Keeping Track: Resubmissions For Tlando And Twirla NDAs, And A BTD For Pomalyst

The latest drug development news and highlights from our US FDA Performance Tracker.

Here's your news in US review and approval news in brief: AbbVie Inc. and Genentech Inc.'s Venclexta (venetoclax tablets) has become the seventh drug to score an approval under the FDA's Real-Time Oncology Review pilot for significant supplemental applications.

Several other companies reeled in supplemental approvals as well, including Regeneron Pharmaceuticals Inc.'s eye drug Eylea (aflibercept) for diabetic retinopathy and Pfizer Inc.'s Fragmin (dalteparin sodium) for venous thromboembolism (VTE) in pediatric patients.

Resubmissions were another theme for the week, as Lipocine Inc. and Agile Therapeutics Inc. sent the new drug applications for their respective products Tlando (testosterone undecanoate) and Twirla (ethinyl estradiol and levonorgestrel) back to the FDA.

Additionally, Celgene's Pomalyst (pomalidomide) landed a breakthrough therapy designation for the treatment of Kaposi sarcoma.

Now, here's your news in less brief:

Venclexta Approval Set New Benchmark For RTOR Review

With the approval of AbbVie and Genentech's Venclexta/Gazyva combination, the agency backed the combination of the BCL-2 inhibitor and CD20-directed cytolytic antibody 15 May for the first-line treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). AbbVie announced the submission of the supplemental new drug application on 7 March.

In the 12-month, 432-patient Phase III CLL14 trial, patients were randomized to receive either Venclexta plus Gazyva or the standard of care control arm of chlorambucil plus Gazyva. The Venclexta arm demonstrated statistical significance on the progression-free survival (PFS) primary endpoint with a 67% reduction in the risk of progression or death compared with standard of care. (Also see "Real-Time Oncology Review Quickly Grows Popular; Venclexta Is Latest To Join Pilot" - Pink Sheet, 11 Mar, 2019.) More data are expected to be presented at an upcoming medical meeting and published in a journal this year, AbbVie reported.

AbbVie and Genentech tout Venclexta regimen's finite 12-month treatment regimen, adding that it provides for a chemotherapy-free option that allows patients to live longer without disease progression.

The RTOR pilot is still in its infancy with its first approval, Novartis AG's Kisqali (ribociclib), coming less than a year ago. But as the number of products that have used the pathway continues to climb, the FDA is starting to give sponsors a clearer idea of how fast they can expect an approval decision under the program. (See sidebar for infographic.) 

Tlando NDA Slated For Fall Action Following Resubmission

The FDA has assigned Lipocine's resubmitted NDA for its oral testosterone therapy Tlando a user fee goal date of 9 November, the company announced 14 May.

A 2018 complete response letter to the company raised a slew of deficiencies about the drug, including a potential increase in blood pressure in hypogonadal man. (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 blood pressure issue was the overwhelming concern at the January 2018 advisory committee meeting, and Lipocine conducted an ambulatory blood pressure monitoring clinical study in response to the CRL. (Also see "Lipocine's Tlando Falls Short At US FDA Advisory Cmte Over Blood Pressure Concerns" - Pink Sheet, 10 Jan, 2018.)

Lipocine announced the findings from the blood pressure study 27 March, with CEO Mahesh Patel noting that "we believe [the results] are in line with a recently approved testosterone replacement therapy." Patel may have been referring to either Clarus Therapeutics Inc.'s oral therapy Jatenzo or Antares Pharma Inc. 's injectable therapy Xyosted (testosterone enanthate), which were approved in March 2019 and September 2018, respectively. (Also see "Keeping Track: Approvals For Mayzent, Mavenclad, Duaklir, Jatenzo And Cimzia" - Pink Sheet, 31 Mar, 2019.) and (Also see "Keeping Track: US FDA Approves Novel Tetracyclines Nuzyra And Seysara; Hemlibra Indication Expands" - Pink Sheet, 7 Oct, 2018.)

If approved, it looks as if Tlando will come with a risk evaluation and mitigation strategy (REMS), as Lipocine explained in its March announcement that the purpose of the blood pressure study was to characterize blood pressure effects of the drug for appropriate regulatory action beyond labeling, including a REMS. This would mark a significant regulatory difference from Jatenzo, which was approved without a REMS. (Also see "Surprise Approval For Clarus' Oral Testosterone Includes Black Box, No REMS " - Pink Sheet, 28 Mar, 2019.)

But Lipocine has taken to the legal arena to go after Jatenzo. The company reported on 3 April that it filed an injunction against Clarus, alleging that Jatenzo infringes six of Lipocine's US patents.

Twirla Heads To FDA For Third Review Cycle

After conducting a comparative "wear" study, Agile has brought its contraceptive patch Twirla (ethinyl estradiol and levonorgestrel) back to the FDA for its third review cycle.

Agile announced the NDA resubmission 17 May, which would position a user fee date of 17 November or earlier with a Class 2 review timeline.

The aim of the wear study was to address the FDA's concerns about Twirla's in vivo adhesion properties, as the agency questioned if the product has similar adhesion performance to Xulane, the generic version of Janssen Pharmaceutical Cos.' contraceptive patch Evra (ethinyl estradiol and norelgestromin).

The wear study, however, does not address questions about the product's safety and efficacy, and Agile explained in October 2018 following a formal dispute resolution process these issues would need to be addressed by an advisory committee during the subsequent review cycle. (Also see "Keeping Track: Xarelto Earns CV Risk Reduction Claim In Quiet Week; Spotlight On Formal Dispute Resolution" - Pink Sheet, 14 Oct, 2018.) and (Also see "Agile's Phase III Data For Twirla Patch Fall Flat, Raise Doubts On Approval" - Pink Sheet, 4 Jan, 2017.)

Agile received its second CRL for Twirla in December 2017, which also cited deficiencies identified during an inspection of a third-party manufacturer facility. (Also see "Keeping Track: So. Much. News." - Pink Sheet, 22 Dec, 2017.) The company noted that it included information on the manufacturing process in its 2019 resubmission. The first CRL came in 2013 after clinical trials demonstrated a higher than desired rate of unintended pregnancies. (Also see "Agile SEC filing reveals FDA rejection for Twirla contraceptive " - Scrip, 19 Mar, 2014.)

Eylea Sets 'High Bar' For Diabetic Retinopathy, Regeneron Says

A 13 May diabetic retinopathy approval for Regeneron's blockbuster vascular endothelial growth factor (VEGF) inhibitor Eylea has "once again set a high bar for the treatment of diabetic eye diseases," company President and CEO George Yancopoulos contends.

In a statement, Yancopoulos pointed to data from the 402-patient Phase III PANORAMA trial, where Eylea, is also indicated for diabetic macular edema, reduced the risk of diabetic patients developing proliferative diabetic eye disease by 85% and 88% when administered every 16 weeks or every eight weeks, respectively. (Also see "PANORAMA Helps Regeneron's Eylea Even Score With Roche's Lucentis " - Scrip, 19 Mar, 2018.)

Eylea contains a distinct dosing advantage over Novartis and Roche's competing VEGF inhibitor Lucentis (ranibizumab). Labeling for Regeneron's product recommends dosing every eight weeks following the first five injections, which are dosed every four weeks, while Lucentis' diabetic retinopathy indication is labeled for monthly dosing. (See sidebar for related story.)

Pfizer Adds Pediatric VTE Indication For Fragmin

Fragmin became the first blood thinner indicated for pediatric patients when the FDA granted a supplemental approval to Pfizer 16 May. The low molecular weight heparin (LMWH) is now indicated for the treatment of symptomatic VTE to reduce the recurrence in pediatric patients 1 month of age and older.

Supporting the pediatric approval was a single trial of patients with symptomatic deep vein thrombosis and/or pulmonary embolism, where 21 of 38 subjects achieved resolution of the qualifying VTE. Additionally, seven patients showed regression, two patients showed no change and no patients experienced progression of the VTE. One patient experienced recurrence.

Fragmin already carried a symptomatic VTE indication in adults to reduce the recurrence in patients with cancer.

Celgene Eyes Late 2019 Kaposi Sarcoma Submission For Pomalyst Following BTD

In receiving a BTD for its thalidomide analogue Pomalyst in Kaposi sarcoma, Celgene expects to submit an sNDA by the end of the year.

The BTD specifically covers Pomalyst for the treatment of patients with human immunodeficiency virus (HIV)-positive Kaposi sarcoma who have previously received systemic chemotherapy and patients with HIV‐negative Kaposi sarcoma, Celgene reported 14 May.

It appears to be the first BTD the FDA has issued for the rare cancer, which results in multiple lesions on the skin and oral mucosa. There are five FDA-approved drugs for the treatment of Kaposi sarcoma, according to Biomedtracker, although all were approved in the 1980s and 1990s.

The breakthrough status is based on a Phase I/II trial in 22 patients conducted under a cooperative research and development agreement with National Cancer Institute. According to results published in the Journal of Clinical Oncology, 16 patients achieved objective tumor responses, including all seven HIV-uninfected patients and nine of 15 HIV-infected patients. Median time to a response was four weeks, and responding patients achieved a decrease in the number of nodular lesions, a decrease in the number of lesions or both. On quality of life measurements, there was a trend to improved satisfaction with appearance on a questionnaire at month 3, and a statistically significant increase in satisfaction on the end-therapy questionnaire.

Celgene noted it also has two additional studies in Kaposi sarcoma planned in partnership with the AIDS Malignancy Consortium: one based in the US "to confirm and extend the results of the NCI study" and one based in sub-Saharan Africa, where the disease remains prevalent.

Pomalyst, a thalidomide analogue, is currently indicated in combination with dexamethasone for the third-line or greater treatment of patients with multiple myeloma who have received therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Fifth Cyramza Approval Comes With Boxed Warning Removal

Eli Lilly & Co. scored a double victory at the FDA 10 May by landing a fifth indication for its human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist Cyramza (ramucirumab) while also having the boxed warning for hemorrhage, gastrointestinal perforation and impaired wound healing removed from the drug's label.

Cyramza is now labeled as a single agent for the treatment of hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with Nexavar (sorafenib), with the approval coming nearly five years after the drug flunked its overall survival (OS) primary endpoint in a Phase III HCC trial. (Also see "Lilly's Cyramza fails in another Phase III study" - Scrip, 11 Jun, 2014.)

Lilly noted in a 13 May release that Cyramza is the first FDA-backed biomarker-driven therapy for HCC patients, and its targeted indication may give it an edge over other second-line treatments with broader HCC indications, like Keytruda (pembrolizumab) and Bristol-Myers Squibb Co.'s Opdivo (nivolumab). Roughly 40% of patients with advanced HCC have an alpha fetoprotein (AFP) of ≥400 ng/mL, and such patients generally have a poorer prognosis relative to the general HCC population, according to the drugmaker.

In the Phase III REACH-2 study supporting approval, Cyramza demonstrated a statistically significant improvement on the OS primary endpoint and also on the secondary endpoint of PFS.

To boot, the FDA lifted the black box warning from Cyramza's label, which could be another competitive boon. Hemorrhage, gastrointestinal perforation and impaired wound healing are now only listed as standard warnings. Keytruda and Opdivo do not have boxed warnings, although Bayer AG's Stivarga (regorafenib) contains one for hepatotoxicity.

Cyramza's label also carries indications for gastric cancer, metastatic non-small cell lung cancer and metastatic colorectal cancer.

Sunovion Touts Mechanism Of Action Of Breakthrough-Designated Schizophrenia Candidate

Sunovion Pharmaceuticals Inc. and PsychoGenics Inc.'s breakthrough-designated schizophrenia candidate SEP-363856 might feature an alternative mechanism of action from other antipsychotic treatments that provides an advance in the treatment paradigm, the company says.

The drugmaker reported the BTD in a 10 May announcement, as the drug demonstrated in a Phase II pivotal trial statistically significant and clinically meaningful improvement in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo after four weeks of treatment in patients with acute exacerbation of schizophrenia.

Sunovion believes the results may be rooted in the drug's mechanism of action. While the exact mechanism is unknown, the company believes that SEP-363856 activates the trace amine-associated receptor 1 (TAAR1) and 5-HT1A (serotonin 1A) receptors rather than binding to dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors akin to currently available antipsychotic drugs.

The drug was discovered using PsychoGenics' SmartCube platform, which features a "mechanism-independent approach," according to Sunovion.

Sunovion's release quotes Shitij Kapur, dean of the faculty of medicine dentistry and health sciences at the University of Melbourne, who commented that, "The results need to be replicated in further studies and broader populations, but, if these results hold, it could be a remarkable advance for patients and health care providers, as well as a great new avenue for exploration of new scientific mechanisms for psychotic disorders.”

Sunovion also noted that SEP-363856 has been generally well tolerated "with notable similarities to placebo treatment in discontinuation rates; proportion of patients experiencing extrapyramidal symptoms or akathisia; and change in metabolic parameters such as weight, lipids, glucose and prolactin."

With PAS Approval, ADMA Biologics Can Commence Bivigam Commercial Production

ADMA Biologics Inc. can now market its primary humoral immunodeficiency treatment Bivigam (immune globulin intravenous [human]) with FDA approval for the company's prior approval supplement (PAS) related to the manufacturing process.

Previously owned by Biotest AG, Bivigam is designed for the treatment of primary humoral immunodeficiency. ADMA acquired Biotest's therapy-related assets in June 2017, although the company had to file a PAS to address issues with Biotest raised in a 2014 warning letter and a 2016 compliance inspection to resume production.

ADMA initially submitted the PAS last year, although the 25 October 2018 user fee goal date was delayed to 18 December 2018 after the company submitted additional information to the FDA. (Also see "Keeping Track: Xarelto Earns CV Risk Reduction Claim In Quiet Week; Spotlight On Formal Dispute Resolution" - Pink Sheet, 14 Oct, 2018.) On 19 December, ADMA announced that it received a CRL for the PAS. The firm did not provide many details, other than that the FDA didn't request any information "pertaining to compliance status, clinical study safety and efficacy nor any information requests regarding third party contract manufacturers and vendors," nor did it request any additional manufacturing runs.

The turnaround was quick, however, as ADMA reported 7 January 2019 that it resubmitted the PAS.

FDA Upgrades Xeomin To First-Line Treatment For Blepharospasm

The FDA has upgraded Xeomin (incobotulinumtoxinA) from a second-line treatment to a first-line treatment for adult patients with blepharospasm (involuntary blinking) following a 10 May approval. Xeomin was previously only approved for adults with blepharospasm who received Botox (onabotulinumtoxinA) as prior treatment.

In a 61-patient randomized, double-blind, placebo-controlled Phase III trial, the treatment group demonstrated a statistically significant improvement in the Jankovic Rating Scale Severity subscore, which measures the severity and frequency of blepharospasm.

The FDA first approved Xeomin, an acetylcholine release inhibitor and neuromuscular blocking agent, for the second-line treatment of blepharospasm in 2010. It also carries indications for the treatment of chronic sialorrhea, upper limb spasticity, cervical dystonia and for the temporary improvement in the appearance of moderate to severe glabellar lines.