Johnson & Johnson obtained accelerated approval from FDA for Sirturo (bedaquiline), a diarylquinolone antimycobacterial drug for multi-drug resistant tuberculosis (MDR-TB), but with a small U.S. patient population and a heavy burden for post-marketing studies, it remains to be seen whether the drug will be a significant profit maker for the pharma.

Bedaquiline also is filed for approval with regulatory authorities in Europe, China and South Africa, with those markets offering larger MDR-TB patient populations.

The approval letter and labeling call for very restricted use with directly observed therapy in a limited number of patients, those for whom an effective treatment regimen cannot be provided from the existing frontline therapy for MDR-TB, which includes the generics isoniazid and rifampin.

Sirturo inhibits mycobacterial ATP (adenosine 5’-triphosphate), an enzyme essential in generating energy in mycobacterium TB Also see "Johnson & Johnson Files NDA Seeking Accelerated Approval Of Bedaquiline In Tuberculosis" - Pink Sheet, 2 July, 2012.. It is indicated for use as part of combination therapy in adult patients with MDR-TB. Recommended dosage is 400 mg daily for two weeks, followed by 200 mg three times a week for 22 weeks, with dosing of the other components of the combination therapy continuing for an additional 24 weeks. The other components come from an armamentarium of five antimycobacterial drugs, all generics first approved to treat TB in the 1950s and 1960s. These include ethionamide, kanamycin, pyrazinamide, ofloxacin and the combination of cycloserine and terizidone.

Originally discovered by J&J subsidiary Janssen R&D LLC, the drug was approved on an accelerated approval basis backed by data from a pair of Phase II trials. Now, J&J must undertake a sizeable confirmatory Phase III trial along with a set of post-marketing studies to maintain the indication. The label includes a black box warning about increased risk of death and possible cardiologic side effects, specifically QT prolongation.

J&J filed its NDA on June 28 and was advised in September that Sirturo would be reviewed by FDA’s Anti-Infective Drugs Advisory Committee on Nov. 28 Also see "J&J’s Bedaquiline Advisory Cmte. Could Test Strength Of Phase II Argument For Tuberulosis Drugs" - Pink Sheet, 25 September, 2012.. That placed it in front of the line among three drugs vying to be the first approved for MDR-TB, as well as the first new mechanism approved for tuberculosis in over 40 years. The other drugs, in earlier stages of development, are Bayer AG’s moxifloxacin, already approved as an anti-infective under the brand name Avelox, and Novartis AG’s PA-824.

Advisory Committee United On Efficacy, But Not Safety

The advisory committee voted unanimously, 18-0, that J&J had provided substantial evidence of efficacy based on a surrogate endpoint that measured time to sputum culture conversion between patients treated with Sirturo and a placebo group Also see "J&J’s Sirturo Gets Panel Endorsement For Accelerated OK, Even As FDA Broaches Full Approval" - Pink Sheet, 29 November, 2012.. The panel also voted, however, that the surrogate endpoint would not be sufficient to provide clinical efficacy data for a standard approval, meaning J&J will need to use an endpoint to determine cure in the post-marketing Phase III study Also see "Janssen’s Sirturo Needs Minor Tweaks To Confirmatory Trial, FDA Panel Says" - Pink Sheet, 3 December, 2012..

The committee was split on the issue of safety, however, with 11 voting that substantial evidence of safety had been provided, and seven panelists vocally arguing that it had not. These concerns derived mainly from 10 deaths of unsubstantiated cause in the 79 treatment arm patients in the larger of the two Phase II trials. Two of 81 placebo arm patients died in the same trial. J&J had noted that trial investigators did not consider the treatment-arm deaths to be related to bedaquiline and one advisory committee member, Carol Hamilton of Duke University Medical Center, admitted the mortality data were troubling but could not find a common theme in the deaths after studying the cases Also see "Janssen’s Sirturo: TB Milestone Awaits After Advisory Committee Hurdle" - Pink Sheet, 27 November, 2012..

Years of Studies Ahead

A J&J spokeswoman told “The Pink Sheet” DAILY that the pharma already has agreed to an outreach and education initiative to explain the potential risks and proper usage of Sirturo to U.S. physicians. This will include a limited distribution scheme for the drug in collaboration with public health authorities, dissemination of educational materials to doctors who treat MDR-TB, and production of a packaging insert and medication guide as specified by FDA.

“As we do for all of our products, we will apply rigorous pharmacovigilance and adverse event reporting,” she added.

In addition to the confirmatory Phase III trial and standard pediatric assessments, FDA also is calling on J&J to conduct seven post-marketing studies in accordance with the approval. These include a patient registry to assess incidence rates of serious adverse events, including deaths, and a prospective, five-year in vitro study to determine minimum inhibitory concentrations (MICs) of MDR-TB isolates. The approval also requests two quality control studies related to that trial to help interpret MIC levels.

Final data from the two quality control studies are due by Sept. 30, 2014, with completion of the MIC study due Sept. 30, 2019. The patient registry will require interim reports each year between 2014 and 2018, with study completion set for December 2018. Another in vitro study, due October 2013, will characterize the potential of bedaquiline and M2 protein as a substrate, inhibitor or inducer of two drug transporters, OATP1B1 and OATP1B3.

Finally, FDA determined that a clinical trial, rather than a non-clinical or observational study, will be needed to assess the safety risk of using Sirturo in HIV patients co-infected with MDR-TB. It requested a drug interaction trial of bedaquiline with Bristol-Myers Squibb Co.’s Sustiva (efavirenz) to determine a safe and effective dosing regimen for co-administration of the two drugs in such patients, with final data due by Sept. 30, 2013.

The confirmatory Phase III trial is to be a randomized, double-blind, placebo-controlled multi-center study to assess long-term outcomes of failure, relapse or death in MDR-TB patients for a period of at least six months following treatment. Protocol submission is due by June 2013, with the trial to report final data in March 2022.

The J&J spokeswoman said the company is not concerned about the breadth of the post-marketing requirements and already has planned the Phase III trial. Bedaquiline also was filed for approval at the European Medicines Agency on Aug. 31, 2012, followed by filings with the Chinese FDA on Oct. 30 and South Africa’s Medicines Control Council on Dec. 6. J&J could not provide any clarity on when regulatory decisions might be received in relation to those filings.

Ex-U.S. Markets Vital To Sirturo’s Prospects

Those potential approvals will be vital to the success of Sirturo, as China, India, Russia and other Eastern European nations are seen as the markets that will have the greatest numbers of MDR-TB patients. MDR-TB is listed as an orphan disease in the U.S., with 98 reported patients in 2011. However, estimates are that 630,000 people worldwide currently have this form of tuberculosis and the World Health Organization expects that patient population to increase to 2 million by 2015.

J&J said Sirturo should be commercially available in the U.S. during the second quarter of 2013, but it would not comment on whether it would apply premium pricing or what the wholesale acquisition price will be.

In a note written just before the advisory committee review of Sirturo, Barclay’s analyst Anthony Butler projected middling prospects, at best, for the drug. Not only is the U.S. patient population minimal, but the largest caseloads are found in many countries with developing health care systems, he wrote Nov. 26.

“We estimate very limited U.S. sales of the agent, and under $300 million in international sales at peak,” Butler said. “Commercial opportunity could be greatly limited by the ability to pay in these developing country markets and the demographics of the patients. While Sirturo symbolizes the ongoing progress of J&J’s infectious disease franchise, we do not see the agent as a strong contribution of revenue growth.”

One side benefit of the FDA approval is that J&J qualifies for a tropical disease priority review voucher, only the second issued in program history. The first went to Novartis in tandem with the 2009 approval of Coartem (artemether/lumefantrine) Also see "FDA Cuts Priority Review Voucher Fee By 32%; No Takers For FY 2013" - Pink Sheet, 17 September, 2012..

The approval letter notes that this will enable J&J to designate a single NDA or BLA for priority review without requirement for meeting any other qualification for priority review. J&J also could transfer the voucher to another drug sponsor, making it an asset potentially useful in business development negotiations. J&J did not comment on its plans for the voucher.

J&J’s Sirturo Approval Tied To Expansive Post-Marketing Study Program

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