On July 29, 2015 Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZ) (the "Company") reported it has selected an optimized Erk inhibitor molecule for development, thus achieving another important milestone in the development of a new class of potential cancer therapies (Press release, AEterna Zentaris, JUL 29, 2015, View Source [SID:1234506752]).

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The MAPK pathway represents a prime target for therapeutic intervention in cancer. Recently approved compounds demonstrate significant antitumor activities and survival benefits for B-Raf and Mek inhibitors. Erk inhibitors may be preferred agents in tumors with aberrant MAPK pathway activity, e.g. in tumors with mutated or wildtype B-Raf, mutated or wildtype ras, and in tumors with acquired resistance to Raf and Mek inhibitors.

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At the 2014 American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s annual meeting, the Company presented an abstract of its work on an Erk inhibitor molecule called "AEZS-134". The abstract was selected by participants in the meeting as one of the 11 high-impact abstracts out of hundreds presented on the topic. Subsequently to this recognition, the Company continued its efforts on the Erk inhibitor program, including identification of an optimized molecule.

An optimized Erk inhibitor compound, AEZS-140, and back-up candidates were identified as a result of the development efforts. AEZS-140 and the back-up candidates demonstrate improved plasma exposure in rodents as well as enhanced anti-tumor efficacy in comparison to the previous lead compound, AEZS-134. Furthermore, AEZS-140 was profiled against several clinical Raf, Mek and Erk inhibitors and demonstrated very competitive activity.

The Company will proceed with the next development steps for AEZS-140 and the back-up compounds, including in depth profiling in vitro and, also, further in vivo tumor models. The Company is seeking proposals from parties who are interested in either co-developing or licensing the compounds.

David A. Dodd, Chairman and CEO of Aeterna Zentaris, commented, "Our strategy includes leveraging some of our promising early-stage drug candidates in order to generate potential long-term value without having to invest in their development. We are pursuing this strategy with respect to our Erk inhibitor development program. A therapeutic agent arising from this program could represent a novel approach to treating types of cancers with acquired resistance to Raf and Mek inhibitors. Our business development team is already engaged in discussions with parties who have previously expressed an interest in our work with Erk inhibitors."

On July 29, 2015 Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151,"Kyowa Hakko Kirin") and Bristol-Myers Squibb Company (NYSE:BMY, "Bristol-Myers Squibb") reported that the companies have entered into a clinical trial collaboration agreement to conduct a Phase 1/2 combination study with mogamulizumab, an anti-CCR4 antibody and Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor (Press release, Bristol-Myers Squibb, JUL 29, 2015, View Source [SID:1234506746]).

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The study, which will be conducted in the U.S., will focus on evaluating the safety, tolerability and anti-tumor activity of combining mogamulizumab and Opdivo as a potential treatment option for patients with advanced or metastatic solid tumors. Prior to this agreement, Kyowa Hakko Kirin, Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. (Tokyo: 4528) entered into a clinical trial collaboration agreement to study the combination of mogamulizumab and Opdivo in Japan.

Mogamulizumab and Opdivo are part of a new class of cancer treatments known as immunotherapies, which are designed to harness the body’s own immune system in fighting cancer by targeting distinct regulatory components of the immune system.

"We are pleased to conduct a combination study with Bristol-Myers Squibb not only in Japan but also in the U.S.," said Yoichi Sato, Director of the Board Managing Executive Officer, Vice President, Head of Research and Development Division of Kyowa Hakko Kirin. "We believe that the planned combination of these two immunotherapies has the potential to deliver better outcomes in patients with advanced cancers than existing treatments."

"Today’s agreement builds on our initial collaboration with Kyowa Hakko Kirin in Japan, which includes our partner Ono Pharmaceutical Co., Ltd., and is the latest example of our continued commitment to evaluating the potential of combination immuno-oncology regimens for patients with metastatic cancer," stated Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb.

The study will be conducted by Kyowa Hakko Kirin. Additional details of the collaboration were not disclosed.

About Mogamulizumab

Mogamulizumab (Brand name: POTELIGEO) is a novel, humanized mAb directed against CC chemokine receptor type 4 (CCR4). Engineered by Kyowa Hakko Kirin’s unique POTELLIGENT Technology, the antibody is designed to kill its target cells through potent antibody-dependent cellular cytotoxicity. Mogamulizumab was launched in Japan in May 2012 for the treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL). The drug was approved for indication expansion and was granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) in March 2014, and with chemotherapy-native CCR4-positive ATL in December 2014. Clinical trials with mogamulizumab are ongoing in the US, EU and other countries.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) as a monotherapy in two cancer indications. On March 5, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

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.

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]).

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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.