FDA Notes Lack Of Proof For Cancer Risk, But Lantus Isn't Out Of The Woods Yet
By Emily Hayes

In an update to an ongoing safety review, FDA has concluded that proof of an increased risk of cancer with Lantus is lacking, but Sanofi-Aventis SA's blockbuster long-acting insulin analog hasn't been totally cleared and data due out this year may be needed to close the case.

Sanofi pointed out that in addition to FDA, drug regulatory agencies in the EU and Japan have conducted reviews of Lantus data and have not required changes in labeling.

A storm erupted worldwide in mid-2009 when four large observational studies of patient registries in European countries were published in Diabetologia, the official publication of the European Association for the Study of Diabetes. Three of the studies and an accompanying editorial in the journal suggested an increased risk for cancer ('Will Sanofi's Lantus Survive Cancer Scare? Studies Suggest A Worrisome Link,' 'The Pink Sheet' DAILY, June 26, 2009).

Stock price initially took a beating but the picture improved greatly as critical commentary about study design trickled in from FDA and leading diabetes organizations ('Sanofi Counts FDA As New Supporter In Lantus Cancer Scare,' 'The Pink Sheet' DAILY,' July 1, 2009). Patients were advised that the studies had limitations, and not to panic and quit the drug.

In two of the studies showing a higher risk of cancer in patients taking Lantus, the numbers of cancer cases were so small that they could have arisen "due to chance," the EASD acknowledged in a statement at the time the studies were published.

No News Is Good News

So official recognition that evidence is lacking should come as no surprise. On Jan. 13, FDA said that it has completed its review of the four observational studies from Europe and has determined that the "evidence presented in the studies is inconclusive, due to limitations in how the studies were designed and carried out and in the data available for analysis. These limitations prevent our ability to attribute the observed cancer risk to Lantus."

Among the shortcomings in the studies, the agency noted that the follow-up periods in the trials were shorter than what would typically be needed to evaluate cancer risk from drug exposure and that little is known about patients' use of insulin products.

FDA also commented that, as part of its review, it has considered results from the five-year, randomized Evaluation of Diabetic Retinopathy Progression in Subjects with Type 2 Diabetes Mellitus Treated with Oral Agents Plus Insulin trial. That study, which compared Lantus to neutral protamine hagedorn insulin in Type 2 diabetics, did not show an increased risk of cancer for patients on Lantus. The agency noted that the study was not specifically designed or powered to evaluate cancer outcomes, however.

Additional Studies To Come This Year

Based on evidence available to date, the agency concluded that health care professionals should continue to follow the recommendations in the drug label when prescribing Lantus and patients should continue taking Lantus unless told otherwise by their health care professional.

While the FDA did not find sufficient evidence of a link to cancer, the agency also made it clear that the review continues and that its findings will be updated over time. Additional trials due out this year could further shed light on the drug's safety profile. For example, Sanofi has amended the protocol of its Outcome Reduction with Initial Glargine Intervention cardiovascular outcomes trial to include an analysis of cancer incidence. The data so far have not shown a risk and full results are due by the end of this year.

FDA also called attention to the fact that Sanofi is conducting three epidemiological studies to evaluate risk and results are due in the middle of this year. In September 2009, Sanofi had announced a comprehensive set of collaborative epidemiology studies designed to assess the potential for increased risk of cancer with diabetes treatment.

Furthermore, the agency said it also may use the Veteran's Administration patient database to perform retrospective analysis of cancer risk.

There is no mention in FDA's communication, however, about the need for Sanofi to perform a prospective study to specifically evaluate cancer risk.

Commercial Impact Unclear

Commercially speaking, just what the FDA news means for Lantus sales is unclear. The product had sales of $1.9 billion in 2009, up 8% from the previous year and equivalent to a 30% share of the market for human insulin analogs, according to IMS Health. The Lantus Solostar prefilled insulin pen delivered another $700 million-plus that year, according to the healthcare information company.

IMS figures further indicate that for the first half of 2010, Lantus had sales of almost $1 billion, representing a 27% market share and a 3% increase from the same period in 2009. Solostar sales in the first half added another $485 million.

In its third quarter 2010 earnings report, Sanofi had reported Lantus brand net sales of €900 million ($1.2 billion), an increase of 6.7% from the same period last year, including U.S. sales of €553 million (+5.9%).

As to whether the cancer scare had affected clinical practice, Sanofi pointed out that following the publication of the June 2009 Diabetologia studies, the FDA, American Diabetes Association, the American Cancer Society and other health organizations recommended no changes in treatment.

However, executives did report in their third-quarter earnings call that sales in the U.S. were flatter, partly due to health reform, general economic conditions that have resulted in less insurance coverage, and competition from other drugs, such as the DPP-4s and GLP-1s.

Nevertheless, Lantus has become the number one diabetes brand worldwide during the third quarter of 2010, president of global operations Hanspeter Spek noted during the Oct. 28 call. Prescribers are delaying the stat of insulin therapy, which is having a negative effect, he acknowledged.

"We will still get the patients, but we will get them later," he said.

Although total prescriptions of Lantus have flattened a bit compared with previous years, there has not been any significant decline in Lantus prescriptions in the U.S. since the initial news about the cancer risk emerged in 2009, commented Donny Wong, an analyst at research firm Decision Resources.

The FDA news "comes as welcome reassurance for patients," though there are unlikely to be any significant changes in the commercial prospects for Lantus, he said.

"Physicians we interviewed in the wake of the cancer scare reported keeping a wary eye out for new research on the matter, but were not overly concerned given the inconclusive nature of the original data," Wong observed.

Wong also noted that the cancer scare does not appear to have dented the product's image within industry - far from it, judging by recent deal-making. In October, Pfizer positioned itself to offer a biosimilar version of Lantus through a deal with Biocon ('Pfizer Teams Up With Biocon In Bid to Dominate Global Biosimilar Insulin Market,' 'The Pink Sheet,' DAILY, Oct. 18, 2010). Eli Lilly and Boehringer Ingelheim are set to co-develop a biosimilar version of Lantus via a recently announced deal ('Lilly/BI Eye Diabetes Leadership In Expansive Risk-Sharing Collaboration,' 'The Pink Sheet' DAILY, Jan. 11, 2011).

 

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