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.

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.