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BioWorld Today Correspondent
In what could well be Europe's largest venture capital investment in biotechnology this year, Probiodrug AG took in more than €36 million (US$53.4 million) in a Series B round to fund a new class of Alzheimer's disease drugs, based on inhibiting glutaminyl cyclase (QC). The company also will allocate part of the proceeds to developing compounds acting on the same target for treating inflammatory indications.
Probiodrug, of Halle, Germany, is taking an integrated, big-pharma-like approach to drug development. It is bringing forward a series of candidate compounds, staggered at intervals of nine to 12 months.
"The first QC inhibitor should reach the clinic within the next two to two and half years," Chief Financial Officer Hendrik Liebers told BioWorld Today. Others will then follow, while separate compounds are in development for peripheral inflammatory conditions.
The company's Alzheimer's program is based on an alternative view of the pathology of the condition. Most current late-stage clinical development programs are focused on disrupting the formation of amyloid beta (Abeta) peptide and its aggregation and deposition into the plaques that are considered the key pathological hallmark of the disease.
Probiodrug is focused on an alternative species, pyroglutamate (pE)-modified Abeta, the formation of which is catalyzed by QC. Increasing age can give rise to altered patterns of amyloid precursor protein processing, resulting in truncated forms of Abeta peptide. Those are susceptible to cyclization at a newly exposed N-terminal glutamate residue. The resulting modified peptide is resistant to protease-mediated cleavage. Its increased hydrophobicity appears to promote aggregation, resulting in mixed fractions of pE-Abeta and unmodified Abeta.
The formation of pE-Abeta was first reported in the mid-1990s by a Japanese group. Probiodrug was the first to observe that the reaction was catalyzed by QC, which was previously thought to work only on N-terminal glutamine residues. "We had the link," Liebers said.
The company reported some of its findings in the October 2008 issue of Nature Medicine, which, Liebers said, helped to drive investor attention. Also in 2008, the company secured intellectual property protection around the target and its use in Alzheimer's and other indications. "That was a major step forward for the company," Liebers said.
Probiodrug is taking a "pragmatic" approach to partnering. "Alzheimer's is a space where at some point in time only the big companies can progress a concept," he said.
The company, which has a work force of 79 full-time equivalents, has its own internal medicinal chemistry group, an intellectual property unit and an animal pharmacology group it gained when it acquired Munich, Germany-based Ingenium AG in 2007.
"Since it's a new approach, and since Alzheimer's has some bottlenecks, we have a program in the animal pharmacology field," he said. It has developed around 10 models. "We are getting the Abeta pathology; we are getting the neuroinflammation and the neurodegeneration," Liebers said.
Targeting QC has been challenging as well. "Inhibiting metalloenzymes as such is not a trivial thing," he said. Specificity is an obvious requirement to avoid off-target effects. "All of that makes the medicinal chemistry pretty sophisticated," he said. The company's medicinal chemistry team also played a key role in establishing dipeptidyl peptidase IV (DPP-4) inhibitors as a new drug class in the treatment of Type II diabetes.
The funding round was co-led by BB Biotech AG, of Zurich, Switzerland, and Paris-based Edmond de Rothschild Investment Partners. Other new investors include Life Sciences Partners, of Amsterdam, the Netherlands, and Biogen Idec New Ventures, of San Diego. Existing investors also participated. Probiodrug has raised around $110 million since its formation in 1997, while its DPP-4 business has realized a further €85 million in revenue and other payments.