BIO 2008: Starpharma's thoroughly modern microbicide

Starpharma has been on the Australian biotech scene for some time now and is progressing very nicely indeed with its wide portfolio of applications for the company's dendrimer-based nanotechnology.

In the last year, it has announced deals with some big names in the biotech and pharma world, including SSL, manufacturer of the world's leading condom brand, Durex; EMD Biosciences, which is part of Merck KgaA.; Unilever, and Stiefel Laboratories, the world's largest independent specialist in dermatological pharmaceuticals.

All of those deals are for distinct, seemingly unrelated applications - one for a coating on condoms, one for a siRNA transfection kit and the other for drug delivery purposes - but all are based on the company's dendrimer technology.

It is also in Phase II expanded safety trials for its microbicide VivaGel, under development for the prevention of transmission of HIV and HSV-2 (genital herpes), and there are potential applications in human papillomavirus (HPV) in the future.

The compound has also been shown in animal models to be an effective contraceptive.

Dr Jackie Fairley, the company's CEO since 2006, describes dendrimers as highly defined large molecules or nano-particles.

"They are much larger than a typical drug and are more similar in size to something like a protein in the body, like albumin," she says. "They are a highly defined synthetic macro-molecule, very versatile in their potential applications."

Dendrimers can be used as drugs themselves, as in VivaGel, but also as drug delivery agents, she says. "They can act as a scaffold to carry other drugs, such as small molecule drugs or protein drugs, and they also can be used in diagnostics and the delivery of siRNA and non-pharmaceutical and non-life science applications.

"If you think of them as a class, an analogy might be something like when the class of silicons were discovered -they had very broad applications in a whole lot of areas."

The technology was first developed some years ago by the now defunct Biomolecular Research Institute and forms the platform technology of Starpharma, which was set up by founding scientist Professor Peter Colman and founding CEO John Raff. It also includes the work of US based Dendritic Nanotechnologies, a company acquired by Starpharma two years ago.

The company constructs dendrimers by taking a small core molecule and then repeatedly adding a lysine branching unit until a spherical nano-particle is created.

SPL7013 is its lead candidate and forms the active ingredient in VivaGel, a topical vaginal microbicide which Starpharma believes is the only microbicide in clinical development for the prevention of transmission of HIV and genital herpes.

"It is a topical gel not dissimilar to something like a lubricant gel," Fairley says. "It is a water-based, colourless, tasteless and odourless gel and it contains one of these dendrimers, which is an antiviral agent. It is delivered using an applicator, 3.5 grams of gel delivered prior to intercourse and the antiviral component of the gel interacts with viral particles which the woman is exposed to, inactivating those particles to prevent them from invading the human cells."

VivaGel has some high level backing, with the US FDA giving it Fast Track status and the US National Institutes for Health granting Starpharma US$20 million for the HIV aspect and further funding for genital herpes.

It is the only genital herpes microbicide trial with funding from the NIH. While the market in the developed world for a topical microbicide is obvious, it is the potential in the developing world that has raised a great deal of interest.

"Condom use, whether it is in developing or developed countries, is extraordinarily low, even though they are a well-established, effective means of preventing the spread of diseases like HIV," Fairley says. "But you would find in areas like Africa where HIV is a huge problem condom usage is quite low.

"Vaccine strategies for HIV and genital herpes have proven to be unsuccessful. None of them have been shown to have acceptable results in trials so as a result of that microbicides offer the only option for prevention apart from abstinence or condoms.

"So there is obvious application in developing countries but this product is a very attractive concept in the developed world as well because women want to have control over their own health outcomes.

"Market research tells us very strongly that women are far more concerned about sexually transmitted diseases than men are and rightly they should be because it is much easier to become infected as a woman. So it's the ability to have control over your own health and protect yourself, independent of whatever happens later in the evening and whether or not a condom is used."

---PB--- Viva VivaGel

Human papillomavirus is another potential application, with in vitro studies carried out by Professor Ian Frazer at the University of Queensland and Dr John Schiller at the National Cancer Institute in the US both demonstrating recently that the compound showed potent inhibition of HPV.

Further, VivaGel has been shown to have a highly contraceptive effect as well. "It appears to act via a couple of different mechanisms, one of which is inhibiting an enzyme called hyaluronidase, which is important in the fertilisation process, and it also inhibits acrosin, which is also important in fertilisation," Fairley says. "It inhibits a couple of key enzymes."

A product that prevents the transmission of HIV and herpes, and is a potent contraceptive is a product category that is pretty attractive. And the hyaluronidase link is providing even more food for thought. Hyaluronic acid, which hyaluronidase acts upon, is found throughout the body but is very concentrated in the joints and in the liquid component of the eye.

"Hyaluronidase activity is higher in arthritic conditions and so something which inhibits that activity would be desirable to try to limit the breakdown of hyaluronic acid," she says. "This drug has a very interesting mechanism. So there are applications in arthritis and also in cosmetic applications, because hyaluronic acid is widely used in cosmetics, both topically and as one of the substances that is injected in cosmetic procedures as a filler for wrinkles."

And there's more. In October last year, Starpharma signed an agreement with SSL, owner of the famous Durex brand, in which the two companies will work together to develop a VivaGel-based coating for condoms to provide additional protection.

Fairley says this opportunity came out of general dissatisfaction with nonoxynol-9, which has been used for many years as a coating but which has proved to be a highly irritant substance, particularly unwelcome in a delicate area of a person's anatomy.

"Condom manufacturers will tell you that they receive complaints that the nonoxynol-9 coated condoms will remove the varnish from a wooden table and the nail polish from women's fingernails. So if you could imagine that coming into contact with vaginal mucosa - not surprisingly it has some relatively harsh effects.

"N-9 has been shown in Africa to increase women's risk of both HIV and human papillomavirus, so there is a desire to replace that with something which is effective but safe."

---PB--- siRNA transfection

While Starpharma is concentrating hard on its VivaGel product, the use of its dendrimer technology is also being explored in a number of areas. In October last year it announced a research project with the Baker Heart Research Institute in Melbourne to develop a novel imaging agent for vascular disease.

In this project, dendrimers will be used as a scaffold on which to orient other molecules. The dendrimer will act as a carrier of an imaging agent, which will track down a specific antibody that binds to the damaged surfaces of blood vessels, and then will be picked up by MRI.

Starpharma's US-based subsidiary Dendritic Nanotechnologies (DNT) is working with Unilever on another imaging application, this time using the Priostar range of dendrimers to analyse the microscopic structure of foods. Priostar will also be used as part of a new siRNA transfection kit called NanoJuice, launched in April, that DNT is developing with EMD Biosciences, an affiliate of Merck KGaA.

"The Priofect dendrimer is just a different class from the others, and in this case we are using the dendrimer as a carrier not of a drug but of siRNAs," Fairley says. "We have retained all the rights for the therapeutic applications of this technology but we have licensed the in vitro use.

"One of the benefits of dendrimers is that unlike the other products that can be used for siRNA transfection, we will include more than one dendrimer type. What we have found is that certain cells like certain transfection-sized dendrimers, so by providing a variety of them, people can tailor what works best for their cells. It is a hugely exciting area and delivery of siRNA therapeutically is the Holy Grail."

And finally, Starpharma has a deal with the German company Stiefel Laboratories in a drug delivery application, in which the dendrimers will be used to deliver drugs through the skin.

"This is a situation where you have an existing dermatological product but the active ingredient in that product is not entirely satisfactory and has some elements you want to improve upon. So you take that same active ingredient and attach it to a dendrimer and the dendrimer acts as a controlled release reservoir of that drug and improves the solubility.

"That is a way of improving existing drugs and is an important area of concentration for Starpharma, because one of the very attractive things in the pharmaceutical industry is to improve upon or extend the life of existing agents, and we find that is an area of quite significant commercial demand."