CalciMedica Charges Ahead Toward First Human Test of Oral Pill for Psoriasis

Xconomy San Diego — 

One of the interesting new ideas in the treatment of autoimmune disease is approaching a critical turning point at San Diego-based CalciMedica. This little company, so close to the ocean you can smell it from the CEO’s office window, is based in part on some intriguing science that got its start at the Immune Disease Institute and Harvard Medical School in Boston.

CalciMedica, founded in October 2006, has raised $19 million since the beginning from GlaxoSmithKline’s SR One investment arm, Sanderling Ventures, and Biogen Idec New Ventures. Much of CalciMedica’s early years were spent toiling away on the basics of biology and chemistry to create new drug candidates. But now it is ready to take a big new step, starting human testing early next year of a once-daily oral pill designed for patients with moderate to severe psoriasis.

This trial could be the start of a big, aggressive development program. Estimates are that between 14 and 24 million people in the U.S. have immune systems that go haywire, attacking healthy tissue like an invading flu bug. They have a chronic, lifelong pain in the case of rheumatoid arthritis, skin lesions if we’re talking psoriasis, or plenty of other symptoms from an estimated 80 other diseases. CalciMedica’s drug, while originally intended for psoriasis, may also be useful someday for other chronic inflammatory diseases like rheumatoid arthritis, ulcerative colitis, and asthma.

“It’s important for us, however far removed we might be from the endpoint, to not lose sight of who’s going to benefit from this,” says CalciMedica’s CEO, Gonul Velicelebi. As she explained to Bruce last year, researchers also are intrigued by the idea of creating alternative drugs that avoid side effects of some immune-suppressing drugs prescribed to prevent organ transplant rejection.

Of course, this is also about tapping into some very big potential markets. Autoimmune patients are often willing to pay big bucks for relief, creating the kind of markets that Big Pharma companies lust for. Total sales of rheumatoid arthritis drugs alone are estimated to grow from $7 billion in 2007 to $17 billion by 2017, according to Datamonitor. And the really big hits in that market-including Amgen’s etanercept (Enbrel) and Abbott Laboratories’ adalimumab (Humira) —are injectable drugs, not oral pills like the ones CalciMedica has in the works.

Gonul Velicelebi

Gonul Velicelebi

The idea at CalciMedica, like the name suggests, is to make drugs that interact with calcium channels on the surface of cells. It got its start when Velicelebi, and two employees from Torrey Pines Therapeutics—Kenneth Stauderman, and Jack Roos—discovered the role of a protein called Stim1 in regulating the activity of certain calcium channels known as CRAC channels. They pooled this knowledge with work from scientific collaborators Anjana Rao, Patrick Hogan, and Stefan Feske in Boston, who described the role of a related protein called Orai1 that acts as a calcium channel, and is activated by Stim1.

Once those two proteins were shown to clearly work together in 2006, the decision was made to go ahead and start a company that put them together. The plan was to zero in on these calcium release-activated calcium (CRAC) channels as a way to tamp down the destructive effects of excessive inflammation. While many cells need to let calcium pass in and out through calcium channels, CRAC channels are of interest because they are specifically found on immune cells, and aren’t thought to play any significant role in other cell types like heart cells, or nerve cells, Velicelebi says.

What really fired up CalciMedica was a finding, published in Nature in 2006, of a teenage boy with an immune deficiency with a precise genetic defect that made it impossible for him to have functioning CRAC channels, Velicelebi says. The boy was given a bone marrow transplant years earlier, and was able to develop a functioning immune system. The boy is otherwise healthy, which suggests that a drug developer inhibiting CRAC channels ought to be able to inhibit inflammation without harming other major organs.

That might not sound like much, but it’s an important vote of confidence for a drug with a mechanism that’s never been tested before in people.

“This is a human validation of the target, which is what pharma is looking for,” Velicelebi says.

CalciMedica has developed its lead candidate, and two backups. They’ve all shown an ability to be given orally in rats, to inhibit CRAC channels, to reduce inflammation, and to remain stable in the bloodstream for once-daily dosing. The company has decided to go after psoriasis as its first application partly because it ought to work against overactive T cells that contribute to skin lesions, it’s easy to get a biopsy to show early effectiveness, and because it’s easier to enroll patients in clinical trials, Velicelebi says.

Plenty of other companies are trying to do similar things. Several Big Pharma companies have internal programs to develop drugs against CRAC channels, based on anecdotal feedback Velicelebi says she has gathered. Several others are clearly interested, because they have entered partnership talks with CalciMedica under confidentiality agreements, she says. The only other active competitor among biotech companies is Lexington, MA-based Synta Pharmaceuticals (NASDAQ: SNTA) which is pursuing CRAC targets through a collaboration with Switzerland-based drug giant Roche.

There are a number of other strategies out there for orally-delivered autoimmune treatments. South San Francisco-based Rigel Pharmaceuticals (NASDAQ: RIGL) has one of the best-known programs, in partnership with AstraZeneca, to develop an inhibitor of a target called syk. Pfizer has made news from mid-stage clinical trials with its oral Jak-3 inhibitor. Plymouth, MI-based Lycera, which hasn’t yet entered clinical trials, has attracted $36 million in venture capital for its concept of developing drugs against other targets, ATPase and Th17. Wilmington, DE-based Incyte (NASDAQ: INCY), along with Eli Lilly, is also going after Jak inhibitors.

CalciMedica has a long way to go before it can prove that its drug is safe and effective in people. Ultimately, the clinical trials for the kind of uses it has in mind can only be run by the biggest drug companies with the biggest budgets. If the drug is shown to be safe in early clinical trials, then it will be time to have more talks with the Big Pharma companies who can take it through the long journey of clinical trials needed for FDA approval. After that, it will be time to talk more seriously about how many people might benefit, and to what extent.

“There is room in the market for lots of different mechanisms,” Velicelebi says. “We need to remember that we’re trying to bring forward a new option for millions of people who suffer from autoimmune diseases. The more treatments out there, the better.”