BIO profile: Apollo prepares for lift-off

Sydney-based Apollo Life Sciences has taken a very smart approach to its business. It has developed a diversified portfolio of products and platforms that enables it to generate revenue while investing heavily in its own R&D, the ultimate goal being needle-free delivery of large molecule drugs.

This approach is no surprise considering its founder and CEO is John Priest, a businessman who has become, in his words, captivated by science. Priest spent two decades helping to turn a tobacco company into the world's leading beverage manufacturer and bottler, now known as Coca-Cola Amatil.

Having done his job with the global giant - which included extensive experience setting up bottling plants in eastern European countries only recently emerged from behind the Iron Curtain - Priest was looking around for an interesting investment opportunity and just happened to meet a few scientists.

"I became captivated by the science and the opportunities that could be opened up by finding better solutions for the problems all we baby boomers will face as we age," Priest says.

"Over the last four or five years I've been building a life sciences company that is focused on two major unmet needs." Those two needs are large molecule therapeutics, and delivery platforms that get the therapeutics to where they are needed most, without needles.

"I suspect many people don't realise, until they are facing it themselves, that the newer biotherapeutic drugs generally have to be injected," he says. "And nobobdy likes injections. That's why we're working to develop alternatives."

Apollo Life Sciences has three major strings to its bow: it has developed the world's largest range of human cell-expressed (hcx) recombinant human proteins, which it manufactures and sells internationally under its Apollo Cytokine Research subsidiary; it is working on oral and transdermal delivery platforms for its proteins and other large molecules; and it is developing an over-the-counter business, Apollo Applied Science, using its transdermal platform, to generate revenue to plough back into its research.

The company's ultimate aim is, Priest says, to transform the biotherapeutics marketplace by developing large molecule delivery platforms to enable treatments such as insulin in tablet form and oral and topically applied anti-inflammatories.

"[We want to] be able to satisfy patients' needs by providing a protein that works better than the existing proteins in the market and doing away with needles," he says, "a world where needles are consigned to a very small part of the therapeutic [realm]."

Human expressed proteins

Leading the proteins side of the business is Glenn Pilkington, who is now presiding over further development of Apollo's library of over 80 proteins that it sells to researchers all over the world.

The point of difference for Apollo is that its proteins are expressed in human cells as opposed to bacterial or rodent cells. It has concentrated mainly on proteins that have huge therapeutic markets, such as growth factors and soluble receptors, and cytokines for cancer and auto-immune diseases. It also produces novel proteins for research purposes, such as Noggin.

"Human therapeutics have gone through a development phase that has incorporated several iterations," Pilkington says. "At first everyone produced human proteins in micro-organisms like E.coli ... then they moved into mammalian cells and insect cells, and Apollo is at the stage of a third iteration in making fully human proteins in human cells with fully human post-translational modifications."

Post-translational modifications (PTMs), such as phosphorylation and glycosylation, are a crucial part of protein synthesis. Glycosylation in particular has been a stumbling block to E.coli-expressed proteins, as the bacteria do not have the cellular machinery to add sugar structures. Rodent expressed proteins have different kinds of sugars, meaning immunogenicity is a problem.

"A major PTM is adding of sugars or glycosylation," Pilkington says. "In most cases sugar is a significant proportion of the mass of the protein. It can represent anywhere between 25 and 75 per cent of the mass so it affects the folding of the protein, and because of that it can affect the activity of the protein.

"It also affects the access of the protein surface to molecules such as antibodies or T cells - so if parts of the molecule are exposed, that can actually create immunogenicity issues. It can also affect the accuracy of assays for measuring natural proteins in serum such as ELISA type assays, because if you inject the protein without those sites being covered, it generates more antibodies to the uncovered or exposed sites, and then you have a much stronger activity of the antibodies with the non-human expressed assay standard, compared to the native human protein.

"A major issue is also the immunogenicity of non-native human proteins in use in humans - this has been a serious issue with, for example, erythropoetin (EPO) generating autoimmunity in patients with kidney disease. The EPO protein generated in Chinese hampster ovary (CHO) cells was immunogenic, eventually resulting in loss of the EPO activity these patients."

Pilkington says sugars are one of the most important PTMs because they affect folding, activity and half-life in serum. Companies like Amgen and Johnson & Johnson have tried to overcome serum half-life issues by methods such as PEGylation, which is in itself a synthetic construction which may also affect immunogenicity in the long term.

"The remaining issues for the biopharmaceutical industry are immunogenicity, and inaccuracies in the assays and that's what Apollo is all about, overcoming those two major issues."

Delivery systems

Now that you have the human cell-expressed protein overcoming the immunogenicity issue, how do you use it therapeutically? In addition to hcx, Apollo's major breakthrough has been the development of oral and transdermal delivery systems that should transform the market.

What Apollo aims to achieve, and early trials suggest it will, is to develop effective systems that can take large water-soluble molecules like antibodies across the gut, and large water-soluble proteins across the skin. Apollo, under the guidance of science director Greg Russell-Jones, has developed two delivery platforms: Oradel, for oral delivery, and TransD, a transdermal carrier. Oral delivery of insulin, and oral and transdermal delivery of TNF blockers, are the first targets.

In the past two months, Apollo has successfully completed Phase 1 toxicology trials for orally delivered insulin, and results from preclinical studies have indicated that oral doses of Apollo's TNF blocker ALS-00T2 significantly reduced inflammation to a comparable degree to subcutaneous injection of the molecule.

Oradel is able to entrap proteins up to antibody size in a protective coating, preventing degradation in the gut. It also uses targeting agents to promote absorption of the molecule from the intestine.

"There are two issues to solve in the oral delivery of proteins," Russell-Jones says. "If you put insulin into the stomach the first thing it does is chew it up, so you have to stop it degrading. The gut also has a mechanism to stop things from getting out, so then you have to have something to transport the drug.

"What we have done with our technology is to combine two things - we have a way of wrapping proteins up to protect them and we have multiple transport systems to get from the gut to where it's needed. We are using natural transport systems in the body to take the drug across the gut and into circulation."

Russell-Jones says Oradel is a major breakthrough and is nicely complemented by the TransD drug delivery system, which will be more suitable than tablets for some inflammatory diseases.

"The skin is a very unique organ in that the drainage is different to the rest of the body," he says. "With TransD we can apply very high concentrations of a drug locally, where we want it, and by the time it diffuses out, the concentration is very low. If you inject the same treatment, you have very high concentrations at the site of injection but very low concentrations where you want the therapeutic activity.

"Apollo has made a major breakthrough in that we do have a delivery technology that delivers large proteins through the skin. Patents have been lodged and we'll be giving scientific presentations on it in due course, and it will be the basis of our clinical trials. It has been a major breakthrough for us to get here."

Lift-off

Apollo already has an operating business producing proteins for research and therapeutic applications under its Apollo Cytokine Research banner. It is moving ahead with its Apollo Applied Science OTC business, with several products on the market bringing in some cash. What it really wants to do, which coincidentally will generate the highest value in terms of both effectiveness and earnings, is to help people with needle-free biotherapeutics," John Priest says.

"The biggest, highest value is to be able to provide some of these products with regulatory approval to patients," he says. "These are large and growing markets with unmet needs for convenient, pain-free drug delivery. We are very excited at the prospect of making a serious contribution."

Apollo Cytokine Research is exhibiting as part of the Australian Pavilion at BIO 2007.