Could a biomarker rescue Lumiracoxib [Joicela], formerly known as [Prexige]? A genome-wide study identifies a strong assossiation of the HLA allele DQA1*0102 with Lumiracoxib [Joicela]-related serious liver injury

April 23, 2011 – In the history of flawed and/or market-withdrawn drugs, Lumiracoxib [Joicela], formely known as [Prexige], may only be a footnote, hardly comparable to the attention received by the high flying but ill-fated Rofecoxib [Vioxx], Troglitazone [Rezulin], and more recently Rosiglitazone [Avandia].

However, Lumiracoxib [Prexige] may make a mark after all in the history of pharma beyond its missed revenue opportunity or beneficial impact on patients. The drug is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s inhibitors, such as the infamous Rofecoxib [Vioxx], seem all but off the market in the US because of their cardiovascular side effects. Lumiracoxib [Prexige] seems to bind to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Rofecoxib [Vioxx] shadow: minimal cardiovascular side effects, high selectivity, rapid clearing from the circulation and absorption into the inflamed joint.

Lumiracoxib [Prexige] received European marketing authorization in November 2006 and was launched in parts of Europe the following year. Because of its own safety shortcomings such as rare but potentially fatal liver injury at higher doses, from 2007 onwards, Lumiracoxib [Prexige] was withdrawn from most European markets, as well as from the Australian and Canadian markets. Lumiracoxib was never approved by the American Food and Drug Administration (FDA), mostly for safety reasons.

Could the biomarker DQA1*0102 rescue Lumiracoxib?

In a recent study by Singer et al., published in 2010 in Nature Genetics 42, pages 711-714, a case-control genome-wide association study was performed on 41 Lumiracoxib-treated patients with liver injury (cases) and 176 matched Lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x10 to -10). These findings were replicated in an independent set of 98 Lumiracoxib-treated cases and 405 matched Lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10 to -12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501 -HLA-DQB1*0602 -HLA-DRB5*0101 -HLA-DQA1*0102, most significant allele P = 6.8 x 10 to -25, allelic Odds ratio = 5.0, 95% CI 3.6 – 7.0).

In princip, these results offer the potential to improve the safety profile of Lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from Lumiracoxib treatment. In fact, Novartis Pharma, the makers of Lumiracoxib, applied with the European Medicines Agency (EMEA) for a centralized marketing authorisation for Lumiracoxib [Joicela], in December 2009. According to this application, Lumiracoxib [Joicela] was intended, in a 100 mg film-coated tablet form, to be used for symptomatic relief in the treatment of osteoarthritis of the knee and hip in patients who are non-carriers of the DQA1*0102 allele. In essence, patients who test negative for the DQA1*0102 allele are expected to have a low risk for the development of serious liver side effects and could therefore safely take the drug. Those patients who test positive for the DQA1*0102 allele, however, should not get the drug.

This approach would constitute the first example throughout the pharmaceutical industry where a biomarker strategy rescued a drug, previously withdrawn from the markets because serious adverse effects (i.e., liver injury).  For the pharmaceutical industry, such a strategy for rescuing drugs previously flawed by serious drug adverse effects may hold tremendous appeal (cases such as Exanta, Galvus, etc., come to mind), even if the ultimate market for such rescued drugs may be nowhere near the original projections.

Lumiracoxib [Joicela] and its companion test: Not quite there yet

As we learned by mid-April 2011 from an announcement by the European Medicines Agency (EMEA), the application of the marketing authorisation for Lumiracoxib [Joicela] was withdrawn by Novartis. At the time of the withdrawal it was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP).

In its official letter, the company stated that its decision to withdraw the application was based on its inability to address the CHMPs request to provide additional data within the time frame allowed in the centralised registation procedure. We should take note here that withdrawal of an application does not prejudice the possibility for the company to make a new application at a later stage. In any case, more information about Lumiracoxib [Joicela] and the state of the scientific assessment at the time of withdrawal will be made available in a question-and-answer document. This document, together with the withdrawal letter from the company, will be published on the Agency’s website after the next CHMP meeting on 16 to19 May 2011.

EMEA: Rare atypical fractures of the femur is a class effect of medicines containing bisphosphonates

April 15, 2011 – From a press release as of today, we learn the following (text unchanged from  EMEA press release):

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded that rare atypical fractures of the femur are a class effect of bisphosphonates.

The CHMP confirmed that the benefits of bisphosphonates in the treatment and prevention of bone disorders continue to outweigh their risks, but that a warning of the risk of atypical femoral fractures should be added to the prescribing information for all bisphosphonate-containing medicines in the European Union. Such a warning had already been included in the product information for alendronate-containing medicines across Europe, following a review by the CHMP’s Pharmacovigilance Working Party in 2008. It will now be extended to the whole bisphosphonate class.

Prescribers of bisphosphonate-containing medicines should be aware that atypical fractures of the femur may occur rarely. If an atypical fracture is suspected in one leg, then the other leg should also be examined. Doctors who are prescribing these medicines for osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.

Patients who are taking bisphosphonate-containing medicines need to be aware of the risk of this unusual fracture of the femur. They should contact their doctor if they have any pain, weakness or discomfort in the thigh, hip or groin, as this may be an indication of a possible fracture.

The marketing authorisation holders of bisphosphonate-containing medicines have been asked to closely monitor this issue.

Notes

• Bisphosphonates include alendronic acid, clodronic acid, etidronic acid, ibandronic acid, neridronic acid, pamidronic acid, risedronic acid, tiludronic acid and zoledronic acid.

• The review of centrally authorised bisphosphonates was conducted in the context of a formal review under Article 20 of Regulation (EC) 726/2004, as amended.

• The current European public assessment reports (EPARs) for the nine centrally authorised medicines containing bisphosphonates concerned by these referrals (Aclasta, Adrovance, Bondenza, Bondronat, Bonviva, Fosavance, Ibandronic acid Teva, Vantavo and Zometa) can be found on the Agency’s website.

The review of nationally authorised bisphosphonates was conducted in the context of a formal review under Article 31 of Directive 2001/83/EC, as amended.

Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine: Update on Reports of Hepatosplenic T-Cell Lymphoma (HSTCL) in Adolescents and Young Adults

April 15, 2011 – The American Food and Drug Adeministration (FDA) informed today that it  continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL) primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine. TNF blockers include Infliximab [Remicade], Etancercept [Enbrel], Adalimumab [Humira], Certolizumab Pegol [Cimzia], and Golimumab [Simponi].

HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.

Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine; however, there have also been cases reported in patients receiving azathioprine or mercaptopurine alone.

The recommendations by FDA are as follows:

• Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

• Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.

• Know that people with rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or meracaptopurine.

Read the Drug Safety Communications for other specific recommendations for Healthcare Professionals and Patients and the Data Summary for additional information. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: www.fda.gov/MedWatch/report.htm.

Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

(This text is slightly adapted from the original text released by FDA, accessible here).