Agios Pharmaceuticals Announces FDA Orphan Drug Designation Granted to AG-120 for Treatment of IDH1-Mutant Positive Acute Myelogenous Leukemia

On June 10, 2015 Agios Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has granted the company orphan drug designation for AG-120 for treatment of patients with acute myelogenous leukemia (AML) (Press release, Agios Pharmaceuticals, JUN 10, 2015, View Source;p=RssLanding&cat=news&id=2058334 [SID:1234505391]). AG-120 is an oral, first-in-class IDH1 mutant inhibitor being evaluated in a Phase 1 clinical trial in patients with advanced hematologic malignancies that carry an IDH1 mutation.

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The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the U.S. Orphan drug designation provides to Agios certain benefits, including market exclusivity upon regulatory approval if received, exemption of FDA application fees and tax credits for qualified clinical trials.

"Receiving orphan drug designation for AG-120 is an important milestone as we continue to move this program to late-stage development," said Chris Bowden, M.D. chief medical officer of Agios. "We are pleased with the progress we are making in the clinic and look forward to presenting new data from our ongoing Phase 1 study of AG-120 at the Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) later this week. We believe that AG-120, which is on track to initiate multiple expansion cohorts in the next month, has the potential to play a significant role in shifting the treatment paradigm for IDH1-mutant positive hematologic cancers from the conventional chemotherapy approach."

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia in adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society the median age is 66. Less than 10 percent of U.S. patients are eligible for bone marrow transplant, and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

FDA Agrees with OncoGenex’ Phase 3 AFFINITY Protocol Amendment

On June 10, 2015 OncoGenex Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has agreed to the Company’s proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan (Press release, OncoGenex Pharmaceuticals, JUN 10, 2015, View Source [SID:1234505390]). The amendment includes the addition of a co-primary endpoint designed to prospectively evaluate the survival benefit of custirsen in men who are at increased risk for poor outcomes when treated with cabazitaxel for metastatic castrate-resistant prostate cancer (CRPC).

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"There are limited effective treatment options for men with metastatic CRPC who have risk factors for poor outcomes and who fall into a poor prognosis category. Recent findings from the SYNERGY trial showed a significant survival benefit in this group of patients," said Cindy Jacobs, PhD, MD, Chief Medical Officer and Executive Vice President of OncoGenex. "We have applied this key insight from the SYNERGY trial to the AFFINITY protocol to better evaluate this vulnerable subpopulation of men who have poor prognosis and shorter survival time."

The FDA is in agreement with plans for prospectively defining a poor prognostic subpopulation in the Phase 3 AFFINITY trial. OncoGenex, in collaboration with study investigators, has defined a simple 5-criteria characterization for poor prognosis in prostate cancer based on the Phase 3 SYNERGY trial, which includes: poor performance status, elevated prostate specific antigen (PSA), elevated lactate dehyrdogenase (LDH), decreased hemoglobin, and the presence of liver metastasis. Patients with poor prognosis will be identified as having 2 or more of these 5 well-recognized high-risk criteria. The proposed change for AFFINITY is also consistent with custirsen’s mechanism of action, since custirsen was designed to address treatment resistance which may be more prevalent in this subpopulation.

In the revised statistical analysis plan for the AFFINITY trial, the hypothesized hazard ratio (HR) for the poor prognosis subpopulation is specified to be 0.69 with the critical HR ≤ 0.778. The hypothesized HR for the intent-to-treat patients (ITT population) remains unchanged as 0.75 with the critical HR ≤ 0.820.

Timing for the final analysis of the poor prognosis subpopulation is projected to occur by the end of 2015, while the final analysis for the ITT population is projected to occur in the second half of 2016. FDA and OncoGenex have further agreed that an interim analysis will occur for the ITT population when the final analysis for the poor prognosis subpopulation occurs. This interim analysis will have both futility and early efficacy criteria defined for the ITT population. If the earlier final analysis on the poor prognostic subpopulation shows a survival benefit for custirsen, OncoGenex could initiate a regulatory submission. The entire trial could also be stopped early due to efficacy based on the interim assessment for the ITT population by the Independent Data Monitoring Committee (IDMC).

"Findings from the SYNERGY trial recently presented at ASCO (Free ASCO Whitepaper) have provided important insight into the patient population in whom custirsen treatment is most relevant," said Scott Cormack, President and CEO of OncoGenex. "We are pleased that the FDA has agreed with our amendment and look forward to announcing top-line results at the end of this year and in 2016."

OncoGenex has also initiated a review with the European Medicines Agency (EMA) for the proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan, and expects to have this completed in the second half of 2015.

A retrospective analysis of data from the Phase 3 SYNERGY trial recently presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) showed a benefit with custirsen therapy when added to first-line docetaxel chemotherapy in men with metastatic CRPC who had a poor prognosis. The analysis showed that over 40 percent of men in the trial had at least 2 of the 5 common risk factors for poor prognosis as stated above. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone.

AFFINITY is being conducted at 95 global clinical trial sites and earlier this year, the IDMC recommended the trial continue following the completion of an interim futility analysis. The trial is fully accrued, and the protocol amendment does not affect the conduct of the study.

DelMar Pharmaceuticals to Present at the BIO International Convention on June 17, 2015

On June 10, 2015 DelMar Pharmaceuticals reported that it will be presenting at the BIO International Convention being held June 15-18, 2015, in Philadelphia, PA (Press release, DelMar Pharmaceuticals, JUN 10, 2015, View Source [SID:1234505389]).

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Jeffrey Bacha, DelMar’s president and CEO, will present on Wednesday, June 17, 2015, at 10:15 a.m. EDT, in Theater 4 of the Pennsylvania Convention Center. Mr. Bacha will provide an update on the Company’s drug development programs with its lead product candidate VAL-083 (dianhydrogalactitol), including DelMar’s ongoing Phase 1/2 trial in refractory glioblastoma multiforme (GBM), the most common and deadly form of brain cancer, and upcoming clinical development plans in non-small cell lung cancer (NSCLC).

About the BIO International Convention

The BIO International Convention is considered one of the world’s largest, most influential biotech meetings and regularly attracts 15,000 of the most powerful biotech and pharma players from 65 countries, offering powerful business partnering, networking and education that go far beyond professional development. DelMar management will be available during the conference for meetings with potential drug development and commercialization partners from the biopharmaceutical industry. For more information, please visit View Source

About VAL-083

VAL-083 is a "first-in-class", small-molecule chemotherapeutic. In more than 40 Phase 1 and 2 clinical studies sponsored by the U.S. National Cancer Institutes, VAL-083 demonstrated safety and efficacy in treating a number of cancers including lung, brain, cervical, ovarian tumors and leukemia. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia and lung cancer and has received orphan drug designation in Europe and the U.S. for the treatment of gliomas.

As a potential treatment for glioblastoma, VAL-083’s mechanism of action appears to be unaffected by the expression of MGMT, a DNA repair enzyme that causes chemotherapy resistance to front-line treatment with Temodar (temozolomide).

DelMar is currently studying VAL-083 in a multi-center Phase I/II clinical trial for patients with refractory glioblastoma multiforme (GBM) in accordance with the protocol that has been filed with the U.S. Food and Drug Administration (FDA). Eligible GBM patients must have failed both Avastin (bevacizumab) and Temodar (temozolomide) unless either of these therapies was contraindicated. (ClinicalTrials.gov Identifier NCT01478178).

The four current sites for the VAL-083 clinical trial include: The University of California, San Francisco (UCSF); The Mayo Clinic, Rochester MN; The Sarah Cannon Cancer Research Institute (SCRI), Nashville TN; and the SCRI affiliate site at Florida Cancer Specialists in Sarasota FL. DelMar anticipates opening additional clinical sites as the trial progresses. Further information on this clinical trial can be found on the company’s website at www.delmarpharma.com.

Curis to Present CUDC-907 Clinical Data at the 20th Congress of the European Hematology Association and the 13th International Congress on Malignant Lymphoma

On June 10, 2015 Curis reported that data for CUDC-907 will be presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), being held from June 11 – June 14, 2015 in Vienna, Austria as well as at the 13th International Congress on Malignant Lymphoma (ICML), being held from June 17 – June 20, 2015 in Lugano, Switzerland (Press release, Curis, JUN 10, 2015, View Source [SID:1234505383]).

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Curis and its study investigators will present data from the Phase 1 study of CUDC-907, Curis’ proprietary oral, dual histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) inhibitor that is being studied in the ongoing expansion stage of a Phase 1 trial, with a focus on patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The U.S. FDA recently granted Orphan Drug Designation to CUDC-907 for the treatment of DLBCL.

Additional information on the presentations can be found below.

CUDC-907 Presentations:

20th Congress of EHA (Free EHA Whitepaper):
Date/Time: Friday, June 12, 2015, 17:15 – 18:45 CEST
Abstract Number: P325 (Poster)
Presentation Title: A Phase 1 trial of CUDC-907, an oral, first-in-class, dual inhibitor of HDAC and PI3K, in patients with refractory or relapsed lymphoma and multiple myeloma.

Presenter: Jaye Viner, MD

13- ICML:
Date/Time: Thursday, June 18, 2015, 15:35 – 16:55 CEST (Session 6)
Abstract No: 080 (Oral)
Presentation Title: A first-in-human trial of CUDC-907, an oral, first-in-class, dual inhibitor of HDAC and PI3K, in patients with refractory/ relapsed lymphoma and multiple myeloma.

Presenter: Anas Younes, MD

ARIAD and Paladin Announce Commercial Distribution Agreement for Iclusig (Ponatinib) in Canada

On June 10, 2015 ARIAD and Paladin Labs reported that ARIAD has granted Paladin exclusive rights to distribute Iclusig (as ponatinib hydrochloride) in Canada for its newly approved indications (Press release, Ariad, JUN 10, 2015, View Source [SID:1234505387]). Paladin is focused on acquiring or in-licensing innovative pharmaceutical products for the Canadian market.

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Health Canada recently approved Iclusig for the treatment of adult patients with all phases of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive, or where there is prior TKI resistance or intolerance. Iclusig will be made available through a controlled distribution program, whereby prescribers who have completed the certification procedure will be able to prescribe Iclusig.

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"Paladin has a proven track record of successfully commercializing innovative pharmaceuticals in Canada and will be a strong partner for us," said Marty J. Duvall, executive vice president and chief commercial officer of ARIAD. "Through this commercial distribution agreement, we are confident that Iclusig will become available for appropriate patients with Ph+ leukemias who otherwise would have limited treatment options available."

Under the terms of the agreement, ARIAD will continue to be the Marketing Authorization Holder of Iclusig in Canada, and Paladin will be responsible for distribution, sales and marketing, medical affairs, and pricing and reimbursement activities. Paladin will book sales of Iclusig in Canada while ARIAD will supply packaged drug to Paladin.

"Iclusig has shown promising clinical evidence to address this serious unmet medical need," said Mark Beaudet, President of Paladin. "We are excited to add this important medicine to our core pharmaceutical-product offering in Canada through our collaboration with ARIAD."

CML is a cancer of the white blood cells that according to the Chronic Myelogenous Leukemia Society of Canada affects 1 in 100,000, with about 5,500 Canadians living with the disease. In 2010, more than 550 people in Canada were estimated to be diagnosed with CML, and 480 people were estimated to be diagnosed with ALL.

About Iclusig (as ponatinib hydrochloride)

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Indications in Canada

ICLUSIG is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive or where there is prior TKI resistance or intolerance.

Marketing authorization with conditions is based on response rate. There are no trials demonstrating increased survival or improvement in symptoms with ICLUSIG. In the pivotal trial, the majority of the hematological responses occurred within 1 month. Consider discontinuing ICLUSIG if a hematological response has not been achieved by 3 months (90 days).

ICLUSIG for this indication has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the conditional nature of the authorization.

Contraindications

Do not use in patients who are hypersensitive to ponatinib or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
Do not use in patients who have unmanaged cardiovascular risk factors, including uncontrolled hypertension. Hypertension may contribute to the risk of arterial thrombotic events. Blood pressure should be monitored and managed to avoid hypertension.
Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels.
Serious Warnings and Precautions

ICLUSIG has serious warnings and precautions for: vascular occlusion, heart failure, hemorrhage, hepatotoxicity, myelosuppression, and pancreatitis.

ICLUSIG should only be prescribed and monitored by a physician who has completed the certification with the ICLUSIG Controlled Distribution Program and who is experienced in the use of antineoplastic therapy and in the treatment of CML or Ph+ ALL.

Vascular Occlusion (arterial and venous thrombosis and occlusions), occurred in 24% (129/530) of ICLUSIG-treated patients with and without cardiovascular risk factors (including patients less than 50 years old). In clinical trials, serious treatment-emergent arterial thrombosis (cardiovascular, cerebrovascular, and peripheral vascular) and occlusions were seen in 14% of the ICLUSIG-treated patients including fatal myocardial infarction, fatal cerebral infarction, stroke, disseminated intravascular coagulation, and arterial stenosis sometimes requiring urgent revascularization procedures. Some of these events occurred within 2 weeks of starting treatment with ICLUSIG. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or consider discontinuation in patients who develop arterial thrombotic events.

Heart Failure (in some cases, fatal), including left ventricular dysfunction and ejection fraction decreases, occurred in 8% of ICLUSIG-treated patients, 5% of which were serious.

Hemorrhage events (some fatal) including intracranial hemorrhage, hemorrhagic gastritis, (fatal), hemorrhagic cerebral infarction (fatal). Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia.

Hepatotoxicity (including fatal acute hepatic failure) has been reported. Monitor hepatic function prior to and during treatment. Consider ICLUSIG dose interruption followed by dose reduction or discontinuation in patients with hepatotoxicity.

Myelosuppression (thrombocytopenia, neutropenia, and anemia).
Pancreatitis (7%) and elevations in amylase (2% grade 3 or greater) or lipase (12% grade 3 or greater) have been reported.

ICLUSIG has not been studied in patients with renal impairment.

Most Common Adverse Reactions

Overall, the very common adverse reactions (≥ 10%) were platelet count decreased, rash, dry skin, abdominal pain, neutrophil count decreased, headache, lipase increased, fatigue, constipation, myalgia, arthralgia, nausea, anemia, ALT increased, hypertension, and AST increased.