(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione

doxorubicin

Jan. 25, 2013

LINK

Heat–activated liposome encapsulated doxorubicin – NIHR Horizon …Heat–activated liposome encapsulated doxorubicin (ThermoDox) for hepatocellular carcinoma.

Zhejiang Hisun Pharma inlicenses China rights to liver cancer drug (ThermoDox) from Celsion Corporation

About ThermoDox

The study is designed to evaluate the efficacy of ThermoDox® in combination with RFA when compared to patients who receive RFA alone as the control. The primary endpoint for the study is progression-free survival (PFS) with a secondary confirmatory endpoint of overall survival.  ThermoDox® has been granted orphan drug designation in both the U.S. and Europe.  In addition to meeting the U.S. FDA and European EMA enrollment objectives, the Phase 3 Study has also enrolled a sufficient number of patients to support registration filings in China, South Korea and Taiwan, three of the largest potential markets for ThermoDox® around the world.

Terms of the Deal

Under the terms of the agreement, Hisun will pay $5 million to Celsion immediately, while Celsion will provide Hisun with support for its ThermoDox® manufacturing development program. This payment is non-refundable and comes in advance of Celsion’s expected reporting of results from its pivotal Phase III trial (the HEAT Study) in hepatocellular carcinoma (HCC), also known as primary liver cancer later this month.

In addition, the companies anticipate signing an agreement in which Celsion provides Hisun an exclusive option to license ThermoDox® for the Greater China market, which includesChina, Hong Kong and Macau. This option period will be secured by a second $5 millionpayment that must be received by Celsion from Hisun within 60 days after execution of the Technology Development Agreement.  The key provisions of the anticipated license agreement have been negotiated and agreed to by the parties and provide a basis for a definitive contract.  These provisions are:

• A credit of $10 million from the two payments ($5 million for the technology development agreement and $5 million for the exclusive option) toward a non-refundable upfront license payment of $25 million due to Celsion at signing of the definitive license agreement.
• An approximate 10 year total value to Celsion of well over several hundred million US dollars, which includes:
  • $55 million in upfront milestone and regulatory milestone payments within the next 18 months;
  • $45 million in milestone payments for reaching certain sales targets; and
  • Escalating double-digit royalties on net sales of ThermoDox® in the Greater China Territory.
• Hisun will serve as both the manufacturer and distributor of the ThermoDox® drug product for the Greater China Territory, and also take responsibility for local regulatory activities including submitting approvals in China to the state Food and Drug Administration (sFDA).

Deal Rationale

“Pursuing this arrangement with Hisun allows us to evaluate the fastest path to the Chinamarket, potentially the largest opportunity in the world for ThermoDox®.  A long-term partnership will provide the greatest synergies with respect to sales, marketing, distribution, and manufacturing, which could ensure significant value to the ThermoDox® asset,” saidMichael H. Tardugno, Celsion’s President and Chief Executive Officer.  “In addition, this partnership provides Hisun and Celsion with immediate access to an accelerated pathway for sFDA review and approval of ThermoDox®, a business strategy with exceptional potential to serve China’s HCC population, and strong, uncompromised economics for both parties.”
Mr. Hua Bai, CEO and Chairman of Hisun, stated, “We are extremely excited to pursue this arrangement with Celsion.  Hisun is well positioned to provide ThermoDox® — potentially one of the most important and innovative drugs to treat HCC to patients in China, the world’s largest market. China is one of the countries with the highest HCC incidence and mortality and, up until now, there has not been any standard of care for treating HCC in China.

This joint effort will most likely facilitate the local manufacturing and commercial launch inChina, thereby providing physicians with more options for better care and prolonging the survival of HCC patients.  In the meantime, we are also hopeful that this collaboration will enable Hisun to increase its focus on more innovative drugs.  Given the fact that we are a leading Chinese pharmaceutical company with international standards of R&D and manufacturing technology, Hisun will seek to manufacture and supply the global markets, along with distribution exclusivity in Greater China.  This venture will help spearhead Hisun’s globalization in manufacturing and commercialization capabilities.”

About Primary Liver Cancer 
Primary liver cancer is one of the most deadly forms of cancer and ranks as the fifth most common solid tumor cancer. The incidence of primary liver cancer today is approximately 26,000 cases per year in the United States, approximately 40,000 cases per year in Europeand is rapidly growing worldwide at approximately 750,000 cases per year, 55 percent of which are in China, due to the high prevalence of Hepatitis B and C in developing countries. . The World Health Organization estimates that primary liver cancer may become the number one cancer worldwide, surpassing lung cancer, by 2020.
The standard first-line treatment for liver cancer is surgical resection of the tumor; however, 90% of patients are ineligible for surgery. Radio frequency ablation (RFA) has increasingly become the standard of care for non-resectable liver tumors, but the treatment becomes less effective for larger tumors. There are few non-surgical therapeutic treatment options available as radiation therapy and chemotherapy are largely ineffective in the treatment of primary liver cancer.

Doxorubicin  trade name Adriamycin; also known ashydroxydaunorubicin) is a drug used in cancer chemotherapy. It is an anthracyclineantibiotic, closely related to the http://en.wikipedia.org/wiki/Natural_product” rel=”nofollow”>natural product daunomycin, and like all anthracyclines, it works by intercalating DNA, with the most serious adverse effect being life-threatening heart damage. It is commonly used in the treatment of a wide range of cancers, includinghematological malignancies, many types of carcinoma, and soft tissue sarcomas.

The drug is administered intravenously, as the hydrochloride salt. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.^[2] Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.

Doxorubicin is available in liposome-encapsulated forms as Doxil, Caelyx and Myocet.

Doxorubicin is commonly used to treat some leukemias and Hodgkin’s lymphoma, as well as cancers of the bladder, breast, stomach,lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.^[2] Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere, CA), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP, CHOP(cyclophosphamide, Adriamycin, vincristine, prednisone) and FAC (5-fluorouracil, Adriamycin, cyclophosphamide).

Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi’s sarcoma.^[7]

Cartoon diagram of two doxorubicin molecules intercalating DNA, from PDB1D12.