Imitation is not just the sincerest form of flattery. When combined with machine learning, molecular mimicry is how Metaphore Biotechnologies designs novel treatments in autoimmune disease, oncology—and metabolic disorders, the therapeutic area of its first collaboration, an up-to-$600 million-plus partnership with Novo Nordisk announced today.

Novo Nordisk will partner with Metaphore Biotechnologies to develop up to two advanced obesity management treatments, the companies said. Novo Nordisk will apply Metaphore’s MIMIC™ platform to develop the two treatments, which will be designed to target multiple obesity-related targets.

These include the glucagon-like peptide 1 receptor (GLP-1R), which Novo Nordisk has successfully targeted through its blockbuster GLP-1R agonist semaglutide, approved to treat type 2 diabetes as Ozempic® and to treat obesity as Wegovy®.

Uli Stilz, PhD, head of Novo Nordisk’s Bio Innovation Hub

“We believe we can create uniquely efficacious agents with unique properties using this platform,” Uli Stilz, PhD, head of Novo Nordisk’s Bio Innovation Hub, told GEN Edge. “We believe the platform will enable us to discover therapeutic agents with durability, long half-life leading to infrequent dosing. And lastly, we believe the platform also will enable us to uniquely design single molecules, antibodies which can be scaled. So, manufacturing scalability is also one of the key considerations.”

MIMIC is designed to capture the interactions between molecules, enabling Metaphore to map the essential features of a molecule that elicit a highly specific action, or pharmacophore. The platform systematically isolates pharmacophores in order to design novel mimetic compounds allowing the company to program such properties as function, specificity, selectivity, and multi-targeting.

Metaphore was launched in 2021 by Flagship Pioneering, the funder/developer of biotech startups which brought the company out of stealth mode last year with an initial commitment of $50 million. Metaphore will partner with Flagship’s in-house drug development unit, Pioneering Medicines, and Novo Nordisk to jointly conduct R&D programs and advance them through foundational activities and preclinical development. Novo Nordisk has agreed to advance the programs into clinical studies.

Novo Nordisk also agreed to pay Metaphore up to $600 million in upfront, development, and commercial milestone payments, plus tiered royalties on annual net sales of licensed products, to be shared between Metaphore and Pioneering Medicines. Novo Nordisk will reimburse R&D costs and participate in a future financing round for Metaphore.

Inspiration from butterfly owl

“Mimicry is one of the oldest tricks that nature uses when it’s evolutionarily advantageous,” Metaphore co-founder and founding CEO Lovisa Afzelius, PhD, told GEN Edge. “We often show the picture of the butterfly owl where its wings are showing the pattern of an owl, and by just showing those functional features, it’s actually able to exert the power of an owl, even though it’s just that little, little butterfly.”

Metaphore Biotechnologies co-founder and founding CEO Lovisa Afzelius, PhD

“And we said, ‘What if we can do this in the molecular world? What if we could identify exactly what is that pharmacophore that actually drives function? Because if we can exert those exact spatial features that a pharmacophores that are required to drive downstream function, we can actually reduce the problem at hand by a google-fold, massively reducing the problem. And in doing so, we can make molecular design programmable.”

Using MIMIC, Metaphore and partners can identify a pharmacophore to mimic, finely map its surface to create a mold, then use the mold to develop new molecules that mimic the function of the original pharmacophore. The specific properties of the mimic can be fine-tuned through machine learning, creating a therapeutic that is optimized to elicit a highly specific function or action.

“We generate thousands of different protein variants and see how they actually interact. Then we use this data to train our machine learning systems. In doing so, we can actually create a single amino acid resolution map of that molecular interface and extract the dynamic pharmacophoric features that are required to fulfill the function that we’re looking to optimize,” Afzelius explained. “Then, we can more or less use this as an in silico mode to then start casting novel sequences toward those pharmacophoric features, and obtain completely novel sequences that maintain that function.”

That function, Afzelius added, can be further optimized to yield any drug development properties that need to be included in the final therapeutic.

Metaphore reasons that MIMIC can radically reduce the scale of the computational challenge that it and other drug developers face when designing new drugs, by allowing for precise prediction of how changes to a mimic will meaningfully impact its function. Those changes can be programmed into the novel drug in order to generate a desired biological response.

Third Flagship partner

Metaphore is the third company founded by Flagship Pioneering to collaborate with Novo Nordisk under a broader strategic partnership between the biotech giant and the funder/developer aimed at bringing to market novel treatment approaches for cardiometabolic and rare diseases.

“At Metaphor, we are delighted to work with one of the world leaders in the field, and really tapping into their vast sort of understanding and knowledge of the area of obesity management,” Afzelius said.

Under the strategic partnership, launched in 2022, Novo Nordisk provides funding for initiated research programs and has an exclusive option to license each program. The partners aim to launch three to five research programs within the first three years of their collaboration.

That goal has been fulfilled, since Novo Nordisk has ongoing collaborations launched in January with two other Flagship Pioneering companies, the AI-based drug developer Cellarity and Omega Therapeutics, a developer of programmable epigenomic messenger RNA (mRNA) therapies.

Novo Nordisk plans to use Cellarity’s platform to develop a small molecule therapy based on counteracting novel biological drivers of metabolic dysfunction-associated steatohepatitis (MASH), the liver disease once known as nonalcoholic steatohepatitis (NASH). Novo Nordisk is also applying Omega’s platform technology to develop an epigenomic controller that is designed to enhance metabolic activity as a part of a potential new treatment approach for obesity management.

Based in Cambridge, MA, Novo Nordisk’s Bio Innovation Hub was formally launched in 2021 as an R&D unit designed to partner with academic institutions, emerging biotechs, and established companies. The Hub was designed to connect startups with Novo Nordisk’s deep knowledge of disease and a century of translational and drug development capabilities, with the goal of accelerating development of new therapies based on innovative ideas.

Also in 2021, Metaphore was founded with the aim of making accessible what until now have been intractable drug targets, as well as unlocking breakthroughs that outperform current drugs.

Metaphore is based in Cambridge, MA, and employs about 40 people.

“We’re looking to grow quite significantly during the course of the year, working on the breadth of pipeline projects that we currently are pursuing,” Afzelius added.

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