DUBLIN – Pieris Pharmaceuticals Inc. has laid down a big marker for its credentials in respiratory disease through an alliance with Astrazeneca plc under which it is receiving $57.5 million in up-front and near-term milestone payments and up to $2.1 billion more in development milestones and commercial payments, as well as tiered royalties on product sales.

The lead asset in the agreement is PRS-060, an interleukin-4 receptor alpha (IL-4R alpha) inhibitor in development for asthma, which is due to enter the clinic in the second half of this year. Pieris will be responsible for the phase I study in healthy volunteers, although London-based Astrazeneca will foot the bill. Pieris retains an option on U.S. co-development and co-commercialization after phase IIa trials.

The alliance includes four other programs, and Pieris will also have U.S. co-development and co-commercialization options on two of those. Pulling the trigger on those options would alter the headline value of the deal, but either way, the company is now playing in the big league in terms of innovative approaches to respiratory disease.

The pact represents a second strategic domain for the U.S.-German firm. It has already staked out a broad position in immuno-oncology through a wide-ranging $1.2 billion alliance with Les Laboratoires Servier SAS, which it entered earlier this year. (See BioWorld Today, Jan. 6, 2017.)

The common denominator in each is Pieris' anticalin technology, a post-antibody scaffold derived from lipocalins, a family of proteins involved in transporting hydrophobic molecules such as vitamins, steroid hormones and secondary metabolites. Invented by Pieris founder Arne Skerra at the Technical University of Munich, anticalins can be engineered to engage a wide variety of protein targets by modification of up to four hypervariable loops. The single polypeptide chains are much smaller than antibodies, have high thermostability and can be manufactured in both bacterial and eukaryotic expression systems.

The agreement with Servier is focused on bispecific molecules. The deal with Astrazeneca is based on the development of monospecific anticalins that can be delivered to the lungs.

Inhaled biologics have long been a tantalizing possibility for biotechnology firms, but the commercial reality has so far failed to match the promise. Inhaled insulins have failed to wean all but a handful of diabetic patients off their daily injections. Delivery technology in the latter product segment has improved substantially in recent decades, while the inhalers developed for pulmonary delivery of insulin have simply been too clunky for most patients.

"This is nothing like inhaled insulin," Stephen Yoder, CEO of Boston-based Pieris told BioWorld Today. "This is a localized approach to addressing disease locally." One particular member of the lipocalin family, tear lipocalin, is also present in the lung epithelium, which, he said, may indicate that a lipocalin-based drug molecule will have a good tolerability profile in that milieu.

STAYING POWER

The upcoming phase I study will focus on healthy volunteers only – patients will not be exposed to PRS-060 until phase IIa studies start. The partners aim to be selective in terms of patient stratification and recruitment. They will focus on those with a T helper cell type 2 (Th2) phenotype – or a T2 endotype – which is characterized by high levels of nitric oxide (NO). "We believe that is going to be a very good proxy for response to therapy," Yoder said.

In the phase I trial, PRS-060 will be delivered with a nebulizer, but the companies plan to develop a dry-powder formulation for clinical testing soon after. "Partnering with Astrazeneca makes so much sense, because they are world leaders in formulation and devices," Yoder said.

The two companies have not finalized the details on the remaining programs. "There are a number of themes that have been discussed, and some specific target ideas that have been exchanged," Yoder said.

Pieris is among a wave of developers of post-antibody scaffold technologies that have been slow to deliver on their very obvious potential. Part of the reason is the steady incremental improvements that have been made to the incumbent antibody-based technologies over the past decade. But to succeed, the post-antibody companies have had to learn the difference between excellence in protein engineering and excellence in developing differentiated drug programs that offer real value to big pharma partners.

"We're very good at making well-behaved proteins," Yoder said. Pieris only added a focus in pharmacology to its protein engineering skills in recent years. "It is a process," he said.

But having a good technology remains an essential starting point. Anticalins fit the bill in that regard, he claimed. "I believe they have staying power because of their good drug-like properties," he said.

The market has not been very supportive until now – its deal with Servier did little to move the dial on its share price. However, the Astrazeneca deal has. Shares in Pieris (NASDAQ:PIRS) peaked at $3.97 during trading Wednesday, but ended the day at $3.67, up 53 percent.

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