Keeping Track: US FDA Expands Indications For Roche Tecentriq, Lucentis, Approves Second Infliximab Biosimilar

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

Therapeutic biologics dominated FDA approval activity for the week, culminating in the approval of Samsung Bioepis Co. Ltd.'s Renflexis (infliximab-abda), the second biosimilar version of Johnson & Johnson's Remicade to clear the agency. Here's your news in brief:

Earlier, FDA approved expanded indications for two monoclonal antibodies from Roche subsidiary Genentech Inc. The company's immuno-oncologic Tecentriq (atezolizumab) moved to an earlier line of treatment for some bladder cancer patients, and the diabetic retinopathy indication for anti-VEGF Lucentis (ranibizumab) is no longer limited to patients who also have diabetic macular edema.

Biologics also drove the week's additions to FDA's popular breakthrough therapy designation (BTD) program. Novartis AG's CAR-T therapy CTL019 collected its second BTD, while Enzyvant Sciences GMBH's allogeneic thymic tissue therapy RVT-802 became the first product to receive both a BTD and the new Regenerative Medicine Advanced Therapy (RMAT) designation.

FDA also received an NDA for Rigel Pharmaceuticals Inc.'s fostamatinib, an oral SYK kinase inhibitor that Rigel believes could be the first treatment for immune thrombocytopenia to address the underlying autoimmune cause of the disease. AMAG Pharmaceuticals Inc. submitted a supplemental NDA for Makena administration by subcutaneous auto-injector, an option it says patients prefer to the intramuscular injection approved for the progestin to prevent preterm birth.

And a cough-cold product from Vernalis PLC and Tris Pharma Inc. became the latest 505(b)(2) NDA to receive a complete response letter (CRL). At least six products have received CRLs from FDA in 2017; four of the CRLs have gone to new formulations of already-approved drug substances. Here's your news in less brief:

Biosimilar TNF Blocker Competition Rises With Renflexis Approval

Tumor necrosis factor (TNF) blockers account for four of the five biosimilar 351(k) biologics license applications approved by FDA following the April 21 approval of Samsung Bioepis and Merck & Co. Inc.'s Renflexis, which has been given the generic name infliximab-abda.

Renflexis, like Celltrion Inc.'s Inflectra (infliximab-dyyb), will offer an alternative version of J&J's Remicade, a TNF blocker first approved in 1998. Sandoz Inc.'s Erelzi (etanercept-szzs) is a biosimilar of another TNF blocker introduced in 1998, Amgen Inc.'s Enbrel. Amgen crossed the aisle with Amjevita (adalimumab-atto), its biosimilar of AbbVie Inc.'s Humira. Humira is a relative youngster among the original anti-TNF generation; it was first approved in 2002.

Indeed, FDA's familiarity with biosimilars in the class may have contributed to the second-ever biosimilar approval referencing the same product seem almost routine. (Also see "Samsung’s Renflexis: Second US Biosimilar To Janssen’s Remicade, With A Few Firsts" - Pink Sheet, 21 Apr, 2017.)

Expanded Lucentis Diabetic Retinopathy Indication Rests On NIH-Funded Study

FDA approved expanding the diabetic retinopathy indication for Genentech's Lucentis (ranibizumab) to include patients without diabetic macular edema (DME) on April 15, making the VEGF inhibitor the first product approved to treat diabetic retinopathy in patients diagnosed with or without DME.

Lucentis has built up its claims for treatment of diabetic eye disease over the past five years. Lucentis was approved for diabetic macular edema in 2012. A separate indication for the treatment of diabetic retinopathy in patients with DME was added in February 2015, based on data from the same Phase III trials. The trials, known as RISE and RIDE, also supported the breakthrough therapy designation (BTD) for diabetic retinopathy that FDA granted Lucentis in 2014.

The latest approval is based on a data from a National Eye Institute-funded study by the Diabetic Retinopathy Clinical Research Network (DRCR.net), Genentech reported. Genentech also provided support for the study, known as Protocol S, which compared Lucentis to laser therapy in 305 patients with proliferative diabetic retinopathy with and without DME.

The approval was based on an analysis showing that after two years in Protocol S, 56 (37.8%) of the 148 patients without baseline DME in the Lucentis group had a two-step or better improvement in their diabetic retinopathy on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) and 28.4% had a three-step or better improvement, the company said.

Genentech added that in the 41 Lucentis-treated patients with baseline DME, 58.5% had a two-step or better improvement and 31.7% had a three-step or better gain.

Tecentriq Adds First-Line Bladder Cancer Claim For Cisplatin-Ineligible Patients

Roche's Tecentriq (atezolizumab) regained its lead in the competitive bladder cancer immuno-oncology race with FDA's April 17 approval of a first-line claim in cisplatin-ineligible bladder cancer patients, but it is unlikely to hold the title of "first and only" cancer immunotherapy with an indication for initial treatment of the disease for long.

FDA cleared Tecentriq for as initial treatment of locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin chemotherapy under accelerated approval, based on tumor response rate and duration of response data from the Phase II IMvigor210 study. "Up to half of all people with the advanced form of the disease are unable to receive cisplatin chemotherapy as initial treatment," Genentech said.

Tecentriq became the first IO agent for bladder cancer with its initial accelerated approval in May 2016 for two second-line claims: treatment of mUC patients with disease progression during or following platinum-containing chemotherapy and of patients whose disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum chemo. (Also see "Atezolizumab At Last: Roche Makes Its Immuno-Oncology Debut" - Pink Sheet, 18 May, 2016.)

Although less than a year has passed since Tecentriq's first approval, the IO pipeline in bladder cancer has been productive. Bristol-Myers Squibb Co.'s Opdivo (nivolumab) was approved in February 2017 for second-line mUC use in patients who progressed on or after platinum chemotherapy. (Also see "Pressure On Tecentriq: Bladder Cancer Heats Up With Opdivo Approval, Keytruda Filing" - Scrip, 3 Feb, 2017.) FDA is reviewing similar post-platinum claims for AstraZeneca PLC's durvalumab (user fee goal in June or earlier) and Pfizer Inc. and Merck KGAA's Bavencio (avelumab) (Aug. 27 user fee goal).

Merck is even more ambitious in its plans for Keytruda (pembrolizumab), which is under review for both first-line use in cisplatin-ineligible mUC and second-line post-platinum use; both Keytruda mUC applications have June 14 user fee goals.

Expedited Review Designations Could Help Enzyvant RVT-802 To 2018 BLA

Rare disease company Enzyvant anticipates filing a BLA in the first half of 2018 for its tissue-based biologic therapy for the rare congenital immunodeficiency disease complete DiGeorge Syndrome (cDGS) with the help of two expedited review designations from FDA.

Enzyvant's RVT-802 is the first product known to have received both a breakthrough therapy designation (BTD) and the newer regenerative medicine advanced therapy (RMAT) designation. RVT-802 is only the second product to announce an RMAT designation. The RMAT program, established in late 2016 by the 21^st Century Cures Act, is similar to the BTD program in that it offers increased and earlier interactions with FDA.

The RMAT program is administered by CBER's Office of Tissues and Advanced Therapies. Eligible regenerative medicine therapies include cell therapy, therapeutic tissue engineering products, and human cell and tissue products. The first RMAT designation went to Humacyte Inc.'s bioengineered blood vessel Humacyl. (Also see "US FDA First's RMAT Designation: Humacyte Got A 'Quick Response'" - Pink Sheet, 26 Mar, 2017.)

RVT-802 uses "proprietary processes to harvest, culture, and apply allogeneic thymic tissue for the treatment of primary immune deficiency resulting from cDGS," Enzyvant explained. Athymia in cDGS patients results in inability to produce normally functioning T cells and severe immunodeficiency.

The thymic tissue therapy was developed at Duke University and licensed to Enzyvant in January 2017. (Also see "Tech Transfer Roundup: Aduro Hopes Stanford Algorithm Will Optimize Its IO Candidates" - Scrip, 10 Feb, 2017.) Data from Duke's experience "will be used to support" BLA submission, the company said. Preliminary clinical data suggest a survival rate of over 70% for patients treated with RVT-802, according to Enzyvant, while cDGS is usually fatal during the first two years of life.

Novartis CAR-T Therapy CTL019 Earns Second BTD With JULIET Trial

Novartis' chimeric antigen receptor T cell (CAR-T) therapy CTL019 (tisagenlecleucel-T) earned a breakthrough designation for its planned second indication, treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have failed two or more prior therapies. DLBCL accounts for approximately 30% of all non-Hodgkin lymphoma cases, the company noted; 10-15% of DLBCL patients fail to respond to initial therapy or relapse within three months, while another 20-25% relapse after initial response.

The BTD is based on data from Novartis' JULIET study of CTL019, a single-arm Phase II trial that began in 2015 and is expected to enroll 130 adults with DLBCL who had relapsed or refractory disease after two or more lines of therapy, including rituximab and an anthracycline, and who failed or were ineligible for autologous hematopoietic stem cell transplantation (ASCT), according to NIH's clinicaltrials.gov database.

A BLA for CTL019 is already under review for a smaller indication, relapsed and refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL), that also holds a BTD. (Also see "BLA Accepted: Novartis Inches Ahead In CAR-T Race With Kite" - Scrip, 29 Mar, 2017.) The BLA has been granted priority review and likely has a user fee goal in September 2017.

Kite Pharma Inc.'s CAR-T candidate KTE-C19 (axicabtagene ciloleucel) also holds a BTD for DLBCL, along with transformed follicular lymphoma and primary mediastinal B-cell lymphoma. The Kite CAR-T product is also under review at FDA; Kite's BLA for relapsed or refractory aggressive non-Hodgkin lymphoma patients who are ineligible for ASCT is estimated to have a November 2017 user fee goal. (Also see "Keeping Track: US FDA Approvals Binge Continues With Dupixent, Ocrevus And Zejula; Two CAR-T Are Under Review" - Pink Sheet, 31 Mar, 2017.)

Rigel Expects FDA Action On ITP Therapy Fostamatinib In Early 2018

Rigel announced submission of an NDA for the SYK kinase inhibitor fostamatinib to treat patients with immune thrombocytopenia (ITP) on April 17. The company has previously said it expects a decision from FDA in the first quarter 2018, which would correspond to standard review for the new molecular entity.

ITP patients are treated with therapies that aim to modulate the immune system or stimulate platelet production, ranging from steroids and TPOs to splenectomy. Fostamatinib, on the other hand, "may address the underlying autoimmune cause of ITP by impeding platelet destruction," Rigel stated. The drug would be the first ITP candidate to inhibit SYK kinase, which Rigel describes as "a key player in the immune process that leads to platelet destruction in ITP."

The NDA includes three Phase III FIT studies, the randomized placebo-controlled Studies 047 and 048 and an open-label extension, Study 049. A total of 163 patients with ITP, an orphan autoimmune disease, are included in the NDA, the company said.

The company highlighted its post hoc calculations of fostamatinib efficacy in Studies 047 and 048. The company combined stable and transient responders to find an overall response rate of 29% for fostamatinib compared with 2% for placebo.

AMAG Emphasizes Patient Preference For Makena Auto-Injector

AMAG Pharmaceuticals' sNDA for a new Makena (hydroxyprogesterone) delivery device includes data from a survey of treatment preferences along with data from a 120-patient pharmacokinetic study establishing comparable bioavailability between the approved intramuscular injection form of the progestin and the new subcutaneous auto-injector product, the company reported April 17. AMAG expects a six-month review timeline with a fourth quarter 2017 user fee goal.

Makena, a branded progestin in indicated to reduce the risk of preterm birth in women pregnant with a single baby who have a history of singleton spontaneous preterm birth, is facing the expiration of orphan drug exclusivity in February 2018. AMAG, which acquired the product with its 2014 purchase of Lumara Health, has focused on improving the convenience and usability of Makena. A preservative-free single dose formulation was added to the original multi-dose vial presentation in early 2016. (Also see "Keeping Track: Gazyva, Afinitor Get New Indications; PTC's Translarna Gets Refuse To File" - Pink Sheet, 29 Feb, 2016.)

The new Makena auto-injector was developed with Antares Pharma Inc., which holds patents on the auto-injector device that run until 2026.

AMAG's treatment preferences survey included 183 women, some of whom were experienced with IM progestin injections and some who would be eligible to receive future therapy based on their obstetric history. "Based on product descriptions, patients would prefer the Makena subcutaneous auto-injector due to the decreased time needed to administer the injection, the shorter needle, and the lack of visibility of the needle during the injection process," the company said.

FDA Turns Down Vernalis' Extended-Release Cough Formulation CCP-07

Vernalis announced a complete response letter for CCP-07 on April 21, one day after the user fee goal for the extended-release liquid formulation of a prescription immediate-release cough and cold product. CCP uses Tris Pharma's OralXR+ particulate-based technology.

"The CRL did not raise any concerns with the formulation or pharmacokinetic profile of CCP-07," Vernalis said. The company only specified that FDA "did identify outstanding items that need to be addressed prior to the resubmission and approval of the NDA."

Another Vernalis/Tris extended-release liquid formulation of an Rx immediate-release cough and cold therapy is also under review at FDA. CCP-08 has an Aug. 4 user fee goal. The companies have two other formulations in active development, with the goal of achieving proof of concept by the end of 2017.