EMEA state that animal studies support no increased risk of malignancy from contamination of nelfinavir (Viracept) with ethyl mesilate (EMS)

30 October 2008. Related: Antiretrovirals, Side effects.

As the previous issue of HTB went to press the European Medicines Agency (EMEA) released a statement (printed below) relating to their review of animal toxicology studies that were designed to address the risks from contamination of nelfinavir manufactured by Roche (Viracept). [1]

The agency has also published a question and answer resource for patients that is available online. [2]

The manufacturing problem, identified last summer, resulted in some batches of nelfinavir containing ethyl mesilate (EMS), a known genotoxic substance, and some patients using these batches. This led to the withdrawal of nelfinavir and its EMEA license, rapid toxicology analyses requiring new studies and the proposal of safety registers. [3]

EMEA statement: Studies assessed by the EMEA indicate no increased risk of developing cancer for patients who have taken Viracept contaminated with ethyl mesilate

Following a review of a number of toxicology studies, the European Medicines Agency (EMEA) confirms that there is no increased risk of development of cancer for patients who have taken contaminated Viracept (nelfinavir).

Viracept is an antiviral medicine, used in combination with other antiviral medicines to treat adults, adolescents and children over three years of age who are infected with human immunodeficiency virus (HIV-1), the virus that causes acquired immune deficiency syndrome (AIDS).

In June 2007, the European Commission, on the recommendation of the EMEA, suspended the marketing authorisation for Viracept because some batches of the medicine had become contaminated with high levels of ethyl mesilate, a known genotoxic substance, which may damage the DNA.

Evidence was subsequently provided by Roche, the marketing authorisation holder, that the manufacturing problems that led to the contamination had been resolved. In October 2007 the EMEA’s Committee for Medicinal Products for Human Use (CHMP) recommended that the suspension of the marketing authorisation be lifted. As part of this the CHMP requested a number of toxicology studies to be conducted to better assess the potential harm to patients using Viracept contaminated with ethyl mesilate.

The studies carried out by Roche showed that it is possible to calculate a threshold value below which ethyl mesilate does not cause any irreversible damage (mutations) in the DNA. The CHMP noted that patients or children born to mothers who had taken contaminated Viracept were exposed to ethyl mesilate levels well below this threshold, and therefore that there was no increased risk of developing cancer for these patients compared with those patients who were not exposed to the contaminant.

The Committee therefore concluded that there was no need to monitor patients who had been exposed to high levels of contaminated Viracept through specific patient registries.

Comment

The toxicology studies on which the EMEA decision and statement were based were presented at the IAS conference in Mexico City and are accessible online. [4]

While data from animal studies may provide some reassurance that risks “may” be low (maximum exposure concentrations were calculated as 370-fold lower than the minimum toxic level in animal studies), these cannot be used by the EMEA to say that “patients were at no increased risk of developing cancer”.

At least several thousand patients globally have already been exposed to a known carcinogen and it is difficult to understand why, from a safety and regulatory perspective, anything could be acceptable, other than following this cohort of patients to see whether a higher rate of malignancy actually occurs.

We still need a public report to provide a breakdown of numbers of patients using nelfinavir, which clinics and countries were affected and which are not affected. Why have individual patients not been contacted? Who were most likely to have used the contaminated batches? This should at least be possible in the UK, where the numbers involved are small given that not all batches were recalled.

If current tracking systems are not able to do this, we need to know exactly how far contaminated batches can be tracked in case a similar event occurs.

Individual animal and farm tracing is possible following recent food-related health scares – tracking well highly regulated drug supplies should not be difficult to achieve – at a minimum to an individual clinic, if not patient, level.

As it stands, the EMEA statement appears premature, and includes conclusions that go beyond those supported by the evidence.

References:

1. EMEA press release “Studies assessed by the EMEA indicate no increased risk of developing cancer for patients who have taken Viracept contaminated with ethyl mesilate”. (24 July).
   http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viracept/38225608en.pdf
   
2. EMEA resource. Questions and answers on the follow-up to the contamination of Viracept (nelfinavir) with ethyl mesilate.
   http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viracept/Q&A_Viracept_37580708en.pdf
   
3. For details see HIV Treatment Bulletins from June/July 2007. August/September and October 2007.
   http://www.i-base.info/htb/v8/htb8-6-7/Roche.html http://www.i-base.info/htb/v8/htb8-8-9/Update.html http://www.i-base.info/htb/v8/htb8-10/emea.html
   
4. Mueller L et al. Elevated ethyl methanesulfonate (EMS) in nelfinavir mesylate (Viracept, Roche): animal studies confirm toxicity threshold and absence of risk to patients, 17th International AIDS Conference, 3-8 August, 2008. LBPE1157.
   http://www.aids2008.org/Pag/Abstracts.aspx?AID=16184