Keeping Track: Neurology And Breakthroughs Stay In Spotlight As US FDA Approves Radicava, Imfinzi; TaiMed Submits Ibalizumab

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

FDA slowed – slightly – its recent torrid pace of novel agent approvals, clearing two more new products to bring the 2017 count of new molecular entities and novel therapeutic biologics to 20.

In all of 2016, FDA's Center for Drug Evaluation and Research cleared 22 novel agents, so it should be safe to say that 2017 will exceed the previous year's relatively low count.

The most recent approvals continue two of the top trends for novel agents this year: the re-emergence of innovative central nervous system therapeutics and the popularity of FDA's breakthrough therapy designation (BTD) program.

Mitsubishi Tanabe Pharma Corp.'s Radicava (edaravone), approved May 5 for treatment of amyotrophic lateral sclerosis (ALS), is the seventh novel agent approved by CDER for a nervous system disorder in 2017. Four of those approvals, including Radicava, have been for orphan neurodegenerative conditions.

AstraZeneca PLC's Imfinzi (durvalumab), cleared May 1 for second-line use in metastatic urothelial carcinoma (mUC), is the sixth new cancer treatment approved this year. The immuno-oncologic is also the 10th novel agent approved with a breakthrough designation, so the BTD share of 2017 novel approvals remains at 50%. (Also see "Keeping Track: Breakthroughs Dominate 2017 Novel Agents; US FDA Approves Rydapt, Alunbrig, Tymlos, Brineura" - Pink Sheet, 30 Apr, 2017.)

FDA also received a biologics license application (BLA) for another breakthrough therapy, TaiMed Biologics Inc. and Theratechnologies Inc.'s ibalizumab for multidrug-resistant HIV.

FDA Encouraged Submission Of ALS Therapy Radicava

FDA highlighted its own role in bringing Mitsubishi Tanabe's edaravone to the US when it announced the drug's approval for ALS, commonly known as Lou Gehrig's disease, on May 5.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” Division of Neurology Products Deputy Director Eric Bastings said. In Japan, where edaravone is known as Radicut, the drug was approved for ALS in 2015. It had previously been available in Japan to treat acute stroke. (Also see "Keeping Track: Mitsubishi ALS NDA; Opko’s Rayaldee Approval; Avycaz Label Extension" - Pink Sheet, 27 Jun, 2016.)

Despite FDA's enthusiasm, Radicava was assigned standard review status by the agency, putting the user fee goal date on June 16, 2017.

Radicava is the first ALS therapy approved by FDA since the agency approved Rilutek (riluzole) in 1995. Riluzole is now available generically.

The Radicava approval was based on a 137-patient placebo-controlled trial conducted in Japan. FDA generally prefers that at least some clinical development be done in the US, but has shown great willingness to be flexible with orphan drugs. (Also see "BioMarin's Brineura Approval Shows FDA's Open Door For Orphan Drugs" - Pink Sheet, 2 May, 2017.)

After six months in the trial, patients who received edaravone "declined less on a clinical assessment of daily functioning compared to those receiving a placebo," FDA summarized.

Mitsubishi Tanabe is working to generate more data in ALS patients. At a December 2016 R&D day, the company described an ongoing trial designed to evaluate the drug's safety, efficacy, and clinically significant effects on long-term prognosis in clinical practice. The trial is slated to run for seven years and will enroll 700 patients; as of October 2016, 220 were registered. The primary endpoints are death or permanent artificial respirator.

FDA reported that Radicava's most common adverse reactions in the small trial submitted in the NDA were bruising and gait disturbance. Sodium bisulfite, an ingredient in the drug, can cause anaphylactic symptoms, the agency added.

Ibalizumab Is First HIV Therapy With BTD Submitted For FDA Approval

The HIV/AIDS crisis of the 1980s was the impetus for the creation of the accelerated approval pathway at FDA, but the disease has yet to see an approval under the latest expedited review pathway, the breakthrough therapy designation.

TaiMed's ibalizumab, which was awarded a BTD for treatment of HIV/AIDS in 2015, is the first breakthrough-designated HIV treatment to reach the BLA submission stage. The company announced completion of BLA filing on May 3 for treatment of multidrug resistant (MDR) HIV-1. (Also see "Theratechnologies' Novel AIDS Drug Filed In US" - Scrip, 4 May, 2017.) Theratechnologies will market the antibody.

Ibalizumab has orphan status for MDR HIV-1, but the market is growing as patients become resistant to the highly active antiretroviral therapy (HAART) regimens that have made HIV into a long-term illness. (Also see "Novel Antibody Products Ring The Treatment Changes In HIV" - Scrip, 21 Feb, 2017.)

The other breakthrough-designated HIV treatment, ViiV Healthcare's small molecule HIV attachment inhibitor fostemsavir (BMS-663068), is also in late-stage development. A Phase III trial in heavily pretreated patients is due to complete in 2018.

Both fostemsavir and ibalizumab are designed to prevent HIV's attachment to and entry into CD4+ cells. Ibalizumab, a monoclonal antibody, "binds primarily to the second extracellular domain of the CD4+ T cell receptor, away from major histocompatibility complex II molecule binding sites," Theratechnologies explained, thus preventing HIV from infecting those immune cells while "preserving normal immunological function."

TaiMed requested priority review for the ibalizumab BLA, which would put the user fee goal around the turn of year – Jan. 3, 2018 or earlier.

Imfinzi And Beyond: AstraZeneca Submissions In Oncology And Diabetes

AstraZeneca's week was headlined by FDA's approval of novel immuno-oncologic Imfinzi (durvalumab), but the company's quarterly earnings report highlighted the company's active life-cycle management, including two recent submissions.

Imfinzi (durvalumab), AstraZeneca's PD-L1 inhibitor, was approved May 1 for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Labeling for Imfinzi describes higher response rates in patients with higher levels of expression of PD-L1 protein, and FDA approved Roche subsidiary Ventana Medical Systems Inc.'s PD-L1 (SP263) Assay as a complementary diagnostic. Consistent with previous PD-1/L1 approvals in bladder cancer, FDA did not require use of the diagnostic in the indication, as it would a companion diagnostic. (Also see "US FDA Continues Shift From Companion To Complementary PD-L1 Diagnostics With AstraZeneca Imfinzi Approval" - Pink Sheet, 1 May, 2017.)

As a condition of FDA's accelerated approval of Imfinzi, AstraZeneca must submit the results of its ongoing Phase III DANUBE trial in first-line unresectable stage IV urothelial cancer. The trial is comparing two durvalumab arms – monotherapy and in combination with AZ's CTLA4 inhibitor tremelimumab – to standard of care chemotherapy.

AstraZeneca is hoping for FDA in action in the third quarter of 2017 to broaden the use of its PARP inhibitor Lynparza (olaparib) to second-line ovarian cancer. FDA granted priority review to the company's submission, the company noted in its first quarter sales and earnings material. (Also see "Few Q1 Bright Spots For AstraZeneca Puts Pressure On The Pipeline" - Scrip, 27 Apr, 2017.)

The Lynparza submission is based on data from the Phase III SOLO-2 trial, supported by Study 19. SOLO-2 evaluated the PARP inhibitor as maintenance treatment for platinum-sensitive recurrent ovarian cancer patients with BRCA mutations. Lynparza currently has accelerated approval as for patients with deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Approval of the Lynparza filing also would introduce a tablet formulation of the drug, currently available as capsules. AstraZeneca highlighted the reduced burden for patients the change would allow: instead of 16 capsules a day, patients could take four tablets.

AstraZeneca also touted patient experience as a benefit of a new autoinjector formulation of the once-weekly glucagon-like peptide 1 (GLP-1) agonist antidiabetic Bydureon (exenatide extended-release).

FDA has accepted the autoinjector submission and expects a decision from FDA in 2018, AZ Chief Medical Officer Sean Bohen noted during the company's earnings call. The autoinjector will "make the medicine more convenient for patients to administer," he said. Bydureon is approved for subcutaneous injection and in a dual-chamber pen injector.

Novo Nordisk's Fast-Acting Insulin Aspart Returns To FDA

Novo Nordisk AS expects FDA's second review cycle for its faster-acting insulin aspart (FIAsp) diabetes candidate to reach a decision in autumn 2017. The company resubmitted the NDA in March 2017 as a Class II submission, which carries a six-month user fee goal, Novo Nordisk reported in its first quarter results.

FDA issued a complete response letter for FIAsp in October 2016 that requested additional information related to the immunogenicity assay and the assay used to generate clinical pharmacokinetics data, Novo Nordisk noted. (Also see "Keeping Track: FDA Rejects Mealtime Insulin, Antihistamine; Misses Goal For Another Opioid" - Pink Sheet, 14 Oct, 2016.)

FIAsp is positioned as a successor to Novo Nordisk's older mealtime insulin Novolog (insulin aspart). The company added two excipients to insulin aspart to create FIAsp: Vitamin B3 (niacinamide) "to increase the speed of absorption" and L-arginine, an amino acid, "for stability," Novo Nordisk said.

Pfizer Seeks Psoriatic Arthritis Indication For Xeljanz

Pfizer Inc. submitted two sNDAs to expand use of its Janus kinase inhibitor Xeljanz (tofacitinib) to psoriatic arthritis (PsA), one for the twice-daily immediate-release 5mg tablets and one for the once-daily 11mg extended-release tablets sold as Xeljanz XR. FDA has assigned December 2017 user fee goals for both sNDAs, the company said. (Also see "Pfizer's Xeljanz: The Slow Road To Blockbuster Status" - Scrip, 4 May, 2017.)

The Xeljanz PsA applications are based on two pivotal Phase III trials, OPAL Broaden and OPAL Beyond. Both trials enrolled patients who were inadequate responders to conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Patients in OPAL Broaden were also tumor necrosis factor (TNF) inhibitor naïve, while OPAL Beyond enrolled patients who were inadequate responders to TNF inhibitors. OPAL Beyond "was the first PsA study focused exclusively on this population," Pfizer said.

Both trials met the primary efficacy endpoint compared with placebo. The OPAL Broaden study also included an active control arm of AbbVie's Humira (adalimumab), but Pfizer noted that "the study was not designed for non-inferiority or superiority comparisons between adalimumab and Xeljanz."

J&J Seeks Lower Dose Of Xarelto For Extended Reduction Of VTE Risk

Johnson & Johnson aims to add a new, lower dose of Xarelto (rivaroxaban) for patients who are using the novel oral anticoagulant (NOAC) to reduce risk of recurrent venous thromboembolism (VTE) after at least six months of standard anticoagulation therapy. A 20mg dose is currently approved for the VTE recurrence risk reduction indication, one of the six indications FDA has approved for Xarelto; the sNDA seeks approval of a 10mg dose. Both doses are for once-daily administration.

J&J announced the 10mg sNDA submission on April 28; a standard review would put the user fee goal around February 2018.

The 10mg sNDA is based on data from the EINSTEIN CHOICE study, which enrolled VTE patients who had already been treated with six to 12 months of standard anticoagulation therapy. "The objective of the study was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy," J&J said. Therefore, the trial did not include patients who required "extended anticoagulation at therapeutic doses."

In the EINSTEIN CHOICE trial, patients who received up to 12 months of therapy with either 10mg or 20mg Xarelto once daily "had significantly fewer recurrent VTE compared to those taking aspirin 100mg one daily," the company said, while "all three treatment groups had low rates of major bleeding."