Rheumatology Drug Updates: Apremilast, Golimumab, and More

Pipeline

Apremilast is a twice daily, investigational, oral phosphodiesterase 4 inhibitor. It is being studied in clinical trials as a treatment for psoriatic arthritis.¹ Its manufacturer recently reported clinically meaningful improvements for the primary endpoint (ACR20 at Week 16), as well as other measures of signs and symptoms and physical function improvement in three randomized, controlled, parallel-group, 24-week clinical trials. These studies, known as PALACE 1, 2, and 3, involved more than 1,500 patients with psoriatic arthritis who had received or failed oral disease-modifying antirheumatic drugs (DMARDs), and/or a tumor necrosis factor (TNF)–α inhibitor therapy. Patients received either apremilast as monotherapy or in combination with oral DMARDs. The anticipated filing of its new drug application will likely be in the first quarter of 2013. A European submission is expected in the second quarter of 2013.

Golimumab has had a Biologics License Application (BLA) submitted to the U.S. Food and Drug Administration (FDA) requesting approval of an investigational intravenous (IV) formulation to treat adults with moderately to severely active rheumatoid arthritis (RA).² The results of the phase III, multicenter, randomized, double-blind, placebo-controlled trial of golimumab, an anti–TNF-α monoclonal antibody administered intravenously, in subjects with active RA despite methotrexate therapy (GO-FURTHER) trial, support this application. The trial studied the safety and efficacy of IV golimumab combined with methotrexate (MTX) via a 30-minute infusion at Weeks 0 and 4 and then every eight weeks versus placebo in 592 adults over 24 weeks.

Synavive, a combination of prednisolone and dipyramidamole, was being studied as a safer alternative to steroids for symptom management in patients with moderate to severe RA.³ Clinical trials have ceased due to a lack of improvement of the combination therapy compared with the effects of prednisolone alone.

On July 30, the FDA issued a Complete Response Letter for the supplemental BLA (sBLA) for rilonacept injection for subcutaneous (Sub-Q) use, for the prevention of gout flares in patients initiating uric acid-lowering therapy.⁴ The letter states that the drug cannot be approved in its current form, and the FDA has requested additional clinical data, as well as additional chemistry, manufacturing, and control information.

Yet again, the FDA requested additional clinical data on the oral janus kinase inhibitor tofacitinib to treat RA.⁵ In late July, phase III data from the ORAL Start trial showed that two different doses of tofacitinib were superior to MTX monotherapy in reducing the signs and symptoms via ACR70 in adults (n=958) with moderate to severe active RA, as well as in inhibiting structural damage (as measured by change from baseline in modified Total Sharp Score). No new safety signals were identified.

Drug Approvals/Modifications

Phentermine/topiramate extended-release capsules (Qsymia) are now available through online pharmacies.⁶ Phentermine/topiramate extended release capsules were approved in July. It is the first new FDA-approved weight-loss product to enter the U.S. market in close to 13 years. It is approved for use as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of 30 kg/m2 or greater (obese); or 27 kg/m2 or greater (overweight), in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.⁷ In clinical trials of 52 weeks’ duration, patients lost 11% to 14% percent of their body weight. Prediabetic patients had the most remarkable weight loss. These patients had lower blood glucose levels but also were able to stop taking some of their diabetes medications. This new product is available as capsules in the following doses of phentermine and extended-release topiramate, respectively: 3.75 mg/23 mg; 7.5 mg/46 mg; 11.25 mg/69 mg, and 15 mg/92 mg. It is taken once daily in the morning (to prevent evening insomnia) for 14 days and then escalated to the 7.5 mg/46 mg dose once daily in the morning. It is recommended to discontinue the agent or the dose escalation if 3% weight loss is not achieved after 12 weeks on the 7.5 mg/46mg dose; and to discontinue the agent if 5% weight loss is not achieved after 12 weeks on the maximum daily dose of 15 mg/92 mg once daily. If a patient is receiving the maximum dose and it is to be discontinued, it should be gradually tapered to prevent possible seizures. A dose of 7.5 mg/46 mg should not be exceeded in patients with moderate or severe renal impairment or patients with moderate hepatic impairment. The dosing guideline on the label should be followed.⁷ Contraindications include a known hypersensitivity to sympathomimetic amines, being pregnant, having glaucoma or hyperthyroidism, and taking a monoamine oxidase inhibitor currently or within the last 14 days. The most common adverse reactions with an incidence greater ≥5% in clinical trials were paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Using this agent with other weight-loss products—whether over-the-counter (OTC), prescription, or as supplements—has not been studied and is not recommended. The drug’s cardiovascular morbidity and mortality have not been established. A Risk Evaluation and Mitigation Strategy is available for this agent, mostly pertaining to its contraindication for use in pregnant women.⁸ This includes a Medication Guide and Elements to Assure Safe Use in the form of online healthcare professional training on the safe use of the product and certification of pharmacies that dispense the agent.

Delayed-release prednisone low-dose (1 mg, 2 mg, and 5 mg) known as Rayos, has been FDA approved to treat inflammatory diseases such as RA, polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and chronic obstructive pulmonary disease.^9,10

Drug Safety

A group of pain experts and health officials are urging the FDA to revise prescription labels for opioid medications.¹¹ The group members are specifically requesting that opioids only be marketed to treat severe pain and that dosing be limited to up to 100 mg daily for up to 90 days for nonmalignant pain for noncancer indications. The aim of this petition by Physicians for Responsible Opioid Prescribing is to slow aggressive marketing practices, advertisements, and medical-education programs in order to increase appropriate use of these agents.

The FDA has alerted the public that certain topical OTC analgesics to relieve mild muscle and joint pain have been reported to cause rare cases of serious skin injuries—including first-, second-, and third-degree chemical burns—on the applied areas.¹² These products contain menthol, methyl salicylate, and/or capsaicin. A search of FDA’s Adverse Event Reporting System database (from 1969 through April 21, 2011), the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance database (from 2004 to 2010), and the medical literature identified 43 cases of burns on the application site from these products. Some patients required hospitalization due to burn severity. In many of the cases, the burns occurred after only one application of the product, with severe burning or blistering occurring within 24 hours of the initial use. Of the reported cases, menthol alone and the combination of menthol (>3%) and methyl salicylate (>10%), led to the majority of second- and third-degree burns. Limited cases occurred with capsaicin-containing products. When recommending OTC analgesics to patients, counsel them about how to use them appropriately and inform them about the risk of serious burns. Advise patients to discontinue using a product if they develop new pain, swelling, or skin blistering where this product was applied. If patients experience adverse drug reactions from these products, report them to the FDA MedWatch program using the voluntary reporting form 3500 at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm.

Drug News

In late July, the Korean Food and Drug Administration (KFDA) approved Remsima (infliximab), the first antibody biosimilar to receive regulatory approval based on global clinical trials.13 It is the first anti–TNF-α to garner biosimilar approval. Approval was based on randomized, double-blinded, phase I and III studies with over 830 patients total. This study was conducted in accordance with the guidelines for biosimilar medicines by regulatory agencies including European Medicine Agency. Remsima had similar efficacy to infliximab. KFDA approved this biosimilar product for the same indications as Janssen has approved for the innovator product, which includes RA, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis. Additionally, pediatric Crohn’s disease will automatically be approved following completion of postmarketing surveillance. the rheumatologist

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. Apremilast palace program demonstrates robust and consistent statistically significant clinical benefit across three pivotal phase III studies (PALACE-1, 2 & 3) in psoriatic arthritis. Published September 6, 2012. Available at http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1732178&highlight=. Accessed September 16, 2012.
2. Kenney B. Janssen submits application to FDA requesting approval of Simponi intravenous formulation for treatment of moderately to severely active rheumatoid arthritis. Published September 18, 2012. Available at www.janssenbiotech.com/assets/PressRelease09182012.pdf. Accessed September 20, 2012.
3. Dane L. Zalicus to discontinue development of Synavive for RA. Published September 10, 2012. Available at www.firstwordpharma.com/node/1015948. Accessed September 11, 2012.
4. Regeneron receives complete response letter from FDA for ARCALYST (rilonacept) sBLA for the prevention of gout flares in patients initiating uric acid-lowering therapies. Published July 30, 2012. Available at http://investor.regeneron.com/releasedetail.cfm?ReleaseID=696645. Accessed September 5, 2012.
5. FDA requests more analysis of Pfizer’s tofacitinib data, regulatory decision could be delayed. Published July 31, 2012. Available at www.firstwordpharma.com/forward/emailref?path=node/1006695. Accessed October 8, 2012.
6. DeNoon DJ, Chang L. Weight loss pill Qsymia now for sale. Published September 18, 2012. Available at www.webmd.com/diet/news/20120918/weight-loss-pill-qsymia-now-for-sale. Accessed September 19, 2012.
7. Drugs @ FDA: Qysmia Product Label. Published July 17, 2012. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/022580s000lbl.pdf. Accessed September 19, 2012.
8. Qsymia (phentermine and topiramate) extended-release capsules [Category: anorectic and antiepileptic] Risk Evaluation and Mitigation Strategy. Published July 2012. Available at www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM312598.pdf. Accessed September 19, 2012.
9. FDA approves Horizon’s rheumatoid arthritis drug. Published July 26, 2012. Available at www.reuters.com/article/2012/07/26/us-horizonpharma-fda-arthritisdrug-idUSBRE86P1SV20120726. Accessed September 5, 2012.
10. Horizon Pharmaceuticals. Published July 26, 2012. Available at www.horizonpharma.com/. Accessed September 5, 2012.
11. Dane L. Doctors petition FDA to limit opioid drug access, use. Published July 25, 2012. Available at www.firstwordpharma.com/forward/emailref?path=node/1005043. Accessed September 5, 2012.
12. FDA Drug Safety Communication: Rare cases of serious burns with the use of over-the-counter topical muscle and joint pain relievers. Published September 13, 2012. Available at www.fda.gov/Drugs/DrugSafety/ucm318858.htm. Accessed September 19, 2012.
13. KFDA approves Remsima (infliximab) for autoimmune disease. Published July 23, 2012. Available at www.celltrion.com/EN/05_INVEST/invest03.asp?menu_num=3. Accessed September 19, 2012.