Gilead's hep C failure hurts LG and questions caspase inhibitors


Just days after reporting encouraging phase II data for GS 9450 as a potential treatment for liver damage caused by non-alcoholic steatohepatitis (NASH), Gilead Sciences announced late on Monday that a phase II trial of the same drug in chronic hepatitis C has been terminated on safety concerns, raising serious doubts about the product’s future.

This is yet another setback to Gilead’s plans to diversify its product portfolio away from its phenomenally successful HIV franchise, over which generic companies are launching increasingly bold attacks on its key patents. But the real damage from this news has been inflicted on LG Life Sciences, the Korean company which discovered GS 9450, a caspase inhibitor; LG shares have dipped 11% to a 12-month low of W47,200 in response. This is potentially bad news as well for the overall field of caspase inhibition - GS 9450 was the most advanced candidate - and companies like CytRx, which is seeking a partner for its phase I caspase product (see table below).

Worrying safety signal

Gilead’s official statement on GS 9450 was on the terse side, saying the trial in hepatitis C had been abandoned because of “reports of significant laboratory abnormalities and adverse events in a number of clinical study participants.”

There was no information on the extent or nature of these abnormalities and adverse events, although Gilead is currently assessing the drug’s future clinical development. The omens do not look good, however, and the chances of GS 9450 building on its encouraging data in NASH look slim indeed.

This will naturally be disappointing and frustrating for Gilead, which had highlighted the product as a key pipeline candidate last year, but LG is hurting more. Gilead licensed the product in 2007 for $20m upfront and up to $182m in milestones, and this news looks like being a significant setback to one of LGLS’ most important pipeline candidates.

Questions over caspases

Caspases, otherwise known as cysteine aspartyl proteases, play a critical role in activating apoptosis or programmed cell death. Activating or inhibting caspases, therefore, offers a logical pathway to treat a wide range of disease. Activating caspases within cancer cells can stimulate and accelerate tumour cell death, while inhibiting caspase activity could reduce cell death and therefore tissue damage, such as that involved in NASH.

Despite the apparent suitability of caspases as viable targets to treat a range of acute and chronic diseases, the field appears to have attracted minimal attention so far from pharmaceutical and biotech companies.

According to pipeline data from EvaluatePharma, there are just five caspase activators and only four caspase inhibitors in development, although that is likely now to drop to three when GS 9450 is formally abandoned.

The table below shows the caspase inhibitors in development with Gilead by far the largest company to have dabbled in this field. The classical big pharma companies are conspicuous by their absence, although Pfizer had been involved in the development of what was previously the most advanced candidate, emricasan. However, this candidate was only in Pfizer’s R&D portfolio as a result of its 2005 acquisition of Idun Pharmaceuticals and the product was eventually ditched during phase II trials in 2008. No reason was provided at the time.

Which just leaves CytRx’s iroxanadine as the only other clinical stage candidate. Just last month, CytRx had reiterated its desire to partner or spin out this candidate, along with arimoclomol. Gilead’s news this week could just have poured a large dose of cold water on that ambition.

Caspase inhibitors in active development
Status Product Company Originator Therapeutic Subcategory Indication Summary
  Phase II GS 9450 / LB84451 LG Life Sciences + Gilead Sciences LG Life Sciences Cholagogues Hepatitis C treatment [Phase II]; Liver disorders [Phase II]; Pulmonary fibrosis, idiopathic [Research project]
  Phase I Iroxanadine CytRx Biorex Other cardiovasculars Ulcers, diabetic foot [Phase I]; Diabetic complications [Pre-clinical]; Atherosclerosis [Pre-clinical]; Stroke prophylaxis [Pre-clinical]
  Pre-clinical EP1013 / F1013 EpiCept + GNI Cytovia Anti-virals Hepatitis B treatment [Pre-clinical]; Renal failure, acute [Pre-clinical]
  Research project LB84318 LG Life Sciences + Gilead Sciences LG Life Sciences Cholagogues Liver disorders [Research project]

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