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Novartis drug Zykadia receives FDA Priority Review for first-line use in patients with ALK+ metastatic NSCLC

On February 23, 2017 Novartis reported that the US Food and Drug Administration (FDA) accepted the Company’s supplemental New Drug Application (sNDA) for filing, and granted Priority Review for the expanded use of Zykadia (ceritinib) as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test (Press release, Novartis, FEB 23, 2017, View Source [SID1234517793]). The FDA also granted Breakthrough Therapy designation to Zykadia for the first-line treatment of patients with ALK+ metastatic NSCLC with metastases to the brain.

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"We are committed to advancing our understanding of mutation-driven lung cancer, where there continues to be significant unmet need," said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. "Today’s Priority Review of Zykadia for newly diagnosed patients with ALK+ metastatic NSCLC, including Breakthrough Therapy designation for those with brain metastases, brings us closer to delivering the right treatment to the right patient at the right time."

The sNDA submission for first-line use of Zykadia is based on the primary analysis of ASCEND-4, a global Phase III, randomized, open-label, multicenter clinical trial which evaluated safety and efficacy of Zykadia compared to platinum-based chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ NSCLC. The study was conducted at 134 clinical trial sites across 28 countries, and randomized across 376 patients. The study found:

Patients treated with first-line Zykadia had a median progression-free survival (PFS) of 16.6 months (95% confidence interval [CI]: 12.6, 27.2), compared to 8.1 months (95% CI: 5.8, 11.1) for patients treated with standard first-line pemetrexed-platinum chemotherapy with pemetrexed maintenance. A 45% risk reduction in PFS was obtained in the Zykadia arm compared to the chemotherapy arm (hazard ratio [HR] = 0.55, [95% CI: 0.42, 0.73; one-sided p value <0.001])[1].
In a pre-specified analysis of patients receiving Zykadia without brain metastases at screening, patients experienced a median PFS of 26.3 months (95% CI: 15.4, 27.7), compared with 8.3 months (95% CI: 6.0, 13.7) among patients treated with chemotherapy (HR = 0.48 [95% CI: 0.33, 0.69])[1].
In a pre-specified analysis of patients receiving Zykadia with brain metastases at baseline, the median PFS was 10.7 months (95% CI: 8.1, 16.4) in the Zykadia group versus 6.7 months (95% CI: 4.1, 10.6) in the chemotherapy group (HR = 0.70 [95% CI: 0.44, 1.12])[1]. Intracranial overall response rate (ORR) (72.7%, [95% CI: 49.8, 89.3]) is consistent with whole body ORR (72.5% [95% CI: 65.5, 78.7]).
The most common adverse events (AEs) occurring in more than 25% of Zykadia patients were diarrhea (85% vs. 11% with chemotherapy), nausea (69% vs. 55% with chemotherapy), vomiting (66% vs. 36% with chemotherapy), ALT increase (60% vs. 22% with chemotherapy), AST increase (53% vs. 19% with chemotherapy), gamma-glutamyltransferase increase (37% vs. 10% in chemotherapy), decreased appetite (34% vs. 31% with chemotherapy), blood alkaline phosphate increase (29% vs. 5% with chemotherapy) and fatigue (29% vs. 30% with chemotherapy).

FDA grants Priority Review to applications for drugs that treat serious conditions and, if approved, would provide a significant improvement in treatment safety or efficacy[2]. For applications granted priority review, FDA is to take action within 6 months of submission instead of 10 months under standard review timelines.

Breakthrough Therapy designation is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement on at least one clinically significant endpoint over an available therapy[3]. Novartis has received 13 Breakthrough Therapy designations to date, underscoring the company’s ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients. This latest designation is for the first-line treatment of patients with ALK+ NSCLC with brain metastases and is the second Breakthrough Therapy designation for Zykadia.

Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined[4], and an estimated 1.8 million new cases of lung cancer are diagnosed each year[5]. Among those patients with NSCLC, the most common type of lung cancer, 3-7% are ALK-positive[6].

Novartis’ Commitment to Lung Cancer
Novartis Oncology’s research into targeted therapies has helped transform treatment approaches for patients living with mutation-driven lung cancers. Patients with a mutation-driven NSCLC may be candidates for treatment with targeted therapies[7].

Zykadia was one of the first medicines to be approved following FDA Breakthrough Therapy designation. It is currently indicated for the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib. This indication was approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Zykadia was commercially available in the US less than three and a half years after the first patient entered a clinical trial.

Novartis continues its commitment to the global lung cancer community through ongoing studies of its marketed therapies as well as the exploration of investigational compounds that target genomic biomarkers in NSCLC.

About ASCEND-4
ASCEND-4 was a Phase III randomized, open-label, multicenter, global clinical trial to evaluate the safety and efficacy of Zykadia compared to standard chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ advanced NSCLC who received no prior therapy for their advanced disease. Patients received Zykadia orally at 750 mg/daily or standard pemetrexed-based platinum doublet chemotherapy per label (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for 4 cycles followed by pemetrexed maintenance.

Of 376 patients, 189 (59 with brain metastases) were randomized to Zykadia and 187 (62 with brain metastases) to chemotherapy. Approximately 60% of patients with baseline brain metastases treated with Zykadia did not have prior radiation therapy, the current standard of treatment for baseline brain metastases. Among patients randomized to the chemotherapy arm, 105 (72%) of 145 received an ALK inhibitor as their first treatment after discontinuation of chemotherapy.

About Zykadia
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal "fusion protein" that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC). Zykadia is currently approved in over 64 countries worldwide. Please visit www.NovartisOncology.com/news/product-portfolio/zykadia for additional information.

Zykadia Important Safety Information
Zykadia may cause serious side effects.

Zykadia may cause stomach upset and intestinal problems in most patients, including diarrhea, nausea, vomiting and stomach-area pain. These problems can be severe. Patients should follow their doctor’s instructions about taking medicines to help these symptoms, and should call their doctor for advice if symptoms are severe or do not go away.

Zykadia may cause severe liver injury. Patients should have blood tests prior to the start of treatment with Zykadia, every two weeks for the first month of treatment and monthly thereafter, and should talk to their doctor right away if they experience any of the following symptoms: tiredness (fatigue), itchy skin, yellowing of the skin or the whites of the eyes, nausea or vomiting, decreased appetite, pain on the right side of the abdomen, urine turns dark or brown, or bleeding or bruising more easily than normal.

Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Patients should tell their doctor right away about any new or worsening symptoms, including trouble breathing or shortness of breath, fever, cough, with or without mucous, or chest pain.

Zykadia may cause very slow, very fast, or abnormal heartbeats. Doctors should check their patient’s heart during treatment with Zykadia. Patients should tell their doctor right away if they feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats, blue discoloration of lips, shortness of breath, swelling of lower limbs or skin, or if they start to take or have any changes in heart or blood pressure medicines.

Zykadia may cause high levels of glucose in the blood. People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Patients should have glucose blood tests prior to the start of treatment with Zykadia and during treatment. Patients should follow their doctor’s instructions about blood sugar monitoring and call their doctor right away with any symptoms of high blood sugar, including increased thirst and/or urinating often.

Zykadia may cause high levels of pancreatic enzymes in the blood and may cause pancreatitis. Patients should have blood tests prior to the start of treatment with Zykadia and as needed during their treatment with Zykadia. Patients should talk to their doctor if they experience signs and symptoms of pancreatitis which including upper abdominal pain that may spread to the back and get worse with eating.

Before patients take Zykadia, they should tell their doctor about all medical conditions, including liver problems; diabetes or high blood sugar; heart problems, including a condition called long QT syndrome; if they are pregnant, if they think they may be pregnant, or if they plan to become pregnant; are breastfeeding or plan to breastfeed.

Zykadia may harm unborn babies. Women who are able to become pregnant must use a highly effective method of birth control (contraception) during treatment with Zykadia and up to 3 months after stopping Zykadia. It is not known if Zykadia passes into breast milk. Patients and their doctor should decide whether to take Zykadia or breastfeed, but should not do both.

Patients should tell their doctor about medicines they take, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements. If they take Zykadia while using oral contraceptives, the oral contraceptives may become ineffective.

The most common adverse reactions with an incidence of >=10% were diarrhea, nausea, vomiting, tiredness (fatigue), liver laboratory test abnormalities (requires blood test monitoring), abdominal pain, decreased appetite, constipation, rash, kidney laboratory test abnormalities (requires blood test monitoring), heartburn and anemia. Grade 3-4 adverse reactions with an incidence of >=5% were liver laboratory test abnormalities, tiredness (fatigue), diarrhea, nausea and hyperglycemia (requires blood test monitoring).

Patients should stop taking Zykadia and seek medical help immediately if they experience any of the following, which may be signs of an allergic reaction:

Difficulty in breathing or swallowing
Swelling of the face, lips, tongue or throat
Severe itching of the skin, with a red rash or raised bumps
Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Zykadia. For more information, patients should ask their doctor or pharmacist.

Patients should take Zykadia exactly as their health care provider tells them. Patients should not change their dose or stop taking Zykadia unless their health care provider advises them to. Zykadia should be taken once a day on an empty stomach. Patients should not eat for at least 2 hours before and 2 hours after taking Zykadia. If a dose of Zykadia is missed, they should take it as soon as they remember. If their next dose is due within the next 12 hours, they should skip the missed dose and take the next dose at their regular time. They should not take a double dose to make up for a forgotten dose. Patients should not drink grapefruit juice or eat grapefruit during treatment with Zykadia, as it may make the amount of Zykadia in their blood increase to a harmful level. If patients have to vomit after swallowing Zykadia capsules, they should not take more capsules until their next scheduled dose.

Please see full Prescribing Information for Zykadia.

Truxima™, the first biosimilar mAb in oncology, granted EU marketing authorisation

On February 22, 2017 Celltrion Healthcare reported that the European Commission has approved TruximaTM (biosimilar rituximab) for all indications of reference rituximab in the European Union (EU) (Press release, Celltrion, FEB 22, 2017, View Source;division=R [SID1234531693]). Truxima is the first biosimilar monoclonal antibody (mAb) approved in an oncology indication worldwide.[1] The approval of Truxima builds on Celltrion Healthcare’s strong global clinical biosimilar programme.

"We are excited to offer the first biosimilar mAb in oncology. With our partners across Europe, we will work together to ensure that Truxima is available to the many patients who can benefit from this treatment", said Jung-Jin Seo, Chairman of Celltrion Group, speaking at a meeting of their European partners in Paris. "For healthcare systems burdened with high cost oncology treatments, we are pleased to provide an option that has the potential to offer significant savings whilst ensuring patients retain access to high-quality and effective treatments."

Truxima is approved in the EU for the treatment of people with non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukaemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis and microscopic polyangiitis.[1] This approval is based on the totality of evidence submitted to the European Medicines Agency showing compelling similarity between Truxima and reference rituximab in terms of efficacy, safety, immunogenicity, pharmacodynamics (PD) and pharmacokinetics (PK) in patients with RA and advanced follicular lymphoma, a type of NHL.[2] These trials were conducted in over 600 patients and include data up to 104 weeks.[2]

Dr Bertrand Coiffier, the global principle investigator of the advanced follicular lymphoma study, Head of the Department of Hematology at Hospices Civils de Lyon and Professor at the University Claude Bernard, Lyon, France said, "Biosimilar rituximab has been shown to have comparable efficacy and safety to reference rituximab in a large program of trials providing convincing evidence for the similarity of the two products. This has been recognised by the regulatory authorities, and hopefully this will pave the way for further innovation in this area".

Budget saving impact

Biosimilars have the potential to offer cost savings for healthcare systems and therefore the potential to increase patient access to biological therapies.[3],[4]

"Assuming the price of biosimilar rituximab is 70% compared to reference rituximab, and the market share of biosimilar rituximab is 30% (first year), 40% (second year) and 50% (third year), over this three-year time period the budget savings across the 28 countries of the EU would be around €570 million", said Prof. László Gulácsi, Head of Department of Health Economics, Corvinus University of Budapest; HTA Consulting Budapest, Hungary. "This equates to 49,000 new RA, NHL and CLL patients who could be receiving life-changing treatment which is clearly a huge aggregate health-gain at both a national and EU level."

— Ends—

Notes to editors:

About hematological cancers

Hematological cancers begin in blood-forming tissue or cells of the immune system. There are three common types of hematological cancers: lymphoma, leukaemia and myeloma. There are many types of NHL, the most common group is B cell lymphomas, of which follicular lymphoma and diffuse large B cell lymphoma are the most common. CLL is a type of leukaemia and is characterised by accumulation of monoclonal B cells (a type of white blood cell).

About rheumatoid arthritis

In Europe more than 2.9 million people have RA, many of whom are of working age. On average, every third person with RA becomes work disabled and up to 40 per cent leave work completely within 5 years of diagnosis.[5] Although there is no cure for RA, there are many treatments that can reduce inflammation and ease pain. As with all rheumatic diseases early diagnosis and intervention is key.

About Truxima (biosimilar rituximab)

Truxima is a mAb that targets CD20, a protein found on the surface of most B cells. Overactive B cells can stimulate attack of healthy cells in immune-related diseases such as RA. B cells are also implicated in some types of hematological cancer including NHL and CLL. B cells express CD20 at many stages of their development making the protein a good target for treatments.

Truxima is approved in the EU for the treatment of people with NHL, CLL, RA, granulomatosis with polyangiitis and microscopic polyangiitis. Further details of the approved indications and safety information for Truxima are available in the summary of product characteristics (SmPC).[1]

Overview of Truxima studies

Phase 1 clinical data demonstrated the PK of Truxima and reference rituximab were statistically equivalent over 24 weeks after a single course of treatment, and that their efficacy, PD, immunogenicity and safety were similar up to 2 courses of treatments (up to 72 weeks).[2]

A phase 1 open label extension study showed that switching to Truxima from reference rituximab was similarly effective with comparable safety to continuing Truxima for two years.[2]

Three phase 3 studies in patients with RA, advanced follicular lymphoma and low-tumor-burden follicular lymphoma (LTBFL) are ongoing:

· Truxima showed highly similar efficacy, PK, PD, immunogenicity and safety profiles to reference rituximab in people with RA up to 48 weeks[2]

· Truxima showed equivalent PK to reference rituximab with similar efficacy, PD, immunogenicity and safety profiles up to 8 cycles of treatment (every 3 weeks) in people with advanced follicular lymphoma[2]

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

bluebird bio has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission (Filing, 10-K, bluebird bio, FEB 22, 2017, View Source [SID1234517797]).

Atreca, Inc. Presents New Preclinical Findings for Novel Cancer Immunotherapy Platform at Molecular Medicine Tri-Conference 2017

On February 9, 2017 Atreca, Inc., a biotechnology company focused on developing novel therapeutics based on a deep understanding of the human immune response, reported the presentation of positive preclinical findings in its immuno-oncology program, generated via the Company’s Immune Repertoire Capture (IRC) technology platform (Press release, Atreca, FEB 22, 2017, View Source [SID1234522956]). Atreca’s IRC technology identifies and generates sequences of native antibodies and T cell receptors (TCRs) from active human immune responses, including natively paired and complete variable regions of receptors expressed by specifically selected B- and T-cells. New findings from Atreca’s lead program are being highlighted at the 24th annual Molecular Medicine TriConference, taking place at the Moscone North Convention Center in San Francisco, CA, February 19-24, 2017.

In a presentation, titled "The Immune Repertoire Capture (IRC) Technology Platform," Daniel Emerling, Ph.D., Atreca’s Senior Vice President, Research, is presenting key preclinical findings today at 12:10 p.m. Pacific Time, including:

Atreca’s researchers have used IRC technology to generate functional antibodies from the active immune response of individuals with metastatic disease who experienced a response to therapy.
Several patient-derived antibodies have been shown to bind tumor tissue but not normal tissue, and some antibodies bind multiple tumor types, including lung and breast adenocarcinoma, and renal cell carcinoma.
In a preclinical syngeneic in vivo tumor model, administration of the human variable regions derived from a particular patient antibody (linked to a mouse constant region) resulted in clearance of tumor in a majority of the animals, with concomitant infiltration of immune system cells into tumor tissue. Potential synergy with a checkpoint inhibitor was also observed.
"We are thrilled with the continued momentum of our programs based on successful anti-tumor immune responses in cancer patients undergoing treatment," stated N. Michael Greenberg, PhD, Atreca’s Chief Scientific Officer. "Our most recent data validate our next-generation approach in monotherapy as well as combination therapy, potentially addressing the substantial need to enhance patient responses to checkpoint inhibition. The unique features and capabilities of our platform allow us to pursue diverse applications outside of cancer as well, and we look forward to our progress as we advance toward IND-enabling studies in our lead program."

Atreca applies IRC to generate sequences of native antibodies and TCRs from cancer patients who have responded well to immunotherapy and other treatments, patients with autoimmune disease, vaccinated subjects, and patients who resolve infections. Analyses of the resulting essentially unbiased and error-free repertoires yield insights into immunology, as well as potent antibodies targeting tumors, pathogens, and autoimmune epitopes.

CLEVELAND BIOLABS REPORTS 2016 FINANCIAL RESULTS AND DEVELOPMENT PROGRESS

On February 22, 2017 Cleveland BioLabs, Inc. (NASDAQ:CBLI) reported financial results and development progress for the fourth quarter and year ended December 31, 2016 (Filing, 8-K, Cleveland BioLabs, FEB 22, 2017, View Source [SID1234517857]).

Cleveland BioLabs reported a net loss, excluding minority interests, of $(1.2) million for the fourth quarter of 2016, or $(0.11) per share, compared to a net loss of $(1.4) million, or $(0.13) per share, for the fourth quarter of 2015. Net loss, excluding minority interests, for full year 2016 was $(2.7) million, or $(0.24) per share, compared to a net loss of $(12.6) million, or $(1.79) per share, for full year 2015.

As of December 31, 2016, the Company had $15.2 million in cash, cash equivalents and short-term investments, which, based on the Company’s current operational plan, is estimated to fund operations for at least one year beyond the filing date of our Form 10-K.

Yakov Kogan, Ph.D., MBA, Chief Executive Officer, stated, "The past year was one of significant progress for CBLI. We commenced or continued clinical studies designed to further substantiate the potential of our Toll-like receptor agonists, entolimod, CBLB612 and Mobilan."

"The pursuit of commercialization for entolimod as a medical radiation countermeasure remains our top priority," continued Dr. Kogan. "We are working with the U.S. Food and Drug Administration (FDA) to confirm the bio-comparability of two formulations of entolimod. As requested by the Agency, we have completed the side-by-side analytical comparability analysis of these formulations and plan to submit the report to the Agency in the first quarter of 2017. Once the FDA has reviewed these data and provided its consent, the bio-comparability study in non-human primates will commence. Following completion of the study and discussion of the submitted study results with the FDA, we expect the Agency to resume the review of our pre-EUA dossier. Products with pre-EUA status may be purchased by certain US government stakeholders for stockpiling in the event of a disaster and we believe achievement of this status may also increase interest from foreign governments. In addition, we are evaluating steps needed to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA), and have taken preliminary action with the EMA, which has granted entolimod orphan drug designation for the treatment of acute radiation syndrome, and we continue to evaluate other foreign markets."

Other Operational Highlights

•
Entolimod Oncology Indications. We have completed dosing of 40 patients in a clinical study of the safety and tolerability of entolimod as a neo-adjuvant therapy in treatment-naïve patients with primary colorectal cancer who are recommended for surgery. The goal is to accumulate additional clinical data regarding immune cell response to administrations of entolimod to guide future oncology development. The analysis of the data is ongoing.
•
CBLB612. We have also completed dosing in a Phase 2, randomized, placebo-controlled clinical study of CBLB612 as myelosuppressive prophylaxis in patients with breast cancer receiving doxorubicin-cyclophosphamide chemotherapy and data analysis of this study is in progress.
•
Mobilan. Two randomized, placebo-controlled, dose-ranging studies of Mobilan in men with prostate cancer are currently ongoing in the Russian Federation.

All of these studies are being conducted in the Russian Federation and were supported by development contracts with the Russian Federation Ministry of Industry and Trade, or MPT.

Further Financial Results

Revenue for the fourth quarter of 2016 was $1.0 million compared to $1.3 million for the fourth quarter of 2015. Revenue for full year 2016 was $3.5 million compared to $2.7 million for full year 2015. The revenue changes are primarily due to increased revenue from our Joint Warfighter Medical Research Program (JWMRP) contract with the Department of Defense (DoD) and our recently completed MPT contracts at BioLab 612 and Panacela which were partially offset by a decrease in service contract revenue from Incuron.

Research and development (R&D) costs for the fourth quarter of 2016 were $2.2 million compared to $1.9 million for the fourth quarter of 2015. R&D costs for the full year 2016 decreased to $6.5 million compared to $7.1 million for the full year 2015. The research and development changes were primarily attributable to our streamlined focus of pursuing commercialization efforts for entolimod’s biodefense indication in the United States and European Union, which increased certain R&D costs, but were partially offset by contract performance against the recently modified scope of work for our JWMRP contract to address the formulation questions raised by the FDA during its review of the pre-EUA dossier, and completion of our MPT contracts, which increased certain R&D costs during the year.

General and administrative costs (G&A) for the fourth quarter of 2016 were $0.7 million compared to $1.2 million for the fourth quarter of 2015. G&A costs for full year 2016 decreased to $3.4 million compared to $6.4 million for full year 2015. These decreases were primarily attributable to reductions in personnel and outside professional costs.

At December 31, 2016 the Company had 10,987,166 shares of common stock outstanding. In addition, the Company has 233,367 shares of common stock reserved for issuance pursuant to outstanding stock options with a weighted average exercise price of $41.98 and 2,148,741 shares of common stock reserved for issuance pursuant to outstanding warrants exercisable at a weighted average price of $11.04.