Biologics: Adalimumab Joins the Anti-TNF Line-Up

1. Efficacy
2. Safety
3. Costs/Insurance Coverage
4. Transferring from One TNF to Another
5. The Future

Adalimumab (pronounced ah-dah-LIM-yoo-mab), previously known as D2E7, is the latest anti-TNF-alpha agent to be approved by the Food and Drug Administration (FDA) for "reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active rheumatoid arthritis (RA) who have had insufficient response to one or more DMARDs" (disease-modifying anti-rheumatic drugs).[1] Rheumatologists will have various issues to consider, including effectiveness, safety, route of administration, likelihood of compliance, and costs/insurance coverage, in selecting among the three TNF inhibitors - adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) - for individual patients.

Efficacy

Clinical outcome: The preliminary data provided to the FDA for approval purposes support a profile of clinical response that is similar to etanercept. When taken in combination with methotrexate (MTX), at the end of a year, the placebo (meaning methotrexate alone) vs. 40 mg subcutaneous dose every other week yielded ACR20 of 24% vs 59%, ACR50 of 10% vs 42%, and ACR70 of 5% vs 23%.[2] In the 40 mg. dose group in the ARMADA combination therapy trial, at week 24, an ACR 20 was achieved by 67.2%, an ACR50 by 55.2%, and an ACR70 by 26.9%, all significantly greater than he placebo group.[3]

When taken as monotherapy for 26 weeks, the placebo vs. 40 mg subcutaneous dose every other week yielded ACR 20 of 19% vs 46%, ACR50 of 8% vs. 22%, and ACR70 of 2% vs 12%, according to an unpublished study summarized in the package insert.[1]

Radiologic outcome: In the study in which adalibumab was combined with methotrexate and compared to methotrexate alone, the mean of all radiographic (Sharp) changes were significantly lower in those also taking adalimumab: the total Sharp score (with lower scores representing a lower amount of joint damage), was 2.7 vs. 0.1, erosion score 1.6 vs. 0.0, and joint space narrowing score 1.0 vs. 0.1.[1]

Studies have also supported the efficacy and safety of 40 mg of adalimumab per week and this dose can be used in those patients who do not achieve an optimal clinical response to the every-other-week dosing regimen.

Like all TNF-inhibitors, adalimumab has more rapid onset of action than traditional DMARDs. Onset of response to adalimumab was has been detectable after one week, a point at which the greatest proportion of adalimumab-treated patients had achieved an ACR20.[3]

Safety

General: The various doses of adalimumab have been similarly well tolerated, with most adverse events being mild or moderate. Injection site reactions occurred in 14% of placebo patients vs. 20% of those on adalimumab. The most common adverse events leading to discontinuation of adalimumab were clinical flares (0.7%), rash (0.3%), and pneumonia (0.3%).[1]

Infections, malignancies and demyelinating disorders: Like the other two TNF inhibitors, the adalimumab label carries warnings about serious infections, including sepsis, tuberculosis, fungal infections, and other invasive opportunistic infections). Thus, the usual precaution of screening for TB and other infections should be taken prior to prescribing, and caution should be exercised in considering the use of these drugs in patients with "a history of recurrent infection or underlying conditions which may predispose them to infections, or patients who have resided in regions where tuberculosis and histoplasmosis are endemic," Patients with skin infections or skin ulcers are at particular risk for infections or septicemia.

Rare cases of demyelinating disease have been reported, as well as neurologic flares in patients with pre-existing or recent onset CNS demyelinating disorders.[1]

An increased incidence of non-Hodgkin's lymphoma has been noted. However, since rheumatoid arthritis itself has been associated with an increased risk of lymphoma, the observed lymphomas have been attributed by the FDA to this linkage. Optimal clinical monitoring regarding these potential problems include rapid reporting by patients of fever, chills and other symptoms of infection, examination for adenopathy, questioning about neurologic symptoms and a complete blood count every 6-8 weeks.

Immunogenicity: Adalimumab is the first fully human anti-TNF-alpha monoclonal antibody (IgG1). It has been "engineered through guided selection techniques (phage display technology), a method that mimics natural immunoglobulin gene rearrangement." It contains no non-human components nor any artificially fused human peptide sequences and, therefore, "is indistinguishable in structure and function from naturally occurring human immunoglobulin IgG1."[2] While this theoretically low immunogenicity may obviate the need for concomitant MTX, antibodies do form in some patients and dual use of adalimumab with MTX has been shown to result in a lower rate of antibody development, as well as significant efficacy benefits.[2]

As the latest option, adalimumab offers a more patient-friendly regimen in its one injection every two weeks, compared to etanercept's twice weekly injection and infliximab's IV infusion every eight weeks after an initial three injections at time zero, two weeks later and 4 weeks after that. Based on historical data across a wide range of oral drugs for various diseases, it is well known that compliance improves with fewer doses -- although intravenous dosing offers the benefit of physician observation of each dose, ensuring compliance. For self-injected drugs, one might theoretically expect improved compliance with a regimen of self-injection every two weeks. Such compliance may be further enhanced with the adalimumab option of a pre-filled syringe that makes the technology very patient-friendly. The special "wings" on the adalimumab syringe may make self-injection more feasible for those with severe hand deformity.

According to The Medical Letter, the cost for a year of treatment at the 40 mg every two week dosing is $15,679 (the same as etanercept and in contrast to $16,598 for infliximab).[4] All are significant expenses for patients with chronic disease, although the benefits yielded by TNF inhibitors are certainly dramatic. Real world use may increase or decrease these costs, depending on actual dosing and health insurance coverage. Abbott is providing adalimumab free to Medicare patients who have no drug coverage, such as Medi-gap policies, Medicaid, or state plans for patients of limited means, such as EPIC in New York State. (Similarly, both Centocor and Amgen have patient assistance programs to provide, respectively, infliximab and etanercept to indigent patients.)

If a specific anti-TNF drug is working effectively, I would recommend staying on that drug. Clearly, the drug's chemistry works well in a given patient and switching to another drug does not make much sense. If, however, the drug either has not been effective at all or is beginning to lose its effectiveness, switching makes sense. As the various rationales for choosing one anti-TNF agent over another shake out, with further studies and clinical practice, physicians may decide to switch patients from one to another - or patients may specifically request a switch, for example, to go from twice weekly to twice monthly injections, or from IV to twice monthly injection, if their insurance makes that feasible.

Until now, methotrexate has been the gold standard of treatment for RA. Will that change any time soon? I think so. MTX is likely to fall by the wayside, just as gold did, as we get more experience with the long-term positive and negative effects of the anti-TNF agents.

Although no head-to-head studies have been done and none is likely, clinical efficacy and safety appear to be similar for the three anti-TNF-alpha agents. While one author has suggested that "treatment with adalimumab will set a new standard for symptom control and joint protection," that presumption is only based on the early efficacy studies used to obtain FDA approval.[5] As we have always seen, the realities of effectiveness and safety only become clear when the medical community develops several years of experience with a new agent and is able to discern whether problems develop in post-marketing surveillance. In the absence of findings demonstrating such problems - or increased efficacy or safety for one of the three, many physicians are likely to make their choices based on patient concerns, such as route of administration and costs.