Editor’s note: BioPharma Dive, as part of its Emerging Biotech Weekly, is taking a closer look at competitive areas of startup activity. We aim to give an overview of the companies developing a new technology and what their goals are. This, on biomolecular condensates, is our seventh.
Three weeks ago, a well-funded biotechnology startup called Faze Medicines abruptly shut down.
The specific reasons for Faze’s closure aren’t yet known. In a statement then, Third Rock Ventures, which led Faze’s initial $81 million funding round in 2020, said the company’s scientific progress didn’t “meet our bar for further investment.” Management recommended it close and the board agreed, the investor said.
Faze’s fate is a lesson for a promising field of drug research into “biomolecular condensates” — microscopic, fluid-like droplets found within cells that partake in an array of important functions.
Identified in 2009 in the cells of worms by researchers at the Max Planck Institute of Molecular Cell Biology and Genetics, biomolecular condensates are viewed as a source of new drug targets and an alternate way to treat a range of disorders, from neurological conditions to heart disease and cancer.
Research progress has led to the formation of at least five startups in recent years, several of which have drawn the interest of large pharmaceutical companies. Yet their work remains in early stages and, as Faze’s fall demonstrates, has significant obstacles still to overcome. Here’s where things stand:
What are biomolecular condensates, and how do they work?
Biomolecular condensates are tiny blobs inside cells that are filled with hundreds of proteins, nucleic acids and other molecules.
Under a microscope, condensates look like the shape-shifting contents of an ultra-small lava lamp. They are constantly forming, merging with one another and then, once their job is done, vanishing into the cell’s cytoplasm.
These membraneless-droplets were once ignored by scientific researchers. But they have several purposes. Condensates help organize chemical reactions within a cell. They’re involved in its response to stress as well as in its signaling mechanisms. They can speed up or slow down cellular reactions by bringing molecules together or by keeping them apart.
Since condensates’ discovery, researchers have studied them in greater depth and begun to associate malfunctions within them to disease. Genetic mutations can affect how pieces of condensates function, for instance by making them stickier and unable to dissolve as quickly as they should. Early research has tied aberrant behavior within condensates to cancer, infections and neurodegenerative conditions.
Those properties have made biomolecular condensates an intriguing area of biology for drugmakers to mine for potential therapies.
Still, there are many hurdles ahead, as a team of scientists at one condensate biotech wrote in Nature Reviews Drug Discovery in August. Researchers need to understand the structure and function of specific condensates, as well as how they form. They have to tease apart the signaling and regulatory pathways that misfire within them, figure out how to target them and prove that interfering can treat a disease.
Condensates’ shape-shifting nature, meanwhile, will make reaching them with drugs harder.
“To address each of these challenges, the drug-hunter must understand the individual components of a target condensate as well as the collective behavior of the molecular community,” the authors, who work at Dewpoint Therapeutics, wrote. “However, this remains challenging.”
What makes biomolecular condensates an intriguing drug target?
Small molecules, the chemical-based drugs that have been a mainstay of the pharmaceutical industry for nearly a century, are typically used to block a protein’s action or change how it works. These types of drugs often latch onto the nooks and crannies of a protein, like a molecular lock and key.
But that isn’t always possible. Small molecules can only currently hook onto a fraction of the proteins produced by “druggable” genes, leaving many drivers of disease beyond their reach. Companies and researchers have spent years trying to unlock more targets, with mixed results.
Homing in on condensates could be one way to expand the target universe. Rather than trying to go after a tough-to-drug protein directly, companies could indirectly change its function by using small molecules to interfere with a condensate that protein resides in.
Biotechs could try to stop a condensate from forming or, alternatively, speed up its creation. They might design a medicine to infiltrate the droplet. In their Nature paper, Dewpoint scientists described using drugs to stop a protein from entering a condensate, or forcing it out.
One example is an RNA-binding protein called TDP-43 that, when mutated, causes condensates to harden and is associated with ALS. Dewpoint is developing an ALS drug that’s meant to change the composition of condensates to release the protein.
Another company in the field, Aquinnah Pharmaceuticals, is developing drugs that affect the presence of “stress granules,” a type of condensate the body creates to repair damage but that can become sticky and harmful in neurodegenerative diseases like ALS. It’s zeroing in on stress granules related to TDP-43 as well as other targets, according to CEO Glenn Larsen.
Additionally, as condensates contain so many different molecules, affecting them as a whole could be useful in treating complex conditions, like heart disease or cancer, that can involve many factors. But that hasn’t been proven.
Which companies are working on biomolecular condensates?
With Faze’s closure, there are at least four biotech startups still developing drugs aimed at condensates.
Dewpoint officially launched in January 2019 based on the work of Anthony Hyman, the head of the team of Max Planck researchers that discovered condensates. It’s since raised $287 million in three funding rounds and struck partnerships with Bayer, Merck & Co., Pfizer and biotech Volastra Therapeutics. The company is led by Ameet Nathwani, a former Sanofi and Novartis executive.
Nereid Therapeutics debuted in November 2020 with $50 million in funding from investment firm ATP. Nereid was spun out of the research of Clifford Brangwynne, a former post-doctoral fellow in Hyman’s lab and also a pioneer in the field. (Brangwynne is now a Howard Hughes Medical Institute investigator at Princeton University.)
Transition Bio was seeded that November as well and followed up earlier this year with a $50 million Series A round. The company’s founding research comes from Harvard University professor David Weitz and University of Cambridge professor Tuomas Knowles, who developed a way to study the properties of condensates and design drugs to target them. The startup is run by Greg Miller, who previously worked at Visterra, Concert Pharmaceuticals and Genzyme.
Aquinnah has existed longer than the others, forming in 2014 around research from Ben Wolozin, a neuropharmacologist at the Boston University School of Medicine. The company has publicly disclosed just over $15 million in investments from Pfizer, AbbVie and Takeda. In February, it inked a collaboration with Roche.
Faze was backed by Third Rock and the venture arms of Novartis, Eli Lilly and AbbVie.
Select companies researching biomolecular condensates
|Polaris Partners, Bayer, Softbank Vision Fund, General Catalyst, ARCH Venture Partners
|Third Rock Ventures, Novartis, AbbVie, Eli Lilly
|Northpond Ventures, Taiho Ventures, Bristol Myers Squibb, Lifeforce Capital
|Pfizer, AbbVie, Takeda
*Faze closed in early November. SOURCE: Company press releases
What is the status of the technology?
As condensates are a young field of drug research, the work remains in early stages. Some companies are still building the technologies they’ll eventually use to make drugs, while others have made their development intentions clearer.
Dewpoint appears the furthest along. The company claimed to have over 20 pipeline programs when it closed a Series C round in February, and has said it intends to get into human testing by the end of 2023. Among those prospects are treatments for ALS, an HIV drug being developed with Merck and a treatment for a neuromuscular disorder known as myotonic dystrophy type 1 that it’s working on with Pfizer.
The company is also researching with Bayer possible drugs for diseases of the heart and lungs.
Aquinnah has three programs in preclinical testing and could begin human testing in two to three years, according to CEO Larsen.
Nereid has said it plans to develop drugs for neurodegenerative diseases and certain cancers, but hasn’t disclosed any specific programs. Neither has Transition.
Before it closed, Faze was studying the role of condensates in ALS, cancer and myotonic dystrophy.