On March 31, 2015 RedHill Biopharma reported that they have entered into an exclusive worldwide license agreement under which RedHill has acquired the rights to the Phase II drug candidate ABC294640 and additional intellectual property rights (Press release, RedHill Biopharma, MAR 31, 2015, View Source [SID:1234502885]). ABC294640 is a proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) inhibitor, with anti-inflammatory and anti-cancer activities, targeting multiple inflammatory, gastrointestinal (GI) and oncology indications.

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Under the terms of the agreement, RedHill has acquired the exclusive worldwide development and commercialization rights to ABC294640 and additional intellectual property for all indications. RedHill will pay Apogee an upfront payment of $1.5 million, as well as an additional $4 million in potential milestone payments, and potential tiered royalties starting in the low double-digits.

ABC294640 inhibits SK2, a lipid kinase that catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including TNFα signaling and other inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, ABC294640 blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Preliminary evidence suggests that because of its specificity for targeting SK2, rather than SK1, ABC294640 may have a better therapeutic ratio than nonspecific sphingosine kinase inhibitors or those targeting only SK1.

Apogee received cumulative funding exceeding $14 million to support the development of ABC294640, primarily through grants and contracts from U.S. federal and state government agencies such as the NIH Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) program, including funding from the National Cancer Institute (NCI), the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the Department of Defense (DoD), the FDA Office of Orphan Products Development and the Pennsylvania Department of Health.

With this funding Apogee has completed numerous successful pre-clinical studies with ABC294640 in GI-inflammation, radioprotection and oncology models, as well as a successful Phase I clinical study in cancer patients with advanced solid tumors. The open-label, dose-escalation Phase I clinical study demonstrated the drug’s safety and assessed its pharmacokinetics and pharmacodynamics in cancer patients with advanced solid tumors.

A Phase Ib/II clinical study with ABC294640 for refractory/relapsed diffuse large B cell lymphoma (DLBCL) is planned to commence in the second quarter of 2015 and will be funded by a $1.5 million grant awarded by the National Cancer Institute under the NIH SBIR/STTR program to Apogee in conjunction with the Louisiana State University Health Science Center. The study will include approximately 30 patients and is intended to assess the tolerability of ABC294640 within the DLBCL population, as well as provide a preliminary evaluation of efficacy. A second Phase II clinical study of ABC294640 for the treatment of multiple myeloma is planned, subject to funding by a pending grant from the National Cancer Institute. A third Phase II clinical study is being planned by RedHill in order to evaluate ABC294640 as a radio-protectant and radiation enhancer in cancer patients undergoing radiotherapy.

Furthermore, multiple pre-clinical studies funded by the NIH (BARDA) and the DoD have demonstrated activity of ABC294640 against gastrointestinal injury from accidental acute radiation exposure. Therefore, a possible additional indication of protection against accidental radiation exposure may qualify as a medical countermeasure under the Animal Rule, under which no human efficacy studies would be required for FDA approval.

"With a unique mechanism of action, ABC294640 is a novel potential treatment for multiple inflammatory and oncology diseases with strong unmet medical needs. In particular, the drug may be a unique and important treatment for prevention of severe toxicity and inflammation induced in many cancer patients by radiotherapy, while at the same time potentially enhancing the effectiveness of the radiotherapy treatment," said Dr. Terry Plasse, Medical Director at RedHill. "We are looking forward to further advancing this promising program into clinical studies, and plan a Phase II study to evaluate the ability of ABC294640 to decrease radiotherapy-induced toxicity."

Adi Frish, Senior VP Business Development and Licensing at RedHill added: "With the acquisition of ABC294640 we adhere to RedHill’s multiple-shots-on-goal strategy. The acquisition of this potential blockbuster further expands our late clinical-stage pipeline, reflecting RedHill’s solid commitment to patients suffering from inflammatory and gastrointestinal diseases, including cancer, who are in need of new treatment options. Thanks to the thorough development work conducted by Apogee, ABC294640 is supported by extensive pre-clinical, clinical and CMC package, as well as strong intellectual property protection, and we believe in its potential to become a leading treatment for multiple inflammatory, gastrointestinal and oncology indications. We are excited to continue advancing this important novel drug candidate, and would like to thank our new partners at Apogee for entrusting us with the development and commercialization of ABC294640."

Dr. Charles Smith, President and CEO at Apogee stated: "We are very pleased to be collaborating with RedHill to advance the clinical development of ABC294640 for the potential benefit of cancer patients. We view RedHill as an outstanding partner for this effort, and are particularly impressed by their demonstrated commitment to tackling the difficult problem of improving therapeutic outcomes and the quality of life for cancer patients. Additionally, RedHill’s expertise with gastrointestinal inflammatory diseases provides a very strong foundation for clinical testing of this drug candidate, and we are looking forward to a successful outcome of this collaboration."

In addition to the three ongoing Phase III studies in GI indications (RHB-105 for H. pylori infection, BEKINDA (RHB-102) for gastroenteritis, and RHB-104 for Crohn’s disease), RedHill’s pipeline now includes three proprietary, Phase II-stage, orally-administered, first-in-class small molecule drug candidates intended to treat gastrointestinal and other solid tumor cancers, as well as other potential indications: Mesupron, a urokinase-type plasminogen activator (uPA) inhibitor, RP101 (under an option-to-acquire), a heat shock protein 27 (Hsp27) inhibitor, and the newly-acquired SK2 inhibitor, ABC294640.

About ABC294640

ABC294640 is a first-in-class, proprietary sphingosine kinase-2 (SK2) selective inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting a number of potential inflammatory, oncology and gastrointestinal indications. By inhibiting the SK2 enzyme, ABC294640 blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid that promotes cancer growth and pathological inflammation. ABC294640 has completed multiple successful pre-clinical studies in inflammatory, GI, radioprotection and oncology models, as well as a Phase I clinical study in cancer patients with advanced solid tumors.

On March 31, 2015 Infinity Pharmaceuticals reported that it has exercised its option to buy out all future royalty obligations due to Takeda for sales of duvelisib (IPI-145), Infinity’s dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, in oncology indications (Press release, Infinity Pharmaceuticals, MAR 31, 2015, View Source [SID:1234502884]). The option was purchased in July 2014 for $5.0 million from a Takeda affiliate, and the exercise fee was $52.5 million. Exercising the option eliminates the future obligation to pay Takeda tiered royalties ranging from seven percent to 11 percent on worldwide net sales of duvelisib in oncology indications.

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"Our decision to exercise this option underscores Infinity’s belief in the potential of duvelisib to be a first-in-class dual inhibitor of PI3K-delta,gamma for the treatment of a broad range of hematologic malignancies, or blood cancers, as we continue to advance our registration-focused studies in indolent non-Hodgkin lymphoma and chronic lymphocytic leukemia," stated Adelene Perkins, Infinity’s chair, president and chief executive officer.

On March 31, 2015 Syndax Pharmaceuticals and Merck reported that they have entered into a clinical trial collaboration to evaluate the safety and efficacy of combining Syndax’s entinostat, an investigational epigenetic therapy, with Merck’s KEYTRUDA (pembrolizumab), the first anti-PD-1 therapy approved in the United States (Press release, Merck & Co, MAR 31, 2015, View Source [SID:1234502881]). The Phase 1b/2 study will evaluate this novel combination regimen in patients with either advanced non-small cell lung cancer (NSCLC) or melanoma. The study is expected to begin enrolling patients in the second half of 2015.

Entinostat is an oral, highly selective histone deacetylase (HDAC) inhibitor granted Breakthrough Therapy Designation in combination with hormone therapy in advanced hormone receptor positive (HR+) breast cancer and currently in Phase 3 testing in this indication. Entinostat has been shown in preclinical models to reduce the number and function of host immune suppressor cells thereby enhancing the anti-tumor activity of immune checkpoint blockade. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2.

“We are excited to be working with Merck on this collaboration to evaluate the potential of these two novel therapies to improve clinical outcomes for patients,” said Arlene Morris, president and chief executive officer of Syndax. “We hope that entinostat in combination with KEYTRUDA may build upon the enormous promise of immunotherapy in treating multiple forms of cancer.”

“The broad base of clinical data involving our anti-PD-1 therapy, KEYTRUDA, continues to provide a strong foundation for advancing the study of different novel combination regimens,” said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. “Our collaboration with Syndax is an important example of this effort and our commitment to further the study of breakthrough science in the area of immuno-oncology to help people with cancer.”

The financial terms and additional details of the agreement between Syndax and Merck, through a subsidiary, were not disclosed. The agreement includes a provision where the parties may extend the collaboration to include a potential Phase 3 clinical trial. The planned Phase 1b/2 multicenter, open-label clinical trial will be conducted in two parts. The Phase 1b portion is designed to determine the safety and tolerability of entinostat in combination with KEYTRUDA. The Phase 2 portion is designed to evaluate the efficacy of entinostat combined with KEYTRUDA in patients with advanced NSCLC and melanoma.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 70 clinical trials – across more than 30 tumor types and over 8,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.