Straight To The Source: Treating Depression By Growing New Brain Cells

A short decade after the discovery that adult humans generate new brain cells and only a few years after neurogenesis was linked with depression, BrainCells - the lead company in the field - already has positive clinical data for its small-molecule neurogenesis stimulating candidate for treatment of major depressive disorder.

The success with internally developed BCI-952 not only provides proof of concept that inducing pre-existing neural stem cells in the hippocampus to produce new brain cells can help patients with mood disorders, it offers validation for the company's discovery platform of human-based neural stem cell assays.

It's not often "you get an opportunity to bring something forward that's novel science, that can help people in a very different way," BrainCells CEO Jim Schoeneck said in an interview. "This was such a change to the neuroscience community to realize that neruogenesis was occurring, and then to see the connections with disease. It's really the first time anyone has understood the true biology of psychiatry," he stressed.

BrainCells may be going after a new target, but it's doing so with some old tricks. The company's lead asset is a combination of older products with known safety and efficacy, which presents less risk for drug development and thus could be a valuable tool when pursuing a novel scientific approach. BrainCells' candidate BCI-952 is a combination of low dose buspirone (Bristol-Myers Squibb's BuSpar ) and melatonin. Buspirone is an anxiolytic approved for treatment of generalized anxiety disorder with or without panic and as an add-on to serotonin reuptake inhibitors for treatment of depression or anxiety. Melatonin is a naturally occurring hormone important to regulation of circadian rhythms.

The firm presented the first evidence for its product in late July at NCDEU, a clinical conference. The data not only move the company ahead with its own drug development, they also advance the field of research.

In a double blind, placebo-controlled study involving 142 patients, BCI-952 demonstrated improvements in primary and secondary endpoints in MDD. The New Research Approaches for Mental Health Interventions meeting is co-sponsored by NIH's National Institute of Mental Health and the American Society of Clinical Psychopharmacology.

The six-week Phase II study randomized patients to receive BCI-952 (67), buspirone only (34) or placebo (33). Co-primary endpoints were the Clinical Global Impression-Improvement (CGI-I) and Quick Inventory of Depressive Symptomatology (QIDS SR-16) tests. Secondary endpoints included the CGI-Severity Scale, Inventory of Depression Symptomology-30 and Hamilton Anxiety Scale.

On the CGI-I, the modified intent-to-treat population showed improvement relative to placebo in both last observation carried forward (LOCF) and mixed model repeated measures analyses. Mean scores were statistically significant using MITT/MMRM (p=0.046), a measure FDA agrees is more appropriate than LOCF for imputing missing data in depression trials, BrainCells Chief Science Officer Carrolee Barlow explained in an interview.

The per protocol population analysis, or responders, demonstrated a higher response rate for CGI-I (score <=2) for BCI-952 (58 percent) as compared to buspirone alone (38 percent) (p=0.063) and placebo (36 percent) (p=0.055).

Barlow pointed out that as the completer analysis looks very similar to the MMRM analysis, the two populations "give us a very clear picture; it's very consistent between them."

The results were not uniformly statistically significant for the secondary endpoints, but they did demonstrate numeric advantages for BCI-952.

Rational Psychiatric Drug Development

Having proof of concept that the compound is effective against depression is particularly important because of the novel approach being used. Though the end result is similar to traditional antidepressants, BrainCells' product is aimed at affecting the brain more directly, encouraging the growth of neural stem cells to produce neurontransmitters, rather than affecting reuptake mechanisms in order to keep serotonin, dopamine or norepinephrine in the system to promote neurogenesis.

That should allow for some tangible benefits over the older psychiatric medications.

Because BrainCells' neurogenesis-instigating drugs work directly at the level of the neural stem cell, while reuptake inhibitors work systemically, bathing not only the entire brain but the rest of the body with misdirected serotonin, the neural-targeted drugs avoid side effects like weight gain, sexual dysfunction and gastrointestinal effects associated with current therapies.

Another advantage: no serotonin surge. The serotonin flood caused by current therapies can cause patients to become agitated before they experience positive effects. The new neurogenesis drugs, on the other hand, do not regulate reuptake and thus cause large amounts of serotonin to remain in the system. Instead, they act directly in the brain to cause more neurons to be made that create more serotonin there.

Patients will continue to wait weeks to see an improvement in their condition, however. It is the growth of new neurons, not an increase in neurotransmitter levels, that mysteriously and positively affects anxiety and depression. So the new therapies won't avoid the lag time between starting therapy and seeing an effect. It takes neural stem cells from 28 to 35 days to fully differentiate and function as neurons.

With The End In Mind, Finding The Means

With such clear potential advantages to a neurogenesis product, BrainCells was intent on its target. To find the right compound to start out, the company harnessed its discovery platform of human-based neural stem cell assays.

Agnostic, for the most part, to mechanism of action, BrainCells has screened over 150 different molecular mechanisms and over 1,500 potential therapeutic compounds to identify agents that affect human neural stem cells in ways that mimic the neurongenesis-promoting effects of serotonin, dopamine or norepinephrine.

The first gate in BrainCells' platform is an assay in human neural stem cells in an in vitro setting, Barlow explained. In compounds like BCI-952, each part of the combination is looked at separately and then they are examined together to figure out exactly what ratio produces the best neurogenesis.

Then that ratio is tested in animals. "We dose the animals for about a month and we measure assays having to do with depression and anxiety and cognition. The animals are then sacrificed and we measure the neurogenesis histologically."

That method allows "us to tie everything together all the way from the human neural stem cells to the behavioral benefits in animals," Barlow said. "The dose that worked the best [is] the dose we took into the clinical trial."

Extrapolating from animals to humans paid off. Barlow was enthusiastic about how well the transition panned out. "We tried one dose and it worked," she exclaimed. "And that's just a huge leap in the area of pharmaceutical development."

Aiming At A Blockbuster Market

Globally the market for mood disorder drugs is around $20 billion, with $11 billion or $12 billion of that spent in the U.S., Schoeneck estimated. But, only 30 percent of patients respond to the first therapeutic they try, and only 45 percent to 50 percent ever achieve relief with current therapies, he noted.

BrainCells hopes to reach those patients in particular, either with stand-alone therapies or with drugs that work as an adjunct to current therapies.

While BCI-952 provides proof of concept for the company's hypothesis, BrainCells has other candidates in its pipeline. Brought up through the same system, those other assets also are aimed at that market opportunity.

BCI-540, the firm's lead program, is in development for treatment of depression with anxiety in patients who have failed current therapies. In 2008, it was identified as one of the Top 10 most licensable neuroscience drugs in development - with a potential market opportunity of over $1 billion - at the annual ¹ Windhover Therapeutic Area Partnerships conference (² (Also see "Big Pharma Needs A Nudge To Make More Deals In Neuroscience Space" - Pink Sheet, 26 Nov, 2008.)).

BrainCells in-licensed BCI-540 from Mitsubishi Pharma in 2006, after it failed for efficacy reasons in trials against Alzheimer's disease, and repositioned it based on input from its own assay platform (³ [See Deal]).

It is a bifunctional molecule with an undisclosed novel mechanism of action currently in a Phase IIa study for its lead indication. It also is being studied in post-traumatic stress disorder. According to BrainCells, the extensive database of human data already compiled on the drug shows no evidence of sexual or GI side effects.

The 12-week randomized, controlled Phase IIa study tests the efficacy and tolerability of BCI-540 at an 80 mg dose once or three times a day against placebo. Data are expected in the first half of 2010.

BCI-632, being investigated for mood disorders and cognitive dysfunction, has a novel mode of action thought to have utility in a broad range of CNS diseases. It is in the IND stage. BrainCells hopes to have it ready for a phase IIa study by early 2010.

BrainCells Has Cash On Hand To Move Forward

The privately held biotech closed a B round of financing in April 2008 for just over $50 million, so "we've got cash that will take us past the end of 2010," Schoeneck said. BCI-952 and the other compounds in the firm's pipeline "are assets that are unique in terms of their mechanisms, and so I wouldn't say that we wouldn't listen in partnering … but really what we're looking to do here is to continue to move the drugs forward and consider partners if we find the right [one] at the right time."

BrainCells founder Fred "Rusty" Gage, a researcher at the Salk Institute, discovered that human adults grow new brain cells in 1998, but it wasn't until 2003 that René Hen, a professor of neuroscience and psychiatry at Columbia University Medical Center, linked that neurogenesis to depression and other mood disorders.

Spurred by Hen's work and advancements in adult stem cell technology, Gage and Harry Hixson, a former Amgen president and COO, formed BrainCells in 2003. Hen is on BrainCells' scientific advisory board.

In 2008, AstraZeneca tapped Hen and his laboratory at Columbia for a collaboration to develop next-generation therapies for mood and cognitive disorders based on neurogenesis (⁴ [See Deal]).

NeuroNascent, founded in 2004, also is targeting neurodegenerative disease (Alzheimer's) and nerve damage (ischemia) as well as depression, with small-molecule neurogenic drugs. The company's lead compound, in preclinical testing, aims to promote replacement of damaged neurons, restore neurons critical to cognition and memory and enhance protection against neurodegenerative diseases by promoting growth of new neurons resistant to neurodegenerative conditions.

- Shirley Haley ( ⁵ [email protected] )