Antisense shaken by MS drug trial suspension

Trading in shares of Melbourne drug developer Antisense Therapeutics (ASX:ANP) was halted today, in the wake of after the developers of the promising new multiple sclerosis drug Tysabri withdrew it from the market after a patient died from a rare viral infection of the brain.

The decision by Ireland's Elan Pharmaceuticals and its US partner Biogen Idec to holster the most promising new weapon against MS carved 3 per cent off the value of Ireland's stock market, and caused the value of Biogen Idec's shares to plummet by 65 per cent. Biogen Idec's shares fell 45 per cent to US$37.30, wiping around $10 billion from its market value, and cutting the American Stock Exchange biotechnology index by 6 per cent.

Where Tysabri is a humanised monoclonal antibody, Antisense's lead molecule is a gene-silencing therapy -- but both have the same cellular target, a cellular adhesion molecule (CAM) called VLA-4. Antisense's commercial fortunes are thus linked to those of Elan and Biogen Idec.

In a statement today, Antisense said it recently initiated a Phase IIa trial of its candidate ATL1102 in MS patients, but that the trial was a monotherapy study which tested the drug alone, unlike the Elan/Biogen Idec trial.

Antisense said it was now consulting with its trial investigators and others to ascertain the implications of the Elan/Biogen Idec trial.

Biogen Idec's CEO, Jim Mullen, said it would not take long for the companies to re-evaluate the clinical trials, but it could take some time to figure out a path forward for drug. Elan's CEO, Kelly Martin, said Elan did not believe the FDA wanted the drug removed from the market, and, barring further cases of PLS, the companies hoped to have Tysabri back on the market by the third quarter of this year.

Doubts

But internationally renowned MS researcher Prof Claude Bernard, of Melbourne's La Trobe University, is less confident of the drug's future -- or the future of any other therapy that targets VLA-4, which includes Antisense's candidate, ATL1102.

ATL1102, which has shown high promise in a mouse model of MS, effectively silence the VLA-4 gene in lymphocytes, preventing them expressing the cellular adhesion molecule on their surface.

A variety of lymphocytes, including monocytes, T-cells and macrophages, employ the VLA-4 molecule as a molecular passkey to enter the blood vessels serving the brain. Macrophages, in particular, are key initiators of the inflammatory reaction that primes the immune system to recognise and destroy infectious bacteria and viruses. By blockading the VLA-4 molecule, the drug excludes the lymphocytes from the brain, quenching the inflammatory reaction that, in MS patients, causes T-cells to attack the fatty myelin sheath that insulates the electrical activity of neurons.

MS causes muscle weakness, loss of coordination, and eventually, paralysis, as well as blurred vision, and impaired mental function and memory.

The US Food and Drug Administration approved Tysabri for clinical use only last November, after clinical trials showed it was 66 per cent more effective than a placebo in reducing symptoms and prolonging the intervals between relapsing bouts of MS, and also considerably more effective than current MS drugs, including interferon.

Brain infection

One of the MS patients being treated with a combination of Tysabri and Biogen Idec's established MS drug Avonex died after developing a rare, incurable brain infection, progressive multifocal leukoencephalopathy (PLA). A common polyomavirus infection of the brain causes PLA, and like MS itself, causes progressive demyelination of nerve cells in the brain and spinal cord.

PLA is rare in the general population, and occurs primarily in immunosuppressed individuals -- AIDS patients, people taking immunosuppressant drugs after organ transplants, and cancer patients whose immune systems have been ablated by radiation or chemotherapy.

Elan and Biogen Idec based their decision to withdraw the drug on the death of one patient from PLA and another suspected case. Both patients had been on the combined therapy for at least two years, and the companies noted that there was no evidence of the brain disorder in patients taking Tysabri alone.

They have also halted clinical trials of Tysabri in patients with rheumatoid arthritis and inflammatory bowel disease (Crohn's disease) -- these are also autoimmune, inflammatory disorders.

The withdrawal of Tysabri is a second blow for the Irish biotech -- Elan was previously forced to shelve a promising vaccine against Alzheimer's patients when it caused bleeding from the brain in early clinical trials.

The drug was expected to generate sales of more than $1 billion for the two companies, helping maintain Biogen Idec's revenues as its market-leading MS drug Avonex comes under increasing competition.

Promising beginnings

Bernard said a US research group led by Stanford University's Dr Larry Steinman was the first to demonstrate, in a mouse model of MS, that a monoclonal antibody that blocked VLA-4, dramatically reduced the symptoms of the disease.

"I was privy to the report on the results of their first clinical trial in humans, and it looked very promising indeed -- up to 70 per cent of the 700 patients had shown a significant reduction in symptoms or prolongation of their relapse interval," Bernard said.

"But what was alarming to me was that, after only one year, a number of patients in the experimental group, but not in the control group, had had a significant number of infections like influenza, and two had developed cancer.

"It looked to me like they were opportunistic infections and cancers. Using the monoclonal antibody is rather like using corticosteroids -- you might cure cancer, but you die of infections.

"Unfortunately, the monoclonal antibody is not specific to the autoreactive T-cells that attack myelin in the brain, nor is its activity restricted to the brain."

Asked whether patients severely ill with MS might be prepared to accept the risk of developing PLA, Bernard said, "My feeling is that they would, and unfortunately, biotechnology companies are well aware that patients will accept risks -- some are prepared to risk anaphylactic shock by using beestings every second today.

"My other concern is that this treatment is extremely expensive, and the more expensive a treatment, the less likely medical insurance companies are likely to cover the cost."

-- Additional reporting by Reuters