Addex left reeling by liver safety scare

The future had been looking particularly bright for Addex Pharmaceuticals in recent weeks following positive phase IIb data from its lead programme ADX10059 in GERD, driving shares in the Swiss company to a 12-month high as hopes were raised that a lucrative licensing deal could be struck next year.

However, the last 24 hours have seen large dark clouds emerging to threaten this sunny outlook as liver toxicity concerns appear to have all but ended further development and licensing plans for ‘059. Trading in Addex’s shares was suspended today on early indications of at least a 30% decline in price, although the eventual share price dive could be greater when trading resumes tomorrow given the huge importance of the drug to the company. All hopes now rest squarely on the shoulders of a follow-on product, ADX48621, with Addex predicting the start of phase II trials in Parkinson’s disease and a co-development deal within the next 12 months.

Nasty surprise

Just one month ago hopes were high that Addex could emerge as the leader in the development of metabotropic glutamate receptor (mGluR) modulators, a class of drug that has attracted a great deal of interest from big pharma over the years but with so far limited success (Therapeutic focus - Addex could be leading the mGluR pack, November 17, 2009).

However, the positive data in GERD has now been overshadowed and overtaken by news yesterday that a phase IIb migraine prevention study was being ended prematurely due to a high incidence of liver toxicity associated with the product, after 28 days of treatment and even in the lowest dose group. Today, Addex went a step further and terminated all further development of ‘059 in chronic indications, including long-term treatment of GERD and migraine prophylaxis.

Which only leaves the short-term or even acute use of ‘059 in GERD as the drug’s last chance of resurrection. Full data from another phase IIb four week trial of ‘059 as an add-on therapy to PPIs in GERD is due in January, although it seems even spectacular safety and efficacy data is unlikely to be enough to save the product. Without conducting further lengthy and costly safety trials all potential partners will not want to touch the drug.

Class effect?

In a conference call today, Addex’s senior management stressed their surprise at the liver toxicity scare over ‘059, while strongly refuting any suggestions that the safety concerns could be down to a class effect from mGluR modulators.

This is entirely understandable given Addex’s entire technology platform is based around mGluR modulators, although potential partners will no doubt become more wary and circumspect of the class.

Instead, Addex hinted that it could be down to the specific pharmacological properties of ‘059, although drug-drug interactions, potentially with certain triptans, could not be ruled out at this stage.

As such, the company was keen to stress the structural and pharmacological differences between ‘059 and its follow on product ‘621, on which future hopes of validation now rest. Given that the metabolism of ‘621 is distinct from ‘059 the hope must be that similar liver toxicity issues do not emerge in wider trials of ‘621.

Desperately seeking partner

Although Addex currently has enough cash to last until the end of 2011, the company hinted that efforts to seek a development partner for ‘621 will be ramped up, not only to secure much needed cash and risk/cost sharing but also clinical expertise within the Parkinson’s area.

Phase I studies of ‘621 are complete and Addex plans to initiate a phase II trial in levodopa induced dyskinesia associated with Parkinson’s disease by the end of next year.

One obvious partner would be Addex’s Swiss compatriot, Novartis, currently developing AFQ056 in phase II for Parkinson’s and fragile X syndrome; AFQ056 is a similar mGluR5 antagonist to ‘621 and ‘059.

But having missed out on the opportunity of securing the best possible licensing terms for ‘059, the knock-on effect for any potential deal over ‘621 is likely to be a significantly less attractive or valuable contract.

However, given the way Addex is likely to be left reeling from this setback and the current bleak outlook, it seems likely the company will be more than happy just to secure a partner.

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