On August 17, 2018 Tolero Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company focused on developing treatments for hematologic and oncologic diseases, reported that it has entered into a clinical research collaboration with AbbVie, a research-based global biopharmaceutical company, exploring the potential of combination therapy with AbbVie’s venetoclax and Tolero’s investigational agent, alvocidib, for the treatment of relapsed/refractory acute myeloid leukemia (AML) (Press release, Tolero Pharmaceuticals, AUG 17, 2018, View Source [SID1234528982]).

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Alvocidib is a small molecule inhibitor of cyclin-dependent kinase 9 (CDK9), which controls the expression of a survival factor, MCL-1. Venetoclax is a small molecule inhibitor of B-cell lymphoma-2 (BCL-2). Both MCL-1 and BCL-2 are key proteins used by certain cancer cells to avoid apoptosis, and non-clinical studies have shown that cancer cells can resist inhibition of BCL-2 by using MCL-1 to avoid cell death. Alvocidib is currently in Phase II development for the treatment of MCL-1-dependent AML.

"We are very pleased to announce our clinical research collaboration with AbbVie, as it marks an important step in the development of this novel agent for patients with relapsed/refractory AML," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero. "Preclinical data suggest that the mechanisms of action for venetoclax and alvocidib may synergistically drive apoptosis in cancer cells. We hope to further investigate this hypothesis with our planned trial of this combination therapy in patients with relapsed/refractory AML."

"This is a unique opportunity to bring together and investigate two first and only in class compounds to help patients with AML," said Neil Gallagher M.D., Ph.D, Vice President, Head of Global Oncology Development, AbbVie. "There is an urgent need for new therapies, particularly in patients who either did not respond well to initial therapy or who subsequently relapsed. AML is a complex disease at the cellular level. Therefore, combining alvocidib with venetoclax, which have distinct but potentially complementary mechanisms for targeting the leukemia cells, makes a lot of sense from a scientific perspective."

Under the terms of the agreement, Tolero and AbbVie will equally share all development expenses. Tolero will retain full commercial rights for alvocidib and AbbVie will retain full commercial rights for venetoclax.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a rapidly progressing cancer that is most common in the elderly.1 The disease forms in the bone marrow and impairs the normal function of the bone marrow to make healthy blood cells. Following an intensive regimen of chemotherapy treatment, a large portion of patients experience a relapse or have residual (or refractory) leukemic cells in their marrow. Patients with AML have a poor prognosis and those with relapsed or refractory disease currently have limited treatment options.

About Venetoclax

VENETOCLAX is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.2 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.2 VENCLEXTA/VENCLYXTO targets BCL-2 in order to help restore the process of apoptosis.2 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.2

VENETOCLAX is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.

VENETOCLAX is currently approved in more than 50 nations, including the U.S., and in the EU. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Use and Important Safety Information

Use

What is VENCLEXTA (venetoclax tablets)?

VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment.

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests for TLS. It is important to keep your appointments for blood tests. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

Have kidney or liver problems.
Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
Have a history of high uric acid levels in your blood or gout.
Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection.
The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in Zella 201, a Phase II study in patients with relapsed or refractory MCL-1 dependent acute myeloid leukemia, AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase I clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with (7+3) in newly diagnosed patients with AML (NCT03298984).

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.4 In MCL-1–dependent AML, MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.3,5 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).6,7 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.6 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.3

On August 17, 2018 Taiho Pharmaceutical Co., Ltd. reported that it applied to the Japanese Ministry of Health, Labour and Welfare for an additional indication for unresectable advanced or recurrent gastric cancer for its anticancer agent LONSURF combination tablet T15, T20 (trifluridine and tipiracil) (Press release, Taiho, AUG 17, 2018, View Source [SID1234529758]).

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This application is based on the results of a Phase III TAS-102 Gastric Study (TAGS) trial that compared trifluridine/tipiracil plus best supportive care (BSC) versus placebo plus BSC, in patients with previously treated metastatic gastric cancer refractory to standard therapies.

In the TAGS trial, the primary endpoint of overall survival (OS) was extended significantly with trifluridine/tipiracil compared to placebo, and no new safety signals were observed with the study drug.

Taiho Pharmaceutical anticipates that, if approved, LONSURF will provide a new oral treatment option for patients with gastric cancer.

About Gastric Cancer
In Japan, gastric cancer is the most common cancer by site, with 131,893 people newly diagnosed per year (2013)*1 and 45,531 people losing their lives to it in 2016*2. Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths (after lung and liver cancer), with an estimated 723,000 deaths annually*3. In recent years, the outcome for gastric cancer has improved remarkably, and survival has increased dramatically over the past 10 years. As gastric cancer progresses, treatment options become limited as numerous complications can restrict the usable drugs and preclude intensive chemotherapy. Accordingly, new therapeutic drugs which prolong survival and relieve symptoms in late-stage treatment of metastatic gastric cancer are considered valuable in the treatment of the disease.

About TAGS
The TAGS (TAS-102 Gastric Study) trial is a Taiho-sponsored pivotal Phase III multinational, randomized, double-blind study evaluating LONSURF (trifluridine and tipiracil), plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric cancer refractory to standard treatments. The primary endpoint in the TAGS trial was overall survival (OS), and secondary endpoint measures included progression-free survival (PFS), and safety and tolerability, as well as quality of life. The TAGS trial enrolled 507 adults 18 years and older with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. Amongst other locations, the TAGS trial was conducted in Japan, North America, Europe, Russia and Turkey.

Please see ClinicalTrials.gov for additional details regarding the TAGS trial.
View Source

About LONSURF
LONSURF is an oral anticancer drug, which utilizes the combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity and differs from conventional fluoropyrimidines. FTD is an antineoplastic nucleoside analogue, which is incorporated directly into the DNA, thereby interfering with the function of DNA. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD‐degrading enzyme, thymidine phosphorylase.

In Japan, Taiho Pharmaceutical has been marketing LONSURF for the treatment of metastatic advanced or recurrent colorectal cancer since 2014. In the United States, beginning in 2015, Taiho Oncology, Inc., a U.S. subsidiary of Taiho Pharmaceutical, began marketing the drug for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. In June 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF in Europe and other countries outside of the United States, Canada, Mexico and Asia. In parts of Asia outside of Japan, Jeil Pharmaceutical and TTY Biopharm, which are Taiho Pharmaceutical’s business

On August 17, 2018 Akari Therapeutics, Plc (NASDAQ:AKTX), a biopharmaceutical company focused on the development and commercialization of innovative therapeutics to treat orphan autoimmune and inflammatory diseases, reported its financial results for the first quarter ended March 31, 2018 and highlights its pipeline of Phase II and Phase III clinical trials (Press release, Akari Therapeutics, AUG 17, 2018, View Source [SID1234529061]).

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"We are excited by the range of clinical opportunities that we are currently exploring. We look forward to providing initial clinical data from these trials starting in the fourth quarter of 2018," commented Clive Richardson, acting Chief Executive Officer of Akari Therapeutics. "Akari does not intend to develop all of these programs through to commercialization on its own but rather, intends to partner one or more of its programs. To that end, a robust business development program has been in progress since early 2018 led by Mike Grissinger, an Akari non-executive director and pharmaceutical industry veteran who spent 22 years at Johnson & Johnson in business development leadership roles."

Clinical Development Programs Highlights

Akari’s clinical program is divided into two separate workstreams targeting two different sets of clinical conditions. One group of diseases is where the combined inhibition of the complement and leukotriene pathways provides a potential new treatment solution for a wide range of currently poorly treated orphan inflammatory conditions. The second group of diseases are those where complement dysregulation is the primary driver.

Dual C5 and Leukotriene B4 Program

The increasing recognition that LTB4 may combine with complement dysregulation in the etiology of many autoimmune and autoinflammatory conditions has focused Akari’s clinical development on a number of poorly treated conditions where Coversin’s dual C5 and LTB4 binding provides a potential novel therapeutic solution. These programs include bullous pemphigoid (BP), an inflammatory skin disease in which current treatment is limited to steroids, and immunosuppressants and atopic keratoconjunctivitis (AKC), an eye surface inflammatory disease which can lead to permanent vision loss and for which there are few effective treatment options. Both are rare conditions for which Akari is seeking orphan designation.

Complement Program

Patient treatment in CAPSTONE, the Phase III trial in naïve PNH patients, has commenced. We anticipate introducing a new pen injector in 2019 to facilitate patient use which will accommodate a week’s supply of medication. Within the program to treat patients with a polymorphism that makes them resistant to treatment with Soliris, Akari recently began treating a second PNH patient under an investigational new drug application (IND) in the U.S. This patient has responded well (LDH <1.5xULN at day 28). In all, three Soliris resistant patients have now been treated with Coversin; two with PNH and a third with a thrombotic microangiopathy (TMA). All PNH patients remaining on treatment have the option of entering into the Akari long term safety program. Nine PNH patients have been treated in aggregate for over 11 patient years with no drug related SAEs to date.

Akari has also opened a clinical program targeting thrombotic microangiopathies (TMA) including atypical haemolytic syndrome (aHUS). We expect to provide an update on Akari’s TMA program in Q4 2018.

First Quarter 2018 Financial Results

As of March 31, 2018, the Company had cash of $23.8 million, as compared to cash of $28.1 million as of December 31, 2017.
Operating expenses, which include research and development (R&D) expenses and general and administrative (G&A) expenses, were $4.3 million in the first quarter of 2018, as compared to $8.3 million in the same quarter the prior year.
R&D expenses in the first quarter of 2018 were $1.0 million, as compared to $6.0 million in the same quarter the prior year. The decrease was due primarily to an R&D tax credit of approximately $3.8 million received in the first quarter of 2018 and lower manufacturing costs of $1.4 million associated with Coversin clinical trial material, offset by an increase in clinical trial expenses.
G&A expenses in the first quarter of 2018 were $3.3 million, as compared to $2.3 million in the same quarter last year. This increase was due primarily to higher legal, accounting and other professional service fees.
Total other income for the first quarter of 2018 was $3.0 million, as compared to total other expense of $4.3 million in the first quarter of 2017. This change was primarily attributed to $2.9 million of other income in the first quarter of 2018 compared to $4.3 million of other expense in the same period in 2017 related in both instances to the change in fair value of the stock option and warrant liabilities.
Net loss for the first quarter of 2018 was $1.3 million, compared to a net loss of $12.6 million for the same period in 2017. This year over year decrease in net loss was due primarily to lower R&D expenses in the first quarter of 2018 when compared to the same period in 2017.

On August 17, 2018 Endocyte, Inc. (Nasdaq:ECYT), a biopharmaceutical company developing targeted therapeutics for personalized cancer treatment, reported that two posters will be presented by Endocyte scientists at the ACS National Meeting & Exposition being held in Boston, MA from Aug. 19 – 23, 2018 (Press release, Endocyte, AUG 17, 2018, View Source [SID1234528962]).

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Presentations are as follows:

Abstract # MEDI 425
Title: Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 3: Design and synthesis of pro-PBD conjugates containing a self-immolative substituted disulfide linkers
When: August 22, 2018, from 7:00 pm to 9:00 pm
Session ID: General Poster Session
Location: Galleria, Westin Boston Waterfront

Abstract # MEDI 426
Title: Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 4: Design of novel oxime-based pro-PBD conjugates that release active drug via intramolecular diazepine-ring-closure
When: August 22, 2018, from 7:00 pm to 9:00 pm.
Session ID: General Poster Session
Location: Galleria, Westin Boston Waterfront

Website Information

Endocyte routinely posts important information for investors on its website, www.endocyte.com, in the "Investors & News" section. Endocyte uses this website as a means of disclosing material information in compliance with its disclosure obligations under Regulation FD. Accordingly, investors should monitor the "Investors & News" section of Endocyte’s website, in addition to following its press releases, SEC filings, public conference calls, presentations and webcasts. The information contained on, or that may be accessed through, Endocyte’s website is not incorporated by reference into, and is not a part of, this document.

On August 17, 2018 Mateon Therapeutics, Inc. (OTCQB:MATN), a biopharmaceutical company developing investigational drugs for the treatment of orphan oncology indications, reported that the U.S. Food and Drug Administration (FDA) placed a partial clinical hold on Study OX1222 during a telephone conversation held with the Company on August 16, 2018 (Press release, Mateon Therapeutics, AUG 17, 2018, View Source [SID1234528963]). OX1222 is the Company’s clinical trial of OXi4503 in combination with cytarabine for the treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes. The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503. The FDA is allowing the study to continue to treat and enroll patients using a dose of 9.76 mg/m2 of OXi4503, which the Company previously tested in cohort 5 of Study OX1222.

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The partial clinical hold follows two potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level that was being evaluated in cohort 6 of Study OX1222. These DLTs consist of one patient experiencing hypotension shortly following initial treatment with OXi4503, and another patient experiencing acute hypoxic respiratory failure approximately two weeks after receiving OXi4503 and cytarabine. Both events were deemed "possibly-related" to OXi4503, and both patients recovered following treatment. The protocol for Study OX1222 generally defines a DLT as any grade 3 serious adverse event (SAE) where a relationship to OXi4503 cannot be ruled out. The FDA has indicated that additional data on patients receiving 9.76 mg/m2 of OXi4503 must be evaluated before the Company resumes dosing at 12.2 mg/m2.

"Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed two complete remissions in the four patients that we treated," said William D. Schwieterman, M.D., Chief Executive Officer of Mateon.