RMAT Designation, Gene Therapies Highlight 2017 CBER Transformation

CBER Director Peter Marks says the center implemented a lot in a short amount of time for the RMAT pathway.

After a number of flavorless news years within the US FDA's Center for Biologics Evaluation and Research (CBER), 2017 took a 180 degree turn with several transformative developments for the center, highlighted the introduction of the Regenerative Medicines Advanced Therapies (RMAT) pathway and by the approval of the first US gene therapies.

Then President Obama signed the 21^st Century Cures Act into law on Dec. 13, 2016, and the center immediately began to see the RMAT pathway in action on the following day, when it received its first designation request, CBER director Peter Marks tells the Pink Sheet in an interview.

The CBER staff "managed to implement the processes for handling this RMAT designation remarkably quickly, and although we had a slow stream at first of those coming in, the pace just picked up a little bit," Marks said.

"We've appreciated this designation," Marks added. "It has brought good dialogue with the sponsors that are submitting them. I think it has served as a venue for serious developers in this area."

Marks also pointed to the suite of regenerative medicines guidances the agency released in November, which included recommendations for the expedited development of such therapies. (Also see "Regenerative Medicine Clinical Trials: US FDA Supports Studies Comparing Multiple Agents" - Pink Sheet, 16 Nov, 2017.)

"I think we have a lot of progress very quickly in implementing this," Marks said.

"I think what [the designation and guidances have] also done, I think, is help clarify that there really is a bona fide pathway for these products forward for serious developers," the CBER director added.

The RMAT designation specifically allows for early and frequent communication between sponsors and FDA. Similar to the breakthrough therapy designation, the RMAT designation has the goal of reducing overall product development times. Sponsors may also be eligible for priority review and accelerated approval. Eligible products include cell therapy, therapeutic tissue engineering products, human cell and tissue products and certain gene therapies. (Also see "Kite's Gene Therapy Yescarta Gets Biosimilar Treatment With Second-In-Class Approval" - Pink Sheet, 19 Oct, 2017.)

Marks, however, also noted that CBER may eventually run into resource challenges with the RMAT pathway, as the sponsors "get a breakthrough therapy-like number of meetings and attention from senior leadership within the center," he says. This has been a similar sentiment echoed by the Center for Drug Evaluation and Research (CDER) for the breakthrough program, which has also been a source of pride and exhaustion for the agency.

As of Jan. 12, the CBER director said the center has received 43 RMAT designation requests in total, 12 of which have been granted and six or seven of which are still pending. Sponsors have publicly announced 11 of the designations, according to Informa's Biomedtracker. (See table at bottom of story.) The first announced designation came in March for Humacyte Inc.'s investigational human acellular vessel Humacyl. (Also see "US FDA First's RMAT Designation: Humacyte Got A 'Quick Response'" - Pink Sheet, 26 Mar, 2017.)

Gene Therapy Reviews Were 'Exemplary'

Not to be outdone, however, CBER's transformations continued with the review and approval of the first three US gene therapies: Novartis AG's Kymriah (tisagenlecleucel), Kite Pharma Inc.'s Yescarta (axicabtagene ciloleucel) and Spark Therapeutics Inc.'s Luxturna (voretigene neparvovec-rzyl). (Also see "Spark's Early Christmas Present: US FDA Approves Luxturna For Vision Loss" - Pink Sheet, 19 Dec, 2017.)

The review of the chimeric antigen receptor T-cell (CAR-T) therapies Kymriah and Yescarta, which are respectively indicated for the treatment of B-cell precursor acute lymphoblastic leukemia and large B-cell lymphoma, was done in collaboration with the Oncology Center of Excellence (OCE). OCE played an important role in the clinical review portion, and CBER offered manufacturing, pharmacology and toxicology expertise.

"[Kymriah and Yescarta] actually were quite impressive in terms of the manufacturing issues that had to be addressed, and some of the issues surrounding management of some of the potential adverse events that could occur with those," Marks said. "I think we managed through those very well. I think we worked very well with the companies to come up with programs to help make sure the products will be safely used."

Marks also described the reviews as "exemplary," noting that they "really benefitted" from the collaborative review process.

Luxturna, conversely, involved treating a rare form of blindness, and became the first gene therapy approval for a directly administered gene therapy. The treatment also involved an endpoint called the multi-luminance mobility test (MLMT), which measured the change from baseline to one year in a subject’s ability to navigate an obstacle course at various light levels. (Also see "How To Build An Endpoint: Spark Designed Testing Maze To Study Rare Vision Loss" - Pink Sheet, 15 Oct, 2017.) MLMT was developed by Spark in collaboration with the Office of Tissues and Advanced Therapies, Marks noted.

"And so that combination, I think, of a novel endpoint with a novel therapy was quite nifty," Marks said. "And I think we are hoping that as we move into additional gene therapies that will come through development, that we will continue to be innovative in our approach to obviously not just the gene therapy portion, but also to endpoints that will help get these things across the finish line."

Marks once again stressed CBER's willingness to accept non-traditional endpoints in the appropriate situations.

"For some of the diseases, we are talking about orphan diseases where it could be challenging to use some of our traditional endpoints, and we are very open to the use of novel endpoints, including things like what we used for Luxturna, as well as biomarkers, etc.," the CBER director said.

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Pink Sheet and FDA data

 

Open Media

Pink Sheet and FDA data

 

 

Approvals, Review Times Increase

CBER approved 11 novel biologics in 2017, a rise from the six the center approved in 2016.

The average review time – calculated as date of initial biologics license application (BLA) submission to date of approval – ticked up from 12.2 months in 2016 to 15.5 months in 2017. The 2017 number, however, is significantly bloated by the review time for Dynavax Technologies Corp.'s hepatitis B vaccine Heplisav-B, the BLA for which was originally submitted in June 2012.

The median review time for 2017, conversely, was 11.9 months.

Three of the approvals – the three gene therapies – scored priority review and breakthrough therapy designations. The other eight approvals were deemed standard reviews.

[Editor's Note: Keep track of novel biologic approvals with the Pink Sheet FDA Performance Tracker's CBER Novel Approvals chart.]

RMAT Designations

Sponsor	Product	Indication	Date Announced	Phase When Announced
Humacyte	Humacyl	Human acellular vessel for vascular access to patients in need of life-sustaining hemodialysis	March 20, 2017	Phase III
Enzyvant Therapeutics	RVT-802	Tissue-based therapy for the treatment of complete DiGeorge Syndrome (cDGS)	April 17, 2017	Phase III
Vericel	Ixmyelocel-T	Autologous, expanded multicellular therapy for the treatment of advanced heart failure due to ischemic dilated cardiomyopathy	May 10, 2017	Phase II
Mallinckrodt	StrataGraft Skin Tissue	Regenerative skin for severe burns and other complex skin defects	July 18, 2017	Phase III
Kiadis Pharma	ATIR101	Adjunctive immunotherapeutic on top of bone marrow transplant for the treatment of acute myelogenous leukemia	Sept. 20, 2017	Phase III
Asterias Biotherapeutics	AST-OPC1	Human embryonic stem cell-based therapy for the restoration of function following acute spinal cord injury	Oct. 2, 2017	Phase II
Athersys	MultiStem	Stem cell product for ischemic stroke	Oct. 5, 2017	Phase II
bluebird bio	LentiGlobin	Gene therapy for the treatment of severe sickle cell disease	Nov. 1, 2017	Phase I
Juno Therapeutics	Lisocabtagene Maraleucel	Autologous chimeric antigen receptor modified T (CAR-T) cells for the treatment of r/r aggressive large B cell non-Hodgkin's hymphoma, including diffuse large B-cell lymphoma	Nov. 1, 2017	Phase I
Fortress Biotech	CEVA101	Autologous bone marrow-derived stem cells for the treatment of traumatic brain injury	Nov. 8, 2017	Phase II
Mesoblast	NeoFuse	Mesenchymal precursor cell therapy in the treatment of heart failure patients with left ventricular systolic dysfunction and left ventricular assist devices	Dec. 21, 2017	Phase III

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