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DewDiligence

Re: DewDiligence post# 13669

Friday, 10/10/2008 6:56:10 PM

Friday, October 10, 2008 6:56:10 PM

This article from the current issue of Nature Biotechnology
describes the difficulty of displacing established suppliers
of plasma-derived proteins in spite of the obvious safety
advantage of recombinant alternatives. This may partially
explain the excruciatingly slow uptake of ATryn in Europe.

Fortunately, the ATryn market in the US is an exception to
the above inasmuch as the supply of the approved plasma-
derived product (Thrombate from Talecris) is de minimis.

**This post is best read in conjunction with #msg-30789679**

(Thanks to genisi for posting the article on the Biotech Values board.)

http://www.nature.com/nbt/journal/v26/n10/index.html

›Plasma-Product Companies Outmuscle Small Recombinant Players

By Peter Mitchell
October 2008

Several small biotech companies with recombinant therapeutic proteins are finding it hard to make ground against large players that have traditionally marketed products derived from human- or animal-derived sources, with the large players now also moving into recombinant technology.

As biotechs go head to head with the marketing muscle of these large companies, which have extensive experience dealing with complex hospital procurement systems, they are finding it difficult to gain product share. Indeed, the recent $3.1 billion bid by Melbourne, Australia-based CSL to buy plasma product company Talecris Biotherapeutics [#msg-31416751], based in Research Triangle Park, North Carolina, testifies to the robustness of the plasma product business and suggests that the safety and traceability advantages of recombinant alternatives are no guarantee of market success.

Recombinant alternatives to proteins purified from plasma or human and animal materials were the backbone of the early biotech industry—at least 16 have become blockbusters. For example, recombinant insulin for diabetes now accounts for more than 70% of the worldwide human insulin market. Other successful recombinant products include erythropoietin, interferon alpha and human growth hormone.

One of the main innovators in the recombinant protein sphere has been Genzyme of Cambridge, Massachusetts. Tim Edmunds, Genzyme's vice president of therapeutic protein research, believes there are no longer any convincing reasons to use 'natural' products now that technology can produce large quantities of recombinant proteins by cell culture or transgenic means. [Interesting that he mentions the transgenic option.] He cites several examples of a switch from natural to recombinant product where improved safety has been at least a factor. Genzyme's own Cerezyme (imiglucerase), for example, is a recombinant form of the enzyme glucocerebrosidase to treat Gaucher's disease and was launched as a follow-on to placental-derived enzyme Ceredase (alglucerase). It succeeded partly because there were not enough placentas to meet demand for Ceredase, but also, says Edmunds, "because regulatory agencies were becoming increasingly concerned about human-derived products, even though that has never been an issue with Ceredase itself."

But large, established makers of human plasma proteins like Melbourne's CSL, the world's second-largest producer, have a good record at defending their market shares. Sales for all its products in 2008 topped AU$3.8 billion ($3.1 billion), results in part because of strong brand promotion and constant innovation. CSL's tradition is in human plasma-derived therapeutic proteins, but it is expanding into recombinant technology, too.

CSL's success has attracted a huge amount of investment. In August, CSL managed to raise a loan from merchant bank Merrill Lynch, of New York, to acquire Talecris. The US company is the former plasma product business of Bayer (Lerekusen, Germany), spun off in 2005 to private equity firms Cerberus of New York and Ampersand Ventures of Wellesley, Massachusetts—who have made a small fortune out of the deal. Talecris will add a further AU$1.4 billion ($1.2 billion) to CSL's sales.

Why is the natural-protein business still so attractive? Because, despite their advantages, many recombinant rivals are slow to take off. In some cases, price is certainly an issue—for example, complaints about the cost of Cerezyme are widespread (even though if adjusted for inflation it is cheaper today than when first launched). But cost is not the only, or even the usual, reason.

One example is the recombinant thrombin Recothrom, launched earlier this year by ZymoGenetics of Seattle. Since receiving approval from the US Food and Drug Administration (FDA) in January, Recothrom has been slow to displace natural bovine thrombin, of which the market leader is Thrombin-JMI made by King Pharmaceuticals, located in Bristol, Tennessee. Recothrom is priced at a 15 percent premium over bovine thrombin, but that isn't the problem, says ZymoGenetics chief executive Bruce Carter. Rather, it is because the acute hospitals that use thrombin (for hemostasis in surgery) have a convoluted and lengthy procedure for switching between preferred therapeutics. "Like other recombinant proteins, it is going to take time," says Carter. Meanwhile, companies like King are constantly improving their animal products, for example by removing components like bovine factor V, suspected of causing immunological reactions in patients. [It’s true that plasma-protein companies are gradually improving their purification processes (there are several posts about this on this board); however, it’s misleading to say that bovine factor V—or any other protein found in the source plasma—has been “removed” rather than merely reduced.]

Another problem may be difficulty in proving equivalent efficacy. One example is Altus Pharmaceuticals of Cambridge, Massachusetts, which in August announced the results of its phase 3 study with the enzyme replacement therapy Trizytek for cystic fibrosis–related pancreatic insufficiency. On average, the drug met its primary endpoint, but the level of efficacy shown by the trial was disappointing. For some non-US subjects, the recombinant microbe-derived enzyme produced no response beyond placebo, whereas the porcine-derived enzyme replacement therapies—Trizytek's competing products—showed no such limitation. The announcement slashed Altos' share price by half, as analysts questioned whether the FDA's preference for non-animal-based products will be sufficient to get Trizytek regulatory approval without further trials, despite its weak showing.

The pros and cons of recombinants vary from protein to protein, says Genzyme's Edmunds. "Even commodity proteins, such as serum albumin, can be produced [as a recombinant version] in large quantities using transgenic animals, as GTC Therapeutics [of Framingham, Massachusetts] does," he points out. [Actually, GTC’s albumin program has been shelved, but the point that albumin can be made transgenically is valid.]

Other experts agree. "There is no simple or single explanation for recombinants' limited success in some markets," says David Glover, an immunotherapeutics expert based in Newmarket, UK. "The cost differential between recombinants and blood products can be huge and, for some customers, may not be justified by the minor advantages offered by recombinants.

Glover, formerly a medical director of the British immunotherapeutics company Cambridge Antibody Technology, since acquired by London-based AstraZeneca, notes that many therapeutic proteins offer a limited commercial opportunity. "The financial return on the investment needed to create recombinants may not be sufficient," he says. That, he says, is why Cambridge Antibody Technology passed on the opportunity to make human recombinant antibody replacement products for various immunoglobulin products against some common viral diseases, antidotes to drugs and poisons and antivenoms for specific snake or spider bites. As a result, the only treatment for some of these indications is still sheep antibodies or even horse serum.

The key dynamic for the future is the increasing caution of the regulators. Last October, the FDA told manufacturers of porcine-derived pancreatic enzyme replacement therapies to start preparing new drug applications by April 2008, leading to either approval by April 2010 or removal of their products from the market.

Two sad episodes from the 1980s and 1990s are engraved on doctors' and regulators' consciousness, notes Glover. Children were infected with Creutzfeldt-Jakob disease as a result of being given human growth hormone extracted from cadaver brains; and hemophiliacs were infected with HIV after receiving factor VIII clotting agent taken from pooled plasma donations. Both of these triggered a general market switch from natural products to the recombinant alternative.

Nowadays, pooled or natural human products are much more extensively filtered, purified and tested than they used to be. "But there is always the risk that a previously unknown infective agent, such as a new prion or viral disease, might sneak through before a test was developed to detect it," says Glover. Quite apart from unknown pathogens, there are still many relatively common viruses that are not routinely tested, including West Nile and Japanese encephalitis, as well as rare but very dangerous viruses like Ebola.

The danger of prions is particularly worrying after recent research by a group led by Claudio Soto of the University of Texas in Austin, Texas. Soto and his coworkers found that mixing infectious prions from one species with normal prion proteins from another can create new strains of infectious proteins.

Soto's findings prove that cross-species transmission of proteins could generate numerous infectious foldings of a prion protein—implying a very large 'universe' of possible prions. Some of which, he notes, with likely "dramatic effects." Soto acknowledges that the new findings have "worrisome" implications for the use of animal-derived medical products: "Prions are very sticky and difficult to eliminate, and indeed can be concentrated upon purification of other products." What regulators will make of this, though, he is unwilling to predict: "Their decisions are influenced by political and economic issues as well as science," he says.

To some, it seems that nothing short of another major contamination scare—probably involving the prion disease bovine spongiform encephalopathy—will force the pace of change.‹

<font size=2><font color=red>“The efficient-market hypothesis may be
the foremost piece of B.S. ever promulgated
in any area of human knowledge!”

“The efficient-market hypothesis may be
the foremost piece of B.S. ever promulgated
in any area of human knowledge!”

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