Rheumatology Drug Updates

Pipeline and Approvals

Apremilast, a novel oral PDE4 inhibitor, significantly improved signs and symptoms of moderate-to-severe chronic plaque psoriasis in Phase III clinical trials.¹ Apremilast demonstrated significance at Week 16 in the major secondary endpoints of Physician Global Assessment as well as in assessments of difficult-to-treat areas. The primary endpoint of a 75% reduction in symptoms was met by 33% of active-treated patients, compared to 5% of placebo-treated patients, at Week 16. The drug’s overall safety and tolerability profile was consistent with results from previously reported Phase III psoriatic arthritis trials. No cases of lymphoma or tuberculosis were noted, nor was there an increase in cardiovascular events or serious opportunistic infections. Apremilast is currently also in Phase III clinical trials for psoriatic arthritis and other chronic inflammatory conditions. The manufacturer expects to file for approval in the second half of this year.

As of February 7, 2013, Lilly has discontinued all of its rheumatoid arthritis (RA) Phase II and Phase III (FLEX-M and FLEX-V) trials of Tabalumab (LY2127399) due to lack of efficacy. Tabalumab is a fully human immunoglobulin G subclass 4 monoclonal antibody that inhibits B-cell activating factor (BAFF) protein.² The agent remains in Phase III trials for systemic lupus erythematosus (ILLUMINATE trials) and Phase II trials for multiple myeloma.

Prescription Drug Abuse

It is well known that, in the United States, prescription drug abuse is the fastest-growing drug problem, and is often considered an “epidemic.”³ Prescription drugs are now known to cause more overdose deaths than “street drugs,” with an estimated seven million Americans regularly using these drugs for nonmedical purposes. This abuse has led to nearly 40,000 deaths, costing our healthcare system almost $200 billion annually. According to the U.S. Substance Abuse and Mental Health Services Administration, nearly 23 million Americans have misused prescription pain relievers since 2002, while these agents rank only behind marijuana as a drug of abuse in the U.S.⁴

The increase in unintentional drug overdose deaths in recent years has been driven by increased use of opioids. Oxycodone and methadone products account for roughly two-thirds of all drug overdose deaths. Strategies have been implemented to monitor and curb this growing problem including the implementation of state-run controlled substance prescription monitoring programs (PMPs). These were borne out of President Barack Obama’s National Drug Control Policy, “Epidemic: Responding to America’s Prescription Drug Abuse Crisis,” which includes, among other components, “a functional prescription drug monitoring program in all 50 states.”⁵ As of February 2013, 48 states and one territory had operational PMPs, or had passed enacting legislation.⁶ Most PMPs allow any prescriber in the respective state or territory to register and obtain any patient’s controlled substance prescription utilization. Before these programs were implemented, patients could more easily “doctor shop.” In addition, anyone with prescription drug coverage through health insurance or through a pharmacy benefits manager could regularly fill prescriptions for narcotics and then pay themselves for other prescriptions, thus going undetected as receiving more medication than needed, yet appearing to be medication adherent and not an over-user.

Now, New York State has reclassified hydrocodone products into the controlled substance schedule II (C-II) category, effective on February 23, 2013.⁷ As is the case with other C-II narcotics, no refills are allowed on hydrocodone products. In addition, tramadol and all combinations of tramadol were moved to schedule C-IV status. In New York, prescriptions for tramadol (or other C-III through C-V medications) cannot be filled beyond six months of the date the prescription was written, nor can they be refilled more than five times. All New York State laws and regulations for a schedule IV controlled substance are to be followed.

The FDA has been meeting regularly to discuss the issue of rescheduling hydrocodone, and perhaps other opioids or opioid-like agents. In addition, the FDA issued a draft guidance on abuse-deterrent opioids in January 2013.⁸ This guidance is for manufacturers who hope to develop new opioid formulations. The draft guidance includes information on requirements for new agents in order to prevent abuse and misuse. The FDA hopes that this will encourage manufacturers to continue to produce opioids, but with abuse-deterrent formulations to decrease the prescription drug abuse problem.

Other solutions to tackling the prescription drug abuse epidemic include effective risk mitigation and evaluation strategy (REMS) programs for high-risk agents, proper medication disposal programs, better training of healthcare providers (e.g., prescribers and dispensers of opioids) to raise awareness of this problem, as well as educating parents, young people, and patients. In addition, law enforcement agencies are needed to help decrease drug diversion and abuse by shutting down “pill mills” and identifying and prosecuting other behaviors that enable prescription drug abuse.

Some believe that, if federal laws are changed to be similar to New York State law, many patients with chronic, nonmalignant pain who use opioids will have difficulty obtaining their medications.

Drug Safety

Galloway et al reported an increased risk of shingles and skin and soft tissue infections (SSSIs) in patients treated with tumor necrosis factor (TNF)–α inhibitors.⁹ A serious infection was defined as resulting in a hospitalization, requiring intravenous antibiotics, or causing death. Any postoperative infections occurring within 30 days of surgery were excluded. The researchers evaluated data from the British Society for Rheumatology Biologics Register, a prospective observation cohort study created in 2001, which enrolls all United Kingdom patients with RA that are prescribed an anti-TNF therapy. In the current evaluation, only treatment with adalimumab, etanercept, and infliximab were evaluated. Biologic anti–TNF therapy–treated patients were compared to a cohort of RA patients receiving nonbiological disease-modifying antirheumatic drugs (nbDMARD). All patients were biologic naive at study entry. Follow-up patient information was obtained every six months via a postal questionnaire from the patient and their treating rheumatology group. Shingles and SSSI were analyzed separately.

A total of 15,554 patients were analyzed. There were a total of 11,881 anti-TNF–treated patients and 3,673 nbDMARD-treated patients, a ratio of about 3:1. The incidence of shingles was approximately double in the anti-TNF–treated patients (1.6 per 100 patient-years) compared to the nbDMARD patients (0.8 per 100 patient-years). After adjusting for potential confounders (e.g., age, sex, disease severity, disease duration, comorbidities), the hazard ratio (HR) for shingles was 1.7 in RA patients on anti-TNF therapy. Among the 320 cases of shingles, 20 of 21 were severe and occurred in the anti-TNF–treated patients. The HR for developing shingles was 1.5 in the adalimumab-treated patients; 1.7 for the etanercept-treated patients; and 2.2 for infliximab-treated patients. In addition, 269 SSSIs were reported in the anti-TNF group and 39 in the nbDMARD-treated group. The SSSI incidence rate was 1.6 per 100 patient-years for the anti-TNF–treated patients and 0.7 per 100 patient-years for the nbDMARD-treated patients; this was not statistically significant. Most infections were staphylococcus cellulitis, but there were four cases of necrotizing fasciitis. The authors note that these study findings would support the use of zoster vaccination in this patient population.

In addition, in a recently published study Winthrop et al evaluated the herpes zoster risk in a large U.S. multiinstitutional collaboration in new TNF-α inhibitor–treated patients with RA, and other inflammatory diseases.¹⁰ A total of 33,324 TNF-α inhibitor–treated patients and 25,742 nbDMARD-treated patients were evaluated. Of TNF-α inhibitor–treated patients, there were 310 herpes zoster cases comprising 12.1 per 1,000 patient-years for RA, with baseline corticosteroid use of more than 10 mg daily associated with an increase zoster risk. It did not appear that these patients were at higher risk for zoster compared to those treated with nbDMARDs. Comorbidities and other factors were not known for these patients and they comprised a large number of Medicare and Medicaid recipients. Therefore, it seems that when different criteria and study design is used, it is still unclear whether patients taking anti-TNFs are at a higher risk for developing herpes zoster.

Peginesatide (Omontys), a synthetic erythropoiesis stimulating agent, was recalled in February due to severe hypersensitivity reactions, some fatal.¹¹ The agent was approved by the Food and Drug Administration (FDA) in March 2012 to treat adults with anemia from chronic kidney disease receiving hemodialysis; more than 25,000 people have received it. Severe hypersensitivity reactions occurred in 0.2% of patients, with fatal anaphylactic reactions occurring in 0.02% of patients. During its FDA approval process, peginesatide was endorsed by a 15-to-1 vote, and at that time had no “safety signals.”

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City, a clinical pharmacist at New York Downtown Hospital, and adjunct faculty at Touro College of Pharmacy.

References

1. Bratulic A. Celgene’s psoriasis drug apremilast meets primary endpoint in Phase III study. Published March 3, 2013. Available at www.firstwordpharma.com/forward/emailref?path=node/1061980. Accessed March 4, 2013.
2. Lilly discontinues Phase 3 rheumatoid arthritis program for tabalumab based on efficacy results. Published February 7, 2013. Available at https://investor.lilly.com/releasedetail.cfm?ReleaseID=738769. Accessed February 7, 2013.
3. CDC Grand Rounds. Prescription Drug Overdoses—a U.S. Epidemic. Published January 13, 2013. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm. Accessed February 5, 2013.
4. Substance Abuse and Mental Health Services Administration. The scope of substance abuse in America. Published October 2012. Available at www.samhsa.gov/prevention/nationalpreventionmonth. Accessed February 4, 2013.
5. Epidemic: Responding to America’s prescription drug abuse crisis. Published April 2011. Available at www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/rx_abuse_plan.pdf. Accessed February 5, 2013.
6. Alliance of States with Prescription Monitoring Programs. About the alliance. Available at www.pmpalliance.org/content/about-alliance. Accessed February 4, 2013.
7. New York State Department of Health. Frequently asked questions part C chapter 447 laws of 2012 (Controlled Substance Schedule Changes. Published November 2012. Available at www.health.ny.gov/professionals/narcotic/laws_and_regulations/part_c-chapter_447-laws_of_2012-faq.htm. Accessed February 4, 2013.
8. Liscinsky M. FDA issues draft guidance on abuse-deterrent opioids. Published January 9, 2013. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm334785.htm. Accessed February 4, 2013.
9. Galloway JB, Mercer L, Moseley A, et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2013;72:229-234.
10. Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMA 2013;309:887-895.
11. Geber J. Fatal reactions prompt Omontys recall. Published February 24, 2013. Available at www.medpagetoday.com/HematologyOncology/Anemia/37509. Accessed February 24, 2013.