Takeda Pharmaceutical Co’s late-stage pipeline has suffered a major blow with the news that US regulators have asked for more information about lapaquistat, the Japanese drugmaker’s investigational compound for cholesterol amid fears it may cause liver damage.

The US Food and Drug Administration has requested additional clinical data prior to the firm’s submission of a New Drug Application for TAK-475 (lapaquisat) and also recommended suspension of studies with higher doses, ie 100mg. The latter request comes after the FDA was alerted to an increases in the enzyme transaminase, which may indicate liver damage, with the 100mg dose of TAK-475, “including severe cases,” compared to control groups in a pooled analysis of Phase II and III studies completed in the U.S. and Europe.

Takeda noted that this elevation of transaminase has not been observed to date with the lower doses of TAK-475, ie 50mg, where frequencies are comparable to control groups. However the fact that the FDA wants to see additional clinical studies will delay the filing of Takeda’s scheduled US NDA submission for the drug in the first quarter of fiscal 2008, or between April and September next year.

The company said that it is discussing the structure of the trials with the FDA and talks about the future development of TAK-475 in Europe and Japan, where Phase III and Phase II studies are being conducted respectively, are ongoing with the relevant regulatory authorities. Lapaquisat belongs to a new class of drugs called squalene synthase inhibitors, which decrease circulating low-density lipoprotein cholesterol by the induction of hepatic LDL receptors in a similar manner to statins.

The news has had a shattering effect on Takeda’s stock and its shares fell to their lowest level for 20 years, down by the Nikkei 225’s maximum daily limit of 1,000 yen, or 12%, to 7,060 yen, as investors feared that TAK-475 may never make it to market. The principal problem facing the firm is the lack of any replacement for its blockbuster diabetes drug Actos (pioglitazone), which will face generic competition in 2011, and lapaquisat was supposed to partially fulfil that role.

The fact that Takeda has not launched a new drug in the USA since September 2005 – Rozerem (ramelteon) for sleeping disorders – has also alarmed analysts. As well as TAK-475, its other Phase III drugs include TAK-491, an angiotensin receptor blocker which it hopes to succeed one of its big earners Blopress (candesartan), the proton pump inhibitor TAK-390MR (dexlansoprazole) and the dipeptidyl peptidase-4 inhibitor SYR-332 (alogliptin) for diabetes.