Even in the brazen world of biotech, Berg Pharma stands out for its grand ambitions.
Co-founder Carl Berg, the Silicon Valley real estate billionaire, says his namesake Framingham, MA-based startup is capable of “revolutionizing” healthcare. President and chief technology officer Niven Narain says that Berg can cut the time, and expense, of drug development “in half.” And the company looks more like an established biotech company than a six-year old startup. It has three divisions, including an in-house diagnostics unit. Almost 200 employees. A drug discovery platform. Programs in cancer, diabetes, and Parkinson’s disease in development.
“We see ourselves as fertilizing the Big Pharma community with great, validated clinical assets that can be marketed that are much more safe and effective,” Narain says.
We’ve all heard such claims before. Over the past few decades, scores of companies have sprung up to exploit the latest hot technology, from genomics to systems biology, and most have found the going tougher than they expected. But Berg believes it’s found the secret by putting a whole slew of these methods together. Its drug discovery platform combines elements of biological models, Big Data analytics, artificial intelligence, genomics, proteomics, lipidomics, and metabolomics.
“There are companies that do genomics, companies that do systems biology, who do computational modeling, and who do AI [artificial intelligence], but there’s not one company that’s taken all the elements at play in one complete concentric platform that’s using it as robustly in medicine as we are,” Narain says.
Still, Berg has yet to prove that its approach can produce an effective drug. Its most advanced prospect, an experimental cancer drug called BPM31510, is only in early studies. It has cut a few research deals with the Icahn School of Medicine at Mount Sinai, the U.S. Department of Defense, and the Parkinson’s Institute Clinical Center, all of which are enabling those organizations to tap into its discovery platform to help find disease biomarkers, diagnostic tools, and drugs. But the company doesn’t have the big industry partnership that startup biotechs crave for validation. And many industry observers are taking a ‘wait-and-see’ attitude.
Eric Schadt, one of the leaders in the genomics field, the director of the Icahn Institute for Genomics and Multiscale Biology at Mt. Sinai Medical Center in New York—and an advisor to Berg—put it this way:
“I think many of us share that kind of healthy skepticism about how far they’re going to be able to take this, but of course I am a fan because of my own work trying to solve the same thing. That’s why I joined the [scientific advisory board]— I wanted that data. I wanted to be able to see how far we could go with that data,” says Schadt, an Xconomist. “On one hand, there’s lots of literature to support for the approach they’re taking on the integration of the data, the building of the models. But what there isn’t any publication on, is that the predictions made, the therapeutics made, actually achieve clinical efficacy in a human population—and, of course, that’s the money shot.”
One biotech venture capitalist I spoke with did, indeed, share that skepticism. To be clear, while the VC has plenty of experience in drug discovery, the person chose not to be identified for this story due to a lack of deep, detailed knowledge of Berg’s technology. After delving into the company’s approach, the VC says while it’s “totally reasonable…any claim that it is either totally novel or will single-handedly revolutionize discovery is fluff.”
Berg was formed by Narain, Carl Berg (who ran Cupertino, CA-based Mission West Properties), and Mitch Gray, the head of private equity firm Pathfinder Management. Gray and Carl Berg were looking to build a dermatology unit for one of their businesses about 10 years ago, and met with Narain, at the time the head of cutaneous oncology and therapeutics research at the University of Miami Miller School of Medicine. The investors ended up licensing an experimental cancer drug based on Narain’s work in Miami, and formed a company called Cytotech Labs around it in 2006.
Narain had advised Cytotech for two years when Carl Berg decided it was time to “ramp up” the company. He convinced Narain to join full-time, and the Miami scientist relocated to Boston where the R&D operations of the newly-named Berg started to take shape.
The company has grown significantly from there. It’s filled out its executive team, staffed up to nearly 200 employees, and added marquee names to its group of advisors, like Schadt and Eric Nestler, the chairman of Mount Sinai’s neuroscience department. (Even actor Stanley Tucci is listed as a “senior advisor of patient advocacy.”) Berg has effectively turned itself into a drug discovery and biomarker production shop equipped with various Big Data tools. Narain says the idea at Berg is to “flip” the model of drug discovery by starting out with detailed knowledge of biology, understanding the many pathways in cells and how they change when disease strikes. Then the company uses sophisticated computer tools to figure out how those pathways should be changed—and what type of drug could do. That’s in contrast with the old traditional drug discovery approach of forming a hypothesis about a target, screening for compounds that can hit it, and going from there.
Say Berg is looking at cancer, for example. The company gathers biological samples—blood, tumor tissue, or urine—from a diverse group of people who have cancer, while also getting samples of their healthy tissue (or from other healthy donors). Berg creates cell lines from those tissue samples, and subjects them to various different environments—like the low oxygen, high glucose habitats cancer likes to live in—to mimic the certain disease state the person is suffering from.
Once those cell lines are established, Berg identifies the genes, proteins, metabolites, and lipids that are in them, and generates trillions of data points that come from both the diseased and healthy cells, Narain says.
“We’re the only company that’s integrating all of those ‘omics’ internally, “ Narain says. “The rest of the industry is kind of concentrated on the genomics. I feel that you’ve got to go much deeper than the genomics.”
Berg then puts all of that data into a computer system, which creates what looks like an “airline map,” consisting of big hubs and various lines going in and out of them. The big hubs on that map, say, the New York or Atlanta, represent the key proteins that are causing the biggest difference between health and disease—either because they are in short supply, or because they need to be silenced. Once it has pinpointed these proteins, Berg can engineer replacement versions of the missing ones, or treatments using technology like RNA interference to target the disease-causing ones. Meanwhile, the lines going in and out of each hub, like planes flying to and from the airport, become potential biomarkers for a disease, Narain says.
Berg says that this method cuts out the entire process of screening thousands of chemicals to see which ones might work as drugs, which can take several years and hundreds of millions of dollars. As a result, Narain says, the company can go from “zero to target” in 18 to 24 months, and to a drug in half the time it usually takes.
“I was very excited about a company that actually started with systems biology and this more holistic integration of biology and computation as their driving force. I think it’s very unusual, you’d be hard pressed to find another company like it,” Schadt says. “It’s still a bit of a fantasy to think we can generate all of the types of data needed, but they’re definitely generating high impact data that’s exactly the type that needs to be generated.”
But regardless of the secret sauce it’s whipped up, Berg is facing its fair share of skeptics. Berg is far from the first to try to use computer-generated models to discover drugs—and none of those methods as of yet have really caused a sea change in drug development. Merrimack Pharmaceuticals (NASDAQ: MACK), for instance, combines a high-density protein array—a way to capture how proteins interact with one another—with interactive computer models that researchers can use to figure out what target to attack, or what type of drug they should add, as part of a supposedly capital-efficient way to design drugs. It doesn’t have any FDA approved drugs yet, though the company does have a few candidates in mid- and late-stage studies. Boston’s Nimbus Discovery has a different method, but is early on in its journey—its drug candidates are in preclinical testing.
The VC I spoke with likens Berg’s approach to comparative genomics, which can be used to look at the expression of different genes in different disease states to help find novel drug targets. This is a “very well trodden” method of discovery, according to the VC.
“I believe in the ability of such systems to help identify potentially interesting targets, but historically, there is no support for decades of claims that any new target ID or rational design technology really cuts development time in a systematic, across the board way,” the VC says. “Like any other ‘omics’ technology, output is all dependent on inputs—which are, by definition, flawed since our knowledge base is always limited—and processing of the data.”
Narain counters that his system’s confluence of technologies, such as its ability to combine information on lipids, metabolites, and other markers, gives it a more complete picture of biology than others. And he contends that a pharma company would have spent $500 million to get where Berg is today (though he won’t specify how much Berg has actually spent comparatively). The onus is on Berg, then, to back up the claims, not just by efficiently producing drug candidates and validated biomarkers, but by creating therapies that make a difference.
So far, hints that Berg’s system could produce viable treatments come from petri dish and animal studies, and small early human trials. Narain says, for example, its platform predicted that its cancer drug candidate would reverse what’s called the Warburg effect, meaning by changing the fuel a cancer cell depends on—making it use up more oxygen and less glucose—it could cause that cancer cell to behave like a normal, healthy one. The platform similarly led it to a potential diabetes drug that might be able to stabilize glucose levels, and biomarkers that might be able to predict heart failure or prostate cancer, he says.
Still, that’s nowhere near enough to set the biotech world—which is in the midst of seeing a new generation of cancer immunotherapies charge through late-stage studies—abuzz. What might make waves for Berg is its BMP31510, which is currently in Phase 1b testing.
BMP31510 is a proprietary engineered formulation of ubidecarenone, a coenzyme found in mitochondria that helps produce energy within the cell. Narain says what the company has seen in early testing is that the molecule is able to “shift” the metabolism of a cancer cell, normalizing its function. The idea of messing with the metabolism of cancer cells brings to mind Cambridge, MA-based Agios Pharmaceuticals (NASDAQ: AGIO), which essentially tries to starve cancer cells to death, but Narain notes that Agios is focused only on the range of cancers with certain genetic mutations like IDH1 and IDH2.
“We’re looking at the entire system and saying our drug shifts the metabolism of any cancer cell,” he says. “We’re not cancer specific—this is a broad-spectrum mechanism.”
One potential challenge for Berg is the fact that ubidecarenone is already widely marketed as a nutritional supplement, often under the names coenzyme Q10 or CoQ10. This means that, as Schadt says, Berg is trying to solve a “pretty difficult problem.” Rather than creating a new, patentable molecular entity and testing it, Berg must figure out how to deliver it at the right time, at the right dose, and over the right span of time, and build intellectual property around that.
“Actually delivering that to a living person and having it be a potent enough to have some therapeutic benefit without killing somebody or adversely affecting them is just a hard, hard game to play,” Schadt says. “That’s where I think a lot of skepticism would come if those on the pharmaceutical side took a hefty look.”
The answers will come soon. Berg is running a four-armed Phase 1b trial testing the molecule in a variety of solid tumors. In some of those arms, Berg is combining the drug with chemotherapy drugs like docetaxel or gemcitabine. In another, BMP31510 is being tested alone. Berg expects to enroll a total of more than 200 patients, and is collecting tissue samples before or after treatment, and doing various imaging studies to track the glucose uptake in patients’ tumors. If it sees some significant responses in patients with certain types of cancer—gastrointestinal, or pancreatic, for instance—it might then break out the patients in those groups and start a Phase 2 study of patients with just those cancers. That could happen by the end of the year, Narain says.
Maybe, by then, there’ll be a much clearer picture of what Berg is capable of.
“I think in the next 12 to 18 months you’ll see significant partnerships come out of what we’re doing,” Narain says.