Oligomerix Inc.

Oligomerix Inc. is increasingly confident that small aggregates of the protein tau are a key culprit in the progression of Alzheimer’s disease. It aims to inhibit tau oligomer formation or self-association, the initial steps in aggregation of the protein, and thereby interrupt the disease process at a relatively early juncture.

Oligomerix Inc.

3960 Broadway

Suite 340D

New York, NY 10032

Web Site: www.oligomerix.com

Contact: Jack Pasini, Chief Commercial Officer

Industry Segment: Biopharmaceuticals

Business: Drugs for Alzheimer’s disease

Founded: November2006

Founders: James Moe, PhD, President & CEO; Eliot Davidowitz, PhD

Employees: 8

Financing To Date: $5.5 million

Investors: Wheatley MedTech; Wheatley New York Partners; Durand Venture Associates; ADDF; Private individuals

Board Of Directors: Victor P. Micati (formerly Pfizer); David Dantzker, MD (Wheatley Partners); James Moe; Jack Pasini; Douglas Durand (Durand Venture Associates)

Like many a management team before it, the one at New York City-based start-up Oligomerix Inc. believes the company can leverage fresh insights into the mechanisms of Alzheimer’s disease (AD), to develop disease-modifying therapeutics. Currently marketed treatments, like Aricept (donepezil), can help maintain the mental functioning of some AD patients for up to a few years. But so far, the benefits of this and other drugs fade as the disease progresses. Companies large and small have been pursuing alternatives, many designed to block amyloid proteins that comprise the bulk of the plaques found in brains of Alzheimer’s patients.

All of the amyloid-based drug candidates tested against AD to date have failed in late-stage clinical trials, and now even long-time advocates of this therapeutic approach are acknowledging it may not ever lead the fight forward. In just the past few years, Pfizer Inc., Johnson & Johnson Co., and Eli Lilly & Co. Inc. have seen promising Alzheimer’s drug candidates fail. Baxter International Inc. recorded the latest disappointment in May 2013. Despite the many costly failures, the undeniable need for better treatments provides a powerful impetus for research: the Alzheimer’s Association says there are now about 5.4 million AD patients in the US alone and it expects the number to swell to 7.1 million by 2025, and to 13.8 million by 2050 barring development of new treatments.

Oligomerix executives are increasingly confident that small aggregates of the protein tau are a key culprit in the progression of AD, and are not merely the bystanders or by-products they have typically been considered. The company aims to inhibit tau oligomer formation or self-association, the initial steps in aggregation of the protein, and thereby interrupt the disease process at a relatively early juncture. In disease, tau forms small aggregates, or “oligomers” that result in loss of the protein’s normal function and its gain of toxicity. Its normal function is to stabilize neuronal extensions that enable signal transmission. James Moe, the company’s co-founder, president, and CEO says that growing stacks of data from laboratories around the world suggest the firm’s focus is an appropriate one. “Recent results give a lot of evidence that if you could interfere with tau, it could disrupt progression of the disease. That wasn’t known until a few years ago, and now scientists around the world are coming to this same conclusion, and independently verifying it,” he asserts.

Moe acknowledges that Oligomerix encountered plenty of skepticism in the past because of its theories about tau’s involvement in AD. “When we started looking at extracellular tau five years ago, people said we were crazy because it was thought to be only an intracellular protein.” Lately, he says rejection is giving way to curiosity, and even enthusiasm, because of new research findings. “We’re not saying that amyloid is not part of the disease process, but now that it’s clear that tau has some direct role in disease pathology – and all the amyloid candidates that have failed – people are more interested in what we’re doing,” Moe declares.

Research carried out by leading scientists in the field shows that “tau oligomers can leave neurons, and spread pathology from one neuron to another,” Moe says. The company has identified a mechanism by which this spreading seems to occur, and has made this insight the basis of compound-screening efforts, and also antibody-development efforts at Oligomerix.

Other commercial and academic research entities have considered tau as a drug target over the past several decades, Moe acknowledges. After all, tangles of tau fibrils found in the brain are as much a hallmark of Alzheimer’s disease as amyloid plaques. Even Big Pharmas initiated some research programs focused on tau, but the work was largely abandoned a decade or so ago, when experimental amyloid inhibitors seemed likely to work. “Even we thought the amyloid candidates would come to market, and that our tau-based drugs would be complementary to them,” Moe asserts.

Typically, scientists seeking inhibitors of tau expected that such drugs would have to work inside neuronal cells – never an easy place to enter. Also, Moe notes that investigators have generally sought inhibitors against fibrils of tau using forms of tau containing mutations unrelated to AD, and other modifications such as truncation, rather than targeting the aggregation of the entire protein. Both of these assumptions were reasonable, he says, based on scientific findings at the time. But Oligomerix and its scientific collaborators, including Ottavio Arancio, MD, PhD, at Columbia University, began pursuing some other notions about tau and its role in Alzheimer’s disease.

“We started to look at extra-cellular tau oligomer levels, because we found that their levels were increasing in cerebrospinal fluid as a function of disease stage,” Moe says. He recalls thinking that the presence of extracellular protein might influence neuronal plasticity, and so he began working with Arancio to look in mice at the hippocampus, which is where Alzheimer’s disease begins. “We showed that tau oligomers reduce electrophysiological measures of memory with dose dependence, and so could be a good target,” he asserts. Other labs have duplicated the findings, Moe declares, explaining that this previously unsuspected ability means tau could possibly spread the disease through the brain. Tau oligomers are small, soluble aggregates of multiple tau protein molecules, as distinct from monomers, or single molecules of tau protein. To check out the hunch about the destructive role of tau oligomers, Moe’s research team infused some of these into wild-type mice in an area of the brain important for short-term memory. As it turned out, the wild-type mice given the oligomers showed a reduced fear-conditioning response: in other words, they could not remember, or at least no longer responded in the same way, to stimuli known to cause a particular response.

Moe and his colleagues conducted further experiments that ended up putting the onus on tau oligomers, and shedding light on how these jumbles form. “We can also make monomeric tau that cannot form oligomers, and these have no effect,” Moe asserts, adding that mice given these monomers have the same response to stimuli as those given the delivery vehicle alone.

“Clearly, extracellular tau oligomers are specifically affecting memory and behavior in mouse models of Alzheimer’s disease, and we can show if you knock it down you improve those,” says Jack Pasini, who brings to his current role as chief commercial officer of Oligomerix 30 years of global drug commercialization experience at Pfizer Inc. He is intent on helping the start-up advance its laboratory work to the point that it can attract a Big Pharma to collaborate with the company or license rights to its work. “We feel we are way ahead of anyone who is only now going to begin pursuing tau oligomers as a target, but we need partners to move forward,” Pasini declares. By now, he says Oligomerix is close to finalizing its choice of small molecules, and is developing antibodies suitable to advance as immunotherapeutic agents and also as biomarkers.

Whereas scientists seeking inhibitors of tau have typically screened compounds against pre-cut segments of the protein, Oligomerix screened against the full-length target. Consequently, Moe says his company’s assays have spotlighted molecules that bind to decidedly different structures and will therefore, he believes, have distinctive abilities as drugs. “Our assays select compounds that interfere with tau-tau association that leads to formation of oligomers,” Moe explains. Oligomerix is now working to validate that compounds culled from in vitro screening assays do in fact hit the same targets in animal models. The firm has begun grooming some of these as potential lead drug candidates.

The decision to screen compounds against full-length tau protein, instead of pre-cut segments of it, revealed an unexpected phenomenon that Oligomerix believes can and should inform development of novel drugs for AD. Although it has long been known that tau gets truncated by various proteases in disease, Moe says Oligomerix scientists “discovered that tau oligomers are self-truncating. It starts this whole process all by itself.” Oligomerix is betting that the self-truncation of tau is a vital mechanism underlying Alzheimer’s disease. While still working to prove that is the case, Moe says the firm has patented “antibodies to the cut ends where tau self-truncates, which we call the active fragments.” These fragments are proteolytically active in vitro, he says, musing that they might one day serve as biomarkers for the disease, which is still only formally diagnosed after autopsy. Oligomerix is investigating the possibility of using these cut site sequences it has identified and has filed patent applications for their use as biomarkers.

The extracellular location of tau oligomers for this disease target “makes pharmacologists happy,” Pasini asserts, “because theoretically you could inhibit it with much lower concentrations of drug than you would need to administer to have an effect inside of neurons.”

“Four years ago, it was considered heresy to talk about developing antibodies to bind extracellular tau as a way of treating Alzheimer’s disease. But the field has now embraced extracellular tau as an immunotherapeutic target because it has been shown to be involved in impairment of memory formation and to have a direct role in the spread of disease within the brain,” Moe declares. He figures it is only sensible, given how adept antibodies have proven to be at combating other diseases caused by circulating proteins, such as rheumatoid arthritis and other inflammatory disorders involving TNF, or tumor necrosis factor. Moe also notes that other researchers have demonstrated proof-of-concept for this approach in animal models of neurodegeneration caused by tau aggregation. That said, small molecules that can be manufactured at far lower cost than biological drugs may be the optimal approach for preventive treatments, he points out: they can be given orally instead of by injection, and so are certainly better suited for long-term treatment regimens that might be necessary to combat Alzheimer’s.

Moe and Pasini say they feel good about the compound library Oligomerix obtained through the Michigan High-Throughput Screening Center. Originally compiled at Upjohn, they say the library was from the start culled of compounds known to be toxic or chemically reactive, and then further sifted with regard to drug-like properties before being enriched for diversity. “Many companies have been advancing polyaromatic compounds for AD that are potentially carcinogenic, but they fail a lot of tests and FDA raises the bar, making it difficult for them to win approval,” Moe points out. By contrast, he notes that Oligomerix’ library was long ago purged of problematic structures and has yielded higher-quality candidates. The company has sorted 124 compounds that registered as “hits” in its assays, and selected eight compounds for in vivo validation studies. It has also classified these hits into different structural families, Moe says, focusing on series that are drug-like and face little or no competing intellectual property.

Within a few months, Pasini says Oligomerix expects to have in hand the sorts of animal data that Big Pharmas demand as a minimum before considering any sort of licensing arrangement. “A few years ago, it was a tougher sell, because we didn’t have enough proof-of-concept,” he says. Now that encouraging data are accumulating, the company and its board members are comparing their prospects with benchmark deals like the one struck by AC Immune and Roche, where the Big Pharma agreed to a $418 million-plus deal for a very early-stage research program.

By now, Oligomerix has discussed its theories and assets with about 15 of the top 25 drugmakers in the world. Some have no interest in tau because they are still focused on amyloid, Moe says, and yet he believes Oligomerix will find a worthy partner: there is a lot of soul-searching going on in Big Pharma board rooms, given all the late-stage clinical failures and the billions spent already, he observes. As hard as it has been to come up with a drug that truly helps the growing millions of people afflicted with Alzheimer’s, it’s easy to see why the disease remains an alluring object of discovery research. The company that succeeds in creating a treatment to halt this terrifying disease will have a product worth tens of billions of dollars each year, and great glory besides.

In May 2013, Oligomerix closed a financing round that boosted the total amount raised to date to $5.5 million. Its investors include Wheatley MedTech, Wheatley New York Partners, Durand Venture Associates, the Alzheimer’s Drug Discovery Foundation, and private individuals. [See Deal]