Keeping Track Of User Fee Decisions And Filings: Adakveo, Brukinsa And Fetroja Mark Massive Week Of Novel Approvals

The latest news on US FDA user fee decisions and submissions to the agency.

The US Food and Drug Administration's Center for Drug Evaluation and Research has now given the nod to 38 novel agents in 2019 after issuing a trio of significant approvals to Novartis AG's Adakveo (crizanlizumab-tmca), BeiGene Ltd.'s Brukinsa (zanubrutinib) and Shionogi & Co. Ltd.'s Fetroja (cefiderocol).

If fact, there was so much news this week, we couldn't keep track of it all in one place. See the sidebar for news about products accepted into FDA's expedited review programs.

In other user fee news, Agile Therapeutics Inc. will have to wait another three months for the FDA to make an approval decision on its contraceptive patch Twirla (levonorgestrel and ethinyl estradiol) with the agency extending the user fee date to February 2020.

Coming out on the losing end of the week's user fee news cycle was Lipocine Inc., which failed for a third time to secure an approval for its oral testosterone replacement therapy Tlando (testosterone undecanoate).

Highlighting the submissions and filing news of the week was an AbbVie Inc./Janssen Pharmaceutical Cos. submission of Imbruvica (ibrutinib) under the Real-Time Oncology Review (RTOR) program for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and a priority review for Merck & Co. Inc./AstraZeneca PLC selumetinib for the treatment of neurofibromatosis.

Now, here's your news in less brief:

Adakveo Approval Comes With Giroir's FDA PR Debut

The FDA's 15 November approval of Novartis' vaso-occlusive crisis drug Adakveo was meaningful enough to draw the attention of Brett Giroir, as the newly appointed acting commissioner made his first appearance in an agency press release.

Adakveo, a breakthrough-designated, first-in-class P-selectin inhibitor, is the first targeted therapy approved by the FDA for sickle cell disease. It is labeled for patients ages 16 and older to reduce the frequency of vaso-occlusive crisis, which is a common and painful complication of sickle cell disease.

“Hope has never been higher for people living with sickle cell disease and their families and supporters, with a pipeline of new treatments on the horizon, like the one being approved today, and several initiatives underway to better utilize current tools in the battle against the painful and deadly blood disorder,” Giroir said. “The opportunity before us in the coming months and years is profound and historic.”

Giroir took over the acting commissioner role from Norman Sharpless at the beginning of the month (Also see " Acting Commissioner Giroir Emphasizes 'Transitional' Period, Suggesting Time At US FDA Will Be Short" - Pink Sheet, 14 Nov, 2019.) and has quickly played a visible role in an agency communication. His appearance in a drug-specific approval release also speaks to the potential therapeutic impact of Adakveo, as FDA chiefs rarely appear in such announcements.

Patients receiving Adakveo in the pivotal Phase II SUSTAIN trial had a median of 1.63 health care visits annually for vaso-occlusive crisis compared to a median of 2.98 visits annually for patients receiving a placebo. What's more, 36% of Adakveo-treated patients did not experience a vaso-occlusive crisis versus 17% of placebo-treated patients. (Also see "Keeping Track: Recarbrio Approval Highlights Two-Week Roundup" - Pink Sheet, 19 Jul, 2019.)

Novartis said it expects to launch the drug in "the coming weeks." A company spokesperson told the Pink Sheet that the list price is $2,357 per vial and that most patients get three or four vials per month, which brings the monthly price to $7,071 or $9,428.

But as Giroir noted, Adakveo is just the first approval from expected wave of candidates for sickle cell disease, a long-underserved condition. Global Blood Therapeutics Inc.'s voxelotor, for instance, which is under review at the FDA, is designed to address the underlying cause of sickle cell disease by increasing hemoglobin's affinity for oxygen. (Also see "Sickle Cell Disease Market Snapshot: "The Time Has Come"" - Scrip, 31 Oct, 2019.)

Brukinsa Sprints To Accelerated Approval For MCL

FDA reviewers once again showed off their speed by awarding an accelerated approval on 14 November to BeiGene's Brukinsa for the second-line treatment of adults with mantle cell lymphoma (MCL) after just a four-and-a-half-month review period.

A Bruton’s tyrosine kinase (BTK) inhibitor, Brukinsa now owns the second fastest review time for a novel drug approved in 2019, finishing behind the three-month review for Vertex Pharmaceuticals Inc.'s Trikafta (elexacaftor, tezacaftor and ivacaftor). (Also see "Keeping Track: Vertex’ Trikafta Speeds To US Approval; New Indications For AZ’s Farxiga, J&J’s Stelara, GSK’s Zejula" - Pink Sheet, 24 Oct, 2019.)

The approval, BeiGene's first ever, was primarily based on an open-label, single-arm Phase II trial (BGB-3111-206) of 86 patients, where Brukinsa demonstrated an overall response rate (ORR) of 84%, including a complete response rate of 59% and a partial response rate of 24%. The NDA was also supported by a single-arm Phase I/II trial (BGB-3111-AU-003) of 32 patients, which also achieved an ORR of 84%; the trial's complete response rate was 22% and the partial response rate was 62%. (Also see "Keeping Track: US FDA Greenlights Two More Novel Drugs, But Smacks Down Golodirsen" - Pink Sheet, 23 Aug, 2019.)

"For patients whose disease relapses or becomes refractory, secondary therapies may be successful in providing another remission, and today’s approval will provide patients with another treatment option," Rick Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases, said in a statement.

As a condition of accelerated approval, BeiGene will have to complete its ongoing Phase III trial, BGB-3111-306, which is evaluating Brukinsa and rituximab versus bendamustine and rituximab in patients with previously untreated MCL, according to the approval letter. The primary endpoint is progression-free survival (PFS), while overall survival (OS) is a key secondary endpoint. Enrollment of roughly 500 patients is expected and the completion of the trial planned for October 2026.

BeiGene is also assigned two section 505(o)(3) postmarketing requirements in accordance with the approval. The company must conduct an analysis evaluating the pharmacokinetics and safety of Brukinsa when administered with concomitant CYP3A4 inhibitors, such as ciprofloxacin and diltiazem, using data from ongoing studies, the approval letter states.

The drug maker is also required to conduct in vitro studies to evaluate the effect of a broad range of concentrations of Brukinsa on the potential to inhibit platelet function.

In addition to accelerated approval, Brukinsa also received a slew of other regulatory incentives, including breakthrough therapy designation (BTD), orphan drug designation, and a priority review.

BeiGene said in a statement it expects to launch the drug in the US "in the coming weeks." A company spokesperson told the Pink Sheet that the wholesale acquisition cost of a 30-day supply of Brukinsa will be is $12,935.

Fetroja Nets cUTI Approval With Clean Label

Shionogi's cephalosporin antibacterial Fetroja managed to avoid a black box warning in its label regarding a potential mortality imbalance with a 14 November approval for the treatment of complicated urinary tract infections (cUTI).

Fetroja is specifically indicated to treat cUTI, including pyelonephritis caused by susceptible Gram-negative microorganisms, in patients aged 18 and older who have limited or no alternative treatment options. The drug was designated a qualified infectious disease product (QIDP) for the indication.

"Approval of this indication is based on limited clinical safety and efficacy data for Fetroja," labeling states.

Notably, the label only contains language in the warnings and precautions section regarding the mortality imbalance observed in the open-label, descriptive, Phase III CREDIBLE-CR study, which compared Fetroja with the best available therapy in infections caused by carbapenem resistant pathogens at various anatomical sites.

All-cause mortality in CREDIBLE-CR was higher among patients receiving Fetroja compared with those receiving best available therapy at day 28 (24.8% versus 18.4%) and day 49 (33.7% versus 20.4%). But the label conveys that the imbalance was largely concentrated in populations outside of cUTI, noting that, "The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis."

"Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities," labeling adds.

The FDA remains uncertain as to the cause of the imbalance, although it acknowledged during the review cycle that it might have occurred by chance. (Also see "Possible Mortality Imbalance For Shionogi's Cefiderocol On US FDA Panel Agenda" - Pink Sheet, 14 Oct, 2019.)

Fetroja scored a 14-2 endorsement for approval from the Antimicrobial Drugs Advisory Committee in October. However, a few panelists recommended that labeling include a black box warning to inform prescribers of the potential mortality risk observed in the other infections. (Also see "Cefiderocol Approval Likely After Panel Vote, But Future Still Clouded" - Pink Sheet, 16 Oct, 2019.)

In the pivotal 448-patient APEKS-cUTI study supporting approval, 72.6% of patients in the Fetroja arm met the primary endpoint of microbiological eradication and clinical response compared to 54.6% of patients in the imipenem/cilastatin arm.

The FDA's press release touted the approval as another treatment option in the agency's ongoing efforts to address antimicrobial resistance. In Shionogi's statement, company president and CEO Isao Teshirogi adds that, “Fetroja will fill a very important unmet medical need because of its unique method of penetrating the cell wall of Gram-negative bacteria and its ability to overcome many of the resistance mechanisms that bacteria employ against antibiotics."

Shionogi said it expects to launch Fetroja in early 2020. A company spokesperson declined to comment on the list price.

Fetroja is also being developed for the treatment of hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia/healthcare-associated bacterial pneumonia (HABP/VABP/HCABP), for which it also carries a QIDP designation, although additional study of this indication may be required to further assess the mortality signal.

Twirla Goal Date Extension Could Offer Hope For Agile

The FDA extended the 16 November goal date for Agile's transdermal contraceptive patch Twirla to 16 February 2020, offering the company another ray of hope that the agency might approve the product that it previously slammed.

Agile said in a 14 November announcement that it submitted additional information to the FDA, per the agency's request, concerning topics discussed at the recent Bone, Reproductive and Urologic Drugs Advisory Committee meeting for the product.  At the 30 October meeting, the advisory committee voted 14-1, with one abstention, that the benefits of Twirla outweigh its risks to support approval for the prevention of pregnancy. (Also see "Agile's Twirla Suffers Scathing Critique By US FDA Ahead Of Advisory Cmte. " - Pink Sheet, 28 Oct, 2019.)

The panel's overwhelmingly positive vote threw the company a lifeline for its product after the FDA had offered a blistering critique of the patch in the briefing documents released in advance of the meeting, going so far as to say it does not believe the suboptimal effectiveness – as demonstrated by Pearl Index scores – of Twirla outweighs its risks. (Also see "Agile's Twirla Suffers Scathing Critique By US FDA Ahead Of Advisory Cmte. " - Pink Sheet, 28 Oct, 2019.)

It's not clear which additional data the FDA requested. But despite the agency's negative feelings about the product, the goal date extension shows that it is at least further considering an argument that the available evidence supports approval.

Twirla is in the middle of its third review cycle at the FDA after the drug had previously received two separate complete response letters (CRLs). (Also see "Agile’s Twirla Heads To Advisory Committee: No Mystery Why" - Pink Sheet, 11 Jul, 2019.)

Efficacy Issues Cause Third Tlando Flop At FDA

For a third time, Lipocine's oral testosterone replacement therapy Tlando floundered in garnering the FDA's approval green light, as efficacy issues prevented the drug from clearing the final regulatory hurdle.

The company reported on 11 November that the most recent CRL cites one deficiency: Tlando's efficacy trial failed to meet the three secondary endpoints for maximal testosterone concentrations (Cmax). There were no issues raised regarding the chemistry, manufacturing and controls of Tlando, Lipocine said.

"We are disappointed by the FDA's decision and intend to request a meeting with the FDA as soon as possible to discuss a potential path forward for the approval of Tlando," Lipocine President and CEO Mahesh Patel said in a statement.

It's not the first time Cmax data has prevented Lipocine from cracking the code to regulatory success for Tlando. When Lipocine reported Tlando's second CRL in May 2018, the drugmaker noted that one of the four identified deficiencies included "verifying the reliability of Cmax data and providing justification for non-applicability of the agreed-upon and prespecified Cmax secondary endpoints for Tlando." (Also see "Keeping Track: A CRL For Tlando, An Accelerated Approval For AndexXa, And A Burst Of Supplemental Approvals" - Pink Sheet, 12 May, 2018.)

The FDA raised concerns during Tlando's second review cycle that the drug failed to meet the three Cmax secondary endpoints, which assess for unacceptably high maximal exposures to testosterone. (Also see "Lipocine Testosterone Therapy Faces Safety, Stopping Criteria Concerns At US FDA Advisory Cmte" - Pink Sheet, 8 Jan, 2018.)

But the issues didn't stop there. The Bone, Reproductive, and Urologic Drugs Advisory Committee, which voted 13-6 against approval during the second review cycle, worried about additional components of the application, most notably elevated blood pressure related to the drug. (Also see "Lipocine's Tlando Falls Short At US FDA Advisory Cmte Over Blood Pressure Concerns" - Pink Sheet, 10 Jan, 2018.)

In response to the second CRL, Lipocine conducted an ambulatory blood pressure monitoring clinical study. (Also see "Keeping Track: Resubmissions For Tlando And Twirla NDAs, And A BTD For Pomalyst" - Pink Sheet, 20 May, 2019.)

The company landed its first CRL for Tlando in June 2016, which cited the generalizability of the titration scheme as a deficiency. (Also see "Keeping Track: FDA Approves Epclusa, Designates Four Breakthrough Therapies, Files Burst Of Applications" - Pink Sheet, 4 Jul, 2016.)

Imbruvica/Rituximab Combo To Get RTOR Review For First-Line CLL/SLL

AbbVie and Janssen are taking to an RTOR review in their pursuit of an additional CLL/SLL indication for Imbruvica.

The companies announced on 8 November they submitted a supplemental new drug application under the RTOR program for Imbruvica in combination with rituximab for the first-line treatment of CLL/SLL in patients ages 70 and younger.

Supporting the sNDA are results from the Phase III E1912 study, where 529 patients were randomized 2:1 to receive either Imbruvica/rituximab or chemoimmunotherapy. The Imbruvica/rituximab combination demonstrated superiority over chemoimmunotherapy on the primary endpoint of PFS, as the respective percentages of patients with PFS at a median follow-up at 33.6 months were 89.4% and 72.9%, according to results published in the New England Journal of Medicine.

On the secondary endpoint of OS, 98.8% of Imbruvica/rituximab recipients were alive at three years versus 91.5% of chemoimmunotherapy recipients.

Selumetinib NDA Submission Caps ‘MEK Story’ Collaboration

The NDA submission for selumetinib in neurofibromatosis announced by Merck and AstraZeneca on 14 November is a culmination of a collaborative effort by the National Cancer Institute, the Neurofibromatosus Research Program of the Congressionally Directed Medical Research Programs (NFRP-CDMRP), the Neurofibromatosus Therapeutic Consortium (NTAP) at Johns Hopkins University, and the Children’s Tumor Foundation. Neurofibromatosis is a genetic disorder that causes tumors to grow on nerves throughout the body.

The NDA seeks approval of selumetinib, a MEK 1/2 inhibitor, for treatment of pediatric patients aged three years and older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PNs). Between 30% to 50% of NF1 patients have PNs, or tumors that develop on nerve sheaths.

“The first use of MEK inhibitors as a potential treatment for NF tumors came from an early-stage discovery by Children’s Tumor Foundation-funded researchers, who showed that the repurposed oncology drug selumetinib could affect NF tumor size,” the CTF said. The drug experienced high-profile clinical stumbles in thyroid cancer, non-small cell lung cancer (NSCLC) and uveal melanoma. (Also see "Another Late-Stage Failure For AstraZeneca's Selumetinib" - Scrip, 9 Aug, 2016.)

“Five years ago, the Children’s Tumor Foundation brought together the major funders in the NF field to proactively and strategically coordinate to ensure that NF funding is efficient and not duplicated, and to include the patient voice,” the foundation recalled during winter 2019. The initiative is known as the “MEK Story.”

The key NF organizations have played “distinct and complementary roles,” according to an analysis of the rare disease funding community collaboration prepared by CTF’s Salvatore La Rosa et al. “While NIH and CDMRP have provided the bulk of research dollars across all stages of NF research, CTF has seed funded NF research with a stream of small grants in the basic and translational research area.” Comprehensive clinical testing was conducted by the National Cancer Institute. “Specific funders, like NIH and NTAP, have catalyzed critical steps and funded or co-funded preclinical or clinical stage projects that were essential to both launch and complete MEK clinical trials in people with NF1,” La Rosa et al. say.

The selumetinib NDA is based on data from the SPRINT Phase II Stratum 1 trial sponsored by the NCI Cancer Therapy Evaluation Program (CTEP), AstraZeneca and Merck reported. The study posted an objective response rate of 66%, with 20% or greater tumor volume reduction achieved in 33 of 50 pediatric patients treated with oral selumetinib as twice-daily oral monotherapy, the companies said.

SPRINT trial data also supported the BTD awarded to selumetinib in April 2019 for NF1 with PN. (Also see "Keeping Track: Industry Channels Inner Gottlieb As Commissioner Departs US FDA" - Pink Sheet, 5 Apr, 2019.)

The FDA assigned the selumetinib NDA a priority review, as is usually the case for BTD products. The user fee goal data falls in the second quarter of 2020, likely in May.

BMS Turns IO Duo Toward Hepatocellular Carcinoma

Bristol-Myers Squibb Co. is looking to the dual immuno-oncology regimen of Opdivo (nivolumab) plus Yervoy (ipilimumab) to build on Opdivo’s accelerated approval as a single agent for hepatocellular carcinoma (HCC) previously treated with sorafenib.

The FDA set a 10 March 2020 priority review user fee goal for use of Opdivo plus Yervoy to treat patients with advanced HCC previously treated with the kinase inhibitor sorafenib (Bayer’s Nexavar).

The FDA also granted Opdivo/Yervoy a BTD for the indication. The supplemental biologics license application and the BTD both rest on the Opdivo plus Yervoy cohort of the Phase I/II CheckMate-040 study. The ongoing multicohort Phase I/II study is testing Opdivo or Opdivo-based combinations in patients with advanced HCC with and without chronic viral hepatitis who are naïve, intolerant to or who have progressed during sorafenib therapy. (See sidebar above.)

Supernus ADHD NDA Repurposes Old European Antidepressant

Supernus hopes to bring the first novel treatment for attention deficit hyperactivity disorder (ADHD) to market in late 2020 after announcing submission of an NDA on 11 November. Supernus SPN-812, a serotonin norepinephrine modulating agent (SNMA), is a non-stimulant and would not be a controlled substance, the company said.

The active ingredient in SPN-812 is viloxazine, an antidepressant with a long track record showing safety in Europe. Supernus noted that SPN-812 has new chemical entity status in the US. SPN-812 is an extended-release formulation.

The NDA rests on four placebo-controlled trials, split between pediatric patients 6 to 11 years old and adolescents 12 to 17 years old. (Also see "Supernus’ ADHD Drug Hits Phase III Endpoint As Filing Beckons" - Scrip, 21 Dec, 2018.)

Supernus initiated a Phase III program for SPN-812 in adults in the third quarter of 2019, the company said.