After several years of talks, Professor Mark Pepys' University College London spin-out, Pentraxin, has just signed up GlaxoSmithKline to help it develop a novel treatment for amyloidosis that combines a small molecule and an antibody.
GSK's Senior VP Drug Discovery Patrick Vallance made the deal happen, according to Pepys: Vallance was Head of the Division of Medicine and Professor of Pharmacology at UCL before joining GSK in 2006.
This isn't GSK's first deal with UCL; in February it announced a three-year collaboration with the university's Institute of Ophthalmology. Both illustrate what a fresh-from-academia R&D chief can bring to the party: a willingness to invest in risky early-stage research including in highly specialist therapeutic areas.
These two deals also show GSK's small-unit R&D structure at work. The earlier tie-up will investigate compounds provided by Opthiris, one of GSK's drug performance units (DPUs). DPUs were set up last year by Vallance and CEO Andrew Witty to mimic the autonomy, flexibility and independence of real-world biotech (see "1GSK Tries to Mimic Real World Biotech," IN VIVO, February 2009).
Most of these 50-or-so strong units sit within the established Centers of Excellence for Drug Discovery (CEDDs, the previous iteration of GSK's ongoing R&D experiment). Ophthiris, along with a unit focused on wide-spectrum antibiotics called macrolides, independently-operating Sirtris (a biotech that GSK acquired in 2008) and an academic incubator are stand-alone DPUs that sit outside of the CEDDs.
The academic DPU, run by Pauline Williams, scouts out promising programs among leading academics to help push through early clinical development. Hence, it's involved with this latest Pentraxin deal--but in this case, additional help comes from GSK's BioPharmaceutical CEDD.
An unprecedented pairing
That's because Pentraxin's program combines a small molecule with an antibody--a pairing that's unprecedented in drug development, according to Pepys. The small molecule component is CPHPC, a pallindromic compound which targets serum amyloid P component (SAP).
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 build up of abnormal amyloid proteins in body tissues. They found that binding SAP stabilizes amyloid fibrils - the deformed proteins that cause amyloidosis, but which also are associated with more widespread disorders such as 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," Pepys told "The Pink Sheet" Daily. 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 help the body's normal clearance mechanisms mop up the remaining 10 percent 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.
The challenges of dual mechanism development
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. 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 Pharma, GSK relatively recently has assembled biopharmaceutical capabilities through a series of acquisitions, most notably that of UK-based Domantis 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 use Domantis' technologies concurrently--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 which interferes with SAP's binding to those.
Pepys estimates that the drug-antibody dual treatment will go into clinical trials in two years' time. And although the current collaboration is limited to amyloidosis, given the treatment's potential in other far larger and more lucrative areas like Alzheimer's, "the deal could certainly go that way," Pepys says.
For now, this deal offers GSK a cheap, virtually risk-free means of testing a hypothesis which, if proven, could lead to bigger things--the Big Pharma has a neurosciences-focused CEDD, after all. That's likely driven GSK's interest, too--along with cool science and old friends.
-Melanie Senior (m.senior@elsevier.com)
This article also appeared in "The Pink Sheet" DAILY – March 25, 2009
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