Full article reprinted from Start-Up May 26, 2009
University College London spin-out Pentraxin's February 2009 tie-up with GlaxoSmithKline in amyloidosis showed GSK's willingness to invest in risky, early-stage research. Weeks later, Pentraxin announced promising clinical data with a related program in Alzheimer's, raising the possibility that this alliance may yet expand beyond a specialist niche. Read more...
Full article reprinted from Start-Up May 26, 2009
University College London spin-out Pentraxin Therapeutic Ltd.'s March 2009 tie-up with GlaxoSmithKline PLC around a novel treatment for amyloidosis wasn't a big deal (financials weren't given). But it was noteworthy for showing GSK's small-unit structure at work, and its willingness to invest in risky, early-stage research. Also interesting was the compound in question: a small-molecule and antibody dual treatment that Pentraxin claims is unprecedented in drug development. Then in April 2009, Pentraxin announced promising clinical data with the small-molecule component of the program in patients with Alzheimer's, raising the possibility that this alliance may yet expand beyond a specialist niche—and provide further validation of Pentraxin's approach.
The amyloidosis deal came about thanks largely to GSK's (fairly) fresh-from-academia SVP drug discovery Patrick Vallance, MD, PhD, who joined GSK in 2006 from his position as head of the division of medicine and professor of pharmacology at University College London. He is also one of the architects of GSK's small-unit R&D structure, the latest iteration of which is the drug performance units (DPUs), set up last year by Vallance and CEO Andrew Witty to mimic the autonomy, flexibility, and independence of real-world biotech. This deal--plus an earlier, three-year collaboration with UCL's Institute of Ophthalmology—nicely illustrate that DPU structure at work, notably the academic-focused DPU, which scouts out promising programs among leading academics to help push through early clinical development.
The Pentraxin tie-up also involved GSK's BioPharmaceutical CEDD, given the antibody component of the amyloidosis program. The small-molecule part is CPHPC, a pallindromic compound that targets serum amyloid P component (SAP). Pentraxin founder Professor Mark Pepys and his team, who have been working on SAP for more than 30 years, discovered its role in the pathogenesis of amyloidosis, a rare and often fatal condition caused by the buildup of abnormal amyloid proteins in body tissues. They found that binding SAP stabilizes amyloid fibrils--the deformed proteins that cause amyloidosis but that are also associated with more widespread disorders including Alzheimer's and type 2 diabetes. So clearing SAP, the theory goes, should enable the body to clear away the abnormal proteins.
CPHPC—developed during the '90s in an on-off collaboration with Roche--appears to do the trick. "It causes SAP to be cleared rapidly from the circulation," explains Pepys. By lowering the blood SAP concentration to virtually zero, this removes most of the highly concentrated SAP from amyloid deposits, as the body tries to re-establish equilibrium. In a 31-patient, open-label clinical study, Pepys (who also heads the UCL Centre for Amyloidosis and Acute Phase Proteins) found that patients receiving CPHPC did not accumulate the damaging proteins and preserved organ function.
But this apparently wasn't quite enough. "It didn't make the deposits [of abnormal protein] disappear," he says. That means it wouldn't help the majority of patients who already have major amyloid deposits and damaged organ function by the time they are diagnosed. So Pepys, an immunologist by training, figured that administering an antibody to SAP would target the abnormal protein deposits for attack by the body's normal clearance mechanisms, helping mop up the remaining 10% or so of the protein within organs and tissues. "The drug gave us the opportunity to use an antibody [in addition], since it removes the SAP from the blood but leaves some specifically in the amyloid," he explains. Without the small molecule to clear the SAP from the blood, administering antibodies to target the residual SAP would be impossible as it would cause serum sickness through the formation of antibody-antigen complexes in the circulation. The theory works—at least in amyloidotic transgenic mice, where the one-two punch completely cleared all amyloid deposits.
Amyloidosis--which affects an estimated 80,000 people in the industrialized world, with probably twice as many undiagnosed--is a sensible specialist testing ground for a program that's highly risky. The dual treatment means uncovering not just the safety issues associated with each individual component, but also those that might result from their interaction. "The development hurdles are definitely more than twice those of a single drug," Pepys acknowledges.
GSK is up for the challenge of replicating in man the benefits seen in animals (Pepys estimates that the drug-antibody dual treatment will go into clinical trials in two years' time.) Sure, the funding it will provide—undisclosed early-stage success-based milestones plus drug development milestones and royalties—is small beer from the Big Pharma's perspective. But as well as having a shot, albeit a long one, at what may prove a significant improvement to some tens of thousands of patients' lives, it also gets to flex its newfound large-molecule muscle.
Like most other Big Pharmas, GSK has relatively recently assembled biopharmaceutical capabilities through a series of acquisitions, most notably that of UK-based Domantis Ltd. in December 2006, and alliances. In this deal, GSK will humanize the mouse monoclonal antibody, generate a cell line, and manufacture the antibody for toxicology, Phase I, and Phase II studies. But it will concurrently use Domantis' technologies—focused around single-domain antibodies; smaller but, in theory, equally or more effective than regular antibodies—to generate an 'anti-fibril' antibody that recognizes a common epitope on all amyloid deposits and that interferes with SAP's binding to those.
GSK has a license to the CPHPC-antibody pair in amyloidosis and all other deals associated with amyloid. But given the recent data showing CPHPC's promise in Alzheimer's, the alliance may yet be expanded to grant GSK rights to use CPHPC alone in this disease; certainly "GSK is our first port of call" for a partner, notes Pepys. His team, in collaboration with colleagues from UCL's Institute of Neurology, published data in the Proceedings of the US National Academy of Science showing that CPHPC removed SAP from the brains of five patients with Alzheimer's. Amyloid plaques and neurofibrillary tangles, the pathological hallmarks of Alzheimer's, always have SAP stuck to them, explains Pepys. So although it's not yet clear whether CPHPC will benefit those with Alzheimer's (the trial ran for only three months) there's good reason to think it might. "I've shown that SAP is present in all amyloid deposits, including those in the brain. If it's always present in the disease, it's fair to assume that it's to do with the disease," he elaborates.
Pepys would like to start a two-year, 100-patient study as soon as possible. Potential attractions to a collaborator, GSK or other (apart from the pot of gold that an Alzheimer's treatment would represent): a unique approach. Pepys claims no one else is targeting SAP in Alzheimer's (although Promedior Inc., somewhat paradoxically perhaps, is exploring the protein's role as an anti-fibrotic). Most are instead going for amyloid beta, a glycoprotein thought to be the main constituent of amyloid plaques, or phosphorylated tau protein, which is present in neurofibrillary tangles. Targeting SAP would potentially allow a sort of hedge across the two Alzheimer's camps, because "it binds to both" amyloid beta and tau, Pepys says. He also claims that CPHPC is safe, in part since it is not metabolized at all but is instead excreted in the urine.
-Melanie Senior
Find out how Start-Up's monthly leading intel on emerging medical ventures can help you make critical business decisions. Click here for a free trial.
