A few days before the independent FDA committee review of Human Genome Sciences’ (HGSI) systemic lupus erythematosus (SLE) drug Benlysta (belimumab), the FDA suggested that the drug has marginal efficacy and scary adverse effects. The agency expressed concerns about infection, neuropsychiatric complications, including the risk of suicide, and increased risk of death as a result of the use of the drug. The FDA message to the independent committee, which will convene on Tuesday, is to decide whether the reward is worth the high risk. The FDA has also observed that studies conducted outside the U.S. produced stronger data than the U.S.; these studies were not consistent with the U.S. results. The agency has also observed that the African-American lupus patients had benefited less from Benlysta than did non-African American patients.
What do we make out of this FDA prelude?
To begin with, unless the product to be reviewed for approval is pure water, the major task of the FDA panel is to do exactly what the FDA is asking its panel to do in the case of Benlysta. i.e., weigh the risk against the reward. Before we speculate on the panels’ recommendation, let us have a look at both the disease and the drug.
SLE is a severe autoimmune disease where the immune system attacks and damages vital organs and systems such as the heart, the liver, the kidneys, the lungs, blood vessels, blood, nervous system, joints and skin. SLE symptoms do flare from time to time, and in some instances they become severe and life threatening, which necessitates hospitalization.
B-lymphocyte stimulator (BLyS) is a natural body protein essential for the survival and development of B-lymphocytes into mature antibody-producing plasma cells. Elevated levels of BlyS have been implicated in causing the production of autoantibodies. Inhibition of BLyS inhibits antibody production, which has been confirmed by studies proving that the drug reduces autoantibody levels in SLE and reduces disease activity. Some of Benlysta’s side effects, especially low resistance to infection, can also be explained by the drug’s inhibition of antibody production.
The panel’s judgment of whether the risk or the reward prevails should be based on many criteria, not just the nature and severity of the side effects of the drug. A fair verdict would depend on:
1. The severity of the disease: For life-threatening disease resistant to all conventional treatments, the efficacy of an investigational drug would outweigh the FDA’s hesitation to approve it notwithstanding serious toxicities. For chronic disease with severe progressive symptoms and without effective therapy, a drug with serious adverse effects can still pass the approval test if its efficacy results are clinically and biologically confirmed (beyond doubt) and the drug is expected to change the prognosis of the disease from bad to moderate or good.
2. Biomarkers: The availability of a clinical laboratory test that can pinpoint a patient’s predisposition for developing the drug’s adverse events improves the drug’s chance of approval, as vulnerable candidates would be excluded from taking the drug.
3. Severe but manageable side effects: All drugs with confirmed efficacy that causie manageable side effects have a good chance of approval. In these cases, boxed warnings are included in the drugs’ package information, along with warnings for physicians and patients and recommendations for management.
4. Severe diseases controlled by available treatments: In this case drugs having serious side effects must control symptoms and/or reduce progression much better than the available drugs when used alone, or generate better efficacy when used with the standard of care drugs.
Recognizing these criteria, the question becomes: Where does Benlysta for SLE fit into of the abovementioned scenarios?
The answer is: Benlysta most likely fits possibility #4. Although SLE has no cure, the current treatment regimens have produced significant improvement in the severity of symptoms, diminished the frequency of flares, delayed disease progression, and decreased the impact of SLE complications. As a result, fatalities are rare. The regimen used for mild to moderate lupus is a nonsteroidal anti-inflammatory drugs (NSAID), hydroxychloroquine (Plaquenil) and corticosteroids; all can have important side effects in prolonged use. NSAIDS are associated with stomach bleeding, kidney problems, and an increased risk of heart problems and stroke. Hydroxychloroquine, which is useful in preventing the flares, causes vision problems and muscle weakness. Corticosteroids are potent anti-inflammatory drugs, but prolonged use can cause osteoporosis, high blood pressure, diabetes, and immunosuppression, which increases the risk of infection.
For the life-threatening lupus cases, including lupus nephritis (kidney inflammation), blood vessel inflammation, and central nervous system problems, such as seizures, more aggressive treatment regimens exist. These include high-dose corticosteroids and/or immunsuppressants, such as cyclophosphamide (Cytoxan), azathioprine (Imuran) and mycophenolate (CellCept). Used also, but less frequently, are intravenous gamma globulin and methotrexate. Potential adverse effects of methotrexate are serious and include an increased risk of infection, liver damage, infertility and an increased risk of cancer.
It is worth noting that results from phase 3 trials of Rituxin (rutixumab) have failed to demonstrate significant benefit in patients with lupus nephritis.
So what will the panel probably discuss on Tuesday?
The panel will not draw a comparison between the side effects of the current treatments and Benlysta, as Benlysta will be not be used as monotherapy, but in combination with the standard of care treatments based on the disease severity. Rather, the panel will try to assess the value of adding Benlysta to the current treatments in terms of increased efficacy without adding to the side effect profile. The committee will try to decide whether the extra-efficacy provided is worth adding another drug with potential severe side effects to the already crowded standard of care combinations.
What do we think? After reviewing the clinical trials results time and time again, we tend to feel that, although the addition of Benlysta did not help decrease the dosage of the conventional drugs, especially the steroids, and has not contributed a further decrease in the frequency of the flares, which might be why the FDA described the efficacy results as marginal, Benlysta has, indeed, increased the efficacy to the conventional treatments. The clinical trial efficacy results have met their primary endpoints. With regard to Benlysta’s side effects, these were expected. The fact is, there was no concerning increase in the number of the drop-outs from the trials confirms that the side effects were not prohibiting.
We hope the drug will be approved. Benlysta’s effects encompass the action of Rituximab (inhibition of CD20-positive B cell proliferation and differentiation), in addition to other actions. As rituximab failed efficacy studies on lupus nephritis, we will be happy to see belimumab in the hands of specialists. They will find the best use for it.
Currently, we have no position in HGSI.