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.

On July 19, 2017 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that the United States Patent and Trademark Office has issued a notice of allowance for claims related to the Company’s proprietary liposomal delivery and antisense technology, DNAbilize, including its use in the treatment of cancers, autoimmune diseases and infectious diseases (Press release, Bio-Path Holdings, JUL 19, 2017, View Source [SID1234519839]).

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"We are particularly encouraged by the expanding role of our proprietary liposomal delivery and antisense technology as a treatment for a variety of cancers, autoimmune diseases and infectious diseases. This patent further bolsters our intellectual property position and provides us with additional opportunities to build upon this important technology," said Peter H. Nielsen, Chief Executive Officer of Bio-Path Holdings.

The new patent, titled "P-Ethoxy Nucleic Acids for Liposomal Formulation," (based on Application No. 15/294,223) will provide broad protection for application of the DNAbilize technology in the treatment of a variety of cancers, as well as autoimmune and infectious diseases. DNAbilize is a proprietary liposomal delivery and antisense technology, designed to systemically distribute nucleic acid drugs throughout the human body with a simple intravenous transfusion.

On July 19, 2017 Tiziana Life Sciences plc (AIM: TILS), a clinical stage biotechnology company developing targeted drugs for cancer and inflammatory diseases, reported the enrolment of the first patient in its phase IIa clinical trial with milciclib, a novel inhibitor of cyclin-dependent kinases (CDKs), in patients with refractory hepatocellular carcinoma ("HCC") (Press release, Tiziana Life Sciences, JUL 19, 2017, View Source [SID1234519833]). Top line data from this trial, being conducted in Italy, Israel, Greece and Turkey, is expected in Q4 2018. The primary objective of this multi-centre, multi-country and dose-ranging phase IIa clinical study is to evaluate the safety of milciclib in HCC patients who fail to respond to or are intolerant to the existing standard of care treatment. Subsequently, a phase IIb is planned with the combination of milciclib with the standard of care treatment sorafenib in HCC patients.

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Milciclib is an inhibitor of several cyclin-dependent kinases (CDKs), which are commonly overexpressed in tumours resistant to chemotherapy. Accordingly, the investigational therapy will be tested in patients who have failed to respond to the standard of care treatment, sorafenib (NexavarÒ). Preclinical studies conducted strongly suggest that milciclib acts primarily through downregulation of microRNA (miR) 221 and 222, which are known to be associated with hepatocarcinogenesis and overexpression of these miRs is also believed to be associated with development of resistance to sorafenib in HCC patients.

In previous phase I clinical studies, oral treatment with milciclib was found to be safe and well-tolerated in patients with advanced solid tumours such as thymoma and thymic carcinoma, pancreatic carcinoma and colon cancer.1 The combination of milciclib with gemcitabine, a well-known nucleoside analogue, in a phase I dose-escalation study showed favourable clinical responses in approximately 36% of patients with advanced/metastatic tumours, including patients previously considered to be resistant to gemcitabine.2

Gabriele Cerrone, Chairman of Tiziana Life Sciences, commented: "HCC is a real unmet medical need due to its growing incidence and lack of effective therapy. It is the fifth most common cancer worldwide and the second most common cause of death from cancer worldwide."

Kunwar Shailubhai, CEO & CSO of Tiziana Life Sciences, commented: "Oral treatment with milciclib has been well-tolerated in previous studies with cancer patients. We strongly believe, based on its unique mechanism of action, that the drug may have potential to be developed either as a monotherapy or combo-therapy with sorafenib for treatment of HCC."

Dr. Ilan Yaron, Director of the Department of Medicine at Hebrew University Hadassah Medical Center, Israel and Chief Medical Officer of Tiziana Life Sciences, added: "The prognosis for liver cancer is very poor due to lack of effective therapy. We believe that milciclib holds promise as an effective anti-cancer treatment with a high safety profile."

About HCC
Hepatocellular carcinoma is the fifth most common cancer in men and the ninth in women. Additionally, it is the fifth most common cancer worldwide and the second most common cause of death from cancer worldwide.3 The tumour is associated with chronic hepatitis B and chronic hepatitis C infections, as well as with nonalcoholic steatohepatitis. The prognosis for liver cancer is very poor due to lack of effective therapy.

About Milciclib
Milciclib (PHA-848125AC) is a small molecule inhibitor of several cyclin dependent kinases (CDKs) such as CDK1, CDK4, CDK5 and CDK7. CDKs are serine threonine kinases that play crucial roles in progression of the cell cycle from G1 to S phase. Overexpression of CDKs and other downstream signalling pathways that regulate cell cycles have been frequently found to be associated with development of resistance towards chemotherapies. Oral treatment with milciclib was found to be effective in reducing tumour growth in animal models of HCC, possibly through downregulation of miR-221 and miR-222. In a phase I study, oral treatment with milciclib was found to be well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in thymic carcinoma, pancreatic carcinoma and colon cancer.