Biologics in Development

In a Crowded Market for Renal Cell Carcinoma Treatments, 2 Trials Take Aim at a Common Enemy

Katherine T. Adams

Cabozanitib reduced the risk of disease progression or death by 42% in patients with metastatic renal cell carcinoma (RCC), compared with everolimus (Afinitor), according to results of the METEOR trial. The 658 patients who were enrolled had disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. METEOR met its primary endpoint, a statistically significant increase in progression-free survival (PFS), in the first 375 randomized patients.

The CheckMate-025 study evaluating nivolumab (Opdivo) in previously treated patients with advanced or metastatic RCC was stopped early when the study met its endpoint, superior overall survival (OS), in patients receiving nivolumab compared with the control arm. CheckMate-025 is an open-label study in which patients were randomized to receive either nivolumab 3 mg/kg intravenously every two weeks or everolimus 10 mg tablets daily until documented disease progression or unacceptable toxicity.

Two previous CheckMate trials demonstrated statistically significant one-year survival rates in patients given nivolumab versus those on chemotherapy regimens. Nivolumab currently has indications for metastatic squamous non–small-cell lung cancer (NSCLC) and metastatic melanoma.

Lung cancer trial stopped

Adding tivantinib to erlotinib (Tarceva) improved progression-free survival (PFS) but not OS in patients with previously treated nonsquamous NSCLC. OS was the primary endpoint of the 1,048-patient study, which was discontinued for futility at an interim analysis. Results were published in the Journal of Clinical Oncology.

In a subgroup of 211 patients with high MET tumor expression, researchers did see a trend toward improved OS, with a median OS of 9.3 months in patients given the combination therapy and 5.9 months in those who received only erlotinib. Tivantinib is a selective inhibitor of the MET receptor tyrosine kinase, helping to slow cell proliferation and induce apoptosis in cancer cells that express MET.

Setback in uveal melanoma

Selumetinib combined with dacarbazine chemotherapy for treatment of metastatic uveal melanoma, an orphan disease in which cancer cells grow in eye tissues, failed to improve PFS compared with dacarbazine alone, according to results of the SUMIT study. SUMIT was a randomized, double-blind, placebo controlled trial carried out in 45 centers in 11 countries.

Selumtinib is an oral, small-molecule MEK inhibitor in late-stage development, discovered by Array BioPharma and licensed to AstraZeneca. The drug is also being investigated in phase 3 studies for KRAS-mutant advanced NSCLC and differentiated thyroid cancer, as well as in a phase 2 registration study in patients with type 1 neurofibromatosis.

Uveal melanoma is rare but is the most common form of malignancy in the eye. According to the National Cancer Institute, uveal melanoma incidence is about 4.3 cases per 1 million people.

In other trials involving diseases of the eye:

Xoma’s Phase 3 EYEGUARD-B study of gevokizumab to treat Behçet’s uveitis failed to meet the primary endpoint of time to first acute ocular exacerbation, although it appeared to be well tolerated in the trial. Behçet’s uveitis is a systemic condition that originates with inflammation in the eye and, untreated, can promote cataracts and optic atrophy, lead to vascular injury multiple organs, produce ulcers in the mouth, and genital lesions. In rare cases, it can be fatal, though literature suggests that symptoms “burn themselves out” after about 10 years.

A benefit-risk analysis trial data supports the favorable profile of Genentech’s ranibizumab (Lucentis) 0.5 mg as-needed dosing compared with laser therapy for treatment of diabetic macular edema. A comparative benefit-risk assessment was conducted using the Benefit Risk Action Team Software Tool (BRAT), which includes steps for selection, summarization, organization, and interpretation of data.

Alzheimer’s trials revisited

Two presentations at the Alzheimer’s Association International Conference, in Washington, showed flickers of hope against the frustration researchers face in trying to unlock the secrets of Alzheimer’s disease.

In a posthoc exploratory analysis of gantenerumab, researchers suggested that dosing in the two-year SCarlet RoAD trial in people with early symptoms of Alzheimer’s may have been too low to be clinically effective. Roche stopped the SCarlet RoAD trial last December after preliminary results indicated that the chance of successful completion was very low, but patients in the study continued to be followed. The drug produced non–statistically significant, dose-related reductions on amyloid levels but statistically significant reductions in tau, a protein marker of brain cell degeneration that can be measured in the cerebrospinal fluid.

Meanwhile, a delayed-start analysis produced evidence of slower cognitive decline in some Alzheimer’s patients when solanezumab was taken for a longer period of time than in the original clinical trials. Two initial phase 3 trials of solanezumab—the 18-month EXPEDITION and EXPEDITION2 placebo-controlled studies—failed to reach statistical significance on primary endpoints in patients with mild to moderate disease. But patients with only mild disease and who were given placebo in the initial trials were allowed to cross over to solanezumab in an extension study. In a pooled analysis of 1,322 patients from the two original trials, those given solanezumab for two years in the extension study had statistically significant improvements in cognition. Eli Lilly intends to proceed with a new trial of solanezumab, which is expected to enroll 2,100 patients and take several years to complete.

MS head-to-head trial

Two pivotal studies (OPERA I and OPERA II) evaluating ocrelizumab in people with relapse-remitting multiple sclerosis met their primary and major secondary endpoints. Ocrelizumab significantly reduced the annualized relapse rate over a two-year period compared with interferon beta-1a (Rebif), the primary endpoint in both studies. Patients treated with ocrelizumab also experienced significantly reduced progression of clinical disability compared with interferon beta-1a, measured by the Expanded Disability Status Scale, and a significant reduction in the number of brain lesions, measured by MRI.

Ocrelizumab, under joint development by Genentech and Biogen, is an anti-CD20 monoclonal antibody that selectively targets CD20-positive B cells. These cells are thought to contribute to myelin and axonal damage.

PsA mab superior to placebo

The investigational medicine ixekizumab, a monoclonal antibody that targets interleukin-17A, was statistically superior to placebo in the treatment of patients with active psoriatic arthritis (PsA). Efficacy was demonstrated as the proportion of patients achieving ACR20 in the 24-week SPIRIT-P1 study. Patients who were naïve to biologic disease-modifying antirheumatic drugs were treated with one of two different ixekizumab dosing regimens or placebo. In both regimens, ixekizumab-treated patients demonstrated significant improvements versus placebo in signs and symptoms of active PsA.

Ixekizumab is also being studied in patients with psoriasis, and if Eli Lilly receives FDA approval for ixekizumab next year, the drug would be 1 of 2 IL-17s available for treatment of immunomodulatory diseases. Novartis’s secukinumab (Cosentyx) received FDA approval earlier this year. Amgen ceased development of a third IL-17, brodalumab, in May, after reports surfaced of suicidal thoughts and behavior in patients taking the drug in clinical trials.

Have you heard?

Two large trials both reported marginal or no improvement in OS in women with early-stage breast cancer who were treated with regional nodal irradiation in addition to whole-breast irradiation, but the addition of nodal irradiation did reduce the risk of recurrence and metastatic disease. Because these trials began in 1996 and 2000, some of the currently used therapies, such as trastuzumab (Herceptin) or taxane chemotherapies, were not systematically included in the trial protocols. Results of both trials were published in the New England Journal of Medicine.

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

Selected FDA approvals of biologics and other specialty drugs, April 1–May 31, 2015
New marketing approvals
Date (type) Manufacturer Drug (trade) name; administration Indication Notes
July 2 (NDA) Vertex ivacaftor/lumacaftor (Orkambi); oral tablet Cystic fibrosis (CF) in patients age≥12 with two copies of the F508del mutation Combination tablet adds lumacaftor to ivacaftor (Kalydeco, approved in 2012 for patients age ≥6 with 1 of 9 CFTR mutations). Orkambi had a “breakthrough” designation because of preliminary evidence of a “substantial improvement” over existing CF therapies. The $259,000/year WAC called “egregious” by several prominent CF specialists.
July 24 (NDA) Bristol-Myers Squibb daclatasvir (Daklinza); oral tablet In combination with sofosbuvir (Sovaldi) for the treatment of chronic hepatitis C, genotype 3 (HCV-3) infection NS5A inhibitor is first to treat HCV-3 without coadministration of interferon or ribavirin. Safety and efficacy demonstrated in an open-label trial of 152 treatment-naive and -experienced patients. WAC is $63,000, but because Daklinza must be prescribed with Sovaldi ($84,000), a 12-week course comes at a total cost of $147,000.
July 24 (NDA) AbbVie ombitasvir, paritaprevir and ritonavir (Technivie); oral tablet In combination with ribavirin for the treatment of chronic hepatitis C, genotype 4 (HCV-4) infection without cirrhosis Fixed-dose combination NS5A inhibitor is first to treat HCV-4 without coadministration of interferon. two-arm study included patients with or without coadministration of ribavirin. 100% of patients in Technivie-ribavirin group achieved SVR, vs. 91% in the Technivie-only group.
July 24 (BLA) Sanofi-Aventis/Regeneron alirocumab (Praluent); subcutaneous injection Adjunct to maximally tolerated statin in adults with HeFH or clinical atherosclerotic CV disease who need extra help lowering LDL cholesterol First PCSK9 inhibitor to market is injected to help the body clear excess LDL. HeFH is a genetic disorder that can elevate LDL >200 mg/dL and makes LDL reductions difficult to achieve. WAC price is $40/day.
July 24 (NDA) Novartis sonidegib (Odomzo); oral tablet Recurrent locally advanced basal cell carcinoma For use only in patients who are not candidates for surgery or radiation therapy, Odomzo inhibits the hedgehog pathway. Approval is based on demonstration of ORR in a randomized trial that compared dosage strengths.
New indications of previously approved treatments
July 14 (NDA) AstraZeneca gefitinib (Iressa); oral First-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test Approval is concurrent with labeling expansion of the therascreen EGFR RGQ PCR kit, a companion diagnostic for the detection of EGFR oncogene mutations. Iressa was withdrawn from the market in 2011 after confirmatory trials failed to verify clinical benefit. This approval is for a different population than for Iressa’s initial approval in 2003.
July 24 (sNDA) Onyx carfilzomib (Kyprolis); intravenous injection Relapsed MM. Prescribed with len/dex in patients who have received 1–3 prior lines of therapy, or as monotherapy for patients with ≥2 prior therapies including bortezomib and an IMiD Approval is based on demonstration of improved progression-free survival in the PX-171-009 ASPIRE trial. The revised labeling includes new warnings and precautions for VTE, cardiac toxicities, acute renal failure, pulmonary toxicities, and hypertension.
CV=cardiovascular, HeFH=heterozygous familial hypercholesterolemia, IMiD=immunomodulatory agent, MM=multiple myeloma, NSCLC=non–small-cell lung cancer, ORR=objective response rate, SVR=sustained virologoic response, WAC=wholesale acquisition cost.
Sources: ASCO, FDA, Fierce Biotech, Fierce Pharma, Medscape, New York Times, and manufacturers’ news releases and package inserts.

CMS to face one of its own in debate on drug costs

Most Americans want Medicare to negotiate lower medication prices with drug companies, currently prohibited by law, according to several polls conducted by the Kaiser Family Foundation. In the latest poll, conducted between April 23 and May 31 among 1,849 adults, 87% who were surveyed said they want Medicare to have authority to press drugmakers for greater discounts and lower prices.

Organizations such as America’s Health Insurance Plans (AHIP) are expected to bring further pressure to bear on drugmakers. And now the industry’s biggest lobbying group has hired a former government insider who may live up to those expectation.

On July 15, AHIP unanimously elected former CMS Administrator Marilyn Tavenner to be its president and CEO.


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