Michael D. Dalzell

Last December’s approval of sofosbuvir (Sovaldi) ushered in the era of interferon-free treatment for hepatitis C (HCV). But sofosbuvir’s final labeling — recommending co-administration with pegylated interferon in patients with genotypes 1 and 4 — meant that the days of interferon and its harsh side effects were not quite over for a subset of people with HCV.

Now, two manufacturers are in a race to clear up some unfinished business. AbbVie made a splash at March’s Conference on Retroviruses and Opportunistic Infections, presenting results from six studies of a three-drug cocktail to treat patients with genotype 1 HCV. AbbVie’s regimen consists of the fixed-dose combination of ABT-450 and ritonavir coformulated with ABT-267, dosed once daily, and ABT-333, with or without ribavirin, dosed twice daily. In all six studies, involving more than 2,300 patients, the various combinations demonstrated cure rates of between 90% and 100% after 12 weeks. AbbVie will seek FDA approval of the combination product this spring.

The maker of sofosbuvir, however, is already a step ahead of AbbVie. On February 7, Gilead filed for FDA approval of a fixed-dose combination of sofosbuvir for people with genotype 1 HCV. The once-daily tablet combines sofosbuvir with ledipasvir, an NS5A inhibitor. No ribavirin, no interferon — and no speculation yet about what it will cost. When sofosbuvir hit the market, its average wholesale price was $84,000 for a 24-week supply.

Lung cancer: 2 up

A fast-emerging understanding of the genetic complexities that underlie lung cancer has made the condition a hotbed for drug development. In the first quarter of 2014 alone, four different investigational treatments for non–small-cell lung cancer made news. Two of those dispatches were positive for their manufacturers.

Ramucirumab, a VEGF blocker, showed a statistically significant increase in overall survival when paired with docetaxel. The results were a blessing for Eli Lilly following ramucirumab’s failure last year to meet its primary endpoint in a breast cancer trial. Nonetheless, the drug has already proven itself in a gastric cancer trial, and if it demonstrates further success in trials for liver and colorectal cancer this year, it could eventually become a huge seller.

LDK378 is still young in development, but that didn’t stop Novartis from filing for FDA approval. Novartis based its application on high response rates in a phase 1 study of 78 patients with ALK-positive disease. LDK378 has FDA “breakthrough” status, but that may not be enough to win approval on phase 1 data.

Lung cancer: 2 down

On the downside, Genentech called off a late-stage trial of onartuzumab, one of its biggest pipeline assets, for lack of efficacy. Nicknamed MetMab because it targets the MET pathway, onartuzumab was studied in combination with erlotinib (Tarceva) in patients with EGFR mutations. A 2011 phase 2 study had shown statistically significant improvements in overall survival and progression-free survival (PFS) in patients given onartuzumab with erlotinib, compared with erlotinib alone. Genentech is evaluating the implications of the phase 3 study across the onartuzumab clinical development program.

Pfizer took two on the chin in a pair of studies of dacomitinib, which inhibits HER1/EGFR, HER2, and HER4 kinase activity to prevent cell proliferation. In a head-to-head showdown against erlotinib in patients with advanced, previously treated disease, dacomitinib did not demonstrate an improvement in PFS. In a second trial in a similar population, dacomitinib did not improve overall survival versus placebo.

Pfizer will keep plugging along with dacomitinib, however. Another phase 3 trial — this one against gefitinib (Iressa) in patients with treatment-naïve, EGFR-mutant disease — is to be completed next year.

Did you hear?

Researchers in the United Kingdom have successfully deployed gene-replacement therapy to repair retinal damage in patients who have a form of progressive vision loss. In a six-person trial, University of Oxford ophthalmologists injected a virus into participants’ eyes. The virus acts as a transporter for the CHM gene — the lack of which is a cause of retinal deterioration. Once the virus reaches light-sensing cells in the retina, it infects them, depositing the gene. The gene is then switched on to produce proteins that stop cell degeneration that leads to blindness. Researchers published their results in the Lancet.

President Obama’s fiscal year 2015 budget includes a provision to reduce biologic market exclusivity from 12 years to 7 years. Buried deep within the budget document, the reduction is touted as a way to save $4 billion in Medicaid spending. The budget architects don’t spell out how those savings will be achieved, however. Mysterious, indeed, considering that the FDA has not finalized a regulatory pathway and that no biosimilars have been approved in the United States since recombinant hyaluronidase reached the market in 2005.

Statin add-ons likely to renew a long-forgotten battle

It’s almost easy to forget that 15 years ago, many payers balked at the cost of statins — a fast-growing class that broke the psychological barrier of $1 a pill. Today, statin therapy is a standard of care and is considered cheap insurance against far more costly cardiovascular events.

Now, statin therapy promises to get a lot more expensive if part of a combination regimen with a monoclonal antibody. In January and March, Amgen announced results of two studies of evolocumab, a PCSK9 blocker that allows the liver to clear more LDL cholesterol from the body. These were the last of six phase 3 studies, some involving hard-to-treat patients. Evolocumab was coupled with various statins and strengths, depending on the study.

Numbers for the January study are being saved for a scientific conference later in the year, but they are believed to be similar to the eye-opening LDL-C reductions that approached 60% in phase 2 studies. The study revealed few instances of cognitive impairments, a side effect the FDA asked both Amgen and Sanofi — which is shepherding its own PCSK9 inhibitor, alirocumab, through clinical trials — to monitor. The problem appears to be self-correcting when patients stop taking the drug.

The March study was conducted in patients with homozygous familial hypercholesterolemia, a difficult-to-treat population whose rare condition acts as an LDL-C booster. Significant reductions were seen in almost half of these patients.

Amgen expects to file for regulatory approval for evolocumab later this year.

The outcomes may be life-saving for high-risk populations. The conversations to come about cost and access limitations, though, will be interesting.

SELECTED FDA APPROVALS OF BIOLOGIC AND SPECIALTY DRUGS, JAN. 15–MARCH 14, 2014
Date (type) Manufacturer Drug (trade name); administration Indication Notes
New marketing approval
Feb. 24, 2014 (BLA) AstraZeneca Metraleptin (Myalept); oral Complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Narrow indication does not include people with partial or HIV-related lipodystrophy. The first therapy to treat complications of generalized lipodystrophy, metraleptin carries a black-box warning about infections and a hefty 55-page PI. Safety concerns underlie some of the 15 postmarketing studies required.
New indication
Feb. 12, 2014 Pharmacyclics/Janssen Ibrutinib (Imbruvica) CLL in patients who have received at least one prior therapy It was already indicated for MCL in patients treated previously.
SELECTED FDA-RELATED ACTIVITIES, JAN. 15–MARCH 14, 2014
Manufacturer Drug (trade name) Type of drug Proposed use Notes
Boehringer Ingelheim/Eli Lilly Empagliflozin Sodium glucose co-transporter-2 (SGLT2) inhibitor Reduction of blood glucose levels in people with type 2 diabetes March 5 CRL required correction of manufacturing deficiencies at a BI facility where empagliflozin will be made. No new trials were requested.
AWP=average wholesale price, BI=Boehringer Ingelheim, BLA=biologics license application, CLL=chronic lymphocytic leukemia, CRL=complete response letter, HCV=hepatitis C virus, MCL=mantle cell lymphoma.
Sources: American Society of Clinical Oncology, FDA, FierceBiotech, New York Times, Thompson Reuters, University of Oxford, and manufacturers’ news releases and product labeling.

All clinical trials described in this column are phase 3, randomized, controlled studies unless otherwise specified.