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Pfizer Joins Yale Spinout in Up-to-$830M Protein Degradation Drug Collaboration

Pfizer will use Arvinas’ protein degradation technology to discover and develop new drugs for undisclosed diseases, through a collaboration that the Yale University spinout said today could generate up to $830 million-plus. The companies have signed a multiyea

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Pfizer will use Arvinas’ protein degradation technology to discover and develop new drugs for undisclosed diseases, through a collaboration that the Yale University spinout said today could generate up to $830 million-plus.

The companies have signed a multiyear research collaboration and license agreement through which they have agreed to develop an unspecified number of new treatments based on Arvinas’ proprietary PROTAC® (PROteolysis TArgeting Chimeras) Platform. The novel technology is designed to create small-molecule therapeutics aimed at degrading disease-causing cellular proteins.

Arvinas has agreed to oversee discovery efforts, while Pfizer has responsibility for clinical development and commercialization of any products that may result from the collaboration.

In return for licensing its technology to Pfizer, Arvinas is eligible for up to $830 million in up-front payments, plus payments tied to achieving specified preclinical, clinical, and commercial milestones. Arvinas said it also stands eligible to receive tiered royalties based on global product sales on any products products that may result from the collaboration.

“This marks another key milestone as we continue to expand the use of our targeted protein degradation platform and advance Arvinas's first candidates into the clinic,” Arvinas president and CEO John Houston, Ph.D., said in a statement. “As a global industry leader, Pfizer is uniquely positioned to partner with us as we exploit the potential of PROTACs in multiple disease areas.”

Arvinas says its PROTAC Platform offers the potential for improved performance over traditional small-molecule inhibitors by using the cell's natural and selective ubiquitin-proteasome system, which routinely degrades disease-causing proteins. PROTAC degraders recruit an E3 ligase to tag the target protein for ubiquitination and degradation through the proteasome, a large complex that degrades the ubiquitinated protein into small peptides.

By removing target proteins directly rather than simply inhibiting them, Arvinas reasons, PROTACs can provide multiple advantages over small-molecule inhibitors, which can require high systemic exposure to achieve sufficient inhibition, often resulting in toxic side effects and eventual drug resistance.

PROTAC has demonstrated that a transient binding event at a range of binding sites and affinities can translate into very potent degradation of the target protein in multiple protein targets, according to Arvinas.

“Protein degradation is an area of considerable interest for us, and we look forward to working with Arvinas to determine the potential applicability of this approach across multiple therapeutic areas,” added John Ludwig, Ph.D., Pfizer’s head of medicinal sciences.

The collaboration is Arvinas’ third with a pharma partner. The Yale spinout, established in 2013, launched its other two pharma partnerships in 2015—an up-to-$434 million alliance with Merck & Co., and a partnership “in excess of” $300 million with Genentech, a member of the Roche Group.

Busy Week for Pfizer

The collaboration is Pfizer’s second drug development partnership launched this week, in which the pharma giant saw another collaboration come to an end.

Yesterday, Pfizer and Sangamo Therapeutics began an up-to-$162 million-plus alliance to develop a potential gene therapy to treat amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) linked to mutations of the C9ORF72 gene—the companies’ second gene therapy collaboration.

However, Pfizer today returned to iTeos Therapeutics rights to the immune-oncology candidate EOS200271, a highly selective, clinical-stage IDO1 inhibitor that failed to achieve efficacy or reach its maximum tolerated dose according to interim data from 17 patients in a Phase I trial (NCT02764151).

The study assessed EOS200271 as a monotherapy in patients with malignant gliomas, based on brain penetration of the compound. The study was recruiting patients as of December 14, 2017, the date of the last update posted on ClinicalTrials.gov.

Pfizer and iTeos launched their collaboration in 2014 when the pharma shelled out €24 million ($29 million) upfront to license rights to iTeos' preclinical compounds targeting indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2).

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01Why use a protein degrader?

Targeted protein degraders appear to have distinct advantages over more traditional inhibiting drugs. “Compared to traditional inhibitors, degraders have some potential advantages, such as eliminating scaffolding function, improving potency, and enhancing selectivity,” explains Yu Shen, PhD, director of cancer biology at AbbVie. Another major advantage of protein inhibitors is that they have the potential to treat what are referred to as undruggable proteins. As Nasveschuk points out, “There are some proteins that are just not targetable through ligands. These are ideal targets for protein degradation.” In some cases, the protein’s active site has a geometry that is not readily accessible. In other instances, although it may be possible to bind to a portion of a protein, there is no functional consequence of that binding event. “So, your inhibitor or ligand doesn’t actually do anything to the protein or modulate the disease,” Nasveschuk remarks. Protein degraders represent a novel way to target these undruggable proteins.

Source: www.genengnews.com ↗
02How stable is the antibody?

A crucial question often addressed during preclinical development focuses on the in vivo stability of therapeutic antibodies. Increasing the half-life of a therapeutic antibody has several benefits ranging from higher treatment efficacy to increased advantages for the patients who will have a fewer number of therapy sessions and a reduced cost. Given these compelling benefits, following the identification of therapeutic antibodies with the desired specificity, developers usually subject them to a refinement step to increase their stability. This process is often hindered by the lack of reliable experimental tools to predict the half-life of antibodies in patients. The major hurdle of using mouse models to predict antibody stability in the serum lies in the way immunoglobulin proteins are processed by the organism. In mammals, most proteins circulating in the serum undergo constant uptake by endothelial cells and are routed through the endosomes to the lysosomal compartment for degradation. In the endosomes, immunoglobulin G (IgG) proteins are recognized and bound by a transmembrane protein, called the neonatal Fc receptor (FcRn), which mediates their recycling to the plasma membrane and subsequent release back into the serum. As a result, the half-life of IgGs are significantly extended by this mechanism. Since most therapeutic antibodies belong to the IgG class, this recycling system is very relevant for their relative stability in the body. Remarkably, the relative affinity between IgGs and FcRn is extremely disparate between different species, with the mouse receptor showing a much higher affinity than its human counterpart.

Source: www.genengnews.com ↗
03Undruggable or unscreenable?

Another obstacle to discovering new PPI inhibitors is the lack of libraries designed to hunt for them, points out Philippe Roche, PhD, senior scientist at the Integrative Structural and Chemical Biology team at the Cancer Research Center of Marseilles, France. “If you screen PPIs using libraries that were designed for kinases or GPCRs, that’s why you don’t get a lot of good results,” he says. To that end, his group began assembling a library focused on orthosteric inhibitors of PPIs. The result was 2P2Idb, a hand-curated, structural database cataloguing orthosteric inhibitors of PPIs for which the interface had been 3D characterized. From analyzing these known PPI inhibitors, and what structures they had in common, Roche and his colleagues developed a model to predict whether compounds would likely inhibit PPIs. Using this method, 2P2Idb creates an enriched screening library that dramatically increases the hit rate compared to standard libraries. Having proven their success with a small library of 1600 compounds, they are in the process of expanding the library to 10,000 compounds. Once that’s published, “the idea is to make this library available to labs around the world,” Roche says. “We will provide the library free of charge for people to be able to screen PPI targets.”

Source: www.genengnews.com ↗
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