2014 Brand of the Year

Pharm Exec's Brand of the Year award is itself a brand with staying power—our first recipient was Merck's Gardasil papillomavirus vaccine, which eight years later is still going strong as one of the company's 10 top-selling products. This year's winner, Teva's Copaxone, also pins the needle on the long tail, at 17 years on the market with an equally durable safety profile against its nemesis, the elusive autoimmune disease multiple sclerosis. But lest we be accused of being safely predictable, this year Pharm Exec decided to focus, too, on clinical and marketing achievement for an orphan-status rare disease drug, calling out Bay area start-up Corcept Therapeutics' initiative in repurposing an old drug, mifepristone, for a new indication as the first treatment for Cushing's syndrome, a disabling metabolic disorder that is habitually underdiagnosed. Corcept's KORLYM carries larger potential as the test launch for a new class of medicines to address how the "fight or flight" hormone, cortisol, works as a precursor to many chronic life-threatening conditions that affect millions of patients outside the rare disease space. It's literally a new way to think about disease. — William Looney, Editor-in-Chief

Copaxone: Built To Last

The first prescriptions for Teva's Copaxone were written in the spring of 1997, with peak sales estimated at $250 million. Seventeen years and many billions of dollars later, Teva has returned for an encore with the approval of a newly-formulated Copaxone touting fewer injections, just in time to upstage the potential entrance of generic competition this summer.

By Ben Comer

Specialty drugs for the treatment of chronic disease, along with orphan drugs for rare conditions, are the two most popular areas of biopharmaceutical R&D activity for one obvious reason—optimal return on investment. In the case of chronic diseases, companies turn patients into walking annuities toting a prescription that needs to be filled and refilled perpetually, with a caveat: it's hard to know how a drug will perform for patients 10 or 20 years later, in the real world. Products age along with the patients who take them, sometimes with unexpected results.

Copaxone (glatiramer acetate injection), Israel-based Teva's multiple sclerosis drug and a once unlikely blockbuster, was chosen by Pharm Exec as one of this year's two Brand of the Year awards for its consistent success in this context. Copaxone has been on the market for 17 years, with virtually no serious side effects emerging during that time. According to John Hassler, Teva's VP of marketing for neuroscience, Copaxone is the "market leading therapy for relapsing-remitting forms of multiple sclerosis, with over 40% more total prescription volume than the next closest competitor."

About 35% of all patients taking a drug for MS take Copaxone, or roughly 85,000 patients, adds Mike Derkacz, VP and general manager of Teva's CNS unit. Derkacz held the same title at Cephalon prior to Teva's acquisition of that company in 2011.

Teva has continued to improve the Copaxone brand experience for patients over time, from a new injection device to engaging patients online and off. The company hosted an early online MS patient community—MSWatch.com—"long before the term 'social media' was coined," says Hassler. Shared Solutions, now a part of Teva, made nurses available to patients around the clock beginning in 1997, when Copaxone launched. Shared Solutions, a gold standard in the category, is open to all MS patients, regardless of therapy.

In January, Teva received approval for a new 40mg version of Copaxone that reduces the number of injections from seven a week, to three. Despite the recent Supreme Court decision on Copaxone's patent—which opens the door to potential generic competition as soon as this month—Teva has already recorded strong results from the newly-formulated 40mg version. Seven weeks into the launch, Copaxone 40mg became the most prescribed treatment in terms of new prescriptions for patients with relapsing-remitting MS, the most common form of the disease, and has remained at the top since then, the company says.

Despite competing with at least a half-dozen newer disease-modifying agents for the treatment of MS, some of them oral formulations, Copaxone still managed to lead the category in 2013, with global sales topping $4.3 billion.

Focus on MS patients

Multiple sclerosis, a chronic and potentially debilitating disease, affects some 450,000 people in the US, and over two million lives globally. Symptoms occur due to an autoimmune attack on nerve fibers in the brain and spinal cord, which can damage the protective myelin coating and lead to scarring and nerve damage. As with most autoimmune diseases, the causes of MS aren't well understood; an inflammatory response in the body can be as harmful as it is helpful, and no one is sure exactly what triggers an appearance of Mr. Hyde from the typically Jekyllian, and protective, human immune system.

As a result, MS can feel to otherwise young and healthy patients like it has fallen, unduly, from a clear blue sky. The effects of nerve demyelination present in many different ways, from subtle pain or blurry vision, to an inability to stand or speak, with a host of other problems in between. Symptoms—in the case of patients with relapsing-remitting MS—can suddenly dissipate into thin air as quickly as they arrived, only to reconstitute days, months, or even years later. Not knowing when or to what degree the symptoms will return can be a nightmarish predicament for MS patients, akin to cancer patients in remission long enough to almost forget they had the disease.

The unpredictable progression of MS (along with the failure of available drugs to halt it) is maybe the worst aspect of the disease. Does waking up with stiffness or numb legs indicate a new MS exacerbation, or is it simply due to an especially vigorous exercise effort the day before? When only time can tell, the clock and calendar become sinister partners in an unwelcome alliance; MS patients, a population that skews toward but isn't limited to women in the prime of their lives, can't afford to sit around and wait for what may or may not happen next.

That's why disease awareness is critical, says Melyssa Weible, president of Rx Mosaic Health, a New York-based "specialty-only" PR shop under the Omnicom umbrella. Rx Mosaic has worked on Copaxone for nine years. "When we started working with Teva, MS wasn't oncology, it wasn't being mentioned every day in the news," says Weible. "That's no longer the case."

Star power

MS is at least two to three times more common in women than men, and possibly more than that, according to the National Multiple Sclerosis Society (NMSS). But Teva's celebrity faces of the disease are men: country music star Clay Walker, and Jack Osbourne, a media personality and the son of Black Sabbath front man Ozzy Osbourne.

Jack Osbourne’s documentary-style webisodes offer a candid view of life with MS.

Both men have worked with Teva on disease awareness initiatives—Clay Walker has taken Copaxone for 15 years, says Teva—and Jack Osbourne's surprise diagnosis two summers ago led to a series of candid online webisodes about living with MS, and the misconceptions people have about the disease.

Teva’s patient switch campaign, seen here in a People magazine cover buy, emphasizes the "freedom" of convenience.

"You Don't Know Jack About MS," the joint project sponsored by Teva and created by Osbourne's production company, Schweet Entertainment, debuted last December. Teva also donated $100,000 to the NMSS in recognition of Osbourne's work as an MS advocate and his participation on "Dancing with the Stars," a reality TV program. The webisodes, available at YouDontKnowJackAboutMS.com, feature Osbourne as man on the street, attending a MS patient gathering, and managing family life with a young daughter. Weible says the decision to go with documentary-style webisodes is a reflection of Osbourne's persona and interests. "We wanted to maintain the authenticity that comes with him...he's a reality TV star," says Weible.

During a webisode titled "Many Symptoms," Osbourne and five other patients recount the stories of their first symptoms and diagnosis. The individual experiences vary dramatically, reminding one of the patients of a quote from a physician: "Once you've seen one case of MS, you've seen one case of MS." Osbourne, for example, first visited the doctor due to the sudden onset of blindness in his right eye. Another patient felt an extreme numbness in his leg, and, after attempting to walk it off for 17 minutes, couldn't walk anymore. This discrepancy in the initial symptoms of MS can make an early diagnosis difficult. Osbourne was diagnosed with MS a year and half after his first symptoms emerged, he says.

Clay Walker was diagnosed in 1996, at the age of 26, after experiencing symptoms, including tingling, numbness, and facial spasms. A long-time Copaxone user, Walker has remained active in promoting disease awareness and education. Ten years ago, Walker founded a charity called Band Against MS, and has continued to speak out on behalf of MS patients, and to hold fundraising events. In March 2013, Band Against MS and Teva worked together for a public service announcement campaign intended to remind patients about the importance of adhering to their medications. Titled "Stick With It"—in reference to the daily injections most patients must give themselves—the campaign launched a Facebook page and Teva agreed to make a $1 donation for every "like," up to $25,000.

Since Copaxone is the most prescribed and best-selling MS drug on the market, it makes sense for Teva to invest in non-branded, educational campaigns. After all, if most new patients get a prescription for Copaxone, making more people aware of the symptoms, and the importance of treatment, means more prescriptions and sales. Weible says the goal of the celebrity campaigns is to "share the patient experience with newly-diagnosed patients who may feel isolated, or for patients who have MS and have been treating it for a while," she says. "Dealing with a chronic condition can be isolating and lonely, and patients want to hear from a 'patient like me,' a real-life story," she says.

Teva and Rx Mosaic assisted in hosting a Twitter conference on March 14, 2012, in partnership with the NMSS. "I think we were the first people to ever do a Twitter conference for an ethical healthcare product," says Weible. "We connected a doctor (Dr. Gabriel Pardo, @DocforMS), Clay Walker, and MS patients, and they were able to ask questions in real-time...we were thrilled with the amount of people that participated." The Twitter conference wasn't Copaxone-branded, but participants asked Dr. Pardo questions about Copaxone and several other MS products. It's hard to tell from Twitter how many people participated, and Walker (@ClayWalker) did tweet a link to Copaxone's product information at the conclusion of the one-hour event. The conference hasn't been repeated since, but it exists online as proof that pharma can engage patients using social media channels like Facebook and Twitter.

Social media before Facebook

Long before Dr. Pardo and Walker took to Twitter, Teva and InTouch Solutions, a Kansas-based digital marketing agency, launched MSWatch.com. The site functioned as a resource and community for patients living with MS. Matthew Goyer, VP of client services at InTouch, said patients signing up on MSWatch.com "not only had the ability to interact with the content provided by Teva—all the tips and suggestions and everything else to help manage their MS—but there were also methodologies where they could interact with each other through the patient forum."

Asked why the platform was discontinued—it lives on in Canada, in limited form, at MSWatch.ca—Teva's Hassler says the company is "proud to have been an innovator in developing this online community," but "as the social media landscape evolved, it enabled the MS community to expand the conversation beyond industry platforms."

The patient section of the Canadian site, dubbed MS Oasis, bills itself as a "safe place for the patients and caregivers in the MS community to log treatment and connect with one another." Individuals registering on the website are asked to choose a bird avatar, and then "perch in the tree where you can find resources in the birdhouses and check in on fellow Sanctuary members." There's also a rewards system where visitors "can earn badges just by keeping up with appointments and therapy."

When Pharm Exec visited the site, seven "birds" were chirping in the sanctuary, ostensibly meaning seven people were logged in. Unless users create a therapy journal, there doesn't appear to be a way to communicate directly other than to "chirp" at someone else, similar to liking them on Facebook. Of the birds in the sanctuary when Pharm Exec arrived, none were reachable beyond a chirp.

Digital tools

Teva's Derkacz says Copaxone participates in all of the standard digital marketing channels, including CRM and database marketing, search optimization, display towers and banners, rich media, et cetera, but emphasizes that digital is not a silver bullet. "We're not taking a big gamble on one new innovative idea...we're making sure that we surround the patient and physician with what Copaxone is and what it can do," says Derkacz. "Let them pick the channel and the content they want to consume at the time they want to consume it."

The iTracker app lets patients record injection sites to aid in proper rotation.

Teva's Copaxone iTracker app, which anyone can download for free from the iTunes and Android stores, helps patients manage the injection routine—it's important to rotate the injection site—as well as set therapy reminders and receive prescription refill alerts, among other things. Derkacz says the wow factor for a prescription drug companion app is gone—"almost everyone's got an app"—but says iTracker "has been very well received by patients."

In April, Teva and Intouch launched a new "webTracker" tool which Goyer says is complimentary to iTracker, in that it allows patients who register with Shared Solutions to login to webTracker and track "not just their injections but their overall feeling of well-being and current state of health." The webTracker tool helps patients figure out what to do if they forget a dose or use the wrong injection site, says Goyer. "We developed an algorithm, approved by Teva's regulatory staff, that automatically provides the next step for the patient," he says. "It's a tool that's a lot smarter than the tools have been in the past."

On the physician side, Intouch partnered with Harrison & Star, Teva's professional and direct-to-patient agency, for content and sales messaging materials used by sales reps in the field. Those materials are "all in a digital format and available to reps on the iPad," says Goyer. Mardene Miller, president at H&S, says the physician audience for MS—primarily neurologists—are "more the cerebral type," which seems fitting. "They're also very practical in terms of their clinical view, and they're very patient-oriented," says Miller. Teva fields a team of roughly 200 reps servicing around 7,000 neurologists in the US, says Hassler.

For the Copaxone 40mg launch, H&S developed new creative for both physicians and patients aimed at "reinforcing the overall Copaxone brand promise of trust and experience," says Kathleen Murphy, SVP, group account supervisor at H&S. "Coming soon" ads launched last October, three months prior to approval. The MS community is an active one, says Murphy, and they engage in a variety of digital channels. "But I don't want to underestimate the importance of the personal touch that Shared Solutions has with patients," she says.

Shared Solutions

Not everyone with a question about MS wants to address it to a screen or an algorithm. In preparation for the Copaxone 40mg launch in January, Teva hired an additional 100 people to work in the company's Shared Solutions group, and also added sales reps at a time when other parts of the company are shedding positions.

Shared Solutions was originally an independent third party patient services company, based in Kansas City. Teva acquired the group in 2002, and every executive interviewed for this article—internally and externally — pointed to Shared Solutions as a critical component of Copaxone's success. Anyone with MS, not just Copaxone patients, can use Shared Services free of charge.

"The key, I think, in the launch and success throughout the 17-year history of Copaxone has been Shared Solutions," says Derkacz. Shared Solutions is focused on three areas: assisting patients in getting access to therapy; providing one-to-one injection training to make sure patients have the best experience possible; and promoting adherence.

Shared Solutions has a call center component, where registered nurses answer inbound calls on a 24/7 basis, and also make outbound calls to patients who have signed up to receive them. There's also a field component, where nurses provide injection training at the doctor's office. Derkacz says physicians really appreciate this service. "They don't have the time or resources to do all of this training and hand-holding and educating that we can do for the patient [through Shared Solutions]," he says.

Patients like it, too. Derkacz and Nancy Leone, communications director at Teva, say patients form relationships with the nurses at Shared Solutions, sometimes over years on therapy. Teva has staged meetings at headquarters between patients and nurses who have bonded through Shared Solutions, to dramatic result, says Leone.

Patients are connected with Shared Solutions when they receive the first Copaxone prescription, and the group makes sure there aren't any hiccups in timely access to the drug. Shared Solutions is supporting the campaign to switch Copaxone users to the new formulation by answering questions, and placing calls, to patients who've opted in to the program, says Hassler.

Access to therapy

Copaxone enjoys "the best formulary positioning across the entire category, meaning that we have the least number of NDC blocks," says Derkacz. "You're talking 98% open access to this product." Teva offers a $0 copay option for eligible patients, as well as other kinds of qualified financial assistance. Asked about the CMS reversal and decision not to block copay assistance from drugmakers under Medicare plans, Derkacz said it was the right decision."We know that high co-pays have a negative impact on patient adherence...co-pay assistance can help achieve improved outcomes," he says.

The new Copaxone 40mg formulation is priced at 2% below the current price of Copaxone 20mg, a clear play at winning over the sympathy of payers, who may soon be forced to choose between a daily injection of generic Copaxone, or a three-times weekly version that would cost a good deal more.

On the question of whether payers might force patients onto the generic version of Copaxone 20mg (assuming a generic version is approved by FDA), rather than pay for the more convenient 40mg dose, Derkacz says that's not what Teva has been hearing from payers so far. "We're talking ethics here," says Derkacz. "How do you take a patient who has 200 fewer shots a year and then push them not only back to a once-daily formulation, but one that's unproven?" Teva has expressed doubt, in print and at just about every other opportunity, over the comparative effectiveness and safety of generic Copaxone.

Hassler says Teva expects to switch 30% to 50% of its current Copaxone 20mg patients to the 40mg version. Copaxone 40mg is the same glatiramer acetate discovered in Israel over 30 years ago, but not the same product; Hassler says the switch campaign boils down to this message: "We've taken the number one product in the market place, and we made it better."

Copaxone through the years

After a group of scientists—Michael Sela, Ruth Arnon, and Dvora Teitelbaum—at the Weizmann Institute of Science in Rehovot, Israel, discovered copolymer 1, which would become Copaxone, they shopped it around to several large pharmaceutical companies. All of them declined; no innovative brand drug discovered and developed in Israel had ever been approved by FDA. Copaxone would become the first.

At the time, Teva produced generic medications exclusively, but Sela, from the original discovery team, was friends with Teva's founder and CEO, Eli Hurvitz. Sela and his wife Sara invited Hurvitz and his wife Dalia over to dinner. Sela arranged for a slide projector and screen, and the two couples reviewed data from the previous 17 years of copolymer 1 development. Intrigued, Hurvitz negotiated Teva's rights to the product with the Weizmann Institute, according to Teva.

Copaxone launched in the US in 1997 (and across Europe in 2001) but wasn't terribly convenient for patients. It was a frozen lyophilized product that required reconstitution before a traditional injection. The initial peak sales forecast was $250 million, according to Derkacz. In 2000, the Autoject device was introduced, making it much easier for patients to use. The same year, Copaxone jumped past Bayer's Betaseron to become the second most frequently used MS therapy. In 2002, prefilled syringes were brought to market, which again made administration easier for patients. By 2008, after Biogen Idec's Tysabri had been pulled from and then put back onto the market, Copaxone had become the market leader by prescription volume and demand.

When Novartis's Gilenya (2010), and then Biogen's Tecfidera (2013) hit the market, it was supposed to be curtains for Copaxone. "The reality is while they've gotten some traction, things haven't really changed a lot for Copaxone," says Derkacz. "We've been able to maintain prescription volumes for the most part, though 2013. And it really set the stage nicely for the launch of 40mg."

Generics coming this month?

In January, a Teva-sponsored study published in PLOS ONE aimed to show a difference between Copaxone and a "purported generic" in development. In a release on the study, co-author Michael Hayden, president of global R&D and chief scientific officer for Teva, said the "data from this paper shows the possible significant ramifications of changes in physiochemical properties between Copaxone and a purported generic." He went on to say the study "suggests a distinct potential difference in the impact of a purported generic on the immune system of patients, with possible implications on efficacy and safety in relapse-remitting MS patients. Teva believes the only way to truly understand the impact of these differences is by conducting a full battery of clinical studies."

The active ingredient in Copaxone is a mixture of polypeptides containing a huge number of active amino acid sequences which can't be "accurately characterized using state of the art analytical techniques," says Hassler. "The only way to demonstrate efficacy, safety, and no differences in immunogenicity, is through well-controlled, comparative clinical trials."

It's unclear whether FDA will be sympathetic to this view. Craig Wheeler, CEO of Momenta, one of the lead developers of generic Copaxone, certainly is not. He says Teva is trying to "throw wrenches" into the FDA review process. Wheeler says he wouldn't give Teva his product for research, and doubts Mylan would have either, meaning the generic drug evaluated by Teva must have come from somewhere outside the US.

As for gene expression and the contents of the Teva study, Wheeler says "it's nice to put a big color graph in front of investors, but it doesn't really hold a lot of scientific water." Why not? "If you look at gene expression and how it works, it can vary animal to animal, it can vary by time of day, it can vary temporally," says Wheeler. "If you applied statistics to the data they've shown, you would have a hard time showing that there's any statistical significance in what they're saying."

Teva agrees to disagree, but the possibility of a generic 20mg Copaxone approval is one the company is nevertheless prepared for, says Hassler. "We'll continue to build brand loyalty, and at the end of this I believe most physicians and patients as well as many payers will opt for a clinically proven therapy."

The price of prevention

Copaxone is a disease-modifying therapy, but it doesn't stop the progression of MS. Patients and physicians, as evidenced by the level of utilization, are confident the drug does slow exacerbations of the disease, despite a Cochrane review that found "no beneficial effects on disease progression," and only a "slight beneficial effect in the reduction of risk of relapses in relapse-remitting MS patients." Slight is better than nothing, and patients wouldn't keep injecting themselves everyday if they believed otherwise.

A neurologist and professor at one of America's top academic medical institutions—who asked to remain nameless for this article—said Copaxone's "importance lay in showing that an approach of this type can work, albeit modestly...that said, we have no definite idea of its mechanism of action."

To date, there haven't been any generic versions of disease-modifying MS drugs, which means that when a new product is approved, and priced, all the other products increase up to the new price level. "Pricing of MS drugs is a national scandal," said the professor, responding to a question about potential generic versions of Copaxone. "Anything that makes them more affordable is welcome."

Derkacz says Copaxone "has never been a price leader...and its pricing is largely reflective of investments made to research as the market-leading MS therapy." Derkacz also emphasizes the value and services built in to the cost; those nurses working for Shared Solutions might be free for patients to call, but they don't work for free. If a generic version does launch, how do payers put a value on injection frequency, particularly for patients who've developed injection site reactions?

It's not just MS, of course. Even products that are effectively curative, like Gilead's Sovaldi, for hepatitis C virus, are being challenged on price. For drugs targeting chronic conditions, where patients must take them indefinitely, often for the rest of their lives, pricing pressures will continue and are likely to intensify. Within the current system, the best cost solution is both the simplest and the most difficult: discover a cure, pay a premium, then develop a generic version. MS patients, their families, payers and even some taxpayers are willing to pay a little more in the short term for an assurance that the disease never comes back in the long run.

Ben Comer is Pharm Exec's Senior Editor. He can be reached at bcomer@advanstar.com.

KORLYM: The Cortisol Connection

A repurposed drug shunned by some for ethical reasons has gained fresh momentum as the model for a new line of therapies seeking to mediate the impact of an essential human hormone—cortisol—on a wide range of life-threatening conditions, from diabetes to osteoporosis and even cancer.

By William Looney

Rare diseases are a rich and growing source of innovation in drug discovery—nine of the 27 new medicines approved by the FDA last year were for "orphan" indications affecting fewer than 200,000 people. But numbers alone don't reveal the significance the rare disease segment holds in spreading the institutional roots of innovation to new areas of unmet medical need. What really matters is how the orphan designation has helped broaden the horizons for biomedical entrepreneurs. These are individuals—scientists, academics, and clinicians, often from outside big Pharma—with the grit and vision to launch start-ups featuring medicines that extend treatments to patients underserved by the current R&D paradigm.

The science that yields these breakthroughs is often unconventional, but understanding the patient experience is an absolute pre-condition for success. Victims of rare diseases are angry, disillusioned, and often sadly uninformed: how do you cater to a customer base with a history of interactions with a health system that has very little to offer, and where the average time to an accurate diagnosis is measured in years? Patient expectations are high; researcher's reputations, as well as their wallets, are placed on the line; yet that lining is paved in silver, because ultimately everyone benefits from this expansion of the medicines frontier. Knowledge gained from the investments in rare diseases has led to the development of drugs for more common conditions like cancer, epilepsy, and dementia. The phenomenon even works in reverse, where older medicines in wide use have been repurposed as therapies for these small-population disorders.

A spiffy example is the best suit cloth for insight, so this year Pharm Exec decided to extend its "Brand of the Year" recognition to include an orphan drug for rare disease. We went looking for a medicine that combined three strengths:

» A novel clinical profile.

» An advance in the state of care for a difficult to treat condition, affecting a neglected cohort of patients.

» Distinctive, multi-channel marketing geared to building community awareness around the disease, not the product.

We also considered the human element, embodied in someone who connected an untouched area of science to a new treatment opportunity—entrepreneurs, please step forward—as well as the brand's potential to seed growth in adjacent therapeutic areas, perhaps as the vanguard for an entirely new class of drugs.

Our choice—why?

And then we found it—in KORLYM, the first FDA-approved treatment for endogenous Cushing's syndrome, a serious, debilitating metabolic disorder caused by the overproduction of cortisol, a stress hormone, the effects of which can include hypertension, heart disease, diabetes, depression, chronic fatigue, obesity, and bone loss. An estimated 20,000 people in the US, mostly women, have Cushing's, which qualifies it for rare disease status. However, the real incidence is considered to be higher because it is frequently undiagnosed; many clinicians are unfamiliar with the disease and confuse it with other conditions that are often less lethal.

Signs and symptoms of Cushing’s syndrome

In addition, Cushing's has a strong co-morbidity profile: an estimated 3-5% of all type II diabetic patients have that condition due to the effect of uncontrolled cortisol proliferation on blood sugar levels; cortisol also erodes bone mass and is thus a contributing factor in osteoporosis.

KORLYM does not by itself decrease cortisol production but reduces its dangerous side-effects, especially the high blood sugar levels that usually lead to diabetes in patients with long-term exposure to excess levels of the hormone. Approved by the FDA in February 2012, the KORLYM label is a relatively narrow one, covering Cushing's syndrome patients with type 2 diabetes or glucose intolerance who are not candidates for or who have failed the most common treatment for Cushing's, which is surgery to remove the benign tumors that stimulate overproduction of cortisol.

A hormone that matters: Cortisol's big footprint

However, research indicates that KORLYM's main mechanism of action as a glucocorticoid receptor (GR-II) antagonist, which blocks cortisol from binding in the bloodstream, can improve clinical symptoms for other life-threatening conditions where excess cortisol has been identified as a causative factor. In this regard, KORLYM has potential value above and beyond its current status as one drug for a single rare disease. Could it be instead the vanguard of a much larger therapeutic franchise, one built around medicines that mediate the destructive effects of a single aberrant hormone on the nerves and tissues that keep us whole and healthy?

Corcept Therapeutics, the small, California Bay Area company that brought KORLYM to market, thinks it is. "KORLYM is the first step toward a business that we are creating around a unifying scientific theme, which is to understand how excess cortisol levels influence the incidence and progression of not just one, but potentially dozens, of different conditions," Corcept CEO Joe Belanoff told Pharm Exec.

From a purely medical perspective, the model makes sense: cortisol, which is found in more than 80% of all bodily tissues, is an essential regulator of system metabolism and proper organ function. A review of the clinical literature finds that, in addition to endocrine and metabolic disorders like Cushing's and diabetes, the effects of aberrant high cortisol are felt in CNS diseases, including psychotic depression, post-traumatic stress disorder, alcoholism, and early-stage Alzheimer's; ophthalmologic conditions like glaucoma and central serous retinopathy; osteoporosis; and even oncology, where research shows that cortisol can, in some cases, control the way tumors grow. Corcept is focusing its development pipeline on three main applications, covering psychiatry, metabolics. and cancer.

"The potential indications around this ubiquitous and clinically underrated hormone take us beyond the rare disease state to those chronic areas where we still see large numbers of patients with unmet medical needs," says Belanoff. The implicit message here is KORLYM exists as a prototype for something bigger—a new, multi-platform approach to identifying and treating disease.

Origins of an idea

But before the business model, there was an idea, one whose roots lay firmly in academic soil. In 1991, Alan Schatzberg, a practicing psychiatrist who trained at Harvard, joined the faculty of the Stanford Medical School as chair of its Department of Psychiatry and Behavioral Sciences, where he initiated a research project focused on the symptomatic biological origins of episodic psychotic depression, a little understood subset of major depression, affecting about 15% of diagnosed patients. Schatzberg was motivated by his early interest in the biological roots of mood disorders, which ran counter to the Freudian sentiment among many in the profession that environment is determinative.

Plugging the Awareness Gap: Social Media Steps Up

In the course of this work, Schatzberg discovered a correlation between cortisol and cognitive changes in patients with depressive psychosis, in which use of GR antagonists in test subjects led to a rapid improvement against delusional behavior. The fact that improvement occurred in a short period of time—as little as a week—is significant, as psychotic depression differs from other forms of mental illness by occurring in severe (suicide risk is high) but irregular bursts, after which there are long intervals where the patient is lacking symptoms.

Schatzberg and his colleagues at the Medical School continued to investigate the cortisol link in areas ranging from drug therapy to using imaging technology to identify stress responses in targeted areas of the brain. One volunteer was Belanoff, an undergraduate English major who at age 29 left a trading desk job on Wall Street to go to Columbia University Medical School; in 1992, he landed a residency in psychiatry at Stanford. "I was one of Schatzberg's first interviewees for a residency slot," relates Belanoff. "We hit it off after I told him I was specializing in psychiatry because we knew so little about how the brain works—and even less about the drugs the profession prescribes: why, for example, do we see the biological impact of a drug on mood or cognition in hours, while the broader clinical effects take weeks or even months? We can speculate, on an empirical basis, but precise answers to that question remain elusive."

One of Schatzberg's drug targets was mifepristone, originally identified as RU-486 by Roussel-Uclaf, the now defunct French company that developed it as a tool to induce abortions in women at risk in pregnancy. A synthetic steroid, mifepristone works as a dual action drug with properties that combine to block the female hormone progesterone and prevent the absorption of glucocorticoids in tissue and the bloodstream. The product was approved by the FDA in 2000 as an abortifacient for restricted use, under physician supervision, during the first seven weeks of pregnancy.

Although the abortion tag received top billing, there was a steady trickle of interest in mifepristone's properties as a GR antagonist, inhibiting the actions of cortisol on the brain and other major organs. Indeed, over the past 20 years, Schatzberg and his collaborators produced several dozen peer-reviewed papers analyzing how GR antagonists like mifepristone work in these areas. Given researchers' interest in the dual properties of the drug, the biological mechanisms behind mifepristone became very well known, making it a top candidate for several different clinical indications.

Corcept's anti-cortisol platform

Early on, Belanoff began to see commercial potential in the intriguing scientific knot that cortisol presented to leading academic researchers like Schatzberg. The work at Stanford in investigating links between GR antagonists and the control of episodic psychotic depression had produced a substantial library of intellectual property, much of which was sitting on the shelf. Belanoff, who by this time was looking beyond teaching at the Medical School and his private psychiatry practice, proposed to Schatzberg, among others, to put his Wall Street background to use in creating a start-up company to pursue commercialization of the cortisol research platform.

The first order was to go out and raise funds, and Belanoff developed a pitch for the Bay Area venture capital community focused on the ways mifepristone and a few other compounds might be repurposed as an indication for the symptomatic relief of psychotic depression, where there was no approved drug. Belanoff hit pay dirt with the local VC Sutter Hill Ventures—but only after 13 long interrogations led by ex-Syntex COO Jim Wilson, when the firm finally said it could no longer think of any reason NOT to invest. Corcept Therapeutics was incorporated in May 1998 with Wilson as Chairman, Belanoff as CEO and Schatzberg as a Board member (and passive shareholder). Employing a skeleton staff of 13, the company began working on two fronts: developing a proof of concept and clinical study program specifically focused on mifepristone's use in psychotic depression; and compiling an IP-protected library of selective GR antagonists—presently numbering more than 300, with mifepristone playing a central galvanizing role. Sharing this knowledge asset in collaborations with leading researchers and other external academic experts will also help Corcept improve the science and clinical understanding of how cortisol affects a wide range of diseases.

Despite this clarity of purpose, the hard reality is that Corcept spent 14 of its 16 years as a company without any marketed product. Driving forward an approved indication on psychotic depression using mifepristone has yielded some modestly encouraging trial results, but so far nothing is definitive and the trial has taken longer than expected—a pivotal Phase III trial involving 450 patients with a 1,200 mg dose of mifepristone is underway, with interim findings due at the end of the second quarter. If the trial meets its endpoint—a measurable, rapid reduction in psychosis—the company intends to proceed with a new drug application (NDA). The goal is to finally turn this indication into Corcept's second marketed product. Last December, the company also announced it was filing an investigational new drug (IND) application for a Phase I study on mifepristone as an indication for triple-negative breast cancer, its first foray into oncologics—and yet another specific condition lacking any drug treatment.

Vanguard therapy

KORLYM, however, proved to be the early bet that turned the cards in Corcept's favor, making these additional discovery investments possible. In contrast to the complexities built into a CNS indication, mifepristone's clinical potential for endogenous Cushing's syndrome was recognized as far back as 1985, with more than 50 studies subsequently corroborating its effects.

"When we analyzed the science, it became clear that the controversy around the drug's separate profile as an abortifacient was inhibiting interest in its application to Cushing's. The political baggage was very similar to thalidomide," Belanoff said. "Yet any rational analysis would have to balance that against the high level of efficacy documented in the studies as well as the sheer need—the medicines chest for Cushing's was flat empty."

In fact, the one drug that was in common use, ketoconazole, was under scrutiny for cases of liver damage after long-term exposure to patients.

Fast work from FDA

In 2007, Belanoff and his scientific team initiated a conversation with FDA staff on mifepristone as a treatment for Cushing's, receiving an unexpectedly positive reception. In rapid order, the company secured orphan-drug status for the proposed indication in treating Cushing's with type 2 diabetes—the FDA estimated the eligible population at around 5,000 patients—followed by the filing of an NDA and request for Priority Review, in April 2011.

The NDA package included the results of a 50-patient trial, in which mifepristone delivered "significant improvement" in blood sugar control along with marked reductions in insulin requirements. A REMS proposal was also included to address the dangers associated with the drug's alternative use as an abortifacient. However, when the FDA approved registration status for the drug 10 months later, it decided a full REMS was not necessary because of the small number of physician prescribers and the company's pledge to maintain tight control of distribution through a single designated specialty pharmacy, Dohmen Life Science Services. There is also a post-marketing requirement to report use data (age, sex, dose, and duration) and, of course, any side-effects.

KORLYM made its debut only two months after marketing authorization, in late April 2012. The quick start was aided by the company's advance work on a REMS package; though it turned out it was not needed for approval, the preparation forced management to focus on something that proved critical to building the brand: the patient context. It was noted early on that endocrinologists are very test-oriented in treating Cushing's.

"Because diagnosis is so difficult, repeated testing is the profession's stock in trade, because surgery is the default option once diagnosis is confirmed," Commercial Operations Director John Lyons told Pharm Exec. "We recognized a stronger patient voice was needed to move drug therapy forward in the treatment discussion."

A patient-centric approach also made sense from the clinical perspective. "In Cushing's, every case is unique," says Corcept Chief Commercial Officer Steve Lo. "There is the bewildering multiplicity of symptoms, which also vary by degree, as well as individual variations in relapse rates, which can be high when initial surgery fails, leading to scattershot measures involving additional surgeries, radiation, off-label use of other drugs, or outright removal of the adrenal glands —there is no standard protocol."

According to Lo, this heterogeneity required substantial investment in a different kind of sales force, one with the practice familiarity and the scientific skills to market KORLYM almost on a case-by- case basis. "The clinical inertia around this disease is intense," Lo said. "We couldn't take the approach of a 30-second detail with the boilerplate message KORLYM is the right drug for your patients."

Launch learnings

Like many drugs today, KORLYM posted a slow start. Sales hit $2 million a year after launch but rose faster in the fourth quarter of 2013, where sales hit $4.1 million—a 58% rise over the previous quarter, lifting the full year total to $10.4 million. The company is projecting sales at more than double that for this year, in the $24 million to $28 million range. There is additional room to build; due to its orphan drug status, KORLYM has marketing exclusivity in the US until February 2019.

One key learning from the launch was the importance of defining the boundaries of the prescriber network. Early on, the assumption was that, as in most other rare diseases, the sales potential for KORLYM rested on a select few academic teaching hospitals and the specialist networks around them. Close review of claims data (Cushing's has its own ICD9 diagnosis code) indicated that this would also be the norm for KORLYM. So the focus was to create a team of "medical science liaisons" able to bridge the gap between clinical expertise and the real world of patients.

But actual experience proved otherwise, which slowed uptake in the first few months. "We noticed that, while patients did interact initially with the academic medical centers, there was a tendency for them to disperse back to caregivers at the community level—endocrinologists not affiliated with any of the large networked hospital centers," says Lo. "This was a group of prescribers we weren't covering; in fact, at the time we lacked the bandwidth to do so." Lo noted that Corcept was small enough to respond quickly, making investments in a new 20-member field force geared to this constituency. "The lesson is to subject the claims data to a 'strength test' by actually tracking the patient journey through the health system," he said.

Another lesson was finding the right message that worked with payers. Starting early, management briefed key PBMs on the disease and the drug, focusing on its narrow indication, the small target population, and the huge unmet need along with adjacent co-morbidities, where the amelioration of symptoms in chronic conditions like diabetes translates into big savings on treatment costs. At the ex-factory wholesale price of 87 cents per milligram, treatment costs per patient for KORLYMN can average a pricey $200,000 a year. Nevertheless, the impact is relatively diffuse: according to management, seven large health plans estimated their patient burden under the drug would amount to no more than 20 people.

"There is a clear unmet need for patients in whom standard treatment approaches haven't worked, so payers are recognizing this by placing few reimbursement restrictions," says Lyons.

To defer cost concerns, Corcept provides the drug to uninsured patients through a patient assistance program, SPARK (Support Program for Access and Reimbursement for KORLYM), which also funds co-pays of up to $5,000 annually per patient, based on need. Cases are referred through partnerships with patient advocates like the National Organization for Rare Diseases (NORD).

Messaging on mifepristone

Finally, management took a forthright stance to counter the stigma associated with mifepristone's dual use in terminating early-stage pregnancies. The FDA proved to be a central player in deflecting the negative connotations. It took these head on in its approval release for KORLYM by emphasizing the tight controls on distribution jointly agreed with Corcept—the company actually mimicked the approach taken when mifepristone is prescribed as an abortifacient—along with a black box warning against use of the product during pregnancy. According to Belanoff, "what we found is the FDA actually proved to be a sympathetic ally in establishing the legitimacy of this drug." Corcept is pursuing the same high engagement approach in its pending application for a marketing license for KORLYM at the European Medicines Agency (EMA).

Corcept has also had success with the argument that precedents like thalidomide offer proof that a repurposed medicine with a different indication can be administered safely while providing an option for patients without hope. "The ravage this disease imposes on patients is sufficient to make the case that KORLYM should be available, because alternatives are few and far between," said Dr. Pejman Cohan, a Los Angeles-based endocrinologist who specializes in Cushing's. He points to the difficulty in diagnosing Cushing's as a defense for the drug. "Getting to the root of this disease is a complex, sometimes contradictory task at the individual patient level," said Cohan. "Lab tests are often not definitive, with many false positives, so access to a drug treatment that is safer than invasive surgery and also reversible is a choice both I and my patients like to have."

Physician talk therapy

To reach this year's goal to double KORLYM sales, management is continuing to refine the demographics of the prescribing community while improving its understanding of the patient journey. In contrast to other rare diseases, few endocrinologists treat Cushing's exclusively, especially now that other metabolic disorders like diabetes attract more patients. On top of that, clinical protocols for Cushing's are entrenched—this is not a community of early adopters. "Our biggest hurdle in marketing is taking the physician from zero prescriptions to one, because after they see KORLYM works in that first patient the resistance to trying something new will fade," Lo told Pharm Exec. In other words, education is the focus: it's going to take a little extra time to show practitioners there is a new kid on the block.

William Looney is Pharm Exec's Editor-in-Chief. He can be reached at wilooney@advanstar.com.