Drug Updates

What’s On the Horizon for SLE?

The prescription of drugs for systemic lupus erythematosus (SLE) market will likely grow significantly in the coming years because of important research related to an unmet need, patients who are not satisfied with their treatment, and many promising drugs in the pipeline.^1,2 Some analysts indicate that that expenditures for drugs for lupus totaled $1.1 billion in 2008, with a projected increase to $1.6 billion in 2015. There are three new biologic products in phase III development—atacicept, belimumab, and ocrelizumab/ RG1594. There are others, such as epratuzumab, that are in phase II development.

Belimumab (Benlysta, formerly Lymphostat-B) is an intravenous B-lymphocyte stimulator (BLyS) –specific inhibitor to treat SLE.³ The agent is a human monoclonal antibody that specifically recognizes and inhibits the biological activity of BLyS, which is a naturally occurring protein needed in order for B-lymphocytes to develop into mature plasma cells. In SLE, elevated BLyS levels are thought to contribute to autoantibody production because the levels of autoantibodies can correlate with disease activity. Results of the phase III trial BLISS 52, a 52-week, double-blind, placebo-controlled, multicenter superiority trial, suggested that belimumab plus standard of care can reduce SLE disease activity. A significant improvement in patient response was seen at Week 52 in belimumab-treated patients compared with placebo-treated patients. A delayed time to the first SLE flare and lowering the risk of severe SLE flares were also more favorable with belimumab treatment.⁴ Belimumab was generally well tolerated, with an adverse event rate similar to placebo. The most common adverse effects were headache, arthralgias, upper respiratory infections, urinary tract infections, and influenza. No malignancies were reported. An additional phase III trial (BLISS 76), a 76-week study carried out with the same study design as BLISS 52, is underway to replicate the results of BLISS 52. There were more than 800 patients enrolled in this latter study.

Atacicept is a subcutaneously administered recombinant fusion protein of the TACI receptor and human immunoglobulin G. This agent can bind BLyS as well as a proliferation inducing ligand called APRIL. These characteristics make the agent a potent stimulator of B-cell maturation, propagation, and survival.⁵ The makers of atacicept are currently enrolling patients in a study to evaluate its ability to reduce SLE flares when given twice weekly for four weeks, followed by once weekly up to a year.⁶

Ocrelizumab is a humanized anti-CD20 monoclonal antibody being studied for the management of lupus nephritis.⁷ A phase III efficacy and safety study of ocrelizumab in combination with corticosteroids plus one or two immunosuppressant regimens (SOC) compared to SOC alone in SLE patients with Class II or IV nephritis is ongoing.⁸ The estimated date for primary completion of this trial is January 2013. Finally, epratuzumab, in a 12-week phase IIb trial in 227 SLE patients, showed a 25% treatment advantage over placebo for disease activity. This agent is a humanized anti-CD22 monoclonal antibody that potentially modulates B-cell activity.⁹

There is a large amount of interesting research underway for SLE, and we will see more clinical trial results as these novel agents work their way through the development pipeline.

New Approvals

Morphine sulfate high-concentration solution (100 mg per 5 mL) has been approved by the U.S. Food and Drug Administration (FDA) for the management of opioid-tolerant patients with moderate-to-severe acute and chronic pain, as well as for end-of-life care.¹⁰ Early in 2009, the FDA established an initiative to remove unapproved narcotic formulations from the market, products that were never approved by the FDA. Because of this, they were not subjected to safety, efficacy, bioavailability, or dose-ranging studies, as they are today. The FDA sent warning letters to nine pharmaceutical manufacturers, of which seven manufactured high-concentration morphine sulfate products. When the FDA realized there were no FDA-approved high-concentration morphine sulfate products on the market, they gave the manufacturers a reprieve from the ruling so as not to disrupt patient care. Since then, the FDA has worked with one manufacturer (Roxane) to bring this product to market. As part of this agent’s approval, the manufacturer established a safety profile to focus on the risks of misuse, abuse, and overuse. This product will likely be available with a Risk Evaluation and Mitigation Strategy (REMS).

NP-1 (topical amitriptyline/ketamine) has received orphan drug approval status from the FDA for the management of post-herpetic neuralgia (PHN).¹¹ In phase II studies of patients with PHN, it had at least equivalent effectiveness compared to gabapentin.

Tocilizumab (Actemra) has been approved by the FDA to treat adults with moderate to severe active rheumatoid arthritis (RA) and who have not had an adequate response to one or more tumor necrosis inhibitor therapies.¹² Tocilizumab is the first interleukin-6 receptor antagonist monoclonal antibody approved for the treatment of RA. Prior to approval, tocilizumab was studied in five late-stage studies in more than 4,000 patients, either given alone or in combination with methotrexate or other disease-modifying antirheumatic drugs. This agent is approved for the same use in the European Union (EU) under the brand name RoActemra.

Pipeline

Denosumab (Prolia), currently in phase III clinical trials in the United States, has received a positive opinion from the authorization of marketing by the Committee for Medicinal Products for Human Use of the European Medicines Agency in the EU for the treatment of postmenopausal osteoporosis in women at risk for fractures, as well as for treating bone loss in men with prostate cancer at increased fracture risk.^13,14
Phase III clinical trials have been completed for insulin ultra-rapid acting, rDNA origin (Afrezza). As an inhaled insulin product, its pH-sensitive particles immediately dissolve when in contact with the lung surface, releasing insulin monomers that rapidly cross into the systemic circulation.¹⁵ It achieves peak insulin levels within 12 to 14 minutes of being administered, which mimics mealtime insulin observed in nondiabetics. The new drug application was filed, and it was originally expected to be reviewed by mid-January 2010, so the FDA is likely to act on it soon.
Lidocaine topical patch 5%, a generic version of Lidoderm, had an abbreviated new drug application filed for it on January 21, 2010. Although this agent is FDA-approved for treating pain related to PHN, there are other off-label evidence-based uses for this agent.¹⁶ The first Lidoderm patent is set to expire in mid-March 2010.¹⁷

Safety

Diclofenac gel 1% (Voltaren gel), the topical nonsteroidal antiinflammatory agent used to relieve ostearthritis pain, has undergone a safety change to its label related to hepatic effects, including revised warnings and precautions about the potential for liver function test elevations while receiving treatment with this agent and all diclofenac- containing products.¹⁸ Postmarketing case reports have been identified related to drug-induced hepatotoxicity within the first month of treatment with topical diclofenac (these can occur any time during treatment). Through postmarketing surveillance, severe hepatic reactions have been reported, including fulminant hepatitis with and without jaundice, jaundice, liver necrosis, and liver failure. Some cases led to death or liver transplantation. It is recommended that patients receiving topical diclofenac be monitored with periodic transaminase measurements, particularly in patients receiving long-term therapy. A baseline measurement should be obtained before treatment followed by subsequent measurements (at unspecified intervals). Current data based on clinical trials and other cases suggest that transaminase levels be obtained within four to eight weeks after initiating diclofenac treatment, and subsequently thereafter.

In order to strike a balance between reducing the risk of opioid abuse and maintain patient access for those that need these agents, pharmaceutical industry representatives plan to meet and develop a phased-in approach to discuss these issues. They are speculating that it could include a voluntary physician training program to better educate them about appropriate use of pain medications, and perhaps government certification for prescribing controlled substances.¹⁹ In early 2009, the FDA convened a meeting to discuss REMS for the opioid compounds, specifically fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone, citing an increase in abuse, misuse, and overdose rates within the last 10 years.²⁰ At that time, the FDA’s Office of New Drugs was focusing on extended-release versions of older drugs which contain high doses of opioids which need to be carefully prescribed by physicians properly trained in their safety. At the latest meeting of the Office of New Drugs, the pharmaceutical industry had proposed that the federal Drug Enforcement Administration (DEA) offer voluntary training to prescribers but acknowledged that congressional action would be needed to allow this to happen because it is outside of the DEA agency’s current duties. A public meeting will be held sometime this year to help finalize a plan.

Michele Kaufman is a freelance medical writer based in New York.

What’s On the Horizon for SLE?

New Approvals

Pipeline

Safety

References

Drug UPDATES

Drug UPDATES

Drug Updates

Drug Updates

What’s On the Horizon for SLE?

New Approvals

Pipeline

Safety

References

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