41-34 AbbVie Submits sNDA for Imbruvica in CLL Patients

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AbbVie Submits sNDA for Imbruvica in CLL Patients

AbbVie has submitted a supplemental New Drug Application to FDA based on the randomized, multi-center, open-label phase III RESONATE trial of IMBRUVICA (ibrutinib) versus chlorambucil in treatment-naive chronic lymphocytic leukemia patients aged 65 years or older.

AbbVie announced top-line findings from the trial showing that IMBRUVICA improved progression-free survival and multiple secondary endpoints including overall survival and overall response rate in treatment-naive patients with CLL.

IMBRUVICA is approved for the treatment of patients with CLL who have received at least one prior therapy and CLL patients (including treatment-naive) who have del 17p, a genetic aberration that occurs when part of chromosome 17, the location of the tumor suppressor gene p53, has been lost or deleted.

The RESONATE-2 trial is a Pharmacyclics-sponsored study and its protocol and specific performance goals were established in a special protocol assessment (SPA) with the FDA. An SPA is an agreement with FDA that a phase III clinical trial design, its clinical endpoints and statistical analyses are acceptable to the Agency to support a submission and potential approval.

The trial enrolled 269 treatment-naive patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either ibrutinib 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.

The primary endpoint of the study was PFS as assessed by an Independent Review Committee according to the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR, OS and safety.

Can-Fite BioPharma Ltd. of Petach Tikva, Israel, said FDA has granted the company’s drug candidate CF102 Fast Track designation as a second line treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer. CF102 had already received the FDA’s Orphan Drug designation.

Can-Fite is conducting a phase II study for this indication in the U.S., Europe and Israel. The randomized, double-blind, placebo-controlled study is expected to complete enrollment by the end of the first half of 2016 in 78 patients with Child-Pugh Class B cirrhosis who failed the only FDA approved drug on the market, Nexavar (sorafenib).

Drugs that receive Fast Track designation benefit from more frequent meetings and communications with the FDA to review the drug’s development plan to support approval. It also allows the Company to submit parts of the New Drug Application on a rolling basis for review as data becomes available. Since the Fast Track Program started, from March 1998 through June 30, 2015 a total of 318 Fast Track applications have been received by FDA. The FDA has granted 202 of them, and denied 110, with 6 more pending.

CF102 is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). A3AR is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In Can-Fite’s pre-clinical and clinical studies, CF102 has demonstrated a robust anti-tumor effect via deregulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.

BTG plc of London said that Wellstat Therapeutics’ new drug application for uridine triacetate has been accepted for review by FDA.

The sponsor seeks approval of uridine triacetate as treatment for patients at risk of serious toxicity following an overdose of the chemotherapy agent 5-fluorouracil and patients exhibiting symptoms of serious toxicity within 96 hours of 5-FU administration.

FDA has provided an anticipated Prescription Drug User Fee Act action date in March 2016. Uridine triacetate is being developed by Wellstat Therapeutics. If approved by FDA, BTG will market, sell and distribute uridine triacetate for this indication in the US. Wellstat Therapeutics retains certain rights to exercise an option to co-promote uridine triacetate. Terms of the co-promote have not been disclosed.

In 2009, uridine triacetate received orphan drug designation from FDA as an antidote in the treatment of 5-fluorouracil poisoning and from the European Medicines Agency as a treatment for 5-fluorouracil overdose. Under an expanded access protocol, FDA emergency treatment provisions in the US, and similar emergency use provisions in Europe and the rest of the world, uridine triacetate is currently provided to patients at risk of excess 5-FU toxicity due to overdose and patients exhibiting serious toxicities to 5-FU within 96 hours of 5-FU administration. The NDA for uridine triacetate is based in part on efficacy and safety data from U.S. sites in this protocol.

Published literature suggests that each year, approximately 250,000 to 300,000 patients in the US receive multiple treatments with 5-FU, of which 0.5 percent die from 5-FU toxicity. An estimated 10-20 percent of those patients develop serious, sometimes life threatening, 5-FU toxicity or experience an overdose. Non-fatal 5-FU toxicities can result in hospitalization, intensive care utilization and delays in or discontinuation of chemotherapy.

Uridine triacetate is converted in the body to uridine, a direct biochemical antagonist of 5-fluorouracil toxicity.

FDA and the European Medicines Agency accepted regulatory applications for Gilotrif (afatinib), sponsored by Boehringer Ingelheim, for the treatment of advanced squamous cell carcinoma of the lung, after treatment with first-line chemotherapy.

Gilotrif has also been granted Orphan Drug Designation by the FDA.

The submissions are based on positive data from the phase III LUX-Lung 8 study that showed a significant delay in progression of lung cancer and a significant improvement in overall survival for Gilotrif compared to Tarceva (erlotinib).

Data from LUX-Lung 8 showed that treatment with Gilotrif resulted in superior progression-free survival, reducing the risk of cancer progression by 19 percent, and superior overall survival, reducing the risk of death by 19 percent, compared to Tarceva in this patient population.

More patients had improved overall health-related quality-of-life with Gilotrif than with Tarceva (36 vs. 28 percent). Significantly more patients had an improvement in cough with Gilotrif than with Tarceva (43 vs. 35 percent).

Afatinib, an oral, once daily EGFR-directed therapy, is currently approved in more than 60 countries for the first-line treatment of specific types of EGFR mutation-positive NSCLC (under brand names Gilotrif and Giotrif). Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumor growth when compared to standard chemotherapy.

In addition, afatinib is the first treatment to show an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy. A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (exon 19 deletions) compared to chemotherapy.

AstraZeneca and Peregrine Pharmaceuticals Inc. entered into a cancer immunotherapy clinical trial collaboration.

The collaboration will evaluate Peregrine’s investigational phosphatidylserine-signaling pathway inhibitor, bavituximab, in combination with AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab. The planned phase I/Ib trial will evaluate the safety and efficacy of bavituximab in combination with durvalumab in multiple solid tumors. Peregrine and AstraZeneca will collaborate on a non-exclusive basis.

The phase I part of the trial is expected to establish a recommended dose regimen for the combination and the phase Ib part of the trial will assess the safety and efficacy of the investigational combination. Under the terms of the agreement, the initial trial will be conducted by Peregrine.

Bavituximab targets and modulates the activity of phosphatidylserine, an immune-suppressive molecule expressed broadly on the surface of cells in the tumor microenvironment. Durvalumab is a monoclonal antibody directed against programmed cell death ligand 1. Preclinical data have demonstrated that combining the enhanced T-cell mediated anti-tumor activity of bavituximab with checkpoint inhibitors, like PD-L1 antibodies, prolong the ability of tumor-specific T-cells to continue attacking the tumor.

ICON, a provider of drug development solutions, said it’s working with IBM to help reduce the time and costs of drug development while also offering patients enhanced quality of care by connecting them to relevant clinical trials. ICON said it will tap Watson’s cognitive computing power to help the process of identifying patients who meet the criteria for a clinical trial, and to analyze protocols to assess trial feasibility and identify optimal trial sites.

Initially, ICON is applying Watson Clinical Trial Matching to its breast, lung, colon and rectal cancer trials.

The solution enables ICON to advise sponsors how many patients match their trial criteria, where they are located and how they will recruit them.

IBM’s Watson Health Cloud will facilitate access to de-identified patient data, including 50 million patient records contained in the data set from Explorys. At the same time, ICON enhances IBM Watson’s capabilities by providing expertise into clinical trial protocols and clinical operations.

More than $1.3 billion is spent on patient recruitment by drug developers each year and yet fewer than 5% of cancer patients participate in a clinical trial. It takes 6-12 months to start up a global phase III drug trial and another 12 months to enroll the required number of patients.

“Recruiting the required number of patients for clinical trials is a constant challenge for our customers and can represent more than 30% of total study costs. ICON’s Chief Operating Officer, Steve Cutler, said in a statement. “By applying IBM Watson to our clinical trials, we have the potential to revolutionize clinical trial feasibility, patient recruitment and study start-up timelines which will help our customers take significant time and cost from their development programs.”


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