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Pink Sheet – Proving Ground For “Breakthrough” Status Coming With Impending User Fee Goals

Pink Sheet – Proving Ground For “Breakthrough” Status Coming With Impending User Fee Goals

Novel drug and biologic applications with user fee goals in 2014’s second half cluster around infectious disease – notably hepatitis C, with three “breakthrough” drugs pending, antibiotics and meningitis B vaccines (also designated “breakthroughs”) – and oncology, where the first regulatory tests of the highly anticipated PD-1 immune checkpoint inhibitors are coming up.

With 11 new molecular or biologic entities under review at FDA with “breakthrough” designations, the second half of 2014 will provide the best test yet of the ability of the still-new expedited review program to deliver on its promise of speeding the development of especially promising treatments to market.

The breakthrough therapy NDAs and BLAs are concentrated in the rapidly transforming hepatitis C therapy space, oncology – the perennial hotspot for FDA’s expedited review programs across the board – and meningitis B vaccines, where disease outbreaks at several universities raised alarm.

The agency’s latest expedited approval program, introduced under the FDA Safety and Innovation Act of 2012 for drugs demonstrating early evidence of a substantial improvement over existing therapy for serious/life-threatening diseases, has been a popular addition to FDA’s expedited approval programs.

While there have been a handful of approvals of breakthrough therapies, several of those came late in the process or once the drug was already under regulatory review. As the program was designed to help cut down on development time, its true impact of the program will be better gauged by products that received the designation earlier on – and the slate of products due in the second half should be a better test.

Still To Come In The Second Half

More than 30 NMEs and novel biologics have second half 2014 user fee goals, and the pipeline remains strong beyond that: the 2015 user fee goal slate is already approaching 10 potential novel agents (see chart).

Infectious disease and oncology are the most active areas for NME and novel biologics with impending user fee goals, including a high proportion of applications being reviewed under other expedited review programs, notably priority review, accelerated approval, and the new Qualified Infectious Disease Product status.

In oncology, all the publicly disclosed pending NMEs are expected to receive priority review, and a majority have been submitted for accelerated approval. The three novel cancer treatments approved to date – Novartis’ breakthrough-designated Zykadia (ceritinib), Spectrum Pharmaceuticals Inc./Topotarget AS’ Beleodaq(belinostat), and Eli Lilly & Co.’s Cyramza (ramucirumab) – were all designated orphan drugs with fast-track status, receiving priority review. Zykadia and Beleodaq both received accelerated approval.

Expedited review programs are also prevalent among the pending oncologics. Gilead Sciences Inc.’s idelalisib has breakthrough status for an NDA for relapsed chronic lymphocytic leukemia; the CLL claim is receiving priority review while another idelalisib application, for refractory indolent non-Hodgkin lymphoma, is pending with standard review. Accelerated approval is being sought byMerck & Co. Inc. for its breakthrough-designated pembrolizumab in melanoma, by AstraZeneca PLC for olaparib in BRCA-mutated ovarian cancer, and by Bristol-Myers Squibb Co. for Opdivo(nivolumab) in squamous cell non-small cell lung cancer.

Bucking the trend two years after FDA refused to file an accelerated approval NDA for Novartis’ panobinostat in Hodgkin disease, the company returned to FDA with a conventional relapsed multiple myeloma filing that includes Phase III data (“Novartis Previews Panobinostat PFS Advantage In Myeloma” — Pharmaceutical Approvals Monthly, December 2013).

The agency has already cleared 25 NMEs/NBEs (19 by the Center for Drug Evaluation and Research plus six from the Center for Biologics Evaluation and Research following the July 17 clearance of Pharming NV/Salix Pharmaceuticals Ltd. recombinant C1 esterase inhibitorRuconest), so it is well on pace to match or exceed the tally for 2013 (“CDER Builds Strong Foundation Of NMEs For 2014 As Approval Total Hits 19” — “The Pink Sheet,” Jul. 14, 2014).

With the potential for fast action, however, the breakthrough pipeline has the potential to beat the user fee calendar and further add to that cohort.

Breakthrough Status Gets More Routine

FDA has approved only four designated “breakthrough” therapies to date, and those first approvals necessarily went to products that received the designation relatively late in development (the first designations were announced in January 2013).

Gilead’s HCV therapy Sovaldi was cleared in eight months and Gazyva in 6.3 months, on or faster than the current eight-month clock for priority review NMEs, but not breaking records considering that target used to be six months. The two others came in at a quicker clip, in line with the internal goals often set by the Office of Hematology and Oncology Products – Imbruvica at four and one-half months and Zykadia at four months.

The early experience with breakthrough products also shows that the status offers no guarantee of approval – Novartis’ serelaxin received a “complete response” letter (“Serelaxin Rejection Shows “Breakthrough” Status Doesn’t De-Risk Programs” — “The Pink Sheet” DAILY, May 16, 2014).

The reviews of the products approved so far show breakthrough status does bring more flexible reviews, including non-clinical aspects of the application, like manufacturing, tradename clearance, and inspections. During the Zykadia review, for example, a potential CMC stumbling block was quickly brought to the CDER director and resolved, preserving the fast pace toward approval (“Zykadia Expedited Timeline Challenged By Late-Breaking GMP Concern” — “The Pink Sheet,” Jul. 7, 2014).

The extensive agency resource commitment enabled by the formal breakthrough designation was crucial to the first-cycle approval of Gilead’s Sovaldi (sofosbuvir). When new Phase III data became available late in the review cycle, FDA directed Gilead to seek breakthrough status so the Division of Antiviral Products could put all of its proverbial hands on deck to evaluate a large amount of clinical data in a short period of time (“Better Late Than Never: “Breakthrough” Status Aided Sovaldi’s On-Time Approval” — “The Pink Sheet,” Apr. 14, 2014).

At a Friends of Cancer Research briefing in May, sponsors of approved breakthrough drugs suggested review management improvements based on their experience, calling for still more flexibility and coordination with manufacturing and companion diagnostic review staff and for fewer mandatory meetings (““Breakthrough” Review: FDA And Sponsors Discuss Ways To Improve Efficiency” — “The Pink Sheet,” May 12, 2014).

Breakthrough designations awarded well in advance of NDA submission will show if the program can enhance and speed the clinical development stage as well as it helps to marshal regulatory review resources.

Of the nine breakthrough-designated regimens under review at FDA (eight containing NMEs or NBEs and one for an sNDA for a marketed drug), the status award was announced more than six months before an application was submitted to FDA in three cases: AbbVie Inc.’s interferon-free, all-oral HCV regimen; Merck & Co. Inc.’s pembrolizumab (previously called lambrolizumab), the first candidate in the hotly anticipated PD-1 immune checkpoint inhibitor field; and Gilead’s fixed-dose HCV ledipasvir/sofosbuvir dyad.

Breakthrough Therapies On The Verge Of Breaking Through


Designation Announced

NDA/BLA Submission

Merck’s pembrolizumab for advanced melanoma



AbbVie’s ABT-450/ritonavir, ombitasvir, and dasabuvir regimen for HCV


Announced 4/22/2014

Gilead’s fixed-dose combination of ledipasvir and sofosbuvir for HCV



Gilead’s idelalisib for relapsed chronic lymphocytic leukemia



GlaxoSmithKline’s Promacta(eltrombopag) for new indication of cytopenia in severe aplastic anemia patients insufficiently responsive to immunosuppressants


sNDA submission announced 2/28/2014

Bristol-Myers Squibb’s asunaprevir and daclatasvir for HCV treatment in combination


Announced 4/7/2014

Pfizer’s bivalent recombinant LP2086 meningitis B vaccine


Completion of rolling BLA announced 6/17/2014; initiated around 4/2014

Novartis’ Bexsero (meningitis B vaccine)


Initiation of rolling BLA announced 6/17/2014

Boehringer Ingelheim’s nintedanib for idiopathic pulmonary fibrosis



At least one of the most recent breakthrough awards announced is expected to move rapidly to regulatory submission: Amgen Inc. is targeting a 2014 BLA for accelerated approval of its CD19-targeting bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed or refractory Philadelphia chromosome-negative, B-precursor acute lymphoblastic leukemia, an indication for which Amgen announced breakthrough status on July 1 (“Amgen’s Bispecific Blinatumomab May Be Ready For Leukemia Filing” — “The Pink Sheet” DAILY, Apr. 24, 2014).

The most recent breakthrough designation, however, was awarded to an NDA already under review. Boehringer Ingelheim announced the award for the idiopathic pulmonary fibrosis treatment nintedanib on July 16; the NDA appears to have been submitted in May. Nintedanib is racingInterMune Inc.’s pirfenidone to become the first IPF treatment approved by FDA. While pirfenidone’s NDA, resubmitted after a “complete response” letter, carries a slightly earlier user fee goal, the breakthrough designation puts Boehringer in the lead.

After Sovaldi, The Deluge

The Division of Antiviral Products is facing a significant review challenge in the second half of the year. As if juggling three breakthrough regimens comprising six NMEs and two previously-approved agents is not enough, the division also has a full slate of other applications, including BioCryst Pharmaceuticals Inc.‘s acute influenza treatment peramivir and several HIV treatment combinations.

The most recent priority addition to the antiviral division’s workload is another HCV regimen. On July 15, Medivir AB announced that Johnson & Johnson’s sNDA for an interferon-free combination of their Olysio (simeprevir) with sofosbuvir (Sovaldi) had been awarded priority review.

The intensity of late-stage HCV pipeline activity indicates that the division should not expect its workload to lighten up any time soon, with products like Merck’s breakthrough-designated all-oral regimen of the NS3/4A protease inhibitor MK-5172 and NS5A inhibitor MK-8742 in Phase III (and, thanks to Merck’s recently announced purchase of Idenix Pharmaceuticals Inc., a triple combination regimen coming up fast).

But the debate over Sovaldi’s high cost and the sheer number of novel candidates suggests that the HCV market could move from heady optimism to saturation rapidly. Boehringer Ingelheim GMBHannounced June 20 that it was abandoning pursuit of an interferon-based regimen for its candidate faldeprevir because “the HCV treatment environment has significantly and rapidly evolved” toward all-oral regimens.

The impact on the health of antiviral review staff also remains to be seen.…