Skipping the Needle: Pharm Exec's Brand of the Year

Gilenya is the first FDA-approved oral medication for Multiple Sclerosis (MS), a chronic, disabling illness with a significant but largely undocumented impact on society. Gilenya is a broad pathfinder drug, with the potential to raise the profile of MS as a public health priority, stimulate new science, and motivate clinicians and patients to seek a wider range of approaches to ease the burden of disease. And there is the more dynamic element of market uncertainty that will make for an interesting debut. High cost—and the ramifications of a controversial co-pay program—side effects, and patient compliance are issues for Gilenya that cannot simply be washed down with a swig of water.

On September 23, 2010—161 years after the disease was initially diagnosed —The Wall Street Journal called the FDA approval of Gilenya "another sign of the improving picture for MS treatment." Last month, The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for Gilenya in patients with highly active recurring-remitting MS (RRMS). John Golding, president of the European Multiple Sclerosis Platform (EMSP) called Gilenya a "welcome alternative" for the more than 500,000 people in the EU who live with the disease. Switzerland and Australia have also approved the drug. And several new drugs with a similar oral indication are on the way.

Dr. Jack Burks

Plaudits aside, Gilenya may indeed signify the beginning of long-awaited change in the MS community: It treats the disease in a new way, boasting an ease of use and efficacy profile that many competitors cannot hold a candle to. "It's an area of intense fascination for people," says Trevor Mundel, global head of development for Novartis. "I take my hat off to the patients for participating and for bearing with us ... It was a roller coaster of a program to develop this drug."

First diagnosed in 1849, Multiple Sclerosis currently affects between 250,000 and 350,000 people in the United States, with as many as 200 new cases of MS diagnosed in the US every week, according to the National Institute of Neurological Disorders and Stroke (NINDS). MS strikes women twice as often as men, and usually appears between the ages of 20 and 40, making it the leading cause of disability among young adults in the nation.

MS is a disease of the central nervous system (CNS), affecting the brain and spinal cord. In individuals with MS, the body's own immune system attacks the insulating layer of fatty tissue called the myelin sheath that surrounds and protects the nerves of the CNS. This attack erodes the myelin sheath over time, producing scar tissue (sclerosis), which eventually disrupts the communication between the CNS and the rest of the body. These communication disruptions can lead to mobility and vision impairments, in serious cases resulting in an inability to walk and/or perform many activities of daily living (ADL) skills including cooking, cleaning, exercise, or other activities involving strength, mobility, or endurance. Other possible symptoms of MS include weakness, numbness, loss of muscle coordination, and problems with speech and bladder control.

Pie chart

The impact extends even further into the social interaction space. According to an article by Nicole M. Sabapathy and Clare L. Minahan published in Clinical Rehabilitation and data from the "Sonya Slifka Longitudinal Multiple Sclerosis Study" in 2007, such reduced ability to undertake ADL activities is also associated with higher levels of depression and decreased quality of life in those with MS.

Unfortunately, in addition to being diagnosed with a CNS disease and facing a reduced capacity for mobility-related activities, potential treatments of MS thus far have done little to improve the quality of life and instances of depression among this population. MS is commonly a progressive and relapsing disease; therefore, treatments can only aim to slow the progression of physical disability and increase the time between relapses.

"It is extremely dangerous to use improved 'quality of life' verbiage around these drugs," says Julie Stachowiak—MS patient, PhD, and author of The MS Manifesto. "Many people assume that taking medicine if you have a condition makes you feel better. The MS disease-modifying therapies (DMTs) are different. Often they make us actually feel worse in the immediate than if we hadn't taken them."

Dr. Jack Burks

Some of the most well known MS medications currently on the market are Rebif (Merck Serono), Copaxone (Teva Pharmaceuticals), and Avonex and Tysabri (Biogen Idec). Rebif must be self-injected three times a week at roughly the same time on each injection day and may have side effects including flu-like symptoms, depression, abdominal pain, increased liver enzymes, and blood cell count decreases; Copaxone does not have many of these negative side effects, but can leave itchy, painful welts and must be injected every day; and Avonex is injected only once a week but has many of the same side effects as Rebif. Treatment options with inconveniences and side effects like these can be a breeding ground for patient noncompliance. "It's scary and it took me a long time to get used to. And it's inconvenient to take the injections because when you're in your twenties, you don't really want a set schedule to take meds," says MS patient L. Mello.

Dr. Julie Stachowiak

"DMTs do not fix people with MS; they slow down the rate at which we get worse," adds Stachowiak.

Do Pills Produce Compliance?

The most obvious difference between medications like these and Novartis' Gilenya (fingolimod) is that there's no injection. Gilenya is the first oral medication to gain FDA approval as a first-line treatment for patients with relapsing forms of MS in the United States, administered as a 0.5-milligram pill to be taken once a day. "Many people prefer to take a capsule because they don't like to stick needles into themselves," Dr. Nick LaRocca of the National Multiple Sclerosis Society told the Associated Press in September 2010

Trevor Mundel

Negative patient reactions to injectibles may be why Mundel maintains that one of the biggest differentiating factors of Gilenya is the lifestyle change marked by the convenience of an oral treatment. Up until the FDA advisory committee met last June to hear patients' accounts of their experiences with Gilenya, "the skepticism was overwhelming," says Mundel. However, one patient account may have swayed a panel that was still very uncertain about whether the compound was really a breakthrough. A young woman spoke to the committee about her lifestyle with injectible treatments and shared how she would often cry for half an hour before injecting herself. Mundel believes this testimony and others like it swayed the committee in their decision to make Gilenya a first-line, rather than a second-line, treatment because, "they had to ask themselves, 'What do we say to patients like this one if we have to tell them it won't be a first-line treatment, and that they have to continue on like this?'"

Certainly, at first glance, this shifting of disease treatment and management seems to be quite significant. "If you ask a 22-year-old, 'Do you want a shot every day or a pill every day?', I don't think there's any contest," says chief medical officer for the Multiple Sclerosis Association of America (MSAA) and neurologist Dr. Jack Burks. But Burks cautions that oral delivery of medication has its own inherent problems.

Challenges to Market Takeup

While the obvious assumption may be that the convenience of a pill would cause patient adherence to skyrocket, Dr. Burks warns that commonplace oral medications for MS may cause patients to become blasé, or to take the disease and its treatment regimen less seriously. "If this drug works well and the patients' symptoms of MS are very minimal with Gilenya, I'm concerned it will be like patients on blood pressure medication—unless you keep pushing them, they won't take their medication," he says.

"None of these drugs cures a disease—the disease is still there," advises Burks. "So it's going to be up to the physicians, and the medical community in general, to keep reminding people that the reason they feel so good is because they're on the medication. And in fact, the reminder of taking a shot every day is much more powerful than the reminder of taking a pill every day; we have to be very vigilant."

In fact, there seems to be a greater "If it's not broke, don't fix it" mentality springing up among all those involved—patients, physicians, and analysts alike. "Although the majority of the disease-modifying therapies for MS are currently given via an injectible delivery mechanism—which is inconvenient, painful, and requires specialized storage conditions—compliance is quite high, at 80 percent or higher," notes Datamonitor healthcare analyst Trung Huynh. MS patient L. Mello echoes this sentiment when she says, "The medication I am on is working for me. Why chance switching over when I don't know what will happen?"

Science, History, and Safety

Another point of differentiation for Gilenya may be why and how it affects MS. Mundel translates the science into layman's terms for Pharm Exec: "Gilenya effectively blocks a system that the body has in place to control certain white blood cells—lymphocytes, which are trafficking around your body and through the lymph nodes," he explains. These lymphocytes monitor what's going on in the body, assessing potential invaders and problems. In the case of MS, the lymphocytes get out of control in the body and "go wild," participating in the destruction of the myelin sheath that surrounds the nerves of the CNS. Gilenya effectively contains the rogue lymphocytes, keeping them locked in the lymph nodes and preventing them from reaching the CNS, where they could potentially attack this protective covering. This method is unique among MS treatments in that many other medications kill off the lymphocytes, whereas fingolimod merely traps them.

Serendipity: It Still Plays a Part

In the beginning, no one at Novartis knew exactly how fingolimod worked, or why it worked, or even that it would turn out to be such a breakthrough for MS; the compound started out in the company's transplant department back in 1997. Novartis has a strong background in the transplant area, with drugs such as Neoral, and while fingolimod looked promising at first, it eventually was decided that it was no more effective in the transplant area than anything else out there at the time.

However, as a matter of what amounts to standard operating procedure, Novartis tests any compounds that may affect the immune system for potential effect on MS, through profiling in animal models. So Gilenya was tested in a rat model of MS, with three different variances: First, the rats were given the drug beforehand to prevent them from getting the disease; Second, those already having the MS disease were treated and; Third, one group was allowed to progress quite far in the disease and was treated afterward, at a later stage. "Anything we did—in any of those setups—worked fantastically well," recalls Mundel.

Once promising results like these were documented, switching the compound from the transplant group to the neuroscience group was a bit of an arduous process, but in 2003, a small study of fingolimod was defined to determine whether the same outcome would occur with patients. Both high and low doses were extremely effective in Phase II (begun in 2003), so the company moved on to Phase III—the largest study to date to ever have been launched for an MS drug. Phase III ended in 2009, and in September 2010, FDA gave the green light for Gilenya.

Perhaps because of its potentially lifestyle-changing capabilities, Gilenya qualified for fast track through the FDA. Any drug being developed to treat or prevent a disease for which no current therapy is available is obviously a potential fast-track candidate, but when you take into consideration that, if there are already existing therapies available, the new drug must show some advantage over available treatment, then Gilenya may fit the bill. What this means for Novartis going forward is that further trials must be done to gauge long-term safety and efficacy of Gilenya. "We have a Risk Evaluation and Mitigation Strategy (REMS) in place, we've committed to a 5,000-patient long-term study, and we are studying an even lower dose of Gilenya," says Mundel. There is risk involved, as recent precedents involving cancer drugs show that failure to slow morbidity or symptom progression can lead to a narrower licensing indication or even refusal of a final authorization to market.

Common side effects of Gilenya are similar to those that occur with many other MS treatments, such as headache, flu symptoms, diarrhea, back pain, and liver transaminase elevations. Macular edema is also a significant concern, with an estimated risk at about 4 in every 1,000 patients. The most noteworthy potential side effect of Gilenya, however, may often appear upon taking the first dose. Significantly, patients must take their first dose in their doctor's office, and be observed by a physician for the next six hours for signs of decreased heart rate (bradycardia or bradyarrhythmia). Patients may "feel dizzy or tired or be aware of a slow or irregular heartbeat ... during the first six hours of the first dose," and "heart rate will usually return to normal within one month" of beginning Gilenya, according to the medication guide for patients. In clinical studies, adverse reactions of bradycardia following the first dose were reported in 0.5 percent of patients receiving Gilenya 0.5 mg, according to the Full Prescribing Information document.

"The key is for us to make sure the patients understand the pros and cons," says Dr. Burks. "When I talk with patients I always start with the risks, not the benefits." But just as important as how the physician presents the benefit/risk ratio to the patient, says Burks, is how the manufacturer presents those facts to the physicians. "Drug companies should not be pushing these new treatments as a cure for MS."

With similar caution, Stachowiak warns, "Just because a drug makes it through a two-year trial does not mean that it is safe—or effective for the long-term. I understand why longer-term trials are unfeasible, but trials that last one or two years are not ideal to determine anything about an MS drug."

A Controversial Strategy on Cost

In addition to side effects, another major patient concern is cost. Eight days after the official press release from Novartis announcing Gilenya's FDA approval, Bloomberg reported that Gilenya would cost up $48,000 annually—nearly $1,000 more per month than competing drugs such as Teva's Copaxone.

To offset such cost concerns, Novartis has put several financial-assistance and patient-support plans in place. The Gilenya Co-Pay Support Program is a single point of contact for patients and healthcare providers, offering information, guidance, support, and reimbursement services to assist patients and providers. The program is proving to be controversial with the managed care community due to the fact that in most cases patients receiving the drug will be subject to virtually no co-pay; it will be up to the insurance provider to bear the cost burden of treatment. And Gilenya has been priced very aggressively, on the assumption that the oral dose will prove popular as a differentiating factor with patients. Additionally, to ensure immediate access to treatment, Novartis is offering the option of a free starter product during the benefits investigation period.

"Cost has to be looked at from two perspectives. One is what the managed care companies are going to have to pay—and $48,000 is a lot," says Burks. The other perspective to consider, he says, is the patients'. "When patients hear that number, they just sort of drop to the floor. But what they pay is actually going to be very little."

Marketing: Tread Softly

Gilenya is still flying under the radar in terms of building awareness among the clinical and patient communities. While many neurologists have heard of the drug, no consumer campaign has been launched as of yet. Novartis is currently only promoting Gilenya to healthcare professionals as per the Gilenya full prescribing information. "During this time we are focusing on educating physicians and nurses about the efficacy and safety of Gilenya and the process for initiating patients on therapy," says André Wyss, head of pharma North America and president, Novartis Pharmaceuticals.

But it's the side effects that are inducing the caution. "Novartis' first focus is making sure people understand what this drug does, how it's different, and what the potential adverse events are," says Burks. "And if that means they don't sell quite as many pills this year as they do next year, then that doesn't bother me at all, because I want to make sure that we have an informed patient population."

Wyss says that the company plans to launch its consumer campaign once the company receives DDMAC preclearance comments.

The company spent a great deal of time in advance of approval planning for a variety of scenarios, so that approximately 85 percent of the prelaunch work was done before approval, says Wyss. As a result, the company was able to launch quickly—just a few days after FDA approval.

While much of the work was done in advance, the company is continuing to tap into patient concerns linked to side effects, which must also be taken into consideration. "Novartis has a commitment to understand and, when needed, to refine our benefit/risk profile assessment for all of our marketed therapies," says Wyss. "As Gilenya is a new therapy, we understand the importance of anticipating potential unknown side effects. We will continue to build on that safety experience by expanding into real-world-setting evidence generation programs." Additionally, the company has initiated safety-focused Phase IV studies in the US as part of its efforts to ensure that Novartis continues to evolve the benefit/risk profile on a regular basis in the way that patients, customers, and regulatory partners expect.

"We are very committed to the MS community and have done extensive market research with all of our key audiences, including patients, nurses, and doctors," says Wyss. "We have really put in the time and energy getting to know the MS marketplace to ensure preparedness and a successful launch." Building stakeholder support in a crowded therapeutic space is a challenge, so the emphasis will be on cementing roots to a select community of influentials—starting with specialist prescribers.

A Competition Blowout?

One positive marker for the future of Gilenya is that the competition is feeling the heat. On September 22, 2010, Biogen Idec—maker of Avonex—released a press statement that read, "The long-term safety profile of Gilenya has yet to be established ... We agree with the FDA that there is a need for safety monitoring for Gilenya through a comprehensive Risk Evaluation and Mitigation Strategy (REMS)." Thus, the sensitivity of Novartis to potential side-effects issues is not misplaced, as it appears this will be a key tactic of manufacturers of alternative medicines to maintain their patient base. After all, it's up to Novartis to make the proposition to switch.

Nevertheless, competitors are resigned to sharing more sales with the newcomer, which will benefit from Novartis' size, scale, and marketing muscle. Biogen CEO George Scangos recently told Reuters he was sure that Gilenya would take some market share, but that it was "still too soon" to predict how much. Such fear may indeed be warranted, if analysts are to be believed. According to Bloomberg, analysts are predicting that on average, Gilenya will produce $1.8 billion of annual revenue for Novartis by 2014.

Such predictions of success seem to be the general consensus. "We expect that because of the less invasive method of administration and high efficacy, the orals will eventually usurp the injectible formulations to become the leading therapies in MS. Moreover, we believe Gilenya will become the leading therapy in MS," Datamonitor's Trung Huynh told Pharm Exec. "The introduction of new pipeline drugs will cause the market to peak at $9.7 billion in 2014 across the seven major [country] markets."

One leap for Gilenya that may help forecasts like these come true is the potential for the drug to expand from approval of the more common relapsing-remitting form of MS to the less common but more severe primary-progressive MS (PPMS). While RRMS is characterized by symptom flareups followed by periods of complete or partial recovery (remission) that may last days, weeks, months, or years, PPMS is a more steady onset and progression of disabling symptoms, without the fluctuation of relapses and remission.

Gilenya is currently being studied in PPMS in the three-year, Phase III INFORMS (INvestigating Fingolimod ORal in primary progressive Multiple Sclerosis) study, which is on track to deliver results in 2014. The primary endpoint of INFORMS is to evaluate the effect of Gilenya relative to placebo on delaying the time to sustained disability progression for patients treated for at least 36 months. The company says it is still too early to discuss potential filing timelines or results.

Making the Switch

With forecasts like these, and such positive safety and efficacy profiles, will patients rush en masse to abandon their current treatments in favor of Gilenya? "People have been on these other drugs for a long time and they seem to be doing quite well," says Dr. Burks. "And the fact is, [with Gilenya], you're changing the mechanism of action. And any time you're changing mechanism of action for any treatment—since we don't know the mechanism of MS—I think we have to be cautious. You must remember, neurologists are conservative by nature; we're not therapeutic nihilists, but we are very careful about giving our patients drugs that we don't have the full data on."

Stachowiak also weighs in on the importance of mechanism of action. "As much as I hate injecting, I don't think it is a reason to switch from something that is working for you."

That said, Burks is cautiously optimistic that Gilenya may be the right option for many people, but one that needs to be considered on a case-by-case basis. "If you get a shot every day for 10 years—that's 3,650 shots—I can understand why people would say, 'Okay, enough is enough.' The key is that if we follow the precautions that make sense, then I feel comfortable giving this to patients who I feel will truly benefit from the drug."

The Winning Formula

So what did Novartis do right to earn designation as owner of Brand of the Year? It's an old story that is often neglected in all the studies and reports that call for a "new business model" in R&D. From rescuing a not-so-promising transplant compound to its commercialization as a drug that Datamonitor predicts "will become the leading therapy in MS," the simple persistence of clinicians at the bench was the driving factor in success. "One of the paradigms that we work hard to set up at Novartis is that when we have a new therapy, we try to not be locked in to our assumptions as to where it's going to work; we explore quite broadly in smaller and earlier studies," says Mundel. "We let the compound prove or disprove itself in a wide range of areas ... effectively letting the data drive where a drug ends up."