Finding the Opportunities in Aptamers

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Finding the Opportunities in Aptamers
March 2004
Windhover Information Inc.
The pharmaceutical industry, it?s fair to say, hasn?t completely gotten over its infatuation with small molecules. But it is by no means any longer wedded to them.
Driven by the need for new products and the recognition that even specialty products can generate blockbuster sales, traditional small-molecule players are paying hundreds of millions of dollars for rights to large molecules. For the most part their choices have been limited to antibodies, proteins, and their variations.
But now an emerging middle-ground of molecular options is becoming increasingly interesting?aptamers, oligonucleotides that bind to proteins. Like small molecules and unlike antibodies, aptamers have relatively stable shelf lives, don?t seem to cause much immunogenicity; distribute themselves well in even very dense tissue; and offer some fairly straightforward delivery options, in particular pulmonary delivery. Like antibodies and unlike small molecules, they bind tightly and specifically to protein targets; seem to have relatively low toxicities; and can disrupt disease-causing protein-protein interactions. And unlike both kinds of compounds, aptamers can be created with great rapidity.
Today, at least a dozen distinct aptamer products are being tested in several dozen trials. A dozen companies are pursuing the business. The public markets are increasingly interested: three of the six companies which have gone public since January 1 are developing aptamers. Two of those companies, Eyetech and Corgentech, have signed Big Pharma deals on their lead products.
But business is anything but a straightforward opportunity. Like antibodies, aptamers can?t yet be made into oral pills. Also like antibodies, they?re too large to get across cell membranes and attack intra-cellular targets. They?ve been expensive to make, far more expensive than even antibodies. Up until recently, they have had vanishingly short half-lives. And the IP situation, though less picket-fenced with patents than the antibody field, is hardly clear.
Thus IN VIVO decided to look at the strategies of three representative companies?Corgentech, Coley, and Archemix?each of which is pursuing very different paths to aptamer commercialization based as much on the limitations of their technologies as their opportunities.
Corgentech, for example, is blocking transcription factors with aptamers?an efficient way of treating conditions caused by multiple genes in a pathway. Corgentech solved the problem of getting the aptamer to these intracellular targets with a unique device for a relatively unique condition it can treat ex vivo: its Phase III E2F decoy solves stenosis problems with vein grafts?perhaps a billion-dollar market. But its next two TF-blocking aptamer opportunities aren?t close to the clinic, and the device won?t help with their therapeutic indications.
So what does Corgentech do for an encore? It aims to couple its internal R&D with in-licensing, for one thing. But it?s likely that its next strategic moves will reflect less Corgentech?s aptamer platform capability than the business exigencies of a technology pioneer?s understanding of a high-value product opportunity.
Coley is pursuing a wider scope of aptamer projects, more evenly spaced on a development timeline. Based on its recognition that oligos can turn on the immune system, Coley has created a set of therapeutic and prophylactic aptamers that target TLR9 inside dendritic cells.
The oligonucleotide vaccine approach also allows the company?in theory?to circumvent another big problem with aptamers?their high manufacturing cost. Most therapies require one blocker per target. But vaccines simply wake up the immune system and Coley?s technology apparently wakes it up very efficiently, alerting both of the body?s immune systems, innate and adaptive. Hence, Coley?s products use very small doses, keeping down absolute costs.
But Coley?s approach also creates a different biological risk: its entire business rests on the viability of an admittedly well documented theory of immunology and one target, yet to be validated by a marketed product, at the center of it. And the risk is magnified by fact that its most advanced molecule is being used in three relatively disparate indications. Should it fail in one, the failure will undoubtedly cast greater doubt on its use in the others, contracting its partnering options.
Archemix?s advantage lies in the breadth of its opportunities. It has the broadest patent estate in the aptamer industry and probably the most advanced chemistry skills?that is, the ability to manipulate oligonucleotides to solve cost-of-goods and half-life problems, and thus the widest field of therapeutic endeavor open to it. It is also, however, the least advanced in terms of pipeline, with just one product close to the clinic.
Archemix? basic strategy, therefore, is two-fold. First, it aims to reduce biological, chemical, and medical complexity as far as it can to smooth its path to market: Archemix is going after highly validated, extracellular targets. But its hurry-up strategy also relies on quantity?its unparalleled freedom to create many aptamers without violating other companies? IP. Thus it?s doing as much as it can to create a broad set of aptamer programs, most of which it will try to license.
Taken together, the stories of these three companies ask a basic question: will most of the aptamer pioneers really be able to exploit it as a platform?a source of repeatable pharmaceutical innovation. Or will some combination of IP boundaries and technological hurdles limit its output to a series of one-off products? And thus the investment and partnering quandary for the current aptamer players: will the market and Big Pharma partners see them as part of the first generation, too early for sustained investment?or have enough problems been solved to make aptamers into the must-have technology its adherents claim it to be?