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Ignyta Announces FDA Clearance of IND for RXDX-107

On July 29, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug application (IND) for Ignyta’s new chemical entity RXDX-107, a next-generation alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles (Press release, Ignyta, JUL 29, 2015, View Source [SID:1234506739]).

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Under this IND, the company intends to initiate a new Phase 1/1b, multicenter, open-label clinical trial of RXDX-107 in adult patients. This dose-escalation study is designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of RXDX-107 in patients with locally advanced or metastatic solid tumors.

"The FDA’s determination that our planned Phase 1/1b clinical trial of RXDX-107 may proceed under our IND is a significant milestone for Ignyta," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Although we just recently acquired rights to RXDX-107 from Teva in March, our team has worked hard in the meantime to fully integrate this product candidate into our business and prepare and submit the IND just a quarter later. This IND represents Ignyta’s second successful IND filing with the FDA, and RXDX-107 will be our third product candidate in the clinic. We look forward to beginning to treat cancer patients with this product candidate."

About RXDX-107

RXDX-107 is new chemical entity comprising an alkyl ester of bendamustine encapsulated in HSA to form nanoparticles. RXDX-107 is designed to have increased half-life and improved tissue biodistribution by leveraging the affinity characteristics of albumin for tumor cells, while retaining the unique cytotoxic properties of bendamustine. These improvements may provide meaningful benefit to patients with solid tumors. In preclinical pharmacology studies, RXDX-107 has demonstrated anti-tumor activity in multiple in vitro and in vivo studies, including cell line-based and patient-derived xenograft models of solid tumors.

EISAI’S IN-HOUSE DEVELOPED NOVEL ANTICANCER AGENT LENVIMA(R) RECEIVES BREAKTHROUGH THERAPY DESIGNATION FROM U.S. FDA FOR RENAL CELL CARCINOMA

On July 29, 2015 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported its U.S. subsidiary Eisai Inc. has received a Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for its in-house developed novel anticancer agent Lenvima (lenvatinib mesylate, "lenvatinib") for the potential indication of advanced and/or metastatic renal cell carcinoma (Press release, Eisai, JUL 29, 2015, View Source [SID:1234506735]).

The Breakthrough Therapy designation is an U.S. FDA program intended to expedite development and review of drugs for serious or life-threatening conditions. The benefits of this designation include more intensive guidance on an efficient drug development program and submission strategy, as well as eligibility for rolling review. Preliminary clinical evidence demonstrating the drug may have substantial improvement on at least one clinically significant endpoint over available therapy is required for Breakthrough Therapy designation.

This Breakthrough Therapy designation was based on the results of a Phase II clinical trial (Study 205)1 of lenvatinib in advanced or metastatic renal cell carcinoma following one prior vascular endothelial growth factor-targeted therapy. From the results of the study, the combination of lenvatinib plus everolimus demonstrated a significant extension in progression free survival (PFS), the study’s primary endpoint, compared to everolimus alone. Additionally, lenvatinib alone demonstrated an extension in PFS compared to everolimus alone. Both the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in objective response rate compared to the everolimus alone group. Furthermore, an updated analysis carried out in December 2014 suggested that lenvatinib plus everolimus extends overall survival compared to everolimus alone. The most common treatment-emergent adverse events (TEAE) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher included diarrhea, hypertension and fatigue.

The number of patients with kidney cancer in 2012 was estimated to be approximately 338,000 worldwide, including 58,000 in the United States.2 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney.3 For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment method is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical needs. According to the results of Study 205, lenvatinib plus everolimus showed superior PFS over everolimus alone which is recommended by the National Comprehensive Cancer Network (NCCN) guidelines as a 2nd-line therapy for advanced or metastatic renal cell carcinoma. Currently, no combination therapy for this indication has been approved in the United States, Europe or Japan.

Eisai has shared the results of Study 205 with regulatory authorities to discuss further steps regarding potential submission strategies for an indication covering renal cell carcinoma. Eisai is committed to exploring the potential clinical benefits of lenvatinib in order to further contribute to patients with cancer and their families.

1. About lenvatinib mesylate (product name: Lenvima)
Lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation. Lenvatinib has been confirmed through X-ray co-crystal structural analysis to demonstrate a new binding mode (Type V) to VEGFR2, and exhibits rapid binding to the target molecule and potent inhibition of kinase activity, according to kinetic analysis.4
Currently, lenvatinib has been launched in the United States, Japan and Europe indicated for the treatment of refractory thyroid cancer. In addition, lenvatinib is currently undergoing regulatory review in nine countries around the world. Meanwhile, Eisai is conducting a global Phase III study of lenvatinib in hepatocellular carcinoma as well as Phase II studies of lenvatinib in several other tumor types such as endometrial carcinoma and non-small cell lung cancer. Furthermore, lenvatinib was granted Orphan Drug Designation by regulatory authorities in the United States, Japan and Europe for refractory thyroid cancer.

2. About Study 2051
Study 205 was a multicenter, randomized, open-label study of lenvatinib (18 mg) in combination with the anticancer agent everolimus (5 mg), lenvatinib alone (24 mg), and everolimus alone (10 mg) in patients with advanced or metastatic renal cell carcinoma following one prior VEGF-targeted therapy. 153 patients were randomized in a 1:1:1 ratio to one of three treatment arms to compare the safety and efficacy of these three regimens.

From the results of the study, the combination of lenvatinib plus everolimus demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to everolimus alone (median PFS for the lenvatinib plus everolimus group: 14.6 months vs median PFS for the everolimus alone group: 5.5 months; Hazard Ratio (HR) 0.40 [95% CI: 0.24-0.68], p<0.001). Additionally, median PFS for lenvatinib alone was 7.4 months, demonstrating an extension in PFS compared to everolimus alone (HR: 0.61 [95% CI: 0.38-0.98]).

The study also assessed objective response rate (ORR) and overall survival (OS) as secondary endpoints. Regarding ORR, both the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in ORR compared to the everolimus alone group (lenvatinib plus everolimus: 43%, lenvatinib alone: 27%, everolimus alone: 6%). Furthermore, regarding OS, an updated analysis carried out in December 2014 suggested that lenvatinib plus everolimus extends OS compared to everolimus alone (HR 0.51 [95% CI=0.30-0.88]).

The most common treatment-emergent adverse events (TEAE) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included diarrhea, hypertension and fatigue.

3. About Renal Cell Carcinoma
The number of patients with renal cancer was estimated to be approximately 338,000 worldwide, including approximately 17,000 in Japan, 58,000 in the United States and 115,000 in Europe.2 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney.3 The incidence of renal cell carcinoma in people aged in their late 50s is rising, and is more likely to affect men than women. While the standard treatment method primarily consists of surgery, once the cancer has relapsed or metastasized, the main treatment method becomes chemotherapy using molecular targeted drugs.

4. About the Breakthrough Therapy Designation
The Breakthrough Therapy designation is a program intended to expedite development and review of drugs for serious or life-threatening conditions. Preliminary clinical evidence demonstrating the drug may have substantial improvement on at least one clinically significant endpoint over available therapy is required in order to qualify for this designation. The benefits of this Breakthrough Therapy designation include more intensive guidance on an efficient drug development program, access to a regulatory liaison to help accelerate review time, and eligibility for rolling review as well as priority review.

ARIAD to Receive up to $200 Million Through Iclusig Non-Dilutive Synthetic-Royalty Financing with PDL BioPharma

On July 29, 2015 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported that it will receive $100 million in cash – $50 million upon deal execution late yesterday and an additional $50 million in one year – through a synthetic-royalty financing from PDL BioPharma, Inc. (NASDAQ: PDLI) in exchange for paying PDL a mid-single-digit royalty on future sales of Iclusig (ponatinib) until PDL receives a fixed internal rate of return (IRR) (Press release, Ariad, JUL 29, 2015, View Source;p=RssLanding&cat=news&id=2072149 [SID:1234506731]).

ARIAD also has an option, in its discretion, to receive up to an additional $100 million at any time between 6 and 12 -long-term commercialization of brigatinib," said Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. "We are confident based on the latest clinical data on brigatinib and other ALK‐inhibitors, that brigatinib may be an important new cancer medicine for patients with ALK+ lung cancer. With the funding provided by this royalty transaction, we expect to start the front-line trial by early next year, ahead of our expected filing for initial marketing approval of brigatinib in patients with refractory ALK+ NSCLC."

Dr. Berger added, "This synthetic-royalty financing allows us to access the needed capital at low cost without selling any equity and gives us the greatest flexibility in implementing our corporate strategy."

Royalty Interest Financing Terms

Pursuant to the agreement, ARIAD will pay PDL 2.5% of global net revenues of Iclusig for the first year of the agreement, 5.0% after the first year through the end of 2018, and 6.5% from 2019 until PDL receives a specified very low double-digit IRR. The 6.5% royalty rate would increase to 7.5% if the Company draws down more than $150 million. In all cases, the royalty no longer is payable once PDL receives its predefined IRR.

ARIAD may also buy out the royalty at any time by making a payment to PDL that will, together with royalties paid, provide a specified return to PDL. Furthermore, if after five years from receiving each payment tranche, PDL has not received total payments that are at least equal to the total amounts it has paid to ARIAD, then ARIAD will be required to pay to PDL an amount equal to such a difference.

Upon the occurrence of specified events, such as a change of control of ARIAD, PDL has the right, but not the obligation, to terminate the agreement by requiring ARIAD to repurchase the revenue interests owed to PDL at a predefined price.

Houlihan Lokey acted as sole placement agent and financial advisor for this synthetic-royalty financing transaction. Mintz, Levin, Cohn, Ferris, Glovsky & Popeo, PC represented ARIAD in this transaction.

About Iclusig (ponatinib) tablets

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information.

10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, Celgene, JUL 28, 2015, View Source [SID:1234506730])

10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, United Therapeutics, JUL 28, 2015, View Source [SID:1234506717])