ONIVYDE®
A Promising Future

BACKGROUND

ONIVYDE® (PEP02, MM-398, nal-IRI) is a proprietary liposome encapsulation of irinotecan, a topoisomerase 1 inhibitor. Irinotecan HCl (Camptosar®) is a broad spectrum anti-cancer cytotoxic drug approved for the treatment of colorectal cancer. The nanoliposomal formulation of irinotecan is designed to improve the pharmacokinetics, prolong circulating time, provide sustained release, reroute the drug from sites of toxicity, and increase tumor accumulation via the Enhanced Permeability and Retention (EPA) Effect.

PharmaEngine licensed the Asian (2003) and European (2005) development, manufacturing and commercialization rights of ONIVYDE® from Hermes Biosciences, Inc., South San Francisco, CA. PharmeEngine completed the preclinical studies, filing IND, Phase 1, and Phase 2 clinical studies in gastric cancer and pancreatic cancer during 2003 to 2011. PharmaEngine licensed the European, and Asian rights excluding Taiwan of ONIVYDE® to Merrimack in 2011. Merrimack sponsored a global phase 3 NAPOLI-1 study in metastatic pancreatic cancer patients who failed on prior gemcitabine-based chemotherapy in 14 countries worldwide during 2011 to 2014.

PATIENT RECRUITMENT

PharmaEngine facilitated the patient recruitment of NAPOLI-1 in Taiwan up to 23% of all 417 patients, which made Taiwan the top country in recruitment rate. In 2014, the positive top-line data from this study led Merrimack to grant the license of ONIVYDE® outside of the U.S. and Taiwan to Baxter International Inc. (NYSE: BAX), whose biopharmaceutical division was later spun off as Baxalta(NYSE: BXLT) in 2015. Shire plc (LSE: SHP, NASDAQ: SHPG) then acquired Baxalta in June 2016. Ipsen Group (NXTPA: IPN) licensed in the right of ONIVYDE® in the U.S. from Merrimack in April 2017.

In June 2015, following the new drug applications submission by Merrimack to the U.S. FDA in April, ONIVYDE® was granted the Priority Review Designation. In May 2015, Baxalta and PharmaEngine also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) and an NDA to the Taiwan FDA, respectively. Consequently, ONIVYDE® was granted orphan drug, fast track and priority review status by the U.S. FDA, as well as orphan drug designation and acceptance for review by the EMA. ONIVYDE® was approved by the US FDA and the TFDA in October 2015 and received marketing authorization (MA) from European Commission (EC) in October 2016. Up-to-date, ONIVYDE® was approved for the treatment of metastatic pancreatic cancer in a total of 38 countries worldwide.

Clinical Development

After completion of several preclinical and clinical studies, ONIVYDE® has been approved for pancreatic cancer patients who failed on prior gemcitabine-based treatment. Clinical trials are ongoing in other indications. So far, four phase 1 and three phase 2 trials have been completed. Phase 2 studies in gastric, pancreatic and colorectal cancers were presented at the 2011 ASCO GI, 2011 ASCO Annual Meeting, and 2015 ASCO GI.

In January 2012, Merrimack initiated a pivotal Phase 3 clinical trial of ONIVYDE® (PEP02, MM-398, nal-IRI) for the treatment of patients with metastatic pancreatic cancer who have previously failed with gemcitabine. This study is referred to as NAPOLI-1 (NAPOLI acronym: NAnoliPOsomaL Irinotecan). The primary endpoint was overall survival. Study sites included North America, the European Union, Latin America, Australia and Asia (including Taiwan). The Global Principal Investigator was Professor Daniel von Hoff, M.D., F.A.C.P. of TGen, University of Arizona, Mayo Clinic and Scottsdale Healthcare. NAPOLI-1 was a randomized, open-label Phase 3 study in patients with metastatic pancreatic cancer who received prior gemcitabine-based therapy. The study evaluated two ONIVYDE® regimens, 80 mg/m2 combined with 5-fluorouracil (5-FU) and leucovorin (LV) every two weeks, and 120 mg/m2 as a monotherapy every three weeks. Each ONIVYDE® regimen was compared against the control arm with 5-FU and LV on the primary endpoint of overall survival. A total of 417 patients were randomized across the three arms. Patients were enrolled at 76 sites of the 105 sites initiated in North America, South America, Europe, Asia and Australia. In January 2015, the expanded analyses presented at 2015 ASCO GI further corroborated the top line data presented at the ESMO GI 2014 on achieving overall survival improvement.

RECENT ANALYSIS

The recent updated overall survival analysis of Phase 3 NAPOLI-1 study of ONIVYDE® in combination with fluorouracil (5-FU) and leucovorin achieved a substantial improvement in 12-month overall survival in patients with post-gemcitabine metastatic pancreatic adenocarcinoma when compared to 5-FU and leucovorin alone. These data were presented at the American Society of Clinical Oncology 2016 Gastrointestinal Cancers Symposium (ASCO GI). Updated findings showed one in four patients treated with ONIVYDE® survived a milestone of one year or more: 12-month overall survival estimates of 26% (95% CI, 18-35%) for ONIVYDE® in combination with 5-FU and leucovorin, a 63% improvement when compared to 16% (95% CI, 10-24%) for 5-FU and leucovorin alone. The final report of the NAPOLI-1 study was published in The Lancet(vol. 387, pp. 545-557, Feb. 6, 2016). Compared to fluorouracil (5-FU) and leucovorin alone, the addition of ONIVYDE® generated a hazard ratio (HR) 0.67 (95% CI, 0.49-0.92) of overall survival, i.e., a 33% reduction of mortality risk.

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Market forecast

ONIVYDE® is the first drug approved for treating pancreatic cancer patients who have failed on the first-line treatment. Pancreatic cancer is a highly malignant disease with patients usually diagnosed at an advanced stage. It is the third leading cause of death, with about 43,000 patients dying of this disease in the U.S. every year. In Taiwan, pancreatic cancer is also responsible for about 1,900 deaths every year. Pancreatic cancer will overpass colorectal cancer to be the second leading cause of cancer death, just behind the lung cancer, in 2020.

New clinical indications for the future development of ONIVYDE® include frontline pancreatic, colorectal, gastric, lung, and brain cancers. ONIVYDE® also has the potential to provide synergistic effect of combining with novel anti-cancer agents. The market value of ONIVYDE® will increase tremendously over time.

Indications & Stages

ONIVYDE PEP02

(Irinotecan liposomal injection)

Pancreatic Cancer (2nd-line)
Pancreatic Cancer (1st-line)
Small Cell Lung Cancer (2nd-line)
Various ISTs

References

Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial

Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Lancet. 2016; 387: 545-57

Management of metastatic pancreatic cancer: Current treatment options and potential new therapeutic targets

Sclafani F, Iyer R, Cunningham D, Starling N; Crit Rev Oncol Hematol. 2015; 95: 318-36

Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goere? D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, Arnold D; Ann Oncol. 2015; 26 Suppl 5: v56-68

Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients

Chang TC, Shiah HS, Yang CH, Yeh KH, Cheng AL, Shen BN, Wang YW, Yeh CG, Chiang NJ, Chang JY, Chen LT; Cancer Chemother Pharmacol 2015; 75: 579–86

A multinational phase II study of liposome irinotecan (PEP02) for patients with gemcitabine-refractory metastatic pancreatic cancer

A. H. Ko, M. A. Tempero, Y. Shan, W. Su, Y. Lin, E. Dito, A. Ong, G. Yeh, L. Chen; Br J Cancer 2013; 109: 920–25

A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma

Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A; Ann Oncol. 2013; 24: 1567–73

Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts

Krauze MT, Noble CO, Kawaguchi T, Drummond D, Kirpotin DB, Yamashita Y, Kullberg E, Forsayeth J, Park JW, Bankiewicz KS; Neuro Oncol. 2007; 9: 393-403

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