical study. Atara expects to submit ATA129 for conditional marketing authorization in EBV-PTLD following HCT in the EU in 2018.

About Atara Biotherapeutics, Inc.

Teva Receives FDA Priority Review for First Line Use of TRISENOX® (arsenic trioxide) in Patients with Low to Intermediate Risk Acute Promyelocytic Leukemia (APL)

On September 12, 2017 Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) reported the U.S. Food and Drug Administration (FDA) has accepted for review the company’s supplemental New Drug Application (sNDA) for the use of TRISENOX (arsenic trioxide) injection in combination with all-trans retinoic acid (ATRA) for induction of remission and consolidation in patients with newly diagnosed low or intermediate risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression (Press release, Teva, SEP 12, 2017, View Source [SID1234520484]).

Currently, TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose

APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
"With over 15 years of clinical experience, TRISENOX is an important treatment option for APL patients," said Paul Rittman, Senior Vice President and General Manager, Teva Oncology. "Teva is committed to providing solutions that advance cancer care. We are very pleased that the FDA has accepted the sNDA for priority review as it brings us one step closer to expanding the label for TRISENOX to include use in combination with ATRA for patients with newly diagnosed low to intermediate risk APL."

The FDA has accepted the sNDA for priority review with regulatory action expected in the first quarter of 2018. FDA grants priority review to applications for drugs or biologics intended to treat serious conditions and address unmet medical needs. The sNDA filing includes data from published scientific literature and a review of Teva’s global safety database for arsenic trioxide.

Please see full accompanying Prescribing Information and safety information including Boxed Warning regarding: APL differentiation syndrome, cardiac conduction abnormalities, and electrolyte monitoring.
TRISENOX (arsenic trioxide) Injection

Indications
TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Important Safety Information for TRISENOX (arsenic trioxide) Injection
WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING
APL Differentiation Syndrome: Patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. High-dose steroids have been administered at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously BID), irrespective of the leukocyte count, and continue for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome.
Cardiac Conduction Abnormalities: Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.

Contraindications: TRISENOX is contraindicated in patients who are hypersensitive to arsenic.

APL Differentiation Syndrome: Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome.

Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation: Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion. Monitor ECG weekly and more frequently for clinically unstable patients. For QTc greater than 500 msec, complete corrective measures and reassess the QTc with serial ECGs prior to initiating TRISENOX. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute QT interval value > 500 msec and immediately correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).

Carcinogenesis: The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Embryo-Fetal Toxicity: TRISENOX can cause fetal harm when administered to a pregnant woman. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with TRISENOX.

Lactation: TRISENOX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue breastfeeding during treatment with TRISENOX.

Laboratory Tests: Electrolyte and glucose levels, as well as hepatic, renal, hematologic, and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

Drug Interactions: Avoid the concomitant use of TRISENOX with medications that can prolong the QT/QTc interval or those that can lead to electrolyte abnormalities. Concomitant use of drugs that can prolong the QT/QTc interval with TRISENOX may increase the risk of serious QT/QTc interval prolongation. Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Monitor ECGs and electrolytes more frequently in patients who are unable to avoid concomitant use of these medications and TRISENOX.

Pediatric Use: In a pediatric study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving TRISENOX was similar to that observed in adult patients. Additional drug-related toxicities reported included: gastrointestinal disorders, metabolic and nutrition disorders, respiratory disorders, cardiac failure congestive, neuralgia, and enuresis. One case each of pulmonary edema and caecitis were considered serious reactions. No children less than 4 years of age were enrolled in the trial due to the rarity of APL in this age group.
Patients with Renal Impairment: Exposure of arsenic trioxide may be higher in patients with severe renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.

Patients with Hepatic Impairment: Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.

Most Common Adverse Reactions: Most patients experienced some drug related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

TO REPORT SIDE EFFECTS: Contact us at 1-800-896-5855 or [email protected]
Please see Full Prescribing Information for TRISENOX (arsenic trioxide) Injection

Nektar Therapeutics Initiates PROPEL Clinical Study to Evaluate Combination of NKTR-214, a CD122-Biased Agonist, with TECENTRIQ® (atezolizumab) or KEYTRUDA® (pembrolizumab)

On September 12, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported that it has begun dosing in the PROPEL clinical study which will evaluate the efficacy and safety of NKTR-214, the company’s lead immuno-oncology candidate in combination with approved checkpoint inhibitors, TECENTRIQ (atezolizumab) and KEYTRUDA (pembrolizumab) (Press release, Nektar Therapeutics, SEP 12, 2017, View Source [SID1234520483]). NKTR-214 is an investigational immuno-stimulatory therapy designed to expand specific cancer-fighting T cells and natural killer (NK) cells directly in the tumor microenvironment and increase expression of PD-1 on these immune cells.

Atezolizumab is a monoclonal antibody designed to bind with programmed death-ligand 1 (PD-L1). Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.

"NKTR-214 directly increases the numbers of tumor infiltrating lymphocytes (TILs) in vivo and its unique mechanism is designed to have synergy with all mechanisms of checkpoint inhibition, including the PD-1/PD-L1 pathway," said Mary Tagliaferri, M.D., Senior Vice President of Clinical Development at Nektar Therapeutics. "The PROPEL study is intended to show the synergies of NKTR-214 when combined with either atezolizumab or pembrolizumab and it complements our ongoing PIVOT clinical program which combines NKTR-214 with nivolumab in eight different cancer indications. Many patients fighting cancer lack sufficient TIL populations to benefit from approved checkpoint inhibitor therapies and we believe the combination of NKTR-214 with these agents could expand treatment options for patients in multiple tumor settings."

NKTR-214 targets CD122 specific receptors found on the surface of cancer-fighting immune cells in order to stimulate their proliferation and activation. In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor micro-environment.1,2 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

The Phase 1/2 PROPEL study is a Nektar-sponsored trial that will enroll patients into two separate arms concurrently. The first arm will evaluate an every three-week dose regimen of NKTR-214 in combination with atezolizumab in up to 30 patients in approved treatment settings of atezolizumab, including patients with non-small cell lung cancer or bladder cancer. The second arm will evaluate an every three-week dose regimen of NKTR-214 in combination with pembrolizumab in up to 30 patients in approved treatment settings of pembrolizumab, including patients with melanoma, non-small cell lung cancer or bladder cancer.

Argos Therapeutics Reports on Interim Analysis of Phase 3 ADAPT Trial Presented at ESMO 2017 Congress

On September 12, 2017 Argos Therapeutics Inc. (NASDAQ:ARGS), an immuno-oncology company focused on the development and commercialization of individualized immunotherapies based on the Arcelis precision immunotherapy technology platform, reported on an update on the interim analysis of data from the ongoing Phase 3 ADAPT clinical trial evaluating Rocapuldencel-T for the treatment of metastatic renal cell carcinoma (mRCC) that was presented on September 11, 2017 by Robert Figlin, MD, Professor and Chairman, Division of Hematology and Oncology at Cedars Sinai Medical Center, and co-principal investigator of the ADAPT trial at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, Argos Therapeutics, SEP 12, 2017, View Source [SID1234520482]).

A total of 462 patients with previously untreated advanced or metastatic renal cell carcinoma were enrolled in the ADAPT trial and randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib (combination arm) vs. sunitinib monotherapy (control arm) after undergoing cytoreductive nephrectomy.

As previously reported, as of February 3, 2017, the cut-off date for the most recent interim analysis which was conducted in February 2017, 42.7% of the 307 patients in the combination arm demonstrated an objective response by RECIST criteria, a secondary endpoint in the trial, as compared with 39.4% of the 155 patients in the control arm. Additional data from the trial reported for the first time at the ESMO (Free ESMO Whitepaper) Conference included data related to the duration of tumor response. Patients in the combination treatment arm who demonstrated an objective response had a median duration of response of 8.4 months compared to 6.3 months for patients in the control arm. Additionally, 16% of those patients with an objective response in the combination treatment arm had durable responses lasting at least 30 months compared to 7% of those who had an objective response in the control arm. Also of note, as of the date of the interim analysis, all of the patients in the combination arm who had achieved a duration of response of at least 30 months had maintained those responses through 36 months.

In addition, Dr. Figlin updated immune response data that had been previously reported by the Company, presenting data on 117 patients analyzed for immune response. Samples were collected from patients in the combination arm enrolled at US sites who provided consent for immune monitoring. Of the 117 patients for whom this analysis was completed, 96 (82%) met the criterion for inclusion in the pre-defined subgroup of immune responders, suggesting that Rocapuldencel-T is having its intended effect of stimulating an immune response in the majority of patients. Immune responders are defined as patients who have an increase of more than two standard deviations from the patient-specific baseline in the number of memory T cells (CD8+/CD28+/CD45RA-) at one or more time points. Of note, median overall survival at the time of the February interim analysis had not yet been reached in the subgroup of immune responders (95% CI: 30.1, -). Additionally, consistent with the mechanism of action of Rocapuldencel-T, a statistically significant correlation was observed between the increase from baseline in the number of Rocapuldencel-T-induced memory T cells (CD8+/CD28+/CD45RA-) and overall survival in patients for whom immune response data has been analyzed and who received at least seven doses of Rocapuldencel-T (including both immune responders and non-responders, n=83).

Commenting on the data, Dr. Figlin noted, "Although we did not see a benefit in median overall survival at the February 2017 interim analysis, the data set was relatively immature, with over half of the subjects in both treatment arms still alive. Additionally, for an immunotherapy agent such as Rocapuldencel-T, one might reasonably expect to see a delayed treatment effect, as evidenced by the fact that a statistically significant correlation of the immune response with survival did not emerge until patients had received at least seven doses of Rocapuldencel-T. Thus, median overall survival and other traditional measures of efficacy such as progression-free survival and objective response rate may not be the best endpoints for evaluating the potential benefit of this therapy for patients with limited treatment options, especially in light of the favorable safety and tolerability profile demonstrated to date. Instead, it may be more appropriate to evaluate this agent in light of the potential for a significant "tail-of-the-curve" effect. Thus, my co-principal investigator and I support Argos’ decision to continue the ADAPT trial, and we look forward to reviewing a more mature data set at the next interim analysis, currently planned for the first half of 2018."

As previously reported, the February 2017 interim analysis was conducted by the ADAPT trial’s Independent Data Monitoring Committee (IDMC) after 75% of the originally targeted number of 290 events (deaths) for the analysis of the primary endpoint of overall survival had occurred.

At the time of the analysis, with more than half of the patients still alive in each arm and a median follow-up time of ~20 months, the IDMC concluded that the trial was unlikely to demonstrate a statistically significant improvement in median overall survival in the combination arm and recommended that the trial be discontinued for futility. However, the ADAPT trial principal investigators and Argos considered the data too immature to observe the delayed effects typically associated with immunotherapy and decided to continue the trial pending further review and analysis of the data and discussions with the FDA. In making this determination, Argos considered, among other factors, the degree of maturity of the data set, the mechanism of action of Rocapuldencel-T, which involves the induction of a long-term memory immune response, and the IDMC’s assessment of the safety profile of Rocapuldencel-T. This determination was subsequently further supported by the extended durability of tumor responses in the combination arm, as reported today.

Following the IDMC interim analysis, the Company met with the FDA to discuss the ADAPT trial and the future direction of the Rocapuldencel-T program in April 2017. The FDA agreed with the Company’s decision to continue the ADAPT trial, and further agreed to review a protocol amendment to extend the trial beyond the originally targeted 290 events and a revised statistical analysis plan that the Company plans to submit.

Dr. Figlin’s complete presentation at the ESMO (Free ESMO Whitepaper) 2017 Congress is available for review on Argos’ website at www.argostherapeutics.com. Argos plans to hold a conference call to discuss Dr. Figlin’s presentation on Wednesday, September 20th at 4:30pm ET and will provide logistical information in a subsequent announcement.