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Merck Receives Accelerated Approval of KEYTRUDA® (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy

On September 4, 2014 Merck reported that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA (pembrolizumab) at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor (Press release Merck & Co, SEP 4, 2014, View Source [SID:1234500721]). This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is the first anti-PD-1 (programmed death receptor-1) therapy approved in the United States and received FDA’s Breakthrough Therapy designation for advanced melanoma, which was granted based on the significance of early study findings and the unmet medical need. For the recommended 2 mg/kg dose based on data in 89 patients, the overall response rate was 24 percent (95% CI: 15, 34), with one complete response and 20 partial responses (21/89). At the time of analysis, 86 percent (18/21) of patients with objective responses had ongoing responses with durations ranging from 1.4+ to 8.5+ months, including eight patients with ongoing responses of 6 months or longer. Fourteen percent (3/21) had progression of disease 2.8, 2.9, and 8.2 months after initial response.

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells. Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated adverse reactions and use in pregnancy, see "Selected Important Safety Information" below.

"KEYTRUDA embodies Merck’s unwavering commitment to pursue breakthrough science to help people who are facing the most challenging diseases," said Kenneth C. Frazier, chairman and chief executive officer, Merck. "We are grateful to the people with advanced melanoma who participated in our trials, and the scientific and medical community for the shared effort that has led to the accelerated approval of KEYTRUDA."

"The accelerated FDA approval of KEYTRUDA is a meaningful development for patients with advanced melanoma," said Dr. Omid Hamid, Director of the Melanoma Center at The Angeles Clinic and Research Institute, and a principal investigator for the pembrolizumab melanoma clinical program. "Our new ability to target the PD-1 pathway with KEYTRUDA is a very exciting step in the immunotherapy field."

Merck is conducting ongoing Phase 2 and 3 clinical studies in advanced melanoma, which are designed to provide further confirmatory evidence for KEYTRUDA in this indication. Merck plans to make KEYTRUDA available within one week from today’s FDA approval.

ADHEREX ANNOUNCES SHARE CONSOLIDATION, NAME CHANGE AND TRADING SYMBOL CHANGE

On September 3, 2014 Adherex Technologies Inc. (TSX: AHX; OTC: ADHXF) (the "Company") reported that it gave effect to the consolidation of its outstanding share capital on the basis of one new security for every three outstanding securities (the "Consolidation") (Press release, Fennec Pharmaceuticals, SEP 3, 2014, View Source [SID:1234510425]). In addition, the Company filed a Notice of Alteration with the British Columbia Registrar of Companies changing the name of the Company from Adherex Technologies Inc. to Fennec Pharmaceuticals Inc. to better reflect its current business focus and activities (the "Name Change"). The Company’s Common Shares post-Consolidation will trade on the TSX Exchange under a new trading symbol: FRX.

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The Consolidation will reduce the number the Company’s outstanding common shares (the "Common Shares") from approximately 29.6 million (as last reported in the Company’s most recent Quarterly Report on Form 10-Q), to approximately 9.9 million. Furthermore, as a result of the Consolidation, Adherex’s outstanding common share purchase warrants will be exercisable as follows: (i) with respect to the warrants issued by the Company on or about April 30, 2010 and March 29, 2011 and not tendered as part of the warrant exchange completed on July 29, 2014 (the "Warrant Exchange"), each 54 warrants will entitle the holder to purchase one Common Share at an exercise price of CAD$4.32, (ii) with respect to the warrants that were exchanged in connection with the Warrant Exchange, each three warrants will entitle the holder to purchase one Common Share at an exercise price of USD$1.50, and (iii) with respect to the warrants issued on November 22, 2013, each three warrants will entitle the holder to purchase one Common Share at an exercise price of USD$1.50.

All materials necessary to effect the Consolidation and the Name Change are expected be filed with the Toronto Stock Exchange (the "TSX") today and, subject to TSX approval, it is expected that the Common Shares will commence trading on the TSX under the new name and "FRX" trading symbol, as well as on a Consolidated basis on or about September 5, 2014. Letters of transmittal providing for the exchange of certificates representing pre-Consolidation Common Shares for certificates representing post-Consolidation Common Shares were mailed to registered shareholders today. Any pre-Consolidation Common Shares owned by beneficial holders and any outstanding warrants will automatically be adjusted as a result of the Consolidation and the Name Change and no further action is required to be taken by such shareholders or warrantholders.

Halozyme’s PEGPH20 Program In Metastatic Pancreatic Cancer Receives Fast Track Designation

On September 3, 2014 Halozyme Therapeutics reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for Halozyme’s program investigating PEGPH20 (PEGylated recombinant human hyaluronidase) in combination with gemcitabine and nab-paclitaxel for the treatment of patients with metastatic pancreatic cancer to demonstrate an improvement in overall survival (Press release Halozyme, SEP 3, 2014, View Source [SID:1234500722]). The Fast Track designation process was developed by the FDA to facilitate the development, and expedite the review of drugs to treat serious or life-threatening diseases and address unmet medical needs.

“The FDA’s Fast Track designation for our PEGPH20 program in pancreatic cancer underscores the significant need for new treatment options for pancreatic cancer patients with advanced disease,” stated Dr. Helen Torley, President and Chief Executive Officer. “We look forward to continuing to work with the FDA on this program to explore whether patients with metastatic pancreatic cancer can benefit from this therapy.”

The Fast Track Drug Development Program was established under the FDA Modernization Act of 1997. The program is designed to facilitate frequent interactions with the FDA review team to expedite clinical development and submission of a Biologic License Application (BLA) for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs. Specifically, Fast Track designation facilitates meetings to discuss all aspects of development to support approval. It also provides the opportunity to submit sections of a BLA on a rolling basis as data become available. This permits the FDA to review portions of the BLA as they are received instead of waiting for the entire BLA submission.

Infinity and AbbVie Announce Global Strategic Collaboration to Develop and Commercialize Duvelisib (IPI-145) In Oncology

On September 3, 2014 Infinity Pharmaceuticals and AbbVie reported that they have entered into a global collaboration to develop and commercialize duvelisib (IPI-145), Infinity’s oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, for the treatment of patients with cancer (Press release Infinity Pharmaceuticals, SEP 3, 2014, View Source [SID:1234500720]). Duvelisib has shown clinical activity across a broad range of blood cancers, including indolent non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia (CLL). Infinity is conducting registration-focused trials evaluating the safety and efficacy of duvelisib, including DYNAMOTM, a Phase 2 study in patients with iNHL, and DUOTM, a Phase 3 study in patients with CLL.

Under the terms of the agreement, Infinity will receive an upfront payment of $275 million and is eligible to receive up to $530 million in additional payments for the achievement of development, regulatory and commercial milestones, including up to $405 million for the achievement of milestones through the first commercial sale of duvelisib. In the U.S., the companies will jointly commercialize duvelisib and will share equally in any potential profits. Outside the U.S., AbbVie will be responsible for the conduct and funding of commercialization of duvelisib, and Infinity is eligible to receive tiered double-digit royalties on net product sales.

“We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers,” said Michael Severino, M.D., AbbVie executive vice president and chief scientific officer. “The addition of duvelisib will complement AbbVie’s emerging oncology pipeline and expand our research into combination therapies to generate improved outcomes for cancer patients. We look forward to working with Infinity to bring duvelisib to patients worldwide.”

“This collaboration is an important step toward fulfilling Infinity’s objective of bringing better treatments to patients and further advances our goal of building a sustainable, fully integrated biotechnology company,” stated Adelene Q. Perkins, chair, president and chief executive officer at Infinity. “AbbVie will be a wonderful partner for Infinity, bringing all of the expertise and scale of a successful, well established company, together with the energy, drive, innovation, and nimbleness of a young organization. We look forward to advancing duvelisib through monotherapy studies designed to enable registration and in furthering our shared longer-term vision of combining duvelisib with both current standards of care and novel, targeted therapies.”

Additional Details About the Collaboration
Development and commercialization activities under the collaboration will be managed through a shared governance structure. In the U.S., Infinity and AbbVie will jointly commercialize duvelisib, assuming regulatory approval, with Infinity booking sales, and will share equally in any potential profits or losses. Outside the U.S., AbbVie will be responsible for conducting and funding of any commercialization of duvelisib, and Infinity is eligible to receive tiered royalties on net product sales, with percentages ranging from 23.5 percent to 30.5 percent.

For sales of duvelisib in the U.S., AbbVie and Infinity will share equally the existing royalty obligations to Mundipharma International Corporation Limited/Purdue Pharmaceutical Products L.P., and Infinity will be responsible for these royalty obligations outside of the U.S. Infinity will also be responsible for the existing royalty obligations to Millennium: The Takeda Oncology Company for sales of duvelisib worldwide.

As part of the strategic collaboration, the companies will share responsibility for the conduct of specific trials specified within an agreed-upon global development plan, with each company leading the development of certain trials within the plan. For the initial global development plan agreed to by the companies, Infinity will fund the trials it conducts and the companies will share equally the funding of trials conducted by AbbVie. The agreement includes plans to launch multiple Phase 2 and Phase 3 studies of duvelisib in hematologic malignancies over the next several years.

Conference Call Today at 8:30 a.m. ET/7:30 a.m. CT
Infinity will hold a conference call at 8:30 a.m. to discuss the strategic collaboration announced today. A live webcast of the conference call can be accessed in the Investors/Media section of Infinity’s website at www.infi.com. To participate in the conference call, please dial (877) 316-5293 (domestic) and (631) 291-4526 (international) five minutes prior to start time. The conference ID number is 97402440. An archived version of the webcast will be available on Infinity’s website for 30 days.

About the Development of Duvelisib for the Treatment of Blood Cancers
Infinity and AbbVie are developing duvelisib, an oral inhibitor of Class I PI3K-delta,gamma. The PI3Ks are a family of enzymes involved in multiple cellular functions, including cell proliferation and survival, cell differentiation, cell migration and immunity. The PI3K-delta,gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and mostly non-overlapping roles in immune cell development and function. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of hematologic malignancies.

In 2013, Infinity launched the DUETTSTM (Duvelisib Trials in Hematologic Malignancies) program, a worldwide investigation of duvelisib in blood cancers. As part of the DUETTS program, patient enrollment is ongoing in DYNAMOTM, a Phase 2 monotherapy study designed to evaluate the safety and efficacy of duvelisib in patients with refractory indolent non-Hodgkin lymphoma (iNHL) (ClinicalTrials.gov Identifier NCT01882803), and DUOTM, a Phase 3 monotherapy study designed to evaluate the safety and efficacy of duvelisib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) (NCT02004522). DYNAMO+RTM, a Phase 3 study of duvelisib in combination with rituximab in patients with previously treated follicular lymphoma (NCT02204982), is expected to start in 2014.

Additionally, a Phase 1 study of duvelisib in patients with advanced blood cancers is ongoing (NCT01476657).

Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite.

1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ945) is a small molecule inhibitor of CSF-1R kinase activity within osteoclasts designed to prevent skeletal related events in metastatic disease. Key metabolites were enzymatically and structurally characterized to understand the metabolic fate of BLZ945 and pharmacological implications. The relative intrinsic clearances for metabolites were derived from in vitro studies using human hepatocytes, microsomes and phenotyped with recombinant P450 enzymes. 2. Formation of a pharmacologically active metabolite (M9) was observed in human hepatocytes. The M9 metabolite is a structural isomer (diastereomer) of BLZ945 and is about 4-fold less potent. This isomer was enzymatically formed via P450 oxidation of the BLZ945 hydroxyl group, followed by aldo-keto reduction to the alcohol (M9). 3. Two reaction phenotyping approaches based on fractional clearances were applied to BLZ945 using hepatocytes and liver microsomes. The fraction metabolized (fm) or contribution ratio was determined for each metabolic reaction type (oxidation, glucuronidation or isomerization) as well as for each metabolite. The results quantitatively illustrate contribution ratios of the involved enzymes and pathways, e.g. the isomerization to metabolite M9 accounted for 24% intrinsic clearance in human hepatocytes. In summary, contribution ratios for the Phase I and Phase II pathways can be determined in hepatocytes.