Hoping to succeed where pharma giant Novartis AG failed in a late-stage trial, KPI Therapeutics Inc. is "working on closing out an investment round" to enable a phase II experiment with lead compound dalazatide in inclusion-body myositis (IBM), CEO Charles Magness told BioWorld Insight. "We hope to get that [financing] rolling in the summer-ish time frame," he said.

Seattle-based KPI's approach to IBM – an inflammatory myopathy that attacks the muscles of the arms, legs and throat – goes after effector memory T cells by blocking the voltage-gated Kv1.3 potassium channel. Although orphan indications such as IBM have proved popular with drug developers because their development paths often prove smoother, "sadly for the patients, there isn't much going on in this [disease] area."

Bimagrumab (BYM338), the antibody candidate from Novartis, of Basel, Switzerland, gained breakthrough therapy status from the FDA but blew up in a phase II/III experiment about a year ago. Novartis had signed a potential $1 billion-plus antibody deal with Martinsried, Germany-based Morphosys Inc. in 2007 for discovery work that yielded myostatin-focused bimagrumab. (See BioWorld Today, Dec. 4, 2007.)

KPI's chief operating officer (COO), Craig Philips, said the "big challenge [Novartis] had in the myositis is that it didn't actually address the underlying disease," a condition that often puts patients in wheelchairs, though the process takes about 10 years. "Once the patients are wheelchair-bound, that is a very negative prognostic indicator for long-term health," he said. "I would assume [Novartis'] objective was to try to keep people from getting in a wheelchair. If you can keep them mobile and active, that is positively associated with their overall health state."

He said that, based on what KPI has seen in preclinical models, "we should be able to arrest [IBM] from causing the damage, in this case at the site of the muscles."

In the works elsewhere for IBM is arimoclomol, which was among the molecular chaperone assets that Cytrx Corp., of Los Angeles, sold in 2011 to privately held, Copenhagen-based Orphazyme ApS for up to $120 million. The University of Kansas Medical Center is sponsoring IBM experiments with arimoclomol, which also has been tested for amyotrophic lateral sclerosis and type C Niemann-Pick disease. In IBM, Phoenix Neurological Associates Ltd. has the approved multiple sclerosis (MS) drug Tysabri (natalizumab, Biogen Inc.) in phase I testing. (See BioWorld Today, May 17, 2011.)

endpoints well established

KPI, founded about three and a half years ago, is using technology from the University of California (UC)-Irvine that deploys "a strategy of going after the disease-causing cells in autoimmune disease in a way that is immune-sparing as opposed to immune-suppressing," CEO Magness said. That could provide efficacy while dodging drawbacks of therapies such as Humira (adalimumab, Abbvie Inc.) and Enbrel (etanercept, Amgen Inc.), he said, which "can be effective in treating diseases like rheumatoid arthritis [RA], but they do have some downsides because they are immune-suppressing and can open up patients to infections and cancers."

IBM affects about 22,000 patients in the U.S. and is "a particularly difficult disease to deal with," with no approved therapies, Magness said. "Things like steroids are used off label, which is obviously not a very good treatment option at all," he said, since they bring side effects and don't work very well anyway.

The name of IBM, a progressively disabling disease, "derives from the pathology," wherein T cells infiltrate muscles and "create vacuoles of destroyed tissues," he said. "We've been doing biopsies and analyzing those patients to get a better handle on the specific types of T cells" involved, and the company has "very recently" verified that "indeed it's these [effector memory T cells] that are predominant in this destructive process in patient tissue," he said. "That's why we're pushing so hard to get this trial running later this year. We're working on finalizing the protocol with three or four different clinical sites."

Because IBM is an orphan disease, "patients tend to be clumped in centers of excellence around the country, which is good for us, because there are very directed resources we can go to work with clinically," he said, adding that KPI is "working with the FDA on the regulatory process as well," so that phase II research might be designed in such a way that the path to market is even brisker.

Research done by Novartis benefited KPI because it allowed the pharma firm to "ply the waters, if you will, in terms of trial design," Magness said. "I wouldn't characterize [bimagrumab] so much as a disease-modifying therapy [but] more of a muscle function enhancer. On the one hand, that would probably be good, because the patients really need it, and [the drug] looked promising in the phase II study." The Novartis effort also served as "confirmation of the interest of patients," he said, noting that the company "had a pretty quick accrual rate, but they couldn't quite get to the endpoint where they could get it approved. It's a minus for patients, obviously, not having something like that to help them. But we hope we can follow up with their trail-blazing and come through with an actual disease-modifying therapy."

Along with the phase II in IBM, a phase I trial in lupus is coming down the pike. "Myositis is oftentimes initially confused with lupus and vice versa – they're very similar presentations, particularly in the earlier stages," Magness said, although "IBM can be pretty definitively diagnosed by pathologists when they do a muscle biopsy, because of the unique scarring and changes that take place in the tissue." Other types of myositis "don't have quite that same pathology." Such types include juvenile dermatomyositis (JD), which COO Philips said "may be the next area [where] we could end up in the clinic," since "the channel that we so exquisitely block is implicated in that disease as well." JD is an orphan indication as well, and could mean a pediatric review voucher for KPI. Meanwhile, "a group of four institutions that have already held up their hands for participating in the phase II study" in IBM, he said, and three others may come aboard. The trial is "a nice bite-size step forward. We feel fairly confident that we can fully enroll the study over a relatively short period of time, three to four months," and hit "well-established endpoints" set by the FDA. "We've designed already the phase II and the phase III follow-on study that we aim to kick off," with the second to start quickly after the first is finished, he added.

Topical and eye drops, too

Regarding partners, CEO Magness said the company is taking a "broad approach to things. We've had a lot interest from industry and we have some ongoing discussions" about deals for other regions of the world or even in the U.S. in bigger market opportunities that could be explored. "It's certainly on our radar," he said, citing the "well-trod path" of eventual label expansion for drugs that prove efficacious in autoimmune disorders. "We feel very comfortable about that as a long-term prospect," he said. "We have good animal model data in numerous diseases, ranging from lupus nephritis, RA, MS and skin diseases." The same process underlies them, and is implicated in type 1 diabetes as well, though "there are few [animal] models that would work for us to validate" this, he said. In any case, an IBM or lupus approval "would be an enormous financial windfall."

On the capital subject, he said KPI "would obviously immediately begin fundraising on the next round" after the current one is locked down. "That's just the life of a biotech company." He said he foresees "a lot of good options on the public market" once dalazatide is approved in IBM. "Commercializing [the drug] would not be nearly as costly as something like MS, which would take very large trials to get approved," he noted, and a partner could help with those.

For now, one set of collaborators led by UC-Irvine is moving dalazatide along in IBM; another group in KPI's home city has made known its status as a prospect, too. In lupus, the company has been working with Anne Stevens at Seattle Children's Research Institute for "two or three years," Magness said, adding that "we have a lot of relationships in other areas," including dermatology, neurology and ophthalmology. Behind the injectable dalazatide, KPI has two preclinical products that represent "slight alternates on dalazatide," he said. "They're closely related but different molecules." Topical KPI-150 and eye drop KPI-190 are Kv1.3 inhibitors for atopic dermatitis (eczema) and eye diseases such as uveitis and dry eye syndrome, respectively. KPI is shooting for its first approval of dalazatide in IBM in "the next three-plus years, let's say," and then will rev up the ongoing work with other candidates, Magness said.