On August 23, 2016 Propanc Health Group Corporation (OTCQB: PPCH) ("Propanc" or the "Company"), an emerging healthcare company focusing on development of new and proprietary treatments for cancer patients suffering from solid tumors such as pancreatic, ovarian and colorectal cancers, reported it has executed a contract manufacturing agreement with AmatsiQBiologicals, based in Gent, Belgium (Press release, Propanc, AUG 23, 2016, View Source [SID:1234514679]). The agreement covers the development and GMP (Good Manufacturing Practice) production of certain enzymes for development purposes, including but not limited to first-in-man studies for the Company’s lead product, PRP.

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PRP is the Company’s novel, patented, formulation consisting of two proenzymes mixed in a synergistic ratio to target cancer stem cells in solid tumors. The GMP manufacture of PRP as an injectable drug product requires specialized and detailed activities to be carried out in order to meet the highest quality and safety standards for future human use. It is a significant undertaking by the Company, as it demonstrates the Company’s commitment to initiating first-in-man studies in 2017.

"This major contract represents a significant step forward for the development of PRP," said James Nathanielsz, Propanc’s Chief Executive Officer. "The process towards securing the services of AmatsiQBiologicals was extensive, taking a number of months to draft, plan and execute. I am very confident we have identified a highly capable partner who will assist us with delivering a quality finished product for human use."

"We are very pleased that Propanc has chosen to partner with AmatsiQBiologicals for the development and manufacturing of Propanc’s lead product, PRP," said Annie Van Broekhoven, AmatsiQBiologicals’ Chief Executive Officer. "This project really fits very well with our capabilities and we are confident we can deliver on time the GMP grade PRP material required for Propanc’s clinical studies."

AmatsiQBiologicals, member of the Amatsigroup, is a biopharma contract development and manufacturing organization offering a range of process development and bio-manufacturing services including formulation and sterile fill and finish to customers in the biopharmaceutical industry and beyond. Recently, they have successfully delivered more than 75 R&D projects in less than three years with a focus on building strong relationships with clients.

In addition to the ongoing preclinical activities and planned GMP manufacture of PRP, the Company is also preparing Orphan Drug Designation applications to be submitted in the EU and U.S. in the near future. Furthermore, an outreach program has commenced with the Company’s advisors to determine interest from suitors in licensing PRP and initial feedback has been received.

"We believe PRP represents a valuable strategic addition to our Company’s pipeline and seeking orphan drug designation would add significant protection and upside potential. This is truly an exciting phase for our Company. Nevertheless, we remain committed to executing our plans to progress PRP into the clinic at the earliest opportunity," said James Nathanielsz.

The Company aims to fast track the development of proenzyme related oncology products into clinical trials initially for pancreatic, ovarian and colorectal cancers. According to Global Analyst Reports, the combined world market for pancreatic, ovarian and colorectal cancers is expected to reach over $12 billion by 2020.

On August 23, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to SL-401, a targeted therapy directed to the interleukin-3 receptor (CD123), for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Press release, Stemline Therapeutics, AUG 23, 2016, View Source [SID:1234514678]).

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The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of a drug candidate for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require clinical evidence demonstrating the drug may offer substantial improvement on one or more clinically significant endpoints versus existing therapies.

This Breakthrough Designation request was supported by efficacy and safety data from the Phase 2 trial evaluating SL-401 in BPDCN patients in both the first-line and relapsed/refractory settings.

Ivan Bergstein, M.D., Stemline’s Chief Executive Officer, commented, "We are very pleased that SL-401 has been granted Breakthrough Therapy Designation for BPDCN by the FDA. We continue to work closely with the agency in an effort to make this promising agent available to all BPDCN patients as quickly as possible. Given SL-401’s clinical activity in this CD123+ cancer, coupled with its manageable, non-overlapping safety profile with other oncology agents, we are also enthusiastic about the drug’s prospects in our other enrolling clinical trials in additional CD123+ indications as both a single agent and in combination. We expect to provide further updates around our multiple SL-401 clinical programs later this year."

On August 23, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that Janssen Pharmaceutica NV (Janssen) has submitted a variation to the Marketing Authorization to the European Medicines Agency (EMA) seeking to broaden the existing marketing authorization for daratumumab (DARZALEX) to include treatment of adult patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, AUG 23, 2016, View Source [SID:1234514677]). The submission of the application triggers milestone payments totaling USD 10 million to Genmab from Janssen. The milestone payments were included in Genmab’s financial guidance for 2016 that was published on August 9, 2016. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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"Daratumumab represents a new hope for people suffering from multiple myeloma, a disease which is presently incurable. We look forward to working together with Janssen and the EMA to making daratumumab available to a far wider group of patients," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The submission includes data from two Phase III studies: the CASTOR study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma, and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. The submission also included data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma.

Janssen submitted a supplemental Biologics License Application for daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for treatment of patients with multiple myeloma who received at least one prior therapy to the U.S. Food and Drug Administration in August 2016.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor.

On August 23, 2016 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has accepted Clovis’ New Drug Application (NDA) for accelerated approval of rucaparib and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of February 23, 2017 (Press release, Clovis Oncology, AUG 23, 2016, View Source [SID:1234514676]). In late June 2016, Clovis completed its NDA submission of rucaparib to the FDA for the treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test), and who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy Designation for the proposed indication by the FDA in April 2015.

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"The acceptance of the rucaparib NDA submission represents an important milestone for rucaparib, and for Clovis," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "There is tremendous need for additional therapeutic options for patients with advanced mutant BRCA ovarian cancer and we look forward to cooperating with FDA on the rucaparib NDA review."

"Recurrent ovarian cancer remains a very difficult disease to treat, even among women who carry, or whose tumors have a mutation in the BRCA genes. Despite the available treatment options, few effective therapies are at our disposal. Thus, the opportunity to treat women with germline or somatic BRCA mutations with rucaparib after two prior lines of platinum-based therapy, represents a meaningful step forward for our patients," said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL clinical trial program.

Foundation Medicine, Clovis’ companion diagnostic partner, has submitted a Premarket Approval (PMA) application for its FoundationFocus CDxBRCA to the FDA in June 2016. The test is designed to identify tumor BRCA mutations, including germline and somatic BRCA mutations. The timing of the submission is expected to allow for regulatory approval of the companion diagnostic in a similar timeframe.

About the Submission: Efficacy

The efficacy of rucaparib was assessed in 106 patients from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in patients with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. Median age was 59 years and median number of prior chemotherapy regimens was three.

Study 1 was limited to platinum sensitive patients; Study 2 included platinum sensitive, platinum resistant and platinum refractory patients.

All 106 patients received the starting dose of rucaparib 600 mg twice daily. The major efficacy outcome measure of both trials was objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. All responses were confirmed.

Efficacy results from Study 1 and Study 2 in all patients treated are summarized in the table below:

Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 1 and Study 2


Activity by RECIST 1.1 per Investigator Assessment

Study 1

N=42

Study 2

N=64

Overall1

N=106
Objective Response Rate (95% CI) 60% (43, 74) 50% (37, 63) 54% (44, 64)
Complete Response 10% 8% 9%
Partial Response 50% 42% 45%
Median Duration of Response in months (95% CI)
7.8 (5.6, 10.5) 11.6 (5.5, 18.2) 9.2 (6.6, 11.6)
1 Pooled analysis of Study 1 and Study 2
Confidence Interval (CI)

Nine (9%) of the 106 patients overall had progressive disease as best response. The ORR was similar for patients with germline BRCA-mutant ovarian cancer or somatic BRCA-mutant ovarian cancer and for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

About the Submission: Safety

The safety population is comprised of the 377 ovarian cancer patients treated with starting dose of rucaparib 600 mg twice daily in Study 1 and Study 2.

The Grade 3/4 treatment emergent adverse events (AEs) reported in ≥10% of patients were anemia/decreased or low hemoglobin (25%), fatigue/asthenia (11%) and increased ALT/AST (11%).

The increases in aspartate (AST) and alanine (ALT) aminotransferase levels that were observed were asymptomatic, reversible and were rarely associated with increases in bilirubin. The elevations normalized over time with continued rucaparib treatment.

The discontinuation rate for ovarian cancer patients due to rucaparib-related AEs was 8%.

Myelodysplastic syndrome (MDS) was reported in 1 of 377 (0.3%) patients with ovarian cancer.

In addition, in the ongoing ARIEL3 maintenance trial, a blinded, randomized trial evaluating rucaparib versus placebo, acute myeloid leukemia (AML) was reported in 2 (<0.5%) patients with ovarian cancer. One case of AML was fatal. Both of these patients had received prior treatment with platinum and other DNA damaging agents.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for advanced ovarian cancer.

Specifically, rucaparib is being developed as monotherapy treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test) who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy Designation for this proposed indication by the U.S. FDA in April 2015; and in late June 2016, Clovis completed its New Drug Application (NDA) submission to the FDA. The filing for treatment was accepted and has an action date of February 23, 2017. Rucaparib’s Marketing Authorization Application (MAA) to the European Medicines Agency for the proposed treatment indication is planned for Q4 2016.

Additionally, rucaparib is being developed as maintenance therapy in the ARIEL3 trial (NCT01968213) for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA (commonly referred to as homologous recombination deficiencies, or HRD). Data from ARIEL3 are expected in Q4 2017, which is expected to be followed by the submission of a supplemental NDA for second-line maintenance therapy.

Clovis is also exploring rucaparib in other solid tumor types with BRCA and HRD populations, including prostate, breast and gastroesophageal cancers.

Clovis holds worldwide rights for rucaparib.

About Rucaparib Clinical Development in Ovarian Cancer

The ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) program is a novel, integrated translational-clinical program designed to accurately and prospectively identify ovarian cancer patients with tumor genotypes associated with benefit from rucaparib therapy.

ARIEL2 is a two-part single-arm open label study designed to identify pre-specified tumor characteristics that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor. Part 1 enrolled 204 platinum-sensitive patients and updated results were presented in June 2016. Part 2 enrolled 286 patients with advanced ovarian cancer who have received at least three prior chemotherapy regimens and includes platinum-sensitive, -resistant and -refractory patients. ARIEL2 is evaluating clinical response in patients classified into molecularly-defined subgroups, including germline BRCA-mutant, somatic BRCA-mutant and HRD by a prospectively defined genomic signature.
The phase 2 portion of Study 10, the initial dose finding study, enrolled patients with relapsed, high-grade ovarian cancer associated with a deleterious germline BRCA mutation who received 2-4 prior lines of chemotherapy.
The ARIEL3 pivotal study is a randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance therapy to platinum-sensitive patients can extend the period of time for which the disease is controlled after a positive outcome with platinum-based chemotherapy. Patients are randomized to receive either placebo or rucaparib and the primary endpoint of the study is PFS. The primary efficacy analysis will evaluate, in a step-down process, BRCA-mutant patients, all patients with a HRD signature (including BRCA and non-BRCA), followed by all patients. Target enrollment in ARIEL3 was completed during the second quarter of 2016.
The ARIEL4 confirmatory study (NCT 02855944), expected to begin during the second half of 2016, is a Phase 3 multicenter, randomized study of rucaparib versus chemotherapy in relapsed ovarian cancer patients with BRCA mutations who have failed two prior lines of therapy. The primary endpoint of the study is PFS.
For more information, please visit www.arielstudy.com.
In addition to the ARIEL program in ovarian cancer, the Company is exploring rucaparib in other solid tumor types with BRCA and HRD populations, including two monotherapy prostate cancer studies as well as multiple combination studies, including with inhibitors of PD-L1, are planned to initiate in late 2016 and early 2017.

An abstract based on the ovarian NDA dataset has been accepted for an oral presentation at the ESMO (Free ESMO Whitepaper) 2016 Congress in October 2016.

About Ovarian Cancer

According to the American Cancer Society, more than 22,000 women will be diagnosed with ovarian cancer in the U.S. during 2016. There are often no clearly identifiable initial symptoms, and in an estimated 80 to 85% of ovarian cancer cases, the cancer has spread to other parts of the body before a person is diagnosed and can be treated. Ovarian cancer ranks fifth in cancer deaths and causes more deaths than any other cancer of the female reproductive system. One in four women with ovarian cancer have a germline or somatic BRCA mutation, and new treatment options are needed to treat unique patient populations.