Profile: the sense in Antisense

The scientific community got a little excited about the potential of antisense therapies in the early 1990s, when there was a boom in research and the potential of the mechanism was first being realised.

Then RNA interference came along, with its army of short interfering RNAs stealing the headlines from its older brother. The antisense community has not gone away, however.

In fact, there is already one antisense drug on the market and more in late stage clinical trials. Antisense is 10 years ahead of siRNA-based therapeutics, if not more.

The drug on the market is Vitravene (fomivirsen), a therapy for retinitis caused by HIV-related cytomegalovirus infection. It was approved by the FDA way back in 1998, and is a validation of the technology for its maker, California-based Isis Pharmaceuticals, because it was the world’s first antisense therapy to be approved for clinical use.

More is on the way, with Isis recently signing a licensing deal with Genzyme for its second-generation, cholesterol-lowering antisense drug mipomersen.

Isis is probably the world’s leading antisense pharmaceutical company, with 18 drugs in development. It also has a number of partner biotech companies around the world that assist the company to develop drugs for certain indications.

One of those partner companies is Melbourne’s Antisense Therapeutics, which this year signed a significant agreement with Teva Pharmaceutical Industries, the Israeli pharma that is now in the world’s top 20 and is best known for its Copaxone, a non-interferon therapy for the treatment of relapsing-remitting multiple sclerosis, with global annual sales in excess of US$1billion.

The deal that Antisense has signed with Teva also involves MS and is an antisense therapy known at the moment as ATL/TV1102. The drug was first in-licensed by Antisense from Isis, and the deal now involves on-licensing the drug to Teva for further development into Phase III.

The Teva deal is a boost to Antisense, with up-front fees and milestone entitlements amounting to $6m for the year to 30 June 2008, and there is the potential for milestone payments of up to $100 million, contingent upon successful commercialisation. Isis receives part of these payments under the original licensing deal.

The Teva deal is validation of both the technology and Antisense Therapeutics’ strategy, Antisense’s research director, Dr Christopher Wraight, says. The company’s strategy, with its first drug at least, is to license in interesting prospects from the likes of Isis, use the company’s knowledge of antisense technology, and to bring that to Phase I and Phase II clinical trials.

“We have just reported the successful completion of our Phase IIa trial in MS patients – a big achievement for an Australian company,” Wraight says.

“A lot of the development that has gone into the Antisense therapeutic platform has been done by Isis. They’ve taken the technology to the point where we can now inject antisense drugs subcutaneously – no other delivery formulation is required. We know where the drugs go, they are stable and they are specific.”

---PB--- Pipeline

ATL/TV1102 is a novel antisense drug aimed at reducing disease activity in patients with relapsing-remitting multiple sclerosis. It is an inhibitor of CD49d, a subunit of Very Late Antigen-4 (VLA-4).

The inhibition of VLA-4 is aimed at preventing leukocytes from moving into inflamed tissue, thus halting the progression of disease. At the end of June this year, Antisense reported the results of its Phase IIa trial, showing a significant reduction in new lesions in the brains of RRMS patients.

Another application for VLA-4 inhibitors is asthma, in which inhibition of VLA-4 may reduce the activation of lung inflammatory cells as well as preventing leukocytes from entering the sites of inflammation.

Wraight says the inhaled version of the antisense VLA-4 inhibitor drug appears to be active at very low doses, based on early studies. Teva also has an option on this application.

Also in the Antisense pipeline is ATL1103, designed to inhibit the human growth hormone receptor. One application is acromegaly, a benign tumour of the pituitary gland which causes hypersecretion of growth hormone.

“The end result is over-stimulation of growth hormone receptors in the liver, with the liver then producing too much insulin-like growth factor-I (IGF-I). It’s a two-step process,” Wraight says.

“The problem in patients with acromegaly is that they have too much IGF-1 floating around in their bloodstream, and this causes soft tissue and bone overgrowth, and disproportionate organ growth. There can be serious complications, for example if the heart or kidneys are affected. Treatment involves surgery or pituitary ablation via radiation therapy, and many require further medication to control their IGF-1 levels.

“Our aim is to control IGF-1 levels by inhibiting the responsiveness of the liver to growth hormone. There are some key features of this project that are very exciting from a clinical development perspective – first, we can measure IGF-1 very conveniently via a simple blood test; second, normalisation of IGF-1 levels in the blood are highly indicative of the likelihood of clinical success.

“Even at the early clinical trial stage, we can get a really good feel for how well our drug is travelling by measuring its effect on IGF-1 levels. This is a big advantage as it means you can establish the drug’s activity before committing to more expensive and longer clinical trials”

There is also a potential application in diabetic retinopathy, with some studies suggesting that reduction of IGF-1 levels can be beneficial, he says.

Also in the pipeline is a prostate cancer application, this time targeting the IGF-1 receptor (IGF-1R). Antisense is collaborating with a group in Canada on this project, with a view to developing its ATL1101 candidate as an inhibitor of IGF-1R.

This receptor is best known as a member of the anti-apoptopic family of cell signalling molecules, which prolong cell survival by inhibiting apoptosis. Wraight says it is a surprise that there is not yet a drug approved targeting the receptor, considering the amount of research that has been done, particularly on IGF-1R activity and prostate cell tumourigenesis.

---PB--- Why antisense?

So why antisense as a mechanism, as opposed to the headline-grabbing RNAi? “Because it’s clinic-ready, that’s why,” Wraight says. “It has been developed specifically for use as a therapeutic drug, and you can’t say the same for siRNA.

“Double-stranded RNA-directed gene silencing has been a remarkable scientific discovery. However, RNAi has a long way to go before it will be refined enough for use as a broad clinical therapeutic platform. We’ve had a lot more time – 10 years roughly – to refine the antisense platform for the clinic.”

Antisense is a single-stranded synthetic DNA, or DNA-RNA hybrid, that will bind to a complementary messenger RNA, thereby silencing the message and turning off the gene, as opposed to the double-stranded synthetic siRNAs.

“We can talk for hours about why the focus is on one rather than the other – everyone has their own opinion – and the science itself is very exciting,” he says. “But so is antisense. Antisense is in the real world of treating disease. The question for antisense is not when will it be clinic ready, but instead which disease will we apply it to next?”

Wraight has been involved in antisense research since the early 1990s, when he was working at the Murdoch Childrens Research Institute in Melbourne as head of the Dermal Therapeutics Unit. Together with colleague Professor George Werther, he first became interested when developing an approach to psoriasis, another autoimmune disease, using antisense to silence IGF-1R. It started off with the use of an antisense inhibitor as a research tool, then developed into a concept for a new drug.

To take the psoriasis project further, Wraight knew he needed more funding than was available through the usual grant system. His team achieved proof-of-concept with the psoriasis drug and published a paper in Nature Biotechnology, and then he took off around the world to network and try to find a partner to take the drug to the next stage.

“I did a lot of travelling, went to a lot of meetings, did a lot of networking overseas – North America, Europe – but where do you think we found the partner? Toorak.”

That partner was Antisense Therapeutics, which he joined in 2003. Antisense was started when Toorak-based Circadian Technologies collaborated with Isis to launch a new Australian company to further develop antisense medicines.

Circadian was looking around for the leading antisense program in Australia to complete the picture for the new company, and this was Wraight’s project at the Murdoch Childrens. After a few years running the psoriasis program from the licensor side, he joined Antisense as research director.

In March this year, Wraight was named as the joint winner, with DendriMed research director Dr Raisa Monteiro, of the 2008 Advancing BioBusiness Award, a scheme established by Merck Sharp & Dohme and expat Australian business organisation Advance.

Part of the prize was a trip to BIO in San Diego and a tailored program of meetings with US biotech companies and key people. In all, he spent most of the month of June in the US, learning a great deal along the way.

“As an Australian scientist, it can be hard to find and maintain the contacts that you need in the various sectors of this industry: potential pharmaceutical company partners, investors, scientific collaborators and technology partners,” he says. “What the award does is tailor a series of meetings that allows you to penetrate that very important network in the U.S. It was extremely effective in that regard.

“It was an exciting month. The meetings really influenced the way I thought about R&D planning in early stage projects, and how to deal with large pharmaceutical companies. I was able to experience the way the different parts of the North American life sciences industry interact.

“One thing I hadn’t realised was the importance of physical proximity in the way people interacted. I really noticed this in Cambridge [Massachusetts] for example: venture capital firms located in the midst of iconic medical research institutes and Nobel Prize-winning scientists, right next to big name pharmaceutical companies and biotechs. You can literally walk around the corner and see who you need to see. You could sense the importance of familiarity and personal relationships in these successful US biotech hubs.”