Article reprint from "The Pink Sheet" March 30, 2009
Biogen Idec developed TOUCH, the restricted distribution risk management plan for its monoclonal antibody Tysabri (natalizumab), to save that product from market withdrawal in 2005-2006. Read more...
Article reprint from "The Pink Sheet" March 30, 2009
Biogen Idec developed TOUCH, the restricted distribution risk management plan for its monoclonal antibody Tysabri (natalizumab), to save that product from market withdrawal in 2005-2006.
Now, the company is hoping that the program can come to the rescue of the product a second time. The threat to the product this time is not as dire: a slowdown in the growth of patients on treatment, and not a temporary market withdrawal. The challenge is also less daunting. Biogen does not have to design a new program, convince FDA that it will work and then roll it out into the medical community. The TOUCH program is well in place and has been converted into one of the models for the highly restrictive version of the Risk Evaluation and Mitigation Strategies (REMS) called for by the FDA Amendments Act of 2007.
What the company is doing this time is trying to turn the tight connections created with the key medical specialists (neurologists) and the patient group (multiple sclerosis patients) into a network to short-cut the reaction time to reports of new cases of serious adverse effects associated with the drug. Biogen Cut Two Years Off Response Time The fact that the REMS program was in place presumably played a key role in FDA's restrained response to recent cases of the adverse event behind the withdrawal. Biogen's artful use of the network may help it to further reassure doctors that there are ways to predict and forestall serious side effects and treat them when they occur.
The firm credits TOUCH with reducing the time to develop diagnosis and treatment algorithms for progressive multifocal leukoencephalopathy (PML) the rare but serious adverse event that has plagued Tysabri from its introduction in late 2004 as a treatment for MS and Crohn's disease 1("The Pink Sheet," March 7, 2005, p. 3). Biogen estimates that typically it takes about three years from the identification of a serious problem with use of a product to effective education of practitioners about how to deal with the problem. It takes that long to work through the process of understanding the problems, getting a label change and communicating that change to the medical profession through journals and medical education messages.
With the TOUCH REMS in place, however, Biogen maintains that it was able to change practice and treatment of the PML side effect within less than one year.
Senior VP-Neurology R&D Al Sandrock told the company's March 25 R&D day that having the tight risk management plan in place permitted the firm to accelerate its response to the most recent cases of PML. In fact, the TOUCH program not only accelerated the time to reach doctors with new information after the most recent cases, it also gave Biogen a way to react when the PML cases occurred. Because of the close contact and patient tracking required as part of TOUCH, Biogen was able to try a treatment that the company believed would halt the progression of PML.
The company had informed its call centers about a plasma exchange process to halt the PML effect before the most recent cases occurred. Biogen had been investigating the procedure and talking with neurologists about it since the middle of 2007.
"We actually had our call center aware of this intervention [PLEX]. Fortunately it was out there so that the very first [post-relaunch] PML case, in July of last year, underwent plasma exchange," Sandrock said.
Four out of five Tysabri patients who have experienced PML since the relaunch in 2006 have survived, Sandrock noted. "I would argue," he said, that "the ones that were adequately treated, fully treated based on our paradigm ... are alive."
Following the most recent events and the success of the PLEX treatment in emergency use and in other testing by the firm, Biogen was able to make that information part of the common knowledge about the product quickly. Biogen added the information about PLEX to the product's label in October 2008, and published the research in the Feb. 3, 2009, issue of Neurology.
The ability to react quickly and to deliver messages about potential PML treatments and ways to forestall future cases changes the risk-benefit ratio on the product, Biogen contends. Early in Tysabri's commercial life, it was recognized as an "effective drug with a fatal side effect," the company acknowledges. With the rapidly advancing knowledge about diagnosis of the side effect and potential treatment, that product characterization is improving to a product with "unprecedented effect" and "a manageable side effect," the company said during a slide presentation at the R&D day.
That's an important change in attitude. The company says it's reflected by surveys showing that 74 percent of doctors plan to increase their use of Tysabri over the next six months.
A second set of surveys shows the medical community regaining confidence quickly in the product. In late 2007, about 65 percent of physicians agreed that the drug's benefits outweighed the risks it poses, Biogen reported.
That figure dipped to 45 percent after July 2008, when the first PML case developed in a patient on monotherapy. But in a recent poll, 61 percent agreed that the benefits outweigh the risks.
If the surveys are accurate, then the ability to get information out quickly and into use through the REMS program may be the answer to restart the growth curve for the product.
To help establish PLEX as a standard of care in treating PML, the firm tested plasma exchange in 12 MS patients receiving Tysabri. It found that three 1.5-volume PLEX sessions over five or eight days reduced serum concentrations of natalizumab by a mean 92 percent from baseline by one week after the PLEX sessions.
The October 2008 relabeling also includes information to try to forestall further PML cases. The amended Warnings and Precautions section suggests that patients undergo a baseline MRI scan prior to initiating therapy and that physicians should monitor patients for signs of PML.
If the disease is suspected, the label says to stop Tysabri dosing immediately and evaluate the patient with a gadolinium-enhanced MRI brain scan and possibly a cerebrospinal fluid analysis for JC viral DNA. The JC virus is a type of polyomavirus, named with the initials of the patient in which it was first discovered. It is associated with the development of PML.
Biogen Idec continues to research methods of treating PML. They've found that an old malaria treatment mefloquine (Roche's Lariam and generics) can inhibit JC virus infectivity. Another avenue of the firm's research is attempting to find a screening test that could stratify patients' risk of developing PML before they are treated with Tysabri.
Biogen Works On PML Consortium
While the cases linked to Tysabri have definitely intensified PML's visibility, Biogen points out that the disease also is linked to several other drugs - purine analogs, several other MAbs, alkylating agents and cyclosporine immunosuppressants as well as methotrexate, used widely for induction in moderate to severe autoimmune diseases.
Biogen says that it has joined with several other drug companies in a consortium of companies marketing drugs linked to PML. The consortium recently had its first meeting.
"We're figuring out how we can pool resources and information," Sandrock said. "For example, genome-wide association scans might be possible when you pool cases among various companies.
When Tysabri was reintroduced, the rate of PML was thought to be around 1 in 1,000 treated patients. It occurred only in patients on therapy for more than one year and less commonly in patients on natalizumab monotherapy. "The results that we have now in the post-marketing setting [show] the rate is actually closer to 1 in 4,000," Sandrock said, even using as a denominator only patients who have been exposed to the drug for one year or more.
Armed with its program for early diagnosis and treatment of PML, Biogen Idec is now renewing efforts to build the brand. While the firm isn't likely to meet its previous forecast of 100,000 Tysabri patients by the end of 2010, it now has about 38,000 patients on the drug worldwide.
- Pamela Taulbee
