Keeping Track: Teva's Austedo Clears US FDA, Merck Sitagliptin CV Outcomes Labeling Draws Complete Response

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

FDA's Division of Neurology Products continued its hot streak in 2017 with the approval of Teva Pharmaceutical Industries Ltd.'s Austedo (deutetrabenazine), the fourth novel agent to clear the division this year.

Austedo brings the novel approvals count from the Center for Drug Evaluation and Research (CDER) to 13 in 2017. The four neurology approvals – Austedo for Huntington's chorea, Ocrevus for multiple sclerosis, Xadago for Parkinson's disease, and Emflaza for Duchenne muscular dystrophy – represent the largest therapeutic category among the 2017 approvals class to date.

The week was otherwise quiet for approvals. CDER cleared first pediatric claims for the direct-acting antiviral class of hepatitis C virus therapies, but issued complete response letters (CRLs) for Merck & Co. Inc.'s applications to add data from the TECOS cardiovascular outcomes trial to labeling for its sitagliptin-containing antidiabetic products.

Oncology took center stage among applications recently submitted to FDA. Jazz Pharmaceuticals PLC completed the NDA submission for its breakthrough-designated acute myeloid leukemia therapy Vyxeos, Bristol-Myers Squibb Co. submitted a new indication for the immuno-oncology blockbuster Opdivo, and Amgen Inc. sought to broaden the use of Xgeva to prevent skeletal-related events in multiple myeloma patients. Johnson & Johnson and AbbVie Inc. submitted Imbruvica for its first indication outside of oncology, in chronic graft-versus-host-disease (cGVHD).

The FDA Performance Tracker's listing of breakthrough therapy designations (BTDs) added its first award for a lipid-lowering agent, for Regeneron Pharmaceuticals Inc.'s evinacumab in the treatment of the rare inherited condition homozygous familial hypercholesterolemia (HoFH).

Teva Austedo Label Supports Psychiatric Safety As Point Of Differentiation

FDA approved Teva's Austedo (deutetrabenazine) for treatment of chorea associated with Huntington's disease on April 3 with labeling offering some points of differentiation from generically available tetrabenazine regarding suicidality and depression. As Lundbeck Inc.'s Xenazine, tetrabenazine became the first FDA-approved drug to treat Huntington's chorea in 2008.

Deutetrabenazine is the first deuterated product approved by FDA, Teva stated. The drug was the centerpiece of Teva's acquisition of Auspex Pharmaceuticals Inc., a company focused on modifying drug compounds by substituting deuterium for hydrogen, which can slow the rate of metabolic breakdown of a drug with the goal of improving safety and efficacy. (Also see "Teva Makes A Specialty M&A Play In Deal To Buy Auspex" - Pink Sheet, 30 Mar, 2015.)

Austedo, the deuterated version of the VMAT-2 inhibitor tetrabenazine, was approved as a new molecular entity, but Teva used the 505(b)(2) NDA pathway, allowing reference to data with the older form of the drug. Teva conducted a single 12-week pivotal study comparing Austedo with placebo in 90 ambulatory patients with manifest chorea associated with Huntington's disease.

Austedo carries the same black box warning about the risk of depression and suicide that Xenazine carries, but the deuterated drug's labeling does point to important differences. Among Austedo patients, 2% reported suicidal ideation and 4% reported depression. Xenazine labeling, in contrast, reports a 19% rate of depression in a similar 12-week study. During Xenazine trials, one patient committed suicide, one attempted suicide, and six had suicidal ideation. Labeling for Austedo notes that no suicides or attempts were reported. (Also see "Teva’s Austedo Positioned To Compete With A Generic Rival" - Scrip, 4 Apr, 2017.)

Austedo's dosing is also more convenient than Xenazine's. The Teva drug is taken twice daily, while tetrabenazine is dosed three times a day.

Austedo required two review cycles for approval by FDA. The NDA was originally submitted May 29, 2015, but received a complete response letter on May 27, 2016 that asked Teva to examine blood levels of a metabolite of the drug. (Also see "Keeping Track: FDA Approval Activity Heats Up With Ocaliva, Zinbryta And More" - Pink Sheet, 6 Jun, 2016.) The NDA was resubmitted on Oct. 3, 2016.

Deutetrabenazine is already under FDA review for a second indication, a more commercially significant claim for treatment of tardive dyskinesia that has an Aug. 30 priority review user fee goal. FDA has also granted deutetrabenazine a breakthrough therapy designation for tardive dyskinesia.

FDA CRL Delays Addition Of CV Outcomes Data To Merck Sitagliptin Labeling

Merck's sNDAs seeking to include data from the TECOS cardiovascular outcomes trial (CVOT) to labeling for products containing the company's dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin received a complete response letter (CRL) from FDA, Merck revealed April 7. The company did not disclose CRL details. (Also see "Merck Blocked In Adding CV Claim For Januvia, May Fall Behind Victoza" - Scrip, 7 Apr, 2017.)

Merck had hoped to add a cardiovascular safety claim to labeling for the type 2 diabetes treatments Januvia (sitagliptin), Janumet (sitagliptin and metformin) and the extended-release Janumet XR after the 14,671-patient TECOS trial found no association between sitagliptin treatment and increased risk of major adverse cardiovascular events. (Also see "Sitagliptin Shows No Increased Cardiovascular Risk In Merck’s TECOS Trial" - Pink Sheet, 8 Jun, 2015.)

FDA began requiring CV outcomes trials in 2008 to demonstrate that new type 2 diabetes drugs did not increase CV risk. As data have matured, CV benefit has emerged as the next battleground. FDA approved the first CV risk reduction claim for an anti-diabetic in December 2016, adding an indication for reducing the risk of CV death in patients with type 2 diabetes and established CV disease to the labeling of Eli Lilly & Co. and Boehringer Ingelheim GMBH's SGLT-2 inhibitor Jardiance (empagliflozin). (Also see "Jardiance's Cardiovascular Benefit Claim Bodes Well For Other Products Too" - Pink Sheet, 5 Dec, 2016.)

The TECOS trial data could give Merck's sitagliptin line an advantage over other DPP-4 inhibitors. CVOTs for Takeda Pharmaceutical Co. Ltd.'s Nesina (alogliptin) and AstraZeneca PLC's Onglyza (saxagliptin) both showed signals of increased risk of hospitalization for heart failure, leading FDA to investigate whether there is a CV risk class effect for the DPP-4 inhibitors. (Also see "Diabetes Drug Labels Should Reflect Heart Failure Risk, FDA Panel Says" - Pink Sheet, 14 Apr, 2015.)

Informa's BioMedTracker analysts hypothesize that Merck may have wanted to include data on heart failure hospitalizations showing no increase in TECOS, but FDA may have balked because the study may not have been powered to detect a difference on that single component of the composite major adverse cardiac events (MACE) endpoint.

Gilead Harvoni, Sovaldi Become First Direct-Acting Antivirals For Pediatric HCV

FDA approved sNDAs for Gilead Sciences Inc.'s Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) for treatment of hepatitis C virus (HCV) infection in children ages 12 to 17 years old on April 7, making the drugs the first direct-acting antivirals approved for children and adolescents with HCV. FDA cited estimates that 23,000 to 46,000 children in the US are infected with HCV.

The approvals cover six major genotypes of HCV. Harvoni added an indication for HCV genotype 1, 4, 5 or 6 infection in pediatric patients 12 years and older who weigh at least 77 pounds and who have mild or no cirrhosis. Sovaldi is now indicated for HCV genotype 2 or 3 infection in the same group.

Gilead submitted an open-label multicenter trial including 100 pediatric patients ages 12 and older with HCV genotype 1 infection who were treated with Harvoni, finding "results comparable to those observed in adults." Use of Harvoni in HCV genotypes 4, 5, and 6 was supported with exposure data. The amount of Harvoni in the body of pediatric patients with those genotypes was similar to Harvoni exposure in adults and adolescents with genotype 1 infection, FDA summarized, "as well as similar efficacy and exposure to Harvoni across HCV genotypes 1, 4, 5 and 6 in adults."

The Sovaldi sNDA was based on an open-label clinical trial of Sovaldi plus ribavirin that included 50 pediatric patients aged 12 or older. The pediatric Sovaldi patients also showed results "comparable to those observed in adults," FDA said.

Jazz Vyxeos Positioned For Autumn FDA Action

Jazz completed a rolling NDA submission for its acute myeloid leukemia therapy Vyxeos on March 31, 2017. Given the breakthrough therapy designation already awarded to Vyxeos, a nano-scale liposomal combination of cytarabine and daunorubicin for acute myeloid leukemia, FDA is likely to agree to the company's request for priority review. The user fee goal date will likely be around Oct. 2.

Jazz describes the NDA's indication as treatment of AML, but the product's point of differentiation is emerging as its benefit in older, high-risk AML patients. Such patients often cannot tolerate the standard "7+3" induction regimen of cytarabine and an anthracycline like daunorubicin. The fast track designation that allowed Vyxeos' rolling NDA submission is for treatment of elderly patients with secondary AML, Jazz noted. The company started the rolling submission in September 2016. (Also see "Keeping Track: Chugai Delivers Two Breakthroughs For Roche; FDA Continues To Wrestle With Opioid Regulation" - Pink Sheet, 7 Oct, 2016.) Vyxeos' BTD is also for a more specific group: adults with therapy-related AML or AML with myelodysplasia-related changes.

The Phase III trial supporting both the NDA and the BTD compared Vyxeos with "7+3" chemo as first-line treatment of older patients with high-risk AML. Top-line data showed a median overall survival of 9.6 months vs. 6 months for the conventional regimen. (Also see "Celator Shines At ASCO, Highlights Upside For Jazz" - Scrip, 6 Jun, 2016.) More recently, Vyxeos investigators presented a subgroup analysis of patients after hematopoietic stem cell transplant, which found a 10.25 month median OS for the standard regimen while the Vyxeos arm did not reach median OS. (Also see "AML Pipeline Update: Pharmas Pursue Big Breakthroughs In Niche Spaces" - Scrip, 6 Jan, 2017.)

Opdivo Follows Keytruda Into MSI-H Cancer Space

DNA mismatch repair biomarkers outline the next area of competition for PD-1/PD-L1 inhibitor immuno-oncologics. Both Merck's Keytruda (pembrolizumab) and Bristol's Opdivo (nivolumab) are under review for indications defined by mismatch repair biomarkers associated with less benefit from conventional chemotherapy.

Bristol's Opdivo was awarded an Aug. 2 priority review user fee goal for a new indication for treatment of patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer after prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. The sBLA is based on data from the ongoing Phase II CheckMate-142 trial.

Approximately 15% of CRC patients, and 4-5% of metastatic CRC patients, have dMMR or MSI-H biomarkers, according to Bristol. "Routine testing to confirm dMMR or MSI-H status should be conducted for all CRC patients," the company said.

Merck's Keytruda has a June 9 user fee goal for an indication that is not limited to CRC patients. The goal date reflects a three-month extension for the sBLA for previously treated advanced MSI-H cancer. (Also see "Keeping Track: US FDA Accepts Ertugliflozin, Extends Reviews Of Abaloparatide, New Keytruda Claim" - Pink Sheet, 12 Mar, 2017.) Keytruda has BTD status for both MSI-H metastatic CRC and MSI-H non-CRC cancer patients.

Janssen Bids To Take Imbruvica Beyond Blood Cancer

FDA accepted an sNDA for a new indication for Imbruvica (ibrutinib) for treatment of patients with chronic graft-versus-host-disease (cGVHD), a complication of allogeneic stem cell or bone marrow transplant, after failure of one or more lines of systemic therapy. The sNDA represents the first indication for the Bruton's tyrosine kinase (BTK) inhibitor outside of hematologic cancers. Imbruvica is sold by J&J's Janssen Biotech Inc. and AbbVie subsidiary Pharmacyclics Inc.

A priority review is likely for the cGVHD indication, which was previously awarded a breakthrough therapy designation (BTD). There are "no approved treatments or established standards of care specifically indicated for the condition in patients who have failed initial steroid therapy," Janssen said. The priority review user fee goal would be expected by early August.

The sNDA is based on a single-arm Phase Ib/II trial, PCYC-1129, testing ibrutinib in cGVHD patients who failed first-line corticosteroids and require additional therapy. A Phase III trial is ongoing to evaluate ibrutinib plus corticosteroid versus placebo/steroid as first-line therapy for new onset moderate or severe GVHD, the company noted.

Amgen Seeks To Take Xgeva Beyond Solid Tumors

Amgen hopes to add multiple myeloma to the currently approved indication for Xgeva (denosumab) for prevention of skeletal-related events (SREs) in patients with solid tumors. The company announced submission of an sBLA for the multiple myeloma claim on April 4. A standard review would put the user fee goal around February 2018.

Labeling for Xgeva, a monoclonal antibody that binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone destruction, currently contains a limitation of use noting that Xgeva is not indicated for prevention of SREs in multiple myeloma patients. Bone lesions are common in multiple myeloma, but treatment is limited to bisphosphonates, which are associated with renal toxicity – a significant hurdle, because a majority of multiple myeloma patients develop renal impairment over the course of the disease, Amgen said. Xgeva "is not renally cleared," the company emphasized.

The pivotal trial for the sBLA is the Phase III '482 study, which found subcutaneous Xgeva to be non-inferior to I.V. zoledronic acid in delaying the time to first on-study SRE in newly diagnosed multiple myeloma patients with bone disease, Amgen reported. The trial had less success with its secondary endpoints. Xgeva did not meet secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SREs, the company said. While Xgeva was favored over zoledronic acid in an analysis of overall survival, another secondary endpoint, the difference was not statistically significant.

Amgen touted the 1,718-patient Phase III trial as "the largest international multiple myeloma trial ever conducted."

Regeneron Evinacumab Breakthrough Nod Endorses ANGPTL3 Target

The breakthrough therapy designation awarded to Regeneron's evinacumab for treatment of homozygous familial hypercholesterolemia (HoFH) patients can be seen as an endorsement of the potential of a new mechanism of action in the hypercholesterolemia space. Evinacumab is a monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), a protein that "appears to play a central role in lipoprotein metabolism," Regeneron said.

Regeneron is currently planning a Phase III trial of evinacumab to treat hypercholesterolemia in patients with HoFH. Last year, the company reported interim Phase II data from four patients (of a planned eight) showing that evinacumab reduced LDL-C levels by an additional 55% from baseline at week four when added to current therapy, including maximum statin doses and ezetimibe. (Also see "Regeneron Shows Proof Of Concept For Novel Cholesterol Drug" - Scrip, 3 Jun, 2016.)

Evinacumab is the first product to receive a BTD for a hypercholesterolemia indication. HoFH, an orphan inherited disorder, is the most severe form of hypercholesterolemia.