Biosimilars in Development Near End of Phase 3 Trials

Amgen’s biosimilar candidate ABP501 proved comparable to AbbVie’s adalimumab (Humira) for patients with moderate to severe plaque psoriasis, based on results from a head-to-head phase 3 study. The study met its primary endpoint of improvement from baseline to Week 24. Amgen is also developing biosimilars of cetuximab (Erbitux) and bevacizumab (Avastin).

Amgen’s own etanercept (Enbrel) is the target of biosimilar development. A 52-week study of CHS0214, by Coherus, demonstrated PASI-75 equivalence at Week 12 for the treatment of moderate to severe plaque psoriasis. The trial, which is still ongoing, is measuring mean percent change from baseline and the proportion of subjects achieving 75% improvement in PASI in patients given CHS0214 versus those given etanercept.

Novartis is waiting for FDA approval of a long-acting treatment for boosting white blood cell count, a biosimilar of Amgen’s pegfilgrastim (Neulasta). This is Novartis’s third biosimilar submission, with 10 more planned filings over the next three years. Novartis’s previous filings also targeted Amgen drugs; the FDA is reviewing its application to market a copy of etanercept for rheumatoid arthritis and other auto­immune diseases, and Novartis’s Sandoz subsidiary launched Zarxio, a filgrastim (Neupogen) bio­similar, in September. The company’s other biosimilar prospects include Johnson & Johnson’s infliximab (Remicade) and Genentech’s trastuzumab (Herceptin).

HCV successes at AASLD

Oral combination medicines and regimens made headlines at the American Association for the Study of Liver Diseases (AASLD) 2015 Liver Meeting in San Francisco. Merck’s once-daily elbasvir/grazoprevir tablet showed sustained virologic response 12 weeks after the completion of treatment (SVR12) in 95% of patients with chronic hepatitis C (HCV) who inject illegal drugs. Conducted in patients with HCV genotypes 1, 4, and 6, the C-EDGE CO-STAR study was of interest because limited research has been conducted in patients undergoing treatment for injection drug use.

Other AASLD presentations: In the ongoing TOPAZ-II study, 95% of adults with HCV genotypes 1a or 1b treated with AbbVie’s Viekira Pak (ombitasvir, paritaprevir, ritonavir, dasabuvir) achieved SVR12 after 12 or 24 weeks of treatment. Participants in TOPAZ-II are being followed for 5 years post-treatment to evaluate the long-term impact of SVR12 on the progression of liver disease. … In a systematic review of clinical trial data, patients with HIV and hepatitis C virus (HCV) co-infection, a once-daily regimen of daclatasvir (Daklinza) and sofosbuvir (Harvoni) achieved superior SVR12 compared with a regimen of sofosbuvir/ribavirin. The analysis was conducted by the Boston-­based Health Economics and Outcomes Research Analysis Group and Bristol-Myers Squibb, maker of daclatasvir. Sofosbuvir is manufactured by Gilead.

Pleasing, puzzling CV data

Patients with type 2 diabetes and cardiovascular (CV) disease receiving the glucose-lowering agent empagliflozin (Jardiance), a sodium glucose cotransporter-2 (SGLT-2) inhibitor, were less likely than those taking placebo to die from CV causes, according to results of the large EMPA-REG OUTCOME study. The findings, published in the Nov. 26 issue of the New England Journal of Medicine, were hailed as landmark, as this is the first glucose-lowering drug to show superiority in a CV-outcomes trial. Investigators, however, admitted that they have yet to understand the outcome.

Setbacks in cancer trials

Bevacizumab combined with the chemotherapy agent lomustine for treating first recurrences of glioblastoma did not improve overall survival (OS), according to findings from the EORTC-26101 trial. OS was not statistically different between the two study arms, with a median OS of 9.1 months in the combination group versus 8.6 months in a control arm of patients receiving lomustine alone. Progression-free survival (PFS) data seemed more promising, however—4.17 months among patients receiving the combination treatment versus 1.54 months for the lomustine-alone group. 8.8% of patients in the combination-therapy arm had no progression at 1 year, compared with 1.9% of patients in the lomustine arm. Data were presented at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology.

The introduction of tyrosine kinase inhibitors (TKIs) revolutionized the treatment of gastrointestinal stromal tumors (GIST), but secondary resistance remains an issue. New results from a group of patients who have been followed since 2004 show that those with high- or intermediate-risk GIST and who were given imatinib (Gleevec) after surgery had no gain in OS, but imatinib did appear to have long-term benefit for relapse-free survival. In patients given postsurgical imatinib, relapse-free survival was 84% at 3 years, compared with 66% in an observation group. At 5 years, the rates were 69% and 63% respectively.

Genmab has stopped its study comparing ofatumumab (Arzerra) with Genentech’s rituximab (Rituxan) in the treatment of relapsed follicular non-Hodgkin’s lymphoma (NHL). The decision followed an interim analysis conducted by an independent data monitoring committee. The analysis concluded that ofatumumab was unlikely to show superiority if the trial were to conclude as planned. The trial randomly assigned 516 patients with follicular NHL to receive either ofatumumab or rituximab by intravenous infusion in four weekly doses, with PFS being the primary outcome. Data from the study will be presented at a future scientific conference.

Cholesterol-fighting booster

Adding alirocumab (Praluent) to standard-of-care therapy for low-density lipoprotein (LDL) cholesterol reduction is beneficial, according to a posthoc analysis of the six phase 3 ODYSSEY trials. An injection of alirocumab 75 mg lowered 74% of patients’ LDL to a prespecified target within 8 weeks. The remaining 26% of patients achieved their goal by Week 24 when dosing was increased to 150 mg. Results were based on a pooled analysis of 1,291 patients with high CV risk or heterozygous familial hypercholesterolemia.

Have you heard?

Bioethics International, a not-for-profit organization focused on the ethics and governance of how medicines are researched, developed, and made accessible, published a study ranking large pharma companies by the transparency of their clinical trial results. On average, for each drug, only two thirds of clinical trials that supported new drug approvals in 2012 were disclosed, falling below legal and ethical standards. In addition, almost half of all FDA-reviewed drugs had at least one undisclosed phase 2 or 3 trial.

According to Bioethics International, three of 10 companies—GlaxoSmithKline, Johnson & Johnson, and Pfizer—publicly disclosed all clinical trial results for at least one of their reviewed drugs. The lowest-scoring company, Gilead, disclosed only 21% of trial results for Stribild, its HIV medication.

All clinical studies mentioned in this article are phase 3 unless otherwise stated.

Selected FDA approvals of biologics and other specialty drugs, Oct. 3, 2015–Dec. 31, 2015
New marketing approvals
Date (type) Manufacturer Drug (trade) name; administration Indication Notes
Oct. 16 (BLA) Boehringer Ingelheim idarucizumab (Praxbind); intravenous injection Reversal of anticoagulation effects of dabigatran (Pradaxa) in patients needing emergency surgery or who have life-threatening or uncontrolled bleeding First reversal agent for dabigatran received accelerated approval in a study of healthy volunteers. Continued approval may be contingent on results of an ongoing cohort case series study. WAC is $3,500.
Oct. 27 (BLA) BioVex/Amgen talimogene laherparepvec (Imlygic); intralesional injection Local treatment of unresectable lesions in patients with recurrent melanoma First FDA-approved oncolytic viral therapy is a genetically modified live herpes virus. Injected directly into melanoma lesions, it replicates and causes apoptosis. Average cost: $65,000.
Nov. 5 (NDA) Gilead elvitegravir/cobicistat/emtricitabine/tenofovir (Genvoya); subcutaneous injection; oral tablet HIV-1 in ARV-naive patients or to replace current therapy in patients whose HIV is suppressed; for patients age ≥12 years Approval of 4-in-1 tablet based on four clinical trials of 3,171 patients randomized to Genvoya or another approved HIV treatment, depending on the trial. Genvoya reduced viral loads and was comparable to other treatments. Label carries black box warning about liver toxicity. Annual list price of $31,362 is in parity with its predecessor, Stribild.
Nov. 10 (NDA) Genentech cobimetinib (Cotellic); oral tablet Unresectable or metastatic melanoma with BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf) Coadministration of cobimetinib (a MEK inhibitor) with vemurafenib (a BRAF inhibitor) is designed to counter effects of resistance to a single targeted treatment. In the coBRIM trial, PFS was 12.3 months in combination patients vs. 7.2 months in patients given vemurafenib alone.
Nov. 13 (NDA) AstraZeneca osimertinib (Tagrisso); oral tablet Metastatic, EGFR T790M mutation-positive non–small-cell lung cancer For use in patients with disease progression after treatment with an EGFR tyrosine-kinase inhibitor. FDA also approved a companion diagnostic to detect the T790M mutation. Approval based on surrogate ORR in AURA phase 2 open-label trials.
Nov. 20 (NDA) Millenium/Takeda ixazomib (Ninlaro); oral capsule In combination with lenalidomide (Revlimid) and dexamethasone in patients with MM who have received 1 prior therapy Approval creates first all-oral regimen for MM with a proteasome inhibitor (PI). In the TOURMALINE-MM1 clinical trial of 722 patients, PFS in the study group was 5.9 months greater than in the lenalidomide/dexamethasone/placebo group. $8,670-per-cycle cost is comparable to bortezomib (Velcade), an injected PI from the same maker.
Nov. 24 (BLA) Eli Lilly necitumumab (Portrazza); intravenous injection In combination with gemcitabine and cisplatin for first-line use in patients with metastatic squamous non–small-cell lung cancer In the SQUIRE trial, OS gain vs. chemo-alone arm (1.6 months) was statistically significant, though “marginal,” according to one FDA advisor. An economic analysis at ASCO 2015 found that necitumumab must cost <$1,300 per 3-week cycle to be cost-effective. Its cost: $11,430 per month.
Dec. 16 (BLA) Eli Lilly insulin glargine (Basaglar); subcutaneous injection Improve glycemic control in adults with types 1 and 2 diabetes and children with type 1 diabetes Not technically a biosimilar because it was approved under the 505(b)2 pathway, Basaglar is the first approved follow-on to Sanofi’s Lantus. The long-acting insulin analogue demonstrated similarity in two clinical trials enrolling 1,278 patients.
ARV=antiretroviral, BLA=biologics license application, EGFR=epidermal growth factor receptor, MM=multiple myeloma, NDA=new drug application, ORR=overall response rate, OS=overall survival, PFS=progression-free survival, 505(b)2=abbreviated new drug pathway.
Sources: ASCO, FDA, Fair Pricing Coalition, Fierce Biotech, Medscape, New England Journal of Medicine, New York Times, Physicians First Watch,, Wall Street Journal, and product labeling.

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