Natalizumab has received FDA approval. But as with all approved treatments, questions remain about efficacy and clinical importance compared to existing therapies.
Since the mid-1990s, there has been revolutionary advancement in the understanding of the pathophysiology and treatment of multiple sclerosis. On November 23, the FDA issued an approval letter to Biogen Idec for natalizumab, a totally new approach to the treatment of MS. There are now three immunomodulation classifications available for the routine treatment of MS, including the three interferons, glatiramer acetate, and now a monoclonal antibody.
All of the classes have fundamentally different mechanisms of action. The interferons basically work by shoring up the blood brain barrier, preventing the migration of activated T cells into the central nervous system. Glatiramer acetate works by confusing the immune system into not attacking the CNS and activating protector T cells to actually decrease the inflammatory response within the CNS.
This new product, natalizumab, acts differently.
Managed care implications
It has a WAC price of $1,808 for a 28-day dose. The daily WAC price is nearly $65, compared to approximately $39 for Avenox, Betaseron, and copaxone, and $48 for Rebif when you take into account the 12 versus 13 dispensing units per year.
Natalizumab is also associated with considerable administrative costs, as it is expected to be administered primarily in physician offices and outpatient infusion sites. With Johns Hopkins University, Biogen has been providing educational programs (as is usual with physician-administered drugs) to neurology offices on the intricacies of office-based infusion, including benefit verification, prior authorization procedures, payer coverage policies, and appeal processes. There is instruction on coding and on setting up an infusion suite, and there is a special section devoted to revenue collection and opportunities for the practice. There is no specific HCPCS code for natalizumab, so the nonspecific codes J3490 "Unclassified Drug" or J3590 "Unclassified Biologic" are recommended.
We now have a new development and, in fact, the first entrant from a whole new class of medications available for the prevention of relapses for MS. But managing the patient who is living with MS is still difficult.
If neutralizing antibodies are present, the efficacy of natalizumab will be minimized. There is no test for the antibodies expected in the near future.
There is also the cost associated with natalizumab treatment, especially when administrative costs are considered.
Also, the safety problems of other monoclonal antibodies are well known. Natalizumab has a slight increase in infections and no current evidence of malignancies, but the worldwide experience is limited to a minuscule percentage of the population with MS. In addition, the long term efficacy is unproven in a population that now has open label trial results available for as long as nine years. Finally, there is the real possibility that providers will request combined therapy.
What can managed care do? There are a number of management possibilities available for this new entrant. The choices are to:
- Develop a stepped care approach with one of the interferons and glatiramer acetate as preferred,
- Set up a prior-authorization system to validate lack of efficacy with standard therapeutic options before approving this new, more expensive, therapy,
- Contract with a specialty pharmacy company (SPC) to avoid giving physicians an incentive to capitalize on the revenue stream,
- Implement edits to an AWP discounted reimbursement, similar to what you would pay an SPC,
- Screen data sources for dual therapy and challenge them as off label,
- Establish a tracking system for relapses and subsequent progression of disability, the true endpoint of this devastating disease,
- Contract for or develop a disease management process to maximize the outcome of patients with MS, focusing on preventing the progression of disability and on preventing or managing the comorbid conditions to avoid unnecessary hospitalizations for issues such as uro-sepsis, and
- Demand head-to-head trials with existing therapies.
Tysabri's mechanism of action
Natalizumab is being marketed under the name of Tysabri. In early news releases, the company had proposed the name of Antegren, but changed the name before launch.
This compound is the first of several antibodies in the pipeline targeting different steps in the immune dysfunction that leads to the clinical condition we call MS.
The exact mechanism of action by which natalizumab exerts its effects in multiple sclerosis is not fully defined. MS is believed to develop when activated inflammatory cells, including T cells, cross the blood brain barrier. No one is sure how the inflammatory cells are activated, but the result is the presence of highly active inflammatory cells within the CNS causing destruction of the "insulating" myelin sheath around nerves. Once damaged, the nerves cease functioning normally and the neurologic effects become the symptoms of MS.
Before the inflammatory cells can cross into the CNS, they must bind to the lining of the blood vessels, the endothelium. Natalizumab is thought to work by preventing this binding and hence stopping the migration of the damaging cells.
Structurally, natalizumab is a recombinant humanized IgG4κ monoclonal antibody produced in murine myeloma cells. It binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes (except neutrophils) and inhibits the α4-mediated adhesion of leukocytes to their corresponding receptor. These α4 integrins are a family of integrins that include vascular adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-1), present on the vascular cells of the gastrointestinal tract.
This binding basically disrupts the attachment of leukocytes to the blood vessels and prevents the migration of these activated leukocytes into the inflamed area; in the case of MS this is the central nervous system. Simply put, if the T cells establish a foothold on the endothelium, leukocytes cannot migrate through. Natalizumab prevents the foothold from occurring.
The new treatment consists of a dose of 300 mg of natalizumab mixed with 100 mL of 0.9 percent sodium chloride injection, USP, administered during a one-hour infusion every 28 days. As with all proteins, mixing should be done gently to prevent damage to the large protein molecule. The mixed solution must be administered within eight hours. The product has a labeled shelf life of 15 months when unmixed and stored.
There are no dose adjustments for weight. Natalizumab is classified as pregnancy category C and has not been studied in nursing mothers. There were insufficient numbers of patients over 65 to make a recommendation, and the drug has not been studied in patients under age 18.
The most frequently reported serious adverse reactions with natalizumab were infections. According to the package insert the worldwide experience with natalizumab in both controlled and uncontrolled studies is limited to 1,617 total patients with a medium exposure of 20 months.
As is true of virtually all biologics, there are no head-to-head studies against the standard therapies. No meta-analysis published, but from this writer's uneducated observation, it appears that the actual relapse rate reduction is about the same as has been seen with the more proven therapies. Obviously there are no long term efficacy or safety data available.
One very bothersome finding is the development of neutralizing antibodies that were, according to the prescribing information, detected in approximately 10 percent of patients receiving natalizumab. This became persistent in 6 percent of patients receiving the medication, so much so that it led to a "substantial decrease in the effectiveness."
In fact, the annualized relapse rate of persistently antibody-positive patients was similar to the annualized relapse rate in patients who received placebo. The assay used during the study was unable to detect low to moderate levels of antibody to natalizumab. The effects of low to moderate levels of antibody are unknown.
There is no commercially available neutralizing antibody test available, and the PI does not require its use in clinical practice. This issue appears to be very important to the FDA, as there were numerous requirements in the approval letter, including the development of a screening immunogenicity assay that will detect anti-natalizumab specific antibodies. The requirement is for the developments in the screening assay to be reported to the FDA by March 31, 2007.
This product was approved under the "accelerated approval of biological products" regulations 21 CFR 601.40-46, which allow the use of surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as the basis of approval. Other approved therapies have demonstrated improvement in the delay of disability as measured by the Expanded Disability Status Scale (EDSS).
Because of this, the FDA is requiring Biogen to perform adequate and well-controlled studies to verify and describe the clinical benefit attributable to this product. In particular, the FDA is requiring that Biogen verify that the clinical benefit of reduction in exacerbations is sustained with continued administration.
These studies are due September 2005. The FDA is also requiring that Biogen perform a study of the pharmacokinetics of chronically dosed natalizumab in the presence of glatiramer acetate — a portent of possible combination therapy.
This is the first generation of this class of drug. Time and experience with this antibody will demonstrate whether this class is as safe as the existing immunomodulators or if it is worth the premium pricing. That will be the topic of future essays on Tomorrow's Medicine.