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).

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 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 11, 2015 the U.S. Food and Drug Administration reported that it approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments (Press release, , DEC 11, 2015, View Source [SID:1234508548]).

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"Treating cancer requires not only selecting which drug may be most effective and well tolerated, but ensuring the correct dose is given at proper intervals. While rare, unintentional overdose can occur," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents."

Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal.

Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient’s health care provider will determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.

The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving flourouracil (not due to an overdose). The studies’ primary measure was survival at 30 days or until chemotherapy could resume if prior to 30 days. Of those who were treated with Vistogard for overdose, 97 percent were still alive at 30 days. Of those treated with Vistogard for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days.

Vistogard is not recommended for treating non-emergency adverse reactions associated with flourouracil or capecitabine because Vistogard may lessen the efficacy of these drugs. The safety and efficacy of Vistogard initiated more than 96 hours following the end of treatment with flourouracil or capecitabine have not been established.

The most common side effects of treatment with Vistogard were diarrhea, vomiting and nausea.

The FDA granted Vistogard orphan drug designation, which provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Vistogard was also granted priority review and fast track designations, which are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

Vistogard is marketed by Wellstat Therapeutics Corporation based in Gaithersburg, Maryland.

On December 11, 2015 CEL-SCI Corporation (NYSE MKT: CVM) ("CEL SCI" or the "Company") reported financial results today for the fiscal year ended September 30, 2015 (Press release, Cel-Sci, DEC 11, 2015, View Source [SID:1234508549]). The Company also reported key clinical and corporate developments achieved during and subsequent to fiscal 2015.

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Clinical and Corporate Developments Included:

CEL-SCI raised net proceeds of approximately $21.15 million during fiscal 2015 and an additional $10.6 million subsequent to the end of the fiscal year, to finance its expanding Phase 3 trial in the treatment of head and neck cancer.

During fiscal year 2015 we added 7 countries to our Phase 3 study and we enrolled another 304 patients in the study. This represented a 115% increase in enrollment over fiscal year 2014. We are continuing this trend in the first quarter fiscal 2016.
We had 2 very important corporate developments that suggest our Phase 3 trial is going well and that we have a strong case in our $50+ million arbitration against the former Clinical Research Organization ("CRO"):

In October 2015 Ergomed, the new CRO running our Phase 3 trial, added another $2 million to its existing $10 million investment in our Phase 3 clinical trial, for a total investment of $12 million. Ergomed will receive its funds back only from a successful drug.
Also in October 2015, we signed a funding agreement with Lake Whillans, a firm that specializes in litigation funding. Pursuant to the agreement, CEL-SCI will receive up to $5.0 million in funding for litigation expenses to support arbitration claims against the former CRO. This case is scheduled for "hearing" (trial) in the spring of 2016. Lake Whillans will get its funds back only from the proceeds derived from the arbitration. CEL-SCI now spends $0 on this arbitration.

CEL-SCI expanded the ongoing Phase 1 study with Multikine in HIV/HPV co-infected men and women by adding a another clinical site and a world renowned key opinion leader in the field. Dr. Joel Palefsky of the University of California, San Francisco (UCSF) joined the study in July 2015 as a Principal Investigator. The study is also being conducted under a Cooperative Research and Development Agreement (CRADA) with the U.S. Navy at the San Diego Naval Medical Center.

CEL-SCI reported an operating loss of ($34.30) million in fiscal year 2015 versus an operating loss of ($27.57) million in fiscal year 2014. Of the 2015 fiscal operating loss, the cash used by the company totaled $23.8 million. The legal expenses for the arbitration were $3.6 million and those expenses will not be repeated in 2016 since the company signed an agreement with the litigation funding firm Lake Whillans to fund any remaining arbitration legal fees. This will allow CEL-SCI to focus its expenditures on the Phase 3 trial.

CEL-SCI’s net loss available to common shareholders for the quarter ended June 30, 2015 was ($4,429,137) or ($0.05) per basic share, versus ($2,444,480) or ($0.04) per basic share during the quarter ended June 30, 2014. The net loss available to common shareholders for the nine months ended June 30, 2015 was ($24,830,691) or ($0.32) per basic share, versus ($21,261,925) or ($0.38) per basic share during the same nine months ended June 30, 2014. The increase in net loss for the three and nine month periods of 2015 as compared to the same periods in 2014 was primarily attributable to the increase in operating loss and the non-cash charge for the loss on a debt extinguishment off-set by the gain reported of the non-cash charge for the change in value of derivative instruments caused by a decrease in the Company’s common stock.

The rise in operating loss was largely attributable to an increase in research and development expenses to $20.95 million in fiscal year 2015 compared to $17.0 million in fiscal year 2014. This expense increased based on the additional activity level of the Phase 3 clinical trial, including more clinical centers joining the study and more patients enrolled.

Geert Kersten, CEL-SCI’s Chief Executive Officer said, "We are rapidly enrolling patients in our Phase 3 trial in head and neck cancer and the trial date for our arbitration is near. Both of these efforts are proceeding well, and we look forward to a positive 2016."

About Multikine

Multikine* (Leukocyte Interleukin, Injection) is an investigational immunotherapeutic agent that is being tested in an open-label, randomized, controlled, global pivotal Phase 3 clinical trial as a potential first-line treatment for advanced primary squamous cell carcinoma of the head and neck. Multikine is designed to be a different type of therapy in the fight against cancer: one that appears to have the potential to work with the body’s natural immune system in the fight against tumors.