Press Release from AOP Orphan Pharmaceuticals AG
December 4, 2018
- High rates of durable hematological response and symptom control with good tolerability were reconfirmed with Ropeginterferon alfa-2b after 36 months of treatment.
- Disease Modification by Ropeginterferon alfa-2b was illustrated by high molecular response rates, associated with the ability to reduce allelic burden of both mutant JAK2 and importantly also non-JAK2 mutations which are believed to have a role in disease progression.
- In line with molecular findings, disease or treatment related secondary malignancies including 2 cases of acute myeloid leukemia occurred only in patients receiving HU.
- AOP Orphan ́s submission for marketing authorization of Ropeginterferon alfa-2b in the EU is in the final stage of EMA review.
Vienna, 04 December 2018: AOP Orphan Pharmaceuticals AG (AOP Orphan) announces latest follow-up results on Ropeginterferon alfa-2b in patients with Polycythemia Vera (PV) from CONTINUATION-PV presented at ASH 2018.
CONTINUATION-PV is an open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of Ropeginterferon alfa-2b versus hydroxyurea (HU) or best available treatment (BAT) in patients with PV who previously participated in the PROUD-PV study.
Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15). It is administered once every 2 weeks initially, or monthly after stabilization of hematological parameters. It is expected to be the first interferon approved for PV worldwide. AOP Orphan ́s submission for marketing authorization in the EU is in the final stage of EMA review.
Previously, at 12 months of treatment, Ropeginterferon alfa-2b was shown to be non-inferior to hydroxyurea (HU) in Complete Hematologic Response (CHR) and to have a significantly better safety and tolerability profile. . At 24 months Ropeginterferon alfa-2b achieved a significantly higher CHR of 70.5% versus 49.3% compared with HU/BAT (p=0.0101).
After 36 months of treatment Ropeginterferon alfa-2b sustained higher CHR response rates compared to HU/BAT (70.5% vs. 51.4%; p=0.0122). Further, the composite endpoint, CHR including disease symptom improvement was higher in patients treated with Ropeginterferon alfa-2b compared to HU/BAT (52.6% vs. 37.8%; p=0.0437).
Disease modification evidence:
66.0% of PV patients treated with Ropeginterferon alfa-2b, but only 27.0% having received HU/BAT showed a mutant JAK2 molecular response (p<0.0001) after 36 months. Importantly, molecular response strongly correlated with CHR, emphasizing the clinical relevance of mutant JAK2 allele burden reduction.
Analysis of additional non-JAK2 mutations, which are believed to contribute to disease progression revealed that Ropeginterferon alfa-2b, but not HU was able to reduce their respective mutant allele burden. This suggests that only Ropeginterferon alfa-2b but not HU has the ability to suppress additional clones with different mutations and modify the disease at the molecular level.
In line with molecular findings, disease or treatment related secondary malignancies occurred only in patients receiving HU/BAT, including 2 cases of acute myeloid leukemia, 1 melanoma and 2 basaliomas, whereas 3 malignancies (glioblastoma, seminoma, adrenal neoplasm) most likely unrelated to treatment were reported for patients treated with Ropeginterferon alfa-2b.
A similar number of patients experienced adverse events (89.8% for Ropeginterferon alfa-2b, 90.6% for HU) and treatment- related adverse events (74.8% for Ropeginterferon alfa-2b, 78.7% for HU). The most common (>10%) treatment-related adverse events anemia, thrombocytopenia and leukopenia occurred more frequently with HU, whereas liver enzyme increase was mainly observed with Ropeginterferon alfa-2b.
No new safety signals appeared in the third year of treatment.
Professor Heinz Gisslinger from the Medical University of Vienna, Austria presenting the results at ASH stated, “The observed superior efficacy of Ropeginterferon alfa-2b over hydroxyurea/best-available-therapy after 36 months, is a clear proof of the long-term value of this treatment modality. Thus, Ropeginterferon alfa-2b will provide a valuable and safe new first line therapy for PV patients”.
Professor Jean-Jacques Kiladjian from the Saint-Louis Hospital & Paris Diderot University in France, concluded, “The disease modification capability of Ropeginterferon alfa-2b suggested by a significant reduction of not only mutant JAK2, but also non-JAK2 allele burden and the specific targeting of the malignant clone, holds promise for improvement of progression- free survival and long-term patient benefit.”
About Ropeginterferon alfa-2b
Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15) with improved pharmacokinetic properties offering improved tolerability and convenience. It is administered once every 2 weeks, or monthly during long-term maintenance, and is expected to be the first interferon approved for PV worldwide. AOP Orphan ́s submission for marketing authorization in the EU is currently under EMA review.
Ropeginterferon alfa-2b was discovered by PharmaEssentia, a long-term partner of AOP Orphan. Ropeginterferon alfa-2b has Orphan Drug designation in the European Union, Switzerland and the United States of America.
In 2009, AOP Orphan has in-licensed from PharmaEssentia Corporation the exclusive rights to develop and commercialize Ropeginterferon alfa-2b in PV, other MPNs and CML for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.
About Polycythemia Vera
Polycythemia Vera (PV) is a cancer of the blood-building cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition may result in circulatory disorders such as thrombosis and embolism, as well as malignant transformation to myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2 that make the malignant clone.
About AOP Orphan Pharmaceuticals AG
AOP Orphan is a multinational company with headquarters in Vienna, Austria focusing on clinical research, development and distribution of medicines for rare and complex diseases. The company also provides individualized and customized services to meet and accommodate the needs of physicians and patients across Europe, the Middle East & Asia. Currently AOP Orphan is concentrating on rare and complex diseases in HematoOncology, Cardiology & Pulmonology, and Neurology & Metabolic Disorders.
AOP Orphan Pharmaceuticals AG
Wilhelminenstrasse 91/IIf, 1160 Vienna, Austria
Dr. Christoph Klade, Chief Scientific Officer
- 36 month analysis of ropeginterferon alfa-2b (Ropeg) phase III clinical data in Polycythemia Vera (PV) demonstrates superiority across three key aspects of disease control, including complete hematological response (CHR), disease burden, and molecular response
- A long-term development partner of Ropeg, AOP Orphan’s submission for marketing authorization of ropeginterferon alfa-2b in the EU is in the final stage of European Medicines Agency (EMA) regulatory review
- PharmaEssentia is continuing to discuss with the US Food and Drug Administration (FDA) the best path forward to make ropeginterferon alfa-2b available to PV patients in the US
- PharmaEssentia is planning to initiate a global clinical development program of ropeginterferon alfa-2b in Essential Thrombocythemia (ET)
Ropeginterferon alfa-2b maintains efficacy and safety profile in PV
Ropeginterferon alfa-2b is a novel, single isomer long-acting pegylated interferon in clinical development for treatment of patients with PV. At the 2018 American Society of Hematology (ASH) Annual Meeting, Prof. Heinz Gisslinger from the Medical University of Vienna, Austria presented the 36 month update of ropeginterferon alfa-2b in patients with PV (http://www.bloodjournal.org/content/132/Suppl_1/579).
PharmaEssentia CEO, Kochung Lin, PhD stated “We are very pleased to see that ropeginterferon maintains strong efficacy and good tolerability at 36 months. We truly believe that ropeginterferon is a next-generation and better interferon. We wanted to design a molecule that has a longer half-life and better tolerability, so it can be used at a higher dose and maximize its therapeutic potential. I believe we were successful in our design. The median maintenance dose in the PROUD-PV/CONTINUATION-PV trial is 450mcg. Now we are working very hard to make it available to patients with PV in the US and outside the US.”
After 36 months of treatment, maintenance of higher responder rates (full analysis set) was shown in the ropeginterferon alfa-2b arm compared to hydroxyurea/best available therapy (HU/BAT) for CHR (70.5% vs. 51.4%; p=0.0122) and for CHR plus symptom improvement (52.6% vs. 37.8%; p=0.0437). In contrast to HU/BAT, response rates were steadily increasing in the ropeginterferon arm throughout 24 months of treatment and remained constant after 36 months. Strongly significant molecular response in the JAK2 mutant allele reduction and the ability to reduce the non-JAK2 mutant clone burden suggest potential disease modification capability. Importantly, molecular response strongly correlated with CHR, emphasizing the clinical relevance of mutant JAK2 allele burden reduction.
Safety profile was similar to previous reports and no new safety signals emerged. Rate of adverse events (89.8% vs 90.6%) and treatment-related adverse events (74.8% vs 78.7%) were comparable between ropeginterferon alfa-2b and HU/BAT arms. No new safety signals appeared in the third year of treatment.
EMA submission of ropeginterferon alfa-2b in PV in final stage of review
PharmaEssentia out-licensed the exclusive rights to develop and commercialize ropeginterferon alfa-2b to AOP Orphan Pharmaceuticals AG (AOP Orphan) in PV, other MPNs, and CML for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.
AOP Orphan is the sponsor of PROUD-PV/CONTINUATION-PV clinical program and its submission for marketing authorization of ropeginterferon alfa-2b in the EU is in the final stage of European Medicines Agency (EMA) regulatory review.
Discussions with US Food and Drug Administration (FDA)
PharmaEssentia is in on-going discussions with the FDA on the best path forward to make ropeginterferon alfa-2b available to patients in the US.
Craig Zimmerman, PhD, the Head of US Operations, says “We have had fruitful discussions with the FDA on the best path forward in bringing the ropeginterferon to PV patients in the US. We have strong collaboration and support of the MPN community and medical experts, so we understand the large unmet need that exists in this patient population. We are doing everything we can to successfully bring this product to market.”
Expansion of ropeginterferon alfa-2b clinical program in MPNs
During ASH 2018, several clinical trial updates were presented on the use of interferons and interferon combinations in PV, ET, pre-fibrotic myelofibrosis (MF), and chronic myeloid leukemia (CML). These trials indicate potential interferon utility across multiple indications.
PharmaEssentia will hold preliminary discussion with the FDA in December 2018 on the feasibility of pivotal, phase III global clinical study in HU resistant/intolerant ET patients.
Additionally, because ropeginterferon alfa-2b can be dosed at much higher doses, the company can now investigate its potential effect in certain promising solid tumor indications.
About Ropeginterferon alfa-2b
Ropeginterferon alfa-2b is a novel, long-acting, predominately (>98%) single isomer mono-pegylated proline interferon (ATC L03AB15) with improved pharmacokinetic properties and demonstrated tolerability and convenience. It is administered once every 2 weeks, or once every 4 weeks during long-term maintenance, and is expected to be the first interferon approved for PV worldwide.
Ropeginterferon alfa-2b was discovered and is manufactured by PharmaEssentia in a Taichung plant, which was cGMP certified by EMA in January 2018.
Ropeginterferon alfa-2b has Orphan Drug designation in the European Union, Switzerland, and the United States of America.
About Polycythemia Vera
Polycythemia Vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. This condition may result in cardiovascular complications such as thrombosis and embolism, as well as transformation to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.
PharmaEssentia Corporation (Taipei Exchange:6446) is a global biopharmaceutical company delivering efficacious, safe and cost-effective therapeutic products for the treatment of human diseases while aiming to bring long lasting value to stakeholders. PharmaEssentia was founded in 2003 by a group of Taiwanese-American executives and high-ranking scientists from leading U.S. biotechnology and pharmaceutical companies in order to develop treatments for myeloproliferative neoplasms, hepatitis and other diseases. The company is committed to the improvement of health and quality of life for patients suffering from these diseases. The Company’s world-class cGMP biologics facility in Taichung was certified by the EMA in January 2018 and by the Taiwan Food and Drug Administration (TFDA) in December 2017. The Taichung plant is also designed and operated to be compliant with all US FDA requirements.
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Shan Chi Ku, Director of Business Development and Investor Relations
Telephone: +886-2-2655-7688 #7836
Myeloproliferative Syndromes: Clinical
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Clinical Trials with Agents Other Than JAK Inhibitors
Sunday, December 4, 2016: 4:30 PM
Marriott Grand 8-9 (Marriott Marquis San Diego Marina)
Heinz Gisslinger, MD1, Christoph Klade2*, Pencho Georgiev3*, AleksanderSkotnicki, MD, PhD4, Liana Gercheva-Kyuchukova, MD5*, Miklos Egyed6, Viktor Rossiev, MD7*, Petr Dulicek8*, Arpad Illes, MD, PhD9*, HalynaPylypenko, MD10*, Liliya Sivcheva11*, Jiri Mayer, MD12, Barbara Grohmann-Izay, MD2*, Hans Hasselbalch, MD13, Robert Kralovics, Ph.D.14 and Jean-Jacques Kiladjian, MD, PhD15
1Department of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
2AOP Orphan Pharmaceuticals AG, Vienna, Austria
3University Multiprofile Hospital for Active Treatment “SvetiGeorgi’, Plovdiv, Bulgaria
4Dept. of Hematology, Jagiellonian University, Krakow, Poland
5Teaching Unit of the Hematology Department, Multiprofile Hospital in Krakow, Krakow, Poland
6Department of Internal Medicine, Kaposi Mor Teaching Hospital, Kaposvar, Hungary
7Department of Internal Medicine II, Samara Kalinin Regional Clinical Hospital, Kaposvar, Hungary
8Department of Clinical Hematology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
9Department of Hematology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
10Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine
11First Department of Internal Medicine, Multiprofile Hospital for Active Treatment – HristoBotev, Vratsa, Bulgaria
12Department of Internal Medicine – Hematology and Oncology, Center of Molecular Biology and Gene Therapy, University Hospital and Masaryk University, Brno, Czech Republic
13Department of Hematology, Roskilde University Hospital, Roskilde, Denmark
14CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
15Centre d’InvestigationsCliniques (INSERM CIC 1427), Hopital Saint-Louis and Paris Diderot University, Paris, France
Background:Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients.
Study design:Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naive to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy.
Results:257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naive to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500μg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits).
This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%.
Conclusions:This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV.
Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade: AOP Orphan: Employment. Georgiev: Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer: AOP Orphan Pharmaceuticals:Research Funding; Novartis: Research Funding. Grohmann-Izay: AOP Orphan Pharmaceuticals AG: Employment. Kralovics: Qiagen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Research Funding. Kiladjian: Novartis: Research Funding; AOP Orphan: Research Funding.
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General Manager, U.S.
Meredith Manning joined PharmaEssentia as General Manager for the U.S. in 2020, bringing with her more than 20 years of experience in global commercialization and brand building for biopharmaceuticals and medical devices. She was most recently Chief Commercial Officer at resTORbio™, and previously served as Vice President of Global Product Strategy in Hemophilia for Shire (formerly Baxalta) and Baxter. She previously held a series of marketing leadership roles at Vertex® and Pfizer.
Meredith received a B.S. at Colorado College and an MBA from the University of Chicago Booth School of Business.
Jack Hwang, Ph.D.
General Manager, Taiwan
Jack Hwang joined PharmaEssentia in 2006 and has served as General Manager in Taiwan since 2015. With training in organic chemistry, he has held a series of leadership roles at prior companies, including as Senior Director at Optimer Pharmaceuticals, Senior Group Leader at Array BioPharma®, and earlier as a research scientist at Amgen® and Ligand® Pharmaceuticals.
Jack completed his Ph.D. in organic chemistry and post-doctoral fellowship in natural product synthesis at the University of Pennsylvania.
Albert Qin, M.D. Ph.D.
Chief Medical Officer
Albert Qin, who joined PharmaEssentia in 2017, brings more than 20 years of experience in the biotech and pharmaceutical industry with an emphasis on clinical development. Recent leadership roles include Chief Medical Officer at China Health Group, Chief Scientific Officer and Corporate Officer at SymBio Pharmaceuticals, and Medical Director at ImmunoGen™. Earlier in his career, he held clinical development and R&D roles at Pfizer, Bayer and Biogen®. At Biogen, he did innovative research and made discoveries related to cytokines, immunology, and gene therapy.
Albert completed his medical degree in the Department of Medicine at Shandong Medical University in China and his Ph.D. in biochemistry and molecular pharmacology at Harvard Medical School. He completed a visiting research fellowship at Brigham and Women’s Hospital.
Ching-Leou Teng, Ph.D.
Chairperson of the Board of Directors
Ching-Leou Teng offers extensive pharmaceutical science and development expertise to the PharmaEssentia team. After joining the company as head of operations in 2003, she became Chairperson in 2009. Prior to PharmaEssentia, Ching-Leou held multiple leadership roles in drug delivery research and pharmaceutical development at Ionis™ (formerly ISIS) Pharmaceuticals, and previously served as a reviewer in the Pharmacokinetics Evaluation Branch of the Division of Biopharmaceutics at the Food and Drug Administration (FDA). Early in her career, Ching-Leou was a registered pharmacist at hospitals in Taiwan.
Ching-Leou completed her B.S. in pharmacy at Taipei Medical College, followed by an M.S. in pharmaceutical science at North Dakota State University. She completed her Ph.D. and post-doctoral fellowship at the University of Michigan.
Ko-Chung Lin, Ph.D.
Founder and Chief Executive Officer
Ko-Chung Lin has led PharmaEssentia since 2002, driven by rich and diverse career experiences at leading U.S. pharmaceutical companies. He is recognized for medicinal chemistry advances in pegylation, including the invention of pegylated-interferon, that have led to the development and successful entry of multiple leading therapeutics. Prior to PharmaEssentia, Ko-Chung was head of the Adentri® and pegylated-Avonex® programs at Biogen®. Earlier in his career, he contributed to inventions in HIV in his research roles at Monsanto.
Ko-Chung received B.S. and M.S. degrees in chemistry from National Taiwan Normal University, his Ph.D. from the University of Missouri, and completed a post-doctoral fellowship at the University of Michigan.