FDA Approved Therapy for LAM in Less Than a (20 Year) Decade

Author: Editor

1-McCormack.jpg The FDA-approved sirolimus for use in patients with LAM on May 28, 2015, almost exactly 20 years after The LAM Foundation was founded. The informal tag line for the Foundation back then was ‘an effective treatment in under a decade’, and the Board’s tongue-in-cheek position was that we could ‘use our own discretion’ to decide when the decade started. I am still not sure when the start date was, but I think we can assign the end date for the first effective treatment for LAM as May 28, 2015.

The FDA effort started a few months before the MILES trial was published in The New England Journal of Medicine in April 2011. We had contacted Pfizer to ask if they would consider pursuing an FDA indication for LAM based on the MILES trial result that sirolimus stabilized lung function. After about three months of internal deliberations, Pfizer replied in June 2011 that they would not approach the FDA about changing the sirolimus label, in part because the product was already commercially available and the resource demand of a submission would be significant against a limited market potential and expiring patent for sirolimus. Pfizer (as its predecessor, Wyeth) had already contributed greatly to the LAM effort by supplying sirolimus and financial support in part for the MILES trial, and under the circumstances their response was not unexpected. At the Summit for Drug Discovery in Tuberous Sclerosis meeting in July 2011, however, one of the panelists mentioned an alternative route to FDA approval, called the Citizen’s Petition. A Citizen Petition is a procedure by which a person or persons can petition the government to request that it take certain actions. In this case, the proposal was to petition the government to change the approved product label for sirolimus, even in the absence of an application from the manufacturer for this change.

With help from Gene Sullivan, MD, a LAM Foundation Board member and former Deputy Director of the Division of Pulmonary and Allergy Products at the US FDA, we contacted the FDA about this approach. After reviewing the matter, based on optimism from the MILES trial publication that sirolimus might be approvable for LAM by a more conventional approach, the FDA decided that the most efficient path would be for Pfizer to submit an application, rather than relying on the Citizen Petition procedure. The FDA then actively encouraged Pfizer to apply in May 2012. An atypical regulatory filing pathway highlighting a collaborative approach with the MILES team was judged to be acceptable by the FDA, in which the MILES data sets would be directly submitted to the IND application that I had submitted for the MILES Trial, and Pfizer would be permitted to cross-reference the data. Under these conditions, Pfizer agreed to pursue an indication for sirolimus in LAM. With the help of Gene Sullivan, and the pro bono assistance of a skilled legal advisor, Frank Sasinowski, of the DC law firm Hyman, Phelps and McNamara, the LAM Foundation successfully filed for Orphan Drug Designation for sirolimus in LAM (granted October 31, 2012) and transferred it to Pfizer to assist with waiver of a large filing fee (~ $1 million) that is typically required of companies.

Upon an initial review of the MILES data sets, the FDA expressed optimism that MILES might well be sufficient to support approval. The randomized and double-blind trial design, rigorously maintained despite the complexities of central drug level monitoring and dose adjustments, helped to make the case for efficacy. The FDA further offered that an Advisory Committee, extensive post marketing studies, additional audits, or an Integrated Safety Summary would not likely be required, as long as the FDA review of the full data sets confirmed the summary results. The Cincinnati MILES team, the Data Center in Florida and dozens of people at Pfizer worked for two years on the 2562 page MILES Clinical Study Report (CSR) that was required for filing. The FDA reviewed 3 dataset submissions, and granted Breakthrough Therapy Designation for sirolimus for the treatment of LAM on December 12, 2014, accelerating the review process and providing access to powerful FDA resources for assistance with trial design and regulatory approval. Pfizer submitted the final MILES datasets, the Clinical Study Report and the supplemental New Drug Application (sNDA) to the FDA on Christmas Eve, 2014. Less than six months later, with little activity and few queries, the FDA granted approval.

This stunning outcome exemplifies the remarkable progress that can be made when industry, a clinical investigative team, a patient advocacy group and a regulator put financial considerations and bureaucratic protocol aside to do what is right for patients. The courage and sacrifice of the women who enrolled, considered enrolling, attempted to enroll, wished they could have enrolled, or cheered from the sidelines in the MILES trial made the FDA decision possible. In essence, MILES subjects donated 10-20% of their lung function to get an answer for all LAM patients and for all time; bringing us to this place. There is no question who the heroes are in this story.

Sirolimus is the first drug approved for the treatment of LAM, and one of only a very few drugs approved for a diffuse parenchymal lung disease. What will FDA approval mean for LAM patients? First and foremost, FDA approval is the ultimate endorsement that the ratio of benefit to risk of a therapy is favorable. Physicians will therefore prescribe the drug with greater confidence. Insurers will be more inclined to provide coverage. And finally, the FDA ruling has the potential to facilitate approvals in other countries where patients have had difficulty obtaining the drug. The loss of access to sirolimus for Japanese patients after MILES has been a primary motivator for me personally. As it turned out, Dr. Inoue and Nakata righted that wrong about a year ago, when they obtained Japanese government approval for sirolimus in LAM through submission of MILES data to the Japanese Ministry, launching of their own safety study, and enlistment of the help of a pharmaceutical company. LAM patients in China, Russia, Singapore, Korea and other countries are still struggling to obtain sirolimus, however, and there is more work to do.

We owe a lot of people wine. LAM basic and clinical researchers for providing the scientific basis for MILES; MILES investigators, nurses, coordinators and patients for making the trial a success; Jeff Krischer, Karalyn Hadley, Marisa Couluris and Hye-Seung Lee and the entire team at the Rare Diseases Data Center for assistance with trial design and operations, expert data analyses and seemingly endless responses to FDA, Pfizer and ‘Japanese FDA’ queries; The NIH Rare Diseases Consortium, Bruce Trapnell and all MILES funders; Sheri Selk and the Cincinnati Children’s Translational Research Trials Office staff for 6 years of invaluable MILES trial support; Gene Sullivan for sage advice about trial design and conduct from beginning to end; Matthew Hodgson, Jeannie Bailey and Leslie Korbee for their stellar work as Project Managers for MILES; Leslie also for the pro bono, unfailingly eager and capable assistance she has provided to the LAM community for 8 years; Susan McMahan for her outstanding leadership as the MILES-trialwide coordinator; Frank Sasinowski and Gene Sullivan for all the advice, meetings and document drafting during FDA interactions; Tammy Roads and her coordinators for work on MILES and two years of uncompensated weekend and evening work on the MILES CSR; Eli Katz and Brenda Cooperstone who were early champions at Wyeth and Pfizer for the LAM effort; Sandi See Tai, Dan Levy, and Debi Tran at Pfizer for many months of biweekly CSR conference calls and tireless work on this project; Bob Abraham of Pfizer for his pioneering work on mTOR and his ongoing encouragement; and, last but not least, Sue Byrnes, Tom Laurenzi, Laura Lentz, Sue Sherman and the LAM Foundation Board, donors and staff who provide critical support to the MILES trial, greatly facilitated the FDA approval process and brought the patient voice to every conference table.

Speaking of the FDA—although the agency is not often publicly thanked, I can tell you that Dr. Badrul Chowdhury and his team in the Division of Pulmonary, Allergy and Rheumatology Products bent over backwards for LAM. They proactively encouraged Pfizer to seek an indication, pressured us all to hurry with the completion of the CSR and sNDA filing, and guided us through the shortest regulatory path possible. This has been the LAM story from the beginning; in the end people are people, and whether affected or unaffected; self employed, a member of a multinational company or an official in a federal agency; good people everywhere go out of their way to help when they encounter an eminently worthy cause.