On December 14, 2015 X4 Pharmaceuticals reported the launch of the company’s development strategy for its pipeline of C-X-C receptor type 4 (CXCR4 inhibitors), including two clinical studies initiating in 2016 in refractory cancers with its lead drug candidate, X4P-001 (Press release, X4 Pharmaceuticals, DEC 14, 2015, View Source [SID:1234508555]). The formation of X4 is based on drug compounds that originate from a portfolio of oral CXCR4 inhibitors exclusively licensed from Sanofi.

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Development of X4’s CXCR4 inhibitors will be funded initially through a $37.5 million Series A financing, which the Company recently closed. Maxim Merchant Capital, a wholly owned division of Maxim Group LLC, served as the sole placement agent for the financing, with Cormorant Asset Management serving as lead investor.

Henri Termeer, the former Chairman, president and CEO of Genzyme, and a founding advisor and investor in X4, stated, "X4 has assembled the expertise, drug assets and strategies to build extraordinary value for its constituents, including the potential to have a significant impact on the treatment of cancer."

X4 will launch multiple clinical studies with X4P-001 in 2016 in advanced cancers, including refractory clear cell renal cell carcinoma (ccRCC) and a second solid tumor indication. A second drug program, X4P-002, which is currently in pre-clinical development, is being optimized for the treatment of brain cancers, and is expected to enter the clinic in 2017. Inhibition of CXCR4, a receptor over-expressed in many cancers, is designed to block non-cancerous immuno-suppressive and pro-angiogenic cells from populating the tumor, thereby disrupting the cancer microenvironment and restoring normal immune surveillance functions. The novel mechanism of CXCR4 inhibition increases the ability of T-Cells to track and destroy cancer.

"CXCR4 inhibition is a novel approach to immunotherapy whose potential we are only beginning to explore for the treatment of cancer," said Keith Flaherty, MD, the director of the Henri and Belinda Termeer Center for Targeted Therapies at the Massachusetts General Hospital and co-founder of X4. "Immune system surveillance is the front line of keeping cancer in check and CXCR4 plays a key role in the trafficking of immunosuppressive cells. Inhibition of this receptor may be beneficial in addressing a broad range of cancers, offering the potential to improve both the magnitude and durability of treatment responses."

The development of X4’s clinical candidates will be led by the company’s seasoned management team and founders, who bring unique experience in the study the CXCR4 pathway. The team is led by Chief Executive Officer Paula Ragan, PhD, who brings more than 15 years of experience in senior leadership roles at biotechnology companies, including Genzyme. Other members of the team include:

Robert Arbeit, MD, Senior Vice President of Clinical Development and Translational Research, who served in leadership roles at Idera Pharmaceuticals, Paratek Pharmaceuticals and Cubist Pharmaceuticals;
Alison Lawton, consulting Chief Operating Officer, who has 30 years of global biopharmaceutical experience, including 21 years at Genzyme where she led the regulatory team for the approval of plerixafor, a CXCR4 inhibitor, in 2008.
Alan Walts, PhD, co-founder of X4 and Interim Chairman, spent over 25 years with Genzyme, where his roles included President of Genzyme Pharmaceuticals, Senior Vice President of Corporate Development, and Managing Director of Genzyme Ventures

"With a strong financial foundation and leadership team in place, X4 is well positioned to bring forward CXCR4 inhibitors as an innovative new immunotherapy treatment approach for a broad spectrum of cancers," said Dr. Ragan. "We look forward to executing on our plans for advancing our CXCR4 pipeline programs, and to seeing the early promise of this approach translate in the clinic."

X4’s scientific founder is Renato Skerlj, PhD, whose work in immune-mediated drug discovery led him to become an inventor of both plerixafor, a stem cell mobilizer approved in 2008, and ertapenem, an anti-bacterial approved in 2001. Dr. Skerlj has over 20 years of pharmaceutical experience in the discovery and development of novel therapies. Most recently, he was the Head of Small Molecule Discovery at Genzyme and prior to joining Genzyme, was part of the executive team at AnorMED, a publicly-traded company acquired by Genzyme for $580 million in 2006.

About X4 Pharmaceuticals
X4 Pharmaceuticals is developing novel therapeutics designed to improve immune cell trafficking and increase the ability for T-Cells to track and destroy cancer cells. The company’s oral small molecule drug candidates inhibit the CXCR4 receptor, a pathway which plays a central role in promoting the immunosuppressive and pro-angiogenic microenvironment of many cancers. X4P-001, the company’s lead program, is expected to enter Phase 1/2 testing in refractory clear cell renal cell carcinoma (ccRCC) and other solid tumor indications, and its second program, X4P-002, is in pre-clinical development for oncology applications. X4 was founded and is led by a team with deep product development and commercialization expertise, including several former members of the Genzyme leadership team, and is located in Cambridge, MA.

On December 14, 2015 CTI BioPharma Corp. (NASDAQ and MTA: CTIC) reported that it has received a $10 million milestone payment from Teva Pharmaceutical Industries Ltd. (Teva) related to the achievement of sales milestones for TRISENOX (arsenic trioxide) (Press release, CTI BioPharma, DEC 13, 2015, View Source;p=RssLanding&cat=news&id=2122140 [SID:1234508566]). TRISENOX was acquired from CTI BioPharma by Cephalon, Inc. (Cephalon). Cephalon was subsequently acquired by Teva. The milestone was paid pursuant to an acquisition agreement for TRISENOX entered into with Cephalon under which CTI BioPharma is eligible to receive up to an additional $70 million in payments upon achievement by Teva of specified sales and development milestones related to TRISENOX.

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On December 13, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the US Food and Drug Administration (FDA) granted accelerated approval to Alecensa (alectinib) for the treatment of people with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Press release, Hoffmann-La Roche , DEC 13, 2015, View Source [SID:1234508556]). In the pivotal studies, Alecensa shrank tumours in up to 44 percent of people with ALK-positive NSCLC who progressed on crizotinib (objective response rate [ORR] of 38 percent [95 percent CI 28-49] and 44 percent [95 percent CI 36-53]).

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In a subset of people with tumours that spread to the brain or other parts of the central nervous system (CNS), Alecensa shrank CNS tumours in about 60 percent of people (CNS ORR of 61 percent [95 percent CI 46-74]).

"Alecensa is now approved as a new option for people with ALK-positive NSCLC who progress on or are intolerant to crizotinib," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "Sixty percent of people enrolled in our studies had tumours that had spread to their central nervous systems, and Alecensa shrank tumours in many people in a subset of patients with CNS disease."

Possible serious side effects with Alecensa include liver problems, lung problems, slow heartbeat, muscle pain, tenderness and weakness. The most common side effects of Alecensa include tiredness, constipation and swelling in the hands, feet, ankles and eyelids.

The FDA’s Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious condition based on early evidence suggesting clinical benefit. The indication for Alecensa is approved under accelerated approval based on tumour response rate and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

In addition, Alecensa is being studied for use as an initial (first-line) treatment for people with advanced ALK-positive NSCLC. ALEX is a global, randomised phase III study comparing Alecensa to crizotinib as an initial treatment for people with advanced NSCLC whose tumours were characterised as ALK-positive by a companion VENTANA ALK (D5F3) CDx Assay immunohistochemistry (IHC) test developed by Roche Diagnostics. This study is part of the company’s commitment to convert the current accelerated approval in people with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib to a full approval as an initial treatment.

About NP28761 (Study 1) and NP28673 (Study 2)
Study 1 is a phase II North American, single-arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa (600 mg orally twice daily) in 87 people with ALK-positive NSCLC whose disease progressed on crizotinib. Study 2 is a phase I/II global, single-arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa (600 mg orally twice daily) in 138 people with ALK-positive NSCLC whose disease progressed on crizotinib. People in the phase II studies received 600 mg of Alecensa orally twice daily. In both trials, the primary endpoint was ORR according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1), as evaluated by an Independent Review Committee (IRC). Secondary endpoints included DOR and efficacy against disease that had spread to the CNS (CNS ORR and CNS DOR). A summary of the efficacy and safety data from both studies that support this approval is included below.

The most common Grade 3 or higher adverse events in the pooled analysis of both studies were an increase in muscle enzymes (creatine phosphokinase; 4.6 percent), shortness of breath (dyspnea; 3.6 percent), increased liver enzymes (aspartate transaminase; 3.6 percent, and alanine transaminase; 4.8 percent), evidence of liver dysfunction (hyperbilirubinemia; 2.4 percent), increased blood glucose (hyperglycemia; 2 percent), decreased levels of minerals (hypokalemia; 4 percent, hypophosphatemia; 2.8 percent, and hyponatremia; 2 percent), decreased red blood cells (anemia; 2 percent) and decreased white blood cells (lymphopenia; 4.6 percent).

About Alecensa
Alecensa (RG7853/AF-802/RO5424802/CH5424802) is an investigational oral medicine created at Chugai and is being developed for people with NSCLC whose tumours are identified as ALK+. ALK+ NSCLC is often found in younger people who have a light or non-smoking history. It is almost always found in people with a specific type of NSCLC called adenocarcinoma.

Early studies with Alecensa have shown activity on brain metastases, indicating that the drug may be taken up in the brain. The brain is protected by the Blood-Brain Barrier, a network of tightly joined cells that line the inside of the blood vessels in the brain and spinal cord. One of the ways the Blood-Brain Barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as ‘active efflux’. The active efflux system does not recognise Alecensa, which means that it may travel into and throughout brain tissue.

The Global phase III studies of Alecensa include a companion test developed by Roche. Alecensa is marketed in Japan by Chugai Pharmaceutical, a member of the Roche Group.

On December 14, 2015 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that Genentech Inc., a member of the Roche Group, obtained approval from the U.S. Food and Drug Administration (FDA), for the anti-cancer agent, alectinib hydrochloride (brand name: Alecensa) for the indication of "anaplastic lymphoma kinase (ALK) positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or those intolerant to crizotinib (Press release, Chugai, DEC 13, 2015, View Source [SID:1234508554])."

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"Alecensa was created by Chugai and in July 2014, Japan became the first country in the World to receive approval. We believe that the FDA’s priority review of Alecensa will bring fresh hope for patients in the US living with this disease." said Chugai’s Director and Executive Vice President, Dr. Yutaka Tanaka. "We are extremely pleased that Alecensa can contribute to the treatment of patients with ALK positive NSCLC."

Alecensa was granted Breakthrough Therapy Designation by FDA in June 2013 for patients with ALK positive NSCLC who have progressed on crizotinib. And FDA also granted priority review for Alecensa in September 2015.

The FDA’s Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious condition based on early evidence suggesting clinical benefit. The indication for Alecensa is approved under accelerated approval based on tumour response rate and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ALEX is a global, randomized phase III study comparing Alecensa to crizotinib as an initial treatment for people with advanced ALK-positive NSCLC. This study is part of the company’s commitment to convert the current accelerated approval in people with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib to a full approval as an initial treatment.

Alecensa is a highly selective ALK inhibitor created by Chugai. It has been reported that 2 to 5 percent of patients with NSCLC express a chromosomal rearrangement which leads to fusion of the ALK gene with another gene1. ALK kinase signaling is constantly active in cells with such fusion genes, resulting in uncontrolled growth of tumor cells and transforming the cells into tumor cells2, 3. Alecensa exerts its anti-tumor effect by selectively inhibiting ALK kinase activity to inhibit tumor cell proliferation and induce cell death4. In addition, Alecensa is not recognized by the transporter proteins in the blood brain barrier that actively pump molecules out of the brain. Alectinib is active in the central nervous system and has proven activity against brain metastases.

In Europe, Roche filed the NDA to the European Medicines Agency for the approval of "ALK fusion gene positive unresectable, recurrent/advanced NSCLC" in September 2015. Chugai has out-licensed the rights of Alecensa to Roche in overseas countries including Europe and the US.

In Japan, Alecensa capsule 20mg, 40mg and 150mg is available to patients with "ALK fusion gene positive unresectable, recurrent/advanced NSCLC" and is marketed by Chugai.

1) Biomarker committee of The Japan Lung Cancer Society, Guidelines for ALK gene tests in lung cancer patients
2) Soda et al., Nature. 448: 561-566 (2007)
3) Takeuchi et al., Clin Cancer Res. 15: 3143-3149 (2009)
4) Sakamoto et al., Cancer Cell. 19: 679-690 (2011)

Overview of two pivotal clinical phase I/II trials based on the U.S. approval

The NP28761 study is a phase I/II North American, single arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa in 87 people with ALK positive NSCLC whose disease progressed on crizotinib. (Data cut-off: October 24, 2014)
The NP28673 study is a phase I/II global, single arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa in 138 people with ALK positive NSCLC whose disease progressed on crizotinib. (Data cut-off: primary data cut-off including safety: August 18, 2014, updated IRC data cut-off: January 8, 2015)
People in the phase II studies received 600 mg of Alecensa orally twice daily. In both trials, the primary endpoint was ORR according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1), and evaluated by an Independent Review Committee (IRC). Secondary endpoints included DOR and efficacy against disease that had spread to the CNS (CNS ORR and CNS DOR).

The most common Grade 3 or higher adverse events in the pooled analysis of both studies were an increase in muscle enzymes (creatine phosphokinase; 4.6 percent), shortness of breath (dyspnea; 3.6 percent), increased liver enzymes (aspartate transaminase; 3.6 percent, and alanine transaminase; 4.8 percent), evidence of liver dysfunction (hyperbilirubinemia; 2.4 percent), increased blood glucose (hyperglycemia; 2 percent), decreased levels of minerals (hypokalemia; 4 percent, hypophosphatemia; 2.8 percent, and hyponatremia; 2 percent), decreased red blood cells (anemia; 2 percent) and decreased white blood cells (lymphopenia; 4.6 percent).