Sinopharm in-licenses AEZS-108 with $1 million upfront payment, necessary?

On December 2, Sinopharm A-Think Pharma (国药一心制药) in-licensed greater China rights to zoptarelin doxorubicin (AEZS-108, AN-152) for the treatment of endometrial cancer. The seller, Aeterna Zentaris (NASDAQ: AEZS),  will be entitled to receive a $1 million upfront payment.

AEZS-108 is a doxorubicin-LHRH conjugate, which was first reported by Andrew Schally in 1996[1]. It was designed as a magic bullet which targets cancer cells expressing LHRH receptors. The rationale is similar to that of antibody-drug conjugates.

LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers[2]. Although LHRH receptors are detected in healthy reproductive tissues, they are expressed only at low levels or not at all in other tissues.

The drug has been tested in patients with LHRH receptor positive endometrial cancer[3], ovarian cancer[4], prostate cancer[5], and triple-negative breast cancer. From April 2008 to November 2009, 44 patients with LHRH receptor positive advanced or recurrent endometrial cancer were treated with AEZS-108.

Two patients (5%) had a complete response, eight patients (19%) achieved a partial response, and twenty patients (47%) met the criteria for stable disease. The median time to progression (mTTP) was 7 months, and the median overall survival (mOS) was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).

The current standard therapy for advanced and recurrent endometrial cancer is the combination of cisplatin, doxorubicin, and paclitaxel (TAP therapy) which demonstrated an objective response of 57% and a mOS of 15.3 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (59%), thrombocytopenia (22%).

AEZS-108 achieved a comparable survival with lower toxicity than TAP therapy. In recent years, the combination of carboplatin and paclitaxel (TC therapy) has been commonly used in advanced and recurrent endometrial carcinoma[7,8]. More importantly, AEZS-108 achieved responses in patients who had previously received TC therapy. Aeterna Zentaris is currently conducting a Phase III trial (ZoptEC, NCT01767155) in platinum-paclitaxel pretreated endometrial cancer[9].

According to the analysis from Samreen Agha[10], the patents for AEZS-108 will expire in 2016. Don’t worry! The FDA has granted AEZS-108 orphan drug designation which provides a period of 7-year market exclusivity. Strangely enough, why should Sinopharm pay for intellectual properties which will expire before the approval of the CFDA?

[1] Proc Natl Acad Sci USA. 1996, 93(14), 7269-7273.

[2] Expert Opin Investig Drugs. 2012, 21(6), 891-899.

[3] Int J Gynecol Cancer. 2014, 24(2), 260-265.

[4] Gynecol Oncol. 2014, 133(3), 427-432.

[5] Clin Cancer Res. 2014, doi: 10.1158/1078-0432.CCR-14-0489.

[6] J Clin Oncol. 2004, 22(11), 2159-2166.

[7] Int J Gynecol Cancer. 2008, 18(4), 803-808

[8] Gynecol Oncol. 2008, 109(2), 250-254.

[9] J Clin Oncol 32:5s, 2014 (suppl; abstr TPS5630^).

[10] Samreen Agha. Aeterna Zentaris: A Risk Worth Taking. 2014-09-09.

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