On April 4, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) accepted a supplemental Biologics License Application (sBLA) that seeks to extend the use of Opdivo (nivolumab) to patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (CRC) after prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy (Press release, Bristol-Myers Squibb, APR 4, 2017, View Source [SID1234518453]). The FDA granted the application priority review, and the FDA action date is August 2, 2017.

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"We look forward to working with the FDA towards the goal of providing a new treatment option for patients with metastatic colorectal cancer defined by dMMR or MSI-H biomarkers. These patients have a distinct unmet need, as they are less likely to benefit from conventional chemotherapy and have a shorter overall survival than patients with metastatic colorectal cancer without these biomarkers," said Ian M. Waxman, M.D., development lead, Gastrointestinal Oncology, Bristol-Myers Squibb. "This milestone illustrates Bristol-Myers Squibb’s continued efforts to evaluate the potential of Immuno-Oncology in a broad range of cancers and represents an important advancement in our approach to translational medicine."

The submission was based on data from the ongoing Phase 2 CheckMate -142 trial evaluating Opdivo in patients with dMMR or MSI-H metastatic CRC. The efficacy endpoints include investigator-assessed and blinded independent central review committee-assessed objective response rate (ORR) based on the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, duration of response, progression-free survival and overall survival. Data from this study were presented at the 2017 Gastrointestinal Cancers Symposium in January.

About Colorectal Cancer and dMMR or MSI-H Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. In the U.S., CRC is the third most common cancer and the second leading cause of cancer-related deaths among men and women combined, with more than 134,000 new cases expected to be diagnosed annually.

Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, which leads to microsatellite instability-high (MSI-H) tumors in certain types of cancer, including CRC. Approximately 15% of CRC patients and 4-5% of metastatic CRC patients have dMMR or MSI-H biomarkers. Patients with dMMR or MSI-H metastatic CRC are less likely to benefit from conventional chemotherapy and typically have a poor prognosis, with lower survival rates on conventional chemotherapy than patients whose tumors are mismatch repair proficient. Routine testing to confirm dMMR or MSI-H status should be conducted for all CRC patients.

On April 4, 2017 Amgen (NASDAQ:AMGN) reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and an application for a variation to the marketing authorization to the European Medicines Agency (EMA) for XGEVA (denosumab) (Press release, Amgen, APR 4, 2017, View Source [SID1234518452]). The submissions to regulatory authorities seek to expand the currently approved XGEVA indication for the prevention of skeletal-related events (SREs) in solid tumors to include patients with multiple myeloma. The applications include new data from the pivotal Phase 3 head-to-head ‘482 study, the largest international multiple myeloma trial ever conducted.

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XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is currently indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three previous pivotal Phase 3 head-to-head studies. In these Phase 3 studies, XGEVA demonstrated superiority in the solid tumors studied compared to zoledronic acid. In the U.S., XGEVA has a limitation of use noting that it is not indicated for the prevention of SREs in patients with multiple myeloma.

"Bone lesions are a hallmark of multiple myeloma and often result in bone complications, which can be devastating for patients. Current treatment options for bone complications are limited to bisphosphonates, which are associated with renal toxicity. Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "XGEVA’s unique mechanism of action may offer multiple myeloma patients a novel treatment option that is not renally cleared. We look forward to collaborating with regulatory authorities to make XGEVA available to this patient population with an important unmet medical need."

The sBLA is based on efficacy and safety data from the pivotal Phase 3 ‘482 study, which demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival (OS), another secondary endpoint, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival (PFS) was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA. These results were presented during the late-breaking abstract session at the 16th International Myeloma Workshop.

Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).

About ‘482 Study (NCT01345019)
The ‘482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of SREs in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 subjects (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE and first-and-subsequent on-study SRE and evaluation of OS. PFS was an exploratory endpoint. The safety and tolerability of XGEVA were also compared with zoledronic acid.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is typically characterized by osteolytic bone lesions, which are part of diagnosis (CRAB criteria).3,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

More than 90 percent of patients develop osteolytic lesions during the course of the disease.3 Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and associated with renal toxicity, which is a common complication with myeloma patients.5 Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.7

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons
Clinically significant hypercalcemia has been reported in XGEVA treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

Important EU Product Safety Information

Special Warnings and Precautions: Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA. Hypocalcaemia can occur at any time during therapy. Monitor calcium prior to initial dose, within two weeks of initial dose and if suspected symptoms of hypocalcaemia occur. Severe symptomatic hypocalcaemia has been reported. Consider additional monitoring of calcium level in patients with risk factors for hypocalcaemia or if otherwise indicated based on clinical condition of the patient. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.

Patients with severe renal impairment (creatinine clearance < 30ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia; this risk and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels in these patients is especially important.

Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with XGEVA. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with XGEVA. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to XGEVA administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.

Atypical femoral fracture (AFF) has been reported in patients receiving XGEVA. Discontinuation of XGEVA therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. XGEVA is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months following treatment discontinuation. Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications) or with bisphosphonates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

Adverse reactions in patients receiving XGEVA to prevent the occurrence of skeletal related events: very common (≥ 1/10) dyspnea, diarrhea and musculoskeletal pain; common (≥ 1/100 to < 1/10) hypocalcaemia, hypophosphatemia, tooth extraction, hyperhidrosis and osteonecrosis of the jaw; rare (≥ 1/10,000 to < 1/1000) drug hypersensitivity, anaphylactic reaction, atypical femoral fracture. In three phase III clinical trials, ONJ was confirmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zoledronic acid (primary treatment phase). Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. Hypocalcaemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid. Neutralizing antibodies have not been observed in clinical studies. In the postmarketing setting, severe symptomatic hypocalcaemia (including fatal cases), hypersensitivity (including rare events of anaphylactic reaction) and musculoskeletal pain (including severe cases) have been reported. Please consult the SmPC for a full description of undesirable effects.

Contraindications: Severe, untreated hypocalcaemia; hypersensitivity to the active substance or to any of the excipients; unhealed lesions from dental or oral surgery.

On April 4, 2017 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported the presentation of preclinical data of ROLONTIS from a poster presentation session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Spectrum Pharmaceuticals, APR 4, 2017, View Source [SID1234518451]).

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"We are excited to see positive data continuing to develop in our highest priority program," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "The data shows that in this preclinical study eflapegrastim was found to be more potent in shortening the duration of severe neutropenia. Eflapegrastim was more potent than pegfilgrastim at G-CSF equivalent doses in neutropenic animal models. We are currently enrolling patients in our pivotal trial and continue to expect a BLA filing next year."

Abstract #1347: In vivo efficacy of eflapegrastim in rats with chemotherapy-induced neutropenia

In this study, rats were treated with 50 mg/kg of cyclophosphamide (CPA) intraperitoneally to induce neutropenia. Pegfilgrastim was administered subcutaneously as a single dose of 100 µg/kg on Day 1 and filgrastim was administered subcutaneously at a dose of 20 µg/kg daily for five days on Days 1 to 5. Eflapegrastim was administered subcutaneously as a single dose on Day 1, at doses ranging from 32 µg /kg to 322 µg/kg (or 8.8 µg/kg to 88 µg/kg as G-CSF equivalent). Blood samples were collected for 8 days after drug administration for the measurement of neutrophil counts and the Duration of Severe Neutropenia (DSN).

Results showed the DSN in neutropenic rats treated with eflapegrastim was compared with the DSN in neutropenic rats treated with pegfilgrastim or filgrastim. The DSN was 0.2 days when eflapegrastim was administered as a single dose at 88 µg/kg (as G-CSF equivalent) 24 hours after administering CPA. In contrast, the DSN was 3.04 days with filgrastim administered at a dose of 20 µg/kg for 5 days from Day 1 to Day 5 and 2.8 days with pegfilgrastim administered as a single dose of 100 µg/kg 24 hours after administering CPA. At the lowest eflapegrastim dose of 8.8 µg/kg that was about 1/10 of G-CSF equivalent dose for pegfilgrastim, the DSN in eflapegrastim-treated rats was 2.94 days. Thus, eflapegrastim was found to be more potent in shortening the DSN with a lower G-CSF equivalent dose when compared to either pegfilgrastim or filgrastim.

On April 4, 2017 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform, reported the presentation of data informing the design of a first-in-patient clinical trial for PRS-343, a first-in-class 4-1BB/HER2 bispecific in a poster session at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (AACR (Press release, Pieris Pharmaceuticals, APR 4, 2017, View Source [SID1234518450])).

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Complementing previously disclosed preclinical data demonstrating that PRS-343 elicits robust T cell expansion in the tumor microenvironment while avoiding unwanted peripheral T cell activation in HER2-positive cancer models, the data presented today demonstrate:

PRS-343 elicited robust T cell activation when engaging HER2 on cell lines derived from tumors resistant to trastuzumab therapy, as well as tumor cell lines with elevated HER2 expression in the IHC 2+ range
4-1BB-mediated T cell activation by PRS-343 resulted in the expression of a broad spectrum of inflammatory cytokines associated with anti-tumor immune responses
PRS-343 was well tolerated and led to no significant findings in IND-enabling preclinical safety and non-human primate toxicology studies
Today’s presented data suggest the clinical potential of PRS-343 in a broad population of patients with HER2-expressing cancers," commented Louis Matis, MD, Chief Development Officer of Pieris. "Moreover, the preclinical pharmacokinetic and safety profile of PRS-343 supports the initiation of clinical development, which we anticipate during the first half of this year." A copy of the poster can be viewed here.

About PRS 343:
PRS-343 is a bispecific monoclonal antibody/Anticalin fusion protein comprised of a HER2 tumor-targeting mAb genetically linked to a potent Anticalin specific for the immune costimulatory TNF family receptor 4-1BB (CD137). PRS-343 is being developed as the first 4-1BB based therapeutic to mediate the activation of tumor-specific T lymphocytes selectively within the tumor microenvironment (TME). 4-1BB is a potent costimulatory immunoreceptor and an established marker for tumor-specific infiltrating T lymphocytes (TILs), and is, therefore, an attractive target for cancer immunotherapy. In in vivo preclinical tumor models, PRS-343 has demonstrated potent T lymphocyte activation localized to the TME of established HER2-positive tumors, indicating the potential for both enhanced safety and efficacy.

On April 4, 2017 RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has granted YELIVA (ABC294640) Orphan Drug designation for the treatment of cholangiocarcinoma (Press release, RedHill Biopharma, APR 4, 2017, View Source [SID1234518446]).

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The Orphan Drug designation allows RedHill to benefit from various development incentives to develop YELIVA for this indication, including tax credits for qualified clinical testing, waiver of a prescription drug user fee (PDUFA fee) upon submission of a potential marketing application and, if approved, a seven-year marketing exclusivity period for the treatment of cholangiocarcinoma.

YELIVA is a Phase II-stage, proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation.

Mark L. Levitt, MD, PhD, RedHill’s Medical Director, Oncology, said: "Cholangiocarcinoma is a cancer with a poor prognosis. Patients suffering from this disease have very few treatment options, and they are of limited efficacy. Based on promising preclinical data, as well as results from three previously treated cholangiocarcinoma patients who took part in the Phase I study with YELIVA, we are hopeful that YELIVA could potentially provide a much-needed new treatment option for patients. We are very pleased with the Orphan Drug designation and are advancing our preparations for a Phase IIa study to evaluate the safety and efficacy of YELIVA in patient suffering from unresectable, intrahepatic and extrahepatic cholangiocarcinoma, which we plan to initiate in the third quarter of this year."

Cholangiocarcinoma (bile duct cancer) is a highly lethal malignancy for which there is a strong need for more effective systemic treatments. Approximately 8,000 people are diagnosed with intrahepatic and extrahepatic bile duct cancers annually in the U.S.1, with recent studies showing an increased incidence of cholangiocarcinoma, mainly attributed to recent advancements in diagnosis of this disease2. Surgery with complete resection remains the only curative therapy for cholangiocarcinoma, however only a minority of patients are classified as having a resectable tumor at the time of diagnosis3. Additional treatment options include radiation therapy and chemotherapy; however, the efficacy of these treatments in cholangiocarcinoma patients is also limited. Despite overall advances in the ability to diagnose and treat patients with cholangiocarcinoma, the prognosis for these relapse patients who have failed initial chemotherapy remains very poor, with an overall median survival of approximately one year4. The 5-year relative survival rates of intrahepatic and extrahepatic cholangiocarcinoma patients range between 2% to 30%, depending on the tumor type and stage at diagnosis5.

Final results from the Phase I study with YELIVA in patients with advanced solid tumors confirmed that the study, conducted at the Medical University of South Carolina (MUSC) Hollings Cancer Center, successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity.

Of the three patients with cholangiocarcinoma treated in the Phase I study, all of whom had prior therapy, one subject achieved a sustained partial response (Overall Survival (OS) = 20.3 months) and the other two subjects had prolonged stable disease (OS = 17.6 and 16.3 months).

RedHill plans to initiate a Phase IIa clinical study with YELIVA in patients with advanced, unresectable, intrahepatic and extrahepatic cholangiocarcinoma in the third quarter of 2017. The single-arm study will evaluate YELIVA as a single agent in cholangiocarcinoma patients with a primary endpoint of determining the response rate of cholangiocarcinoma to this treatment.

A Phase II study with YELIVA for the treatment of advanced hepatocellular carcinoma (HCC) is ongoing at MUSC Hollings Cancer Center. The study is supported by a $1.8 million grant from the NCI, awarded to MUSC, which is intended to fund a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, with additional support from RedHill.

A Phase Ib/II study with YELIVA for the treatment of refractory or relapsed multiple myeloma is ongoing at Duke University Medical Center. The study is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee Biotechnology Corp. (Apogee), in conjunction with Duke University, with additional support from RedHill.

A Phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma as well as Kaposi sarcoma patients is ongoing at the Louisiana State University Health Sciences Center. The study is supported by a grant from the NCI awarded to Apogee, with additional support from RedHill.

A Phase Ib study to evaluate YELIVA as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the third quarter of 2017.

A Phase II study to evaluate the efficacy of YELIVA in patients with moderate to severe ulcerative colitis is planned to be initiated in the second half of 2017.

About YELIVA (ABC294640):

YELIVA (ABC294640) is a Phase II-stage, proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anti-cancer and anti-inflammatory activities. RedHill is pursuing with YELIVA multiple clinical programs in oncology, inflammatory and gastrointestinal indications. By inhibiting SK2, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. The Phase I study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA resulted in a rapid and pronounced decrease in S1P levels, with several patients having prolonged stabilization of disease. YELIVA received Orphan Drug designation from the U.S. FDA for the treatment of cholangiocarcinoma. The development of YELIVA was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development.