Yondelis: New approvals in the US and Japan
Yondelis (trabectedin) is a synthetic, marine-derived, intravenous anti-tumour drug originally isolated from the colonial tunicate Ecteinascidia turbinate. It has a novel mechanism of action, binding to the minor groove of DNA and interfering with cell division, gene transcription and DNA repair mechanisms causing apoptosis. It is approved in more than 80 countries for advanced soft tissue sarcoma (STS) after failure of first-line treatment or in patients who are unsuitable for the indicated first-line regimen (doxorubicin or ifosfamide), and for relapsed platinum-sensitive ovarian cancer (OC) in combination with pegylated liposomal doxorubicin (PLD, Doxil [US]/Caelyx [Europe], Janssen). Its first approval in the EU was for STS in 2007, with EMA approval in OC following in 2009, and the US and Japan for STS in 2015.
The US FDA approval of Yondelis is limited to the two most common forms of STS, liposarcoma and leiomyosarcoma, which were included in the pivotal clinical trial. However, we expect the drug to be used in all forms of STS given the limited alternative treatments.
Yondelis is sold by PharmaMar in Europe and is subject to partnerships with Janssen and Taiho Pharmaceuticals in the US/ROW and Japan respectively (deal structures are outlined in Exhibit 3).
Exhibit 3: Yondelis partnership deals
Partner |
Structure |
Economics |
Janssen (formerly Ortho Biotech products) |
August 2001: joint development and commercialisation licence agreement. Marketing rights to Europe (including Eastern Europe) retained by PharmaMar; ROW rights obtained by Janssen (Japan rights returned July 2008). |
Milestones: $20m upfront plus undisclosed milestones. Royalties: escalating double-digit depending on sales. |
December 2011: revised framework agreement for US with $110m of supplementary milestones. Janssen committed to complete two Phase III trials (one in relapsed ovarian cancer and one in L-sarcomas). |
Supplementary development milestones: totalling $110m in 2011-15 (split $25m in each of 2011, 2012, 2013 and 2014 and $10m in H115 – all received). |
Taiho Pharmaceuticals |
March 2009: development/commercialisation licence agreement for Japan. |
Upfront payment: ¥1bn (c $10m). Milestones: includes approval milestone. Royalties: double-digit. |
Source: Edison Investment Research, company data. Note: PharmaMar has exclusive manufacturing rights (supply on cost-plus basis).
Yondelis improved PFS in STS Phase III
The final data from the 577-patient trial Phase III trial, which supported the FDA approval of Yondelis in STS, were presented by Janssen at ASCO in June 2015 (PFS) and at the ESMO European Cancer Congress in September 2015 (final overall survival (OS) data). We note that the US approval application was submitted before the OS data were mature.
Exhibit 4 shows that treatment with Yondelis reduced the risk of disease progression or death (PFS) by 45% compared to dacarbazine (hazard ratio (HR) 0.55, p<0.0001). Median progression-free survival (PFS) was 4.2 months for Yondelis-treated patients vs 1.5 months for dacarbazine.
There was a non-significant numerical trend in median overall survival that favoured Yondelis by two weeks (13.7 months for Yondelis vs 13.1 months for dacarbazine, HR=0.93, p=0.49). The investigators noted that about 70% of patients received subsequent therapies in each group, and that the subsequent therapies were started significantly later in the Yondelis group (6.8 months vs 3.5 months for dacarbazine; HR=0.53; p<0.0001). The earlier use of post-study therapies with anti-cancer activity in the dacarbazine arm may have offset the benefit of Yondelis therapy and confounded the OS analysis.
Exhibit 4: Final data from Yondelis Phase III in STS show PFS benefit
|
|
|
Median (months) or % |
|
Hazard ratio |
p |
Yondelis |
Dacarbazine |
Secondary endpoints |
|
|
|
|
Progression-free survival |
0.55 |
<0.0001 |
4.2 |
1.5 |
Time to progression |
0.52 |
<0.0001 |
4.2 |
1.5 |
Overall response rate |
N/A |
0.33 |
9.9% |
6.9% |
Duration of response |
0.47 |
0.14 |
6.5 |
4.2 |
Primary endpoint |
|
|
|
|
Overall survival |
0.93 |
0.49 |
13.7 |
13.1 |
Additional analysis not listed as secondary endpoint |
|
|
|
Clinical benefit rate (CR+PR+SD≥18wks) |
N/A |
0.0002 |
34.2% |
18.5% |
Source: Demetri et al ASCO abstract June 2015, Pate et al ECCO abstract 3403 September 2015, Edison Investment Research. Note: CR = complete response; PR = partial response; SD≥18wks = stable disease for at least 18 weeks.
The pending launches of Yondelis in the US and Japan will be key drivers of earnings growth. We forecast peak sales in Japan of €130m in STS and assume a 15% royalty rate. In the US we forecast peak sales of $130m STS and assume an 11% royalty on initial sales, rising to 15% in 2020. PharmaMar will also earn a margin on sales of Yondelis raw material to Janssen.
We assume premium pricing in Japan (US$37,500, 40% higher than Europe) and in the US (US$41,250, 50% higher). In both these markets, Yondelis will enjoy orphan drug market exclusivity post-launch (for seven years in the US and 10 years in Japan).
Janssen is conducting an ongoing pivotal Phase III clinical trial of Yondelis in relapsed platinum-sensitive ovarian cancer. The 670-patient study is an event-driven trial (the final OS analysis will occur after 514 deaths) and is not expected to render final results until late 2018, although an interim analysis for futility/efficacy is planned (after 308 deaths). This trial will form the basis of potential marketing applications in the US and other countries where Yondelis is not yet approved for ovarian cancer. We forecast peak US sales of $150m for Yondelis in ovarian cancer if it eventually receives approval – we assume a 65% likelihood of approval.
Recruitment is also ongoing in a number of Phase II trials of Yondelis in combination with other anti-cancer therapies in both STS and ovarian cancer, as well other observational and post-authorisation trials that could support increased utilisation of the drug.
Phase II trials are also underway in meningioma and mesothelioma, which are potential new indications for Yondelis.