Questions LHRH Antagonists

August 18, 2009 Æterna sinks on BPH data; questions LHRH antagonists

Evaluate Vantage

The failure of Æterna Zentaris’ cetrorelix in phase III trials to demonstrate adequate efficacy in treating benign prostatic hyperplasia (BPH) has burst the bubble created by the Canadian company’s recent deal with Sanofi- Aventis over the product (Æterna rockets on Sanofi-Aventis deal, March 10, 2009), sending Æterna’s shares down 60% yesterday to C$1.21.

Whilst clearly a massive disappointment for Æterna, the results also raise further question marks over the viability of the class of drug that cetrorelix belongs to, luteinizing hormone-releasing hormone (LHRH) antagonists, in treating urological disorders and prostate cancer. For Æterna and other companies developing similar compounds, such as Neurocrine Biosciences, hopes for cetrorelix and the class in general now switch to the results of a second pivotal trial of the drug, due in November.

Surprising results

The Sanofi deal, which gave Æterna $30m upfront in return for US rights to the drug in BPH, and encouraging phase II data had raised expectations for positive pivotal trial results. Prior to yesterday’s share price crash, Æterna’s stock had risen five-fold this year to reach a high of C$3.11.

Results from the first phase III efficacy trial, called Z-033 which enrolled 667 BPH patients in the US and Canada, showed no overall efficacy advantage with cetrorelix compared to placebo.

The line taken by the company in its official release of the data and subsequent conference call was one of surprise that the results had not come anywhere close to matching the efficacy previously demonstrated in phase II studies.

The company now appears to be hanging all its hopes for the drug on a positive read out from the second phase III trial, called Z-036 which has enrolled 420 patients mainly in Europe, expected to be released in November.

Until then the ultimate fate of the drug remains in the balance, although analysts are not hopeful given that the second trial is similar in design and that typically the FDA requires at least two positive pivotal data sets for approval to be granted.

As such, even if the second trial is positive, a further confirmatory phase III trial may yet be required, delaying the potential launch of the product by two to three years.

Questions over LHRH antagonists

While agonists of LHRH, such as AstraZeneca’s Zoladex and Takeda’s Lupron, have become effective and hugely commercially successful drugs in treating a range of cancers, particularly prostate tumours, the jury remains out on their antagonist counterparts.

Although LHRH antagonists, including cetrorelix, have been approved and marketed for some years as fertility agents, their use in treating prostate cancer and a range of urological disorders, including BPH, endometriosis and uterine fibroids, has so far failed to impress.

Despite the fact this class of drug has been researched and developed for many years, the following table shows the limited number of LHRH antagonists that have made it into development, just 17 products overall, of which 9 have been discarded and the one approved product subsequently withdrawn due to poor uptake by physicians. Count of LHRH antagonists for urological disorders

Phase Count

Withdrawn 1

Phase III 2

Phase II 1

Phase I 2

Pre-clinical 1

Research project 1

Abandoned - Phase II 3

Abandoned - Phase I 4

Abandoned - Pre-clinical 2

Total 17

Source: EvaluatePharma

The one approved LHRH antagonist, Praecis Pharmaceuticals’ Plenaxis, was launched in 2004 only to be withdrawn less than two years later as very few doctors were prepared to use the drug. The writing had been on the wall for the product following its rejection by no fewer than four major partners on the drug, Aventis, Roche, Amgen and Schering AG.

The table below reveals the currently active LHRH antagonists in development for urological disorders. Aside from cetrorelix, Æterna’s ozarelix and Neurocrine’s elagolix are the next most advanced pipeline candidates.

Having reported somewhat mixed phase II data last year for ozarelix in treating men with lower urinary tract symptoms, Æterna and partner Spectrum Pharmaceuticals initiated a large phase III trial for ozarelix in March, the final data from which will not be available until 2011.

Meanwhile Neurocrine presented less than convincing phase II data earlier this year for elagolix in treating endometriosis which has subdued hopes of finding a partner before phase III trials can start (Neurocrine punished for uncertainty as phase II data rolls in, March 26, 2009). The negative cetrorelix data is unlikely to help Neurocrine’s cause.

Given that Ardana’s failure to secure a partner for another LHRH antagonist, Teverelix LA, ultimately led to the collapse of the UK company a year ago (Ardana admits defeat and calls in administrators, June 30, 2008), the signs continue to look bleak for this class of drug ever proving itself to be an effective new treatment for urological disorders and prostate cancer. LHRH antagonists in development for urological disorders and prostate cancer

Market Generic Product Company Indication Summary Status Name

Praecis Prostate cancer [Withdrawn]; Endometriosis Withdrawn Plenaxis abarelix Pharmaceuticals [Abandoned]

Æterna Zentaris BPH [Phase III]; Endometriosis [Phase II]; Uterine Phase III Cetrorelix cetrorelix + Sanofi- fibroids [Abandoned] Aventis

Æterna Zentaris BPH [Phase III]; Prostate cancer [Phase II]; Ozarelix ozarelix + Spectrum Endometriosis [Phase I] Pharmaceuticals

Endometriosis [Phase II]; BPH [Phase I]; Uterine Elagolix (NBI- Neurocrine Phase II elagolix fibroids [Abandoned]; Prostate cancer 56418) Biosciences [Abandoned]

Phase I TAK-385 - Takeda Endometriosis [Phase I]; Uterine cancer [Phase I]

GTX-758 - GTx Prostate cancer [Phase I]

Endometriosis [Pre-clinical]; Uterine fibroids Pre- Æterna Zentaris ZEN-019 - [Pre-clinical]; BPH [Pre-clinical]; Breast cancer clinical + Solvay [Pre-clinical]; Prostate cancer [Pre-clinical]

GnRH Research antagonist Neurocrine Endometriosis [Research project]; BPH - project back-up Biosciences [Research project]; Uterine fibroids [Abandoned] compound

Source: EvaluatePharma