Drug Updates: Apremilast, Belimumab, and More

According to the Food and Drug Administration (FDA), 35 drugs were approved in the past 12 months, as of this writing, surpassing the number approved in 2009 by two.¹ The recently passed agents include important medical advances in the fields of hepatitis C, where two new agents were approved, and systemic lupus erythematosus (SLE), where belimumab was the first new lupus agent to be approved in 50 years. Innovative processes were used to approve these new medications while not compromising drug safety. Additionally, 24 of the agents were approved in the United States before approval in any other country. Ten of the new agents are for orphan conditions, some are for cancers, and some were approved with genetic tests using principles of personalized medicine. Further, 34 of the 35 were approved on or before their targeted Prescription Drug User Fee Act (PDUFA) review dates. Prospects about drug approvals in 2011 were anticipated to be few, but this does not seem to have happened.

Drug Safety

In a research letter published online in the Archives of Internal Medicine, Powers and Cook stated that approximately half (48%) of the potential “drug safety signals” about adverse events listed on the FDA’s website from 2008 through 2010 resulted in labeling changes. However, most (62%) of these “signals” were listed in an “updated Warnings and Precautions section” without guidance as to what action should be taken.² Four Risk Evaluation and Mitigation Strategy (REMS) and one drug withdrawal were also identified. These “signals” included serious risks and new safety information that were identified through the Adverse Event Reporting System (AERS). It is a significant challenge for the FDA and for drug safety scientists to promptly identify safety signals and efficiently and promptly evaluate them so that the interval of uncertainty between the time a safety signal is identified and when it is resolved is minimized.³ The FDA is not the only group evaluating drug safety signals: The Institute for Safe Medical Practices, also known as ISMP, also screens the AERS database and publishes their own quarterly report. The FDA is currently exploring ways to enhance and analyze drug safety and surveillance.

As reported in The Rheumatologist‘s September 2011 issue (“Drug Updates,”), over-the-counter (OTC) as well as prescription labeling of acetaminophen are undergoing changes to reduce the risk of toxicity.⁴ The United Kingdom is also experiencing similar problems. Significant hepatotoxicity and renal toxicity have been reported in patients associated with too much acetaminophen (paracetamol), according to a recently published study.^5,6 The study’s authors report acetaminophen as the main cause of acute liver failure. Staggered acetaminophen dosing, rather than a one-time ingestion, and delayed presentation to a hospital are common reasons for fatalities and liver transplantation. When patients were asked why they repeatedly ingested more than the recommended dose of acetaminophen, pain relief was often cited as their reason (58%). Since this is a worldwide problem, patients that ingest acetaminophen for pain management should be adequately counseled by their pharmacist and/or physician to prevent toxicity while getting the greatest benefit from it. Those patients with problematic dosing should be closely monitored for multiorgan failure.

Pipeline

Apremilast, an investigational oral phosphodiesterase-4 inhibitor, was recently shown to have a similar benefit in patients with both psoriatic arthritis and ankylosing spondylitis (AS), when used along with methotrexate (MTX).⁷ In a 12-week, placebo-controlled study of patients with psoriatic arthritis, 47% of patients taking apremilast 20 mg twice daily plus MTX achieved an American College of Rheumatology 20 (ACR20), compared with 41% of patients who received apremilast monotherapy (20 mg twice daily). Additionally, 37% of patients treated with apremilast 40 mg once daily plus MTX achieved an ACR20 response, versus 35% of patients who received apremilast monotherapy at the same dose. No treatment differences were considered statistically significant. It is believed that apremilast interrupts the inflammatory cascade in immune cells acting as a pluripotent immunomodulator. For AS, patients received 10, 20, or 30 mg of apremilast twice daily and were compared with placebo-treated patients. After treatment for 85 days, apremilast-treated patients had decreased Bath Ankylosing Spondylitis Activity Index (BASAI) scores of more than 1.5 points, compared with a decrease of approximately 0.75 points for placebo-treated patients (compared with baseline). The differences were not statistically significant. Additionally, there was a mean change from baseline for receptor activator of nuclear factor kB Ligand (RANKL) for apremilast-treated patients versus placebo-treated patients (73.2 versus 108.2; P=0.016). Apremilast represents a promising new oral biologic agent for both of these conditions.

Canakinumab (ACZ885, rilonacept), an investigational interleukin 1–beta protein targeted monoclonal antibody, continues to meet endpoints in children with active systemic juvenile idiopathic arthritis (SJIA).⁸ These data show that in SJIA patients (n=177) aged one to 19 years that were initially treated with ACZ885 for eight weeks then randomized to continue receiving active treatment or placebo, 45% of active-treated patients substantially reduced their oral corticosteroid use within 28 weeks (one of the primary study endpoints). Additionally, active-treatment patients were nearly three times less likely to have a new disease flare compared with placebo-treated patients (75% versus 27%, respectively).

In another study, patients with acute gouty arthritis who were unable to take nonsteroidal antiinflammatory drugs (NSAIDs) or colchicine received canakinumab for six months. Canakinumab was superior to triamcinolone acetate in delaying the occurrence of new gout flares and reducing the number of flares.⁹ The incidence of adverse events was higher for canakinumab (63% and 70%) compared with triamcinolone acetonide (49% and 57%) in two studies. More serious adverse events occurred in canakinumab-treated patients, but no opportunistic infections developed. The FDA has asked the manufacturer to submit additional safety data for consideration. The New Drug Application (NDA) has already been submitted to the FDA.

Thirty-five drugs were approved in 2011.

Data from a small study of 28 patients with mild-to-moderate SLE was presented at ACR.¹⁰ Patients were given four doses of a vaccine against interferon alpha (IFN-α) which showed that the IFN-α signature (in excess in SLE patients) can be down regulated, in essence vaccinating patients against their own IFN-α. The vaccine is called IFN-α-Kinoid and it is a modified IFN-α that lacks IFN-α biological activity. The vaccine is formulated so that it is recognized by the patient’s immune system, which then makes antibodies against its own INF-α. So far, it is well tolerated without significant side effects. This is another early step in a potentially new but investigational therapeutic for SLE.

Lupuzor has been granted approval from the FDA to conduct phase III clinical trials with “fast track” status.¹¹ In a Phase IIa proof of concept trial, the decrease of anti-dsDNA antibodies as a surrogate marker for efficacy and IL-10 was measured to determine its mechanism of action. It is administered by subcutaneous (SC) injection, two weeks apart. Different doses are still being studied.¹²

Methylnaltrexone bromide had its supplemental NDA accepted for the treatment of opioid-induced constipation (OIC). It is a SC injection of a peripherally acting mu-opioid receptor antagonist which counteracts constipating effects of opioids in the gastrointestinal tract without affecting pain-relieving ability. This agent is already been FDA approved for treating OIC in patients with advanced illness receiving palliative care who have not had an adequate response from laxatives.^6-13

Sarilumab (REGN88/SAR153191), a novel, high-affinity, SC-administered, fully human antibody targeting the interleukin-6 receptor (IL-6R), met its primary endpoint in a Phase 2b clinical trial in RA.¹⁴ Patients (n=306) were randomized to receive MTX plus placebo or MTX plus sarilumab (at one of five different doses) for 12 weeks. The primary endpoint was achievement of ACR20, and was attained in 49% of sarilumab-treated patients (at the lowest dose), 72% of sarilumab-treated patients (at the highest dose), and 46% of placebo plus–MTX-treated patients. Secondary endpoints including ACR50, ACR70, and DAS 28 scores also showed significant benefit with sarilumab compared with placebo. The most common side effects in the MTX plus–sarilumab-treated patients were nonserious infections, neutropenia, and liver-function test abnormalities. Serious adverse effects were comparable among the placebo-treated patients and those who received sarilumab. In a Phase 2b study in AS patients who had an inadequate response to NSAIDs, sarilumab did not demonstrate clinically significant or statistically significant improvements in the signs and symptoms of disease.

VX-509, an investigational oral JAK3 inhibitor, met its two primary endpoints in patients with RA in a Phase 2a clinical trial.¹⁵ It was studied in patients (n=204) with active moderate-to-severe RA who had an inadequate response to at least one disease-modifying antirheumatic drug. Patients received either placebo or one of four doses of VX-509, given twice daily for 12 weeks. For the two highest doses, 65% and 66% of VX-509–treated patients achieved an ACR20 versus 29% of placebo-treated patients. Additionally, of the two highest dose levels of VX-509 at Week 12, 35% and 37% of patients, respectively, achieved clinical remission, compared with 7% of placebo-treated patients. A longer-duration trial investigating the potential for additional improvements in RA activity using both once- and twice-daily dosing in combination with methotrexate is planned.

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

References

1. FDA: 35 innovative new drugs approved in fiscal year 2011. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278383.htm. Published November 3, 2011. Accessed November 23, 2011.
2. Powers A, Cook GE. Potential safety signals and their significance. Arch Intern Med. 2011;November 14, 2011 Published Online.
3. Japsen B. FDA is urged to issue more alerts about drug risks. http://prescriptions.blogs.nytimes.com/2011/11/15/f-d-a-is-urged-to-issue-more-alerts-about-drug-risks. Published November 15, 2011. Accessed November 23, 2011.
4. Kaufman MB. Drug Updates and Medication Safety. The Rheumatologist. 2011;5(9):58-59.
5. Barclay L. Acetaminophen: Repeated use of slightly too much can be fatal. www.medscape.com/viewarticle/754104. Published November 22, 2011. Accessed November 23, 2011.
6. Craig DGN, Bates CM, Davidson JS, Martin KG, Hayes PC, Simpson KJ. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity. Brit J Clil Pharmacol. DOI: 10.1111/j.1365-2125.2011.04067.x. (Online First)
7. Walsh, N. ACR: Novel drug shows promise in rheumatoid diseases. www.medpagetoday.com/MeetingCoverage/ACR/29768. Published November 10, 2011. Accessed November 14, 2011.
8. Dennis M. Novartis reports positive late-stage data for Ilaris in juvenile arthritis. www.firstwordpharma.com/forward/email ref?path=node/923656. Published November 7, 2011. Accessed November 29, 2011.
9. Goodman Al. Canakinumab for NSAID-intolerant patients with gout. www.medscape.com/viewarticle/753322. Published November 10, 2011. Accessed November 14, 2011.
10. Gordon S. Vitamin D, interferon alpha vaccine show promise against lupus. http://consumer.healthday.com/Article.asp?AID=658618. Published November 5, 2011. Accessed November 29, 2011.
11. ImmuPharma pipeline. www.immupharma.com/leadcompounds.html. Accessed November 29, 2011.
12. ImmunoPharm. www.immupharma.com/lupus.html. Accessed November 29, 2011.
13. sNDA accepted for relistor for opioid induced constipation in non-cancer patients. www.empr.com/snda-accepted-for-relistor-for-opioid-induced-constipation-in-non-cancer-patients/article/210850. Published August 30, 2011. Accessed November 29, 2011.
14. Sanofi and Regeneron report positive phase 2b trial results with sarilumab in rheumatoid arthritis. http://newsroom.regeneron.com/releasedetail.cfm?ReleaseID=590869. Published July 12, 2011. Accessed November 29, 2011.
15. Dennis M. Vertex’s oral drug meets main goals of mid-stage rheumatoid arthritis trial. www.firstwordpharma.com/forward/email ref?path=node/904385. Published September 6, 2011. Accessed November 29, 2011.