On July 20, 2017 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the U.S. Food and Drug Administration (FDA) granted orphan-drug designation to gilteritinib in patients with acute myeloid leukemia (AML) (Press release, Astellas, JUL 20, 2017, View Source [SID1234519842]). The Orphan Drug Designation program assigns status to drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of diseases or disorders that affect fewer than 200,000 people in the United States.

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"Fewer than 10,000 Americans will be diagnosed with FLT3 mutation-positive AML this year and while that may be a small percentage of the overall population, it is an important group of patients who are deserving of potential new treatments," said Steven Benner, M.D., senior vice president and global therapeutic area head, oncology development, Astellas. "We are grateful to the FDA for acknowledging the unique needs of rare diseases and for providing a path forward for gilteritinib in supporting these patients."

Gilteritinib is a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML. AML is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the American Cancer Society, in 2016 there were an estimated 21,000 new cases of AML diagnosed in the United States and about 10,600 cases resulted in death.

Astellas is currently investigating gilteritinib in various AML patient populations through several planned and already initiated Phase 3 trials, including the registrational ADMIRAL trial in relapsed/refractory FLT3+ AML.

The safety and efficacy of the agent discussed herein are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated. Information about pharmaceutical products (including products currently in development) which is included in this press release are not intended to constitute an advertisement or medical advice.

On July 20, 2017 Aptevo Therapeutics Inc. (Nasdaq:APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics, and Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy, reported that they have entered into an agreement to co-develop a novel immunotherapy bispecific antibody candidate, ALG (Press release, Aptevo Therapeutics, JUL 20, 2017, View Source [SID1234519840]).APV-527, based on Alligator’s first generation bispecific antibody, ATOR-1016. The new bispecific candidate was developed using Aptevo’s bispecific technology platform and includes proprietary binding elements generated by Alligator’s ALLIGATOR-GOLD antibody library. Initiation of cell line development for the manufacturing of clinical material is expected to begin shortly.

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Working under a previously executed material transfer agreement, the companies have engineered and selected ALG.APV-527 as a lead bispecific antibody candidate, featuring a novel mechanism of action targeting 4-1BB, a member of the TNFR superfamily of co-stimulatory receptors found on activated T cells, and an undisclosed tumor antigen widely overexpressed in a number of different types of cancer.

Under the terms of the agreement, the parties will jointly own and share equally in the development costs associated with advancing this candidate through to the end of Phase 2 clinical development. At that time, the parties may opt to out-license the candidate or continue further development separately or in partnership. In addition, the agreement provides an option for the companies to develop a second bispecific antibody candidate based on this novel mechanism of action, which would also be jointly owned and funded by Aptevo and Alligator.

The co-stimulatory receptor 4-1BB is known to play an important role in modulating and augmenting the immune response to cancer by promoting the activation, expansion and enhanced effector function of tumor-specific T cells. It is, therefore, an especially promising target for new immunotherapeutic approaches for cancer treatment. If successfully developed, this new bispecific antibody candidate could have utility in the potential treatment of a broad spectrum of cancers including breast, cervical, non-small-cell-lung, prostate, renal, gastric, colorectal and bladder cancers. While this tumor antigen is widely expressed in multiple types of solid tumors, it shows limited expression on normal tissues, suggesting the potential for tumor-directed immunotherapy with improved efficacy and fewer side effects.

"Our collaboration with Alligator Bioscience has unlocked tremendous synergies, enabling us to capitalize on our companies’ respective expertise in therapeutic antibody engineering," said Marvin L. White, President and Chief Executive Officer of Aptevo. "The addition of a 4-1BB bispecific candidate expands and diversifies Aptevo’s portfolio while demonstrating the flexibility of our ADAPTIR platform in addressing novel mechanisms of action, in addition to redirected T-cell cytotoxicity. Also, importantly, it allows us to pursue an exciting new therapeutic opportunity with broad potential application in the treatment of non-hematological cancers. If proven successful, this new approach would be a significant advance in cancer immunotherapy. We’re extremely pleased to collaborate with Alligator Bioscience in the development of novel tumor-targeting bispecific antibody therapies."

"With five immuno-oncology programs currently in development, each with first- or best-in-class potential, this partnership with Aptevo allows us to further build on the promise of bispecific therapeutics for tumor-directed immunotherapy," said Per Norlén, Chief Executive Officer of Alligator Bioscience. "Our technology platform enables the generation of highly functional antibodies with optimal stability and manufacturing properties, merged into an exceptional bispecific antibody using Aptevo´s ADAPTIR platform. We look forward to advancing our collaboration with Aptevo on this promising new therapeutic approach."

On July 20, 2017 Diffusion Pharmaceuticals Inc. (NASDAQ:DFFN), a clinical stage biotechnology company developing novel small molecule therapeutics for cancer and other hypoxia-related diseases, reported the completion of a major production run of its lead drug candidate trans sodium crocetinate (TSC) (Press release, Diffusion Pharmaceuticals, JUL 20, 2017, View Source [SID1234519838]). This drug supply will be used in its planned Phase 3 trial which will test TSC in the treatment of newly diagnosed inoperable glioblastoma (GBM) brain cancer patients and is of sufficient quantity to support the entire trial. Diffusion plans to initiate this clinical trial by the end of 2017.

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"Diffusion has reached an important milestone for initiating the Phase 3 trial with this successful manufacture of Phase 3-ready TSC," said David Kalergis, Diffusion’s Chairman and CEO. "In its End-of-Phase-2-Meeting response, the FDA required that any TSC used in upcoming Phase 3 studies must be made using commercially-ready processes, both for the active pharmaceutical ingredient (API) and formulated drug product. The necessary advanced production and formulation processes were implemented over the last eighteen months and were cleared with the FDA in June, immediately prior to the successful clinical trial supply production run earlier this month."

Diffusion is now interacting with the FDA on details regarding the design and execution of the planned Phase 3 study, with initiation planned for later this year. The study will focus on newly diagnosed GBM patients who have been judged by their medical team to be inoperable, usually because of the size or location of the tumor. Because of their poor prognosis, these patients are often excluded from participation in other GBM clinical trials. In the Company’s Phase 2 GBM study, the TSC-treated group showed a nearly four-fold increase in survival at two years, when compared to the historical controls.

On July 20, 2017 Exelixis, Inc. (NASDAQ:EXEL) reported a settlement of the company’s dispute with Genentech, a member of the Roche Group, concerning the parties’ collaboration for the development and commercialization of cobimetinib, which is marketed as COTELLIC (Press release, Exelixis, JUL 20, 2017, View Source [SID1234519837]). Effective July 1, 2017, as part of the settlement the companies entered into an amendment (the "Amendment") to the existing Collaboration Agreement, dated December 22, 2006, to revise the revenue and cost-sharing arrangements for the collaboration. The Amendment resolves the companies’ dispute pursuant to the arbitration demand filed on June 3, 2016, and aligns both companies’ interests in advancing cobimetinib as a promising therapy for patients with multiple forms of cancer.

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The Amendment applies to COTELLIC’s initial commercial application in combination with ZELBORAF (vemurafenib), as well as future commercial uses of COTELLIC, alone or in combination. Under its terms, Exelixis continues to be entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase as specified in the original 2006 agreement. However, effective as of July 1, 2017, the revenue applied to the profit and loss statement for the COTELLIC collaboration ("the Collaboration P&L") will be calculated using the average of the quarterly net selling prices of COTELLIC and any additional branded Genentech product(s) prescribed with COTELLIC. Exelixis will continue to share U.S. commercialization costs, while Genentech’s portion of these costs will now be allocated to the Collaboration P&L based on the number of products in the combination. Exelixis will continue to co-promote COTELLIC in the U.S., providing up to 25 percent of the U.S. sales force. Outside of the U.S., Exelixis remains eligible for royalties on COTELLIC sales according to the terms of the original 2006 agreement.

"The settlement and revised revenue and commercial cost-sharing arrangements lay the groundwork for our continued work together to maximize cobimetinib’s potential to help patients," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "Since signing our collaboration agreement with Genentech more than ten years ago, cobimetinib has advanced from our discovery and early clinical efforts into Genentech’s global clinical development organization – where it is now the subject of three ongoing or planned pivotal trials – and into commercial use around the world. With this new framework in place, we look forward to continuing our collaborative efforts with Genentech to maximize this promising medicine’s impact on the treatment of cancer."

Genentech has been responsible for cobimetinib’s clinical development since it opted to further develop the compound following Exelixis’ determination of a maximum tolerated dose in phase 1 clinical trials. Since then, Genentech has undertaken a clinical development program focused on evaluating cobimetinib’s potential in combination with investigational and approved therapies. This program includes three phase 3 pivotal trials: IMblaze370, an ongoing and fully enrolled study evaluating cobimetinib and atezolizumab in third-line advanced or metastatic colorectal cancer; IMspire150 TRILOGY, an ongoing trial evaluating the combination of cobimetinib, atezolizumab and vemurafenib in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable locally advanced melanoma; and IMspire170, a planned study evaluating cobimetinib plus atezolizumab in patients with previously untreated BRAF wild-type metastatic or unresectable locally advanced melanoma expected to start in the third quarter of this year.

About the Cobimetinib Development Collaboration
Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib.

Under the terms of the collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares U.S. commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and fields 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.
Cobimetinib is now approved in multiple countries, including the U.S., European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. The trade name for cobimetinib is COTELLIC. Cobimetinib is also the subject of a clinical development program aimed at evaluating its potential in combination with a variety of investigational and approved therapies in disease settings including metastatic melanoma, triple-negative breast cancer and colorectal carcinoma.
Important: If a patient’s healthcare provider prescribes ZELBORAF (vemurafenib), the patient should also read the Medication Guide that comes with ZELBORAF.
COTELLIC Indication
COTELLIC is a prescription medicine that is used with the medicine ZELBORAF to treat a type of skin cancer called melanoma:
that has spread to other parts of the body or cannot be removed by surgery, and
that has a certain type of abnormal "BRAF" gene.
A patient’s healthcare provider will perform a test to make sure that COTELLIC is right for the patient. It is not known if COTELLIC is safe and effective in children under 18 years of age.
Important Safety Information
Before taking COTELLIC, patients should tell their healthcare provider about all of their medical conditions, including if they:
have skin problems or history of skin problems, other than melanoma
have bleeding problems, any medical conditions and/or on any medications that increase the risk of bleeding
have heart problems
have eye problems
have liver problems
have muscle problems
are pregnant or plan to become pregnant. COTELLIC and ZELBORAF can harm an unborn baby.
Females who are able to become pregnant should use effective birth control during treatment with COTELLIC, and for two weeks after the final dose of COTELLIC.
Patients should talk to their healthcare provider about birth control methods that may be right for them.
Patients should tell their healthcare provider right away if they become pregnant or think they are pregnant during treatment with COTELLIC and ZELBORAF.
are breastfeeding or plan to breastfeed. It is not known if COTELLIC passes into breast milk. Patients should not breastfeed during treatment with COTELLIC and for two weeks after the final dose. Patients should talk to their healthcare provider about the best way to feed their baby during this time.
Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Certain medicines may affect the blood levels of COTELLIC.
Patients should know the medicines they take and keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.
How should patients take COTELLIC?
Patients should take COTELLIC exactly as their healthcare provider tells them. Patients should not change their dose or stop taking COTELLIC unless their healthcare provider tells them to.
Patients should take COTELLIC one time a day for 21 days, followed by seven days off treatment, to complete a 28-day treatment cycle.
Patients can take COTELLIC with or without food.
If a patient misses a dose of COTELLIC or vomits after taking their dose, they should take their next dose as scheduled.
What should patients avoid during treatment with COTELLIC?
Patients should avoid sunlight during treatment with COTELLIC. COTELLIC can make a patient’s skin sensitive to sunlight. They may burn more easily and get severe sunburns. To help protect against sunburn:
When a patient goes outside, they should wear clothes that protect their skin, including their head, face, hands, arms and legs.
They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
What are the possible side effects of COTELLIC?
COTELLIC may cause serious side effects, including:
Risk of new skin cancers. COTELLIC may cause new skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma or basal cell carcinoma).
Patients should check their skin regularly and tell their healthcare provider right away if they have any skin changes including:
new wart
skin sore or reddish bump that bleeds or does not heal
change in size or color of a mole
A patient’s healthcare provider should check the patient’s skin before they start taking COTELLIC, and every two months during treatment with COTELLIC. A patient’s healthcare provider may continue to check the patient’s skin for six months after the patient stops taking COTELLIC. A patient’s healthcare provider should also check for cancers that may not occur on the skin. Patients should tell their healthcare provider about any new symptoms that develop during treatment with COTELLIC.
Bleeding problems. COTELLIC can cause serious bleeding problems.
Patients should call their healthcare provider and get medical attention right away if they get any signs of bleeding, including:
• red or black stools (looks like tar)

• stomach (abdominal) pain
• blood in their urine
• unusual vaginal bleeding
• headaches
• dizziness or weakness
• cough up or vomit blood

Heart problems. A patient’s healthcare provider should do tests before and during treatment to check the patient’s heart function. Patients should tell their healthcare provider if they get any of these signs and symptoms of heart problems:
• persistent coughing or wheezing

• tiredness
• shortness of breath
• increased heart rate
• swelling of their ankles and feet

Severe rash. Patients should tell their healthcare provider right away if they get any of these symptoms:
• a rash that covers a large area of their body
• blisters
• peeling skin

Eye problems. Patients should tell their healthcare provider right away if they get any of these symptoms:
• blurred vision

• see halos
• partly missing vision or loss of vision
• any other vision changes

A patient’s healthcare provider should check the patient’s eyes if the patient notices any of the symptoms above.
Liver problems. A patient’s healthcare provider should do blood tests to check the patient’s liver function before and during treatment. Patients should tell their healthcare provider right away if they get any of these symptoms:
• yellowing of their skin or the white of their eyes

• feeling tired or weak
• dark or brown (tea color) urine
• loss of appetite
• nausea or vomiting

Muscle problems (rhabdomyolysis). COTELLIC can cause muscle problems that can be severe. Treatment with COTELLIC may increase the level of an enzyme in the blood called creatine phosphokinase (CPK) and may be a sign of muscle damage. A patient’s healthcare provider should do a blood test to check the patient’s levels of CPK before and during treatment. Patients should tell their healthcare provider right away if they get any of these symptoms:
• muscle aches or pain

• dark, reddish urine
• muscle spasms and weakness

Skin sensitivity to sunlight (photosensitivity). Skin sensitivity to sunlight during treatment with COTELLIC is common and can sometimes be severe. Patients should tell their healthcare provider if they get any of these symptoms:
• red, painful, itchy skin that is hot to touch

• bumps or tiny papules
• sun rash
• thickened, dry, wrinkled skin
• skin irritation

See "What should patients avoid during treatment with COTELLIC?" for information on protecting the skin during treatment with COTELLIC.
The most common side effects of COTELLIC include:
• diarrhea

• vomiting
• nausea
• sunburn or sun sensitivity
• fever

A patient’s healthcare provider will take blood tests during treatment with COTELLIC. The most common changes to blood tests include:
increased blood levels of liver enzymes (GGT, ALT or AST)
increased blood level of enzyme from muscle (creatine phosphokinase)
decreased blood level of phosphate, sodium or potassium
increased blood level of liver or bone enzyme (alkaline phosphatase)
decreased blood level of a type of white blood cell (lymphocyte)
Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away. These are not all the possible side effects of COTELLIC.
Patients should call their doctor for medical advice about side effects. Patients may report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. Patients may also report side effects to Genentech at (888) 835-2555.
Please see Full COTELLIC Prescribing Information and Patient Information for additional Important Safety Information at www.cotellic.com.

On July 20, 2017 Kite Pharma, Inc. (Nasdaq:KITE), a leading cell therapy company, reported the recent online publication of results in Molecular Therapy from a National Cancer Institute (NCI) study of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive NHL including diffuse large B-cell lymphoma (DLBCL) (Press release, Kite Pharma, JUL 20, 2017, View Source [SID1234519835]). The research, led by James N. Kochenderfer, M.D., an Investigator in the Experimental Transplantation and Immunology Branch of the NCI Center for Cancer Research, and Steven A. Rosenberg, M.D., Ph.D., Chief of the Surgery Branch at NCI’s Center for Cancer Research, was performed pursuant to a Cooperative Research and Development Agreement (CRADA) between NCI and Kite.

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This work follows previously published data in the February 2015 issue of the Journal of Clinical Oncology in which nine patients with chemorefractory aggressive NHL were treated with a single dose of anti-CD19 CAR T cells with a CD28 co-stimulatory domain. Seven of the 9 patients were evaluable for response. Complete remissions (CR) were observed in 5 of the 7 evaluable patients. Four of the 5 CRs are ongoing from 38 to 56+ months after treatment. There were no chronic toxicities attributable to CAR T cells except B-cell aplasia and hypogammaglobulinemia. Importantly, 3 of 4 patients in ongoing CR had recovery of normal polyclonal B cells, showing that durable CRs can be maintained in the absence of continued activity of anti-CD19 CAR T cells.

"We are encouraged to see durable CRs ongoing for more than 3 years, which raises a possibility of cure, from a single infusion of anti-CD19 CAR T cells in patients with chemorefractory DLBCL, a population that previously had no curative treatment options. This study helps us to understand the long-term potential for this anti-CD19 CAR T cell therapy (axicabtagene ciloleucel) in the larger aggressive NHL patient population," said David Chang, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Kite.