San Diego-based BrainCells Inc. surprised the field of psychiatry last August, when a clinical trial showed that it could relieve symptoms of depression with an odd combination of an anxiety drug and a common dietary supplement. Six months later, the company is in the thick of plotting the next steps to turn this into a potential commercial hit.
In its provocative study of 142 patients, BrainCells showed that a low-dose generic buspirone, an anti-anxiety med, and the dietary supplement melatonin were able to achieve “comparable” effectiveness to standard treatments, known as selective serotonin reuptake inhibitors, according to Mauricio Fava, the vice chair of psychiatry at Massachusetts General Hospital. The company has been pretty quiet since then, but I caught up with BrainCells CEO Jim Schoeneck and chief scientist Carrolee Barlow a couple weeks ago at the JP Morgan Healthcare Conference to find out more about where BrainCells is going to take this drug in the future.
The data to support the BrainCells drug is potentially a big deal both scientifically and medically. The new drug is thought to have a completely different way of working than standard meds, by stimulating the growth of new neurons in the brain, what’s known as neurogenesis. The new mode of treatment could have a big impact on mental health, because an estimated 20 million people in the U.S. suffer from depression, the standard drugs don’t work for everybody, and they can cause side effects like weight gain and sexual dysfunction. The BrainCells combination drug didn’t show any side effects like that, so it might be an important new option for millions.
“The depression data we showed has really been the big story over the past few months,” Schoeneck says.
Before anybody gets too excited, this drug isn’t going to arrive at the corner pharmacy anytime soon. BrainCells still has a lot of work to do before it can leap ahead into a pivotal trial that could win FDA clearance to start selling the drug, code-named BCI-952. The earlier trial involved separate pills containing buspirone and melatonin. That’s not really commercially practical because both drugs are cheap and commonly available as individual components, and it’s hard to make sure patients regularly comply with a two-drug regimen.
So BrainCells has been working on turning BCI-952 into a proprietary oral pill that would be taken once a day, before bedtime, Schoeneck says. The company is also working to make sure it has strong intellectual property around this new molecule, he says.
Once the company is confident that it has the formulation right, it will run a similar mid-stage clinical trial. Schoeneck wouldn’t say much about what this trial will look like, but it will be a rigorous study in which patients are randomly assigned to get the drug or a placebo, and doctors and patients won’t know which is which.
The data is obviously important, but the company has been explaining to a lot of its peers in the neurology world how it came up with such a surprising finding without just chalking it up to luck. That requires a bit of explanation of BrainCells’ drug discovery platform. Back in December, Barlow said she was “swarmed” when she gave a poster presentation at the American College of Neuropsychopharmacology (try saying that one five times fast).
BrainCells, as I described in this feature back in December 2008, was built on a combination of technologies from the labs of Fred “Rusty” Gage at the Salk Institute, and Rene Hen and Eric Kandel at Columbia University. The platform uses neural stem cells to create adult brain cells in a laboratory dish. The company can expose these neurons to various experimental drugs, and measure what happens through detailed tests on proliferation, migration, and differentiation of neurons. Once that’s done, it seeks to confirm the results in animals. If BrainCells’ science is on the mark, this should increase the abysmally low success rate of neurology drugs in clinical trials, Schoeneck has said.
Barlow walked me through the interesting backstory of how BrainCells discovered what became BCI-952. The company started with buspirone, a generic drug that’s known to be safe, and modestly effective for anxiety, but never shown to be effective for depression. So BrainCells tried buspirone in combination with about 70 different other medications that were available and known to have clean safety profiles—everything from folic acid, to high blood pressure drugs, to melatonin.
“As we’ve seen over many years, it’s very difficult to treat brain disorders with a single drug,” Barlow says. “It’s often better when physicians have multiple opportunities.”
The combination of buspirone and melatonin looked ideal, based on results from the drug discovery platform, Barlow says. Melatonin already was known to affect mood. It is a naturally occurring hormone that is known to interact with the central nervous system, immune system, and to help regulate the sleep-wake cycle in animals. Some people use it as a dietary supplement to help sleep disorders, headaches and other ailments.
But BrainCells still wasn’t ready to go to the clinic. Correct dosing is notoriously tricky in the world of anti-depressants, as one of the pioneers in the field, Eli Lilly’s fluoxetine (Prozac) proved when it passed just four of its first 13 clinical trials, Schoeneck says. Many anti-depressants actually show lower rates of effectiveness when given in higher doses, he adds. For a small biotech on a budget that doesn’t allow for 13 trials, getting the dose correct off the bat was going to be important.
So BrainCells set out to apply its platform to the question of dosing. It tested about 100 different ratios of buspirone and melatonin, and a number of doses, before finding the ideal balance of safety and effectiveness in the lab dish, which was confirmed later in animal studies, Barlow says. The final dose figure was about one-sixth the amount of buspirone that can be safely given for anxiety, and the amount of melatonin was also far lower than the max. “We weren’t worried on the safety side,” Schoeneck says.
BrainCells was so confident in its platform, that it didn’t even run a traditional dose-escalation study in its first clinical trial. “We were able to zoom in on the ratio, and the dose, using the platform,” Schoeneck says. “We did not have to do that in the clinic. I can tell you as we talk to people at other companies, it makes them go ‘Wow’ because in the psychiatric area so many companies have to do dose-ranging studies.”
So the company essentially picked one ideal dose based on its discovery platform, and confirmed it in its first clinical trial of 142 patients. But BrainCells still has more work to do with the platform to show it can regularly reproduce results like that.
As it happens, the company will soon find the answer to that question. The company expects mid-stage clinical results from its second drug candidate, BCI-540, before the end of March. This is a drug candidate originally developed by Japan-based Mitsubishi Pharmaceuticals for Alzheimer’s, Schoeneck says. The product failed in a mid-stage study of that use. BrainCells obtained a license to the product after its platform suggested it could be effective for patients with both depression and anxiety, a tough group of patients to effectively treat. This time, BrainCells is trying two different versions—one pill taken once daily, versus another that’s taken three times a day.
As with any clinical trial, this isn’t a sure thing. “We unfortunately don’t have the data available yet,” Schoeneck says. “This” pointing to a bandage on his finger “is actually not from biting my fingernail. I accidentally cut myself at home the other day,” he joked.
Obviously, the BCI-540 data will be critical to what kind of year BrainCells has. The company has enough cash to operate until the first or second quarter of 2011, since it pocketed a hefty $50 million in venture capital back in April 2008. It will either need to raise more capital, or secure a Big Pharma partnership, at some point, Schoeneck says.
Cash requirements could be considerable. BrainCells doesn’t know yet how many patients will be required to enroll in clinical trials for its drugs, but since a new depression treatment has the potential to be used by millions of people, the agency may require a really large database to prove the safety of the BrainCells drugs in clinical trials. But even without that, BrainCells says the data from August has grabbed the attention of folks in Big Pharma.
“Certainly the clinical information from us last year has taken their interest up fairly dramatically,” Schoeneck says. “Now they are trying to figure out, how do we plug this into our discovery platforms, what’s the best place to utilize it.”
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