Full of promise

Oral mucositis, sometimes known as stomatitis, is a frequent and often seriously debilitating complication of chemotherapy and radiotherapy. The mucosa of the mouth becomes inflamed and, depending on the severity, this can lead to extreme ulceration and pain, leaving the patient unable to eat or drink. 

It is estimated that 40 per cent of all patients who receive chemotherapy develop some degree of oral mucositis. The statistics are worse in patients who receive both chemotherapy and radiotherapy (for head and neck cancer), with significant, severe disease seen in over 90 per cent of this population. There is no effective treatment for oral mucositis and it can have a devastating impact on patients. They also have an increased risk of infection and the disease can be so severe that chemotherapy may need to be reduced or delayed.

How does it happen?
The occurance of oral mucositis is a complex process involving many players. Briefly, the DNA in the cells lining the mouth and throat is damaged by chemotherapy or radiation, causing activation of a number of signalling pathways, leading to an increase in the levels of pro-inflammatory cytokines and other molecules that cause epithelial cell death.

Positive feedback signalling loops exacerbate the problem and the mounting loss of protective mucosal cells leads to sores in the mouth and throat. These sores amplify inflammatory signals and the inflammation, cell damage and pain increase.

What's available
There is an abundance of interventional strategies that one can use in order to try to prevent, or treat, oral mucositis. These include coating agents, pain palliation products, antiseptics, anti-inflammatories, anti-infectives, mucosal barriers and mouthwashes. However, there is very little evidence to support their effectiveness and many of these options are advocated without rigorous evidence to support their use.

Up and coming
Amgen is developing a promising new treatment for the condition called Palifermin (Kepivance). It is a recombinant human form of keratinocyte growth factor (KGF), an endogenous epithelial tissue growth factor that stimulates the growth of cells on the surface of the mouth and intestinal tract.  Palifermin was filed for approval in the US and Europe in 2004 and was launched in the US in January 2005. Its official approved indication is for mucositis in patients with haematological malignancies undergoing high-dose chemotherapy, with or without radiation, followed by a bone marrow transplant.

It is also in ongoing studies in other mucositis-induced settings and in January 2005 a phase III trial began using weekly doses of the drug in patients with advanced head and neck cancer receiving radiation therapy and chemotherapy. Key evidence of Palifermin's effectiveness, which supported its approval in the US, came from three phase III clinical trials. These studies showed that the drug reduced the incidence and severity of oral mucositis. In one of the trials (n = 212), it significantly reduced the incidence of Grade 4 oral mucositis from 62 per cent to 20 per cent, compared with placebo.

Grade 4 is the most severe level of oral mucositis and equates to the patient being unable to eat or drink. Grade 3 mucositis is also classified as a severe form and at this stage the patient can consume a liquid diet only. In this trial, the incidence of Grade 3 or 4 mucositis was 63 per cent in patients treated with Palifermin and 98 per cent in the placebo group. The median duration of Grade 3 or 4 mucositis was nine days for those treated with placebo and just three days for the Palifermin group.

Moreover, results showed a significant reduction in the use of opioid analgesics and parenteral nutrition. These results suggest that the drug may have benefits in terms of cost of treatment in addition to outcome improvements. The main adverse events associated with Palifermin in phase III trials were rash, pruritus, erythema, mouth/tongue disorders and taste alteration. However, these were all reversible, mild-to-moderate and did not interfere with treatment.

Further developments
Saforis is a patented oral suspension of L-glutamine that is in the phase III stage of development. Glutamine is an amino acid that is essential in the healing and regeneration of mucosal cells and Saforis is designed to deliver high levels of it directly into oral mucosa cells. The drug was originally developed by Aesgen which has since been acquired by MGI Pharma.

Saforis has shown promising results in trials to date, including a reduction in the severity of mucositis by 64 per cent compared with placebo in 195 patients. Adverse events associated with Saforis have been mild and similar to placebo. However, until both drugs go head-tohead, it is impossible to compare them accurately.

Further down the development pipeline is CG 53135, a recombinant human fibroblast growth factor-20 protein.This is being developed by CuraGen and the company began a phase II clinical trial in January 2005 using a single dose of the treatment.

The Author
Pipeline is written by Helen Commander, Adis International, using information derived from Adis Clincial Trials Insight and R&D Insight. For more information on Adis services contact Camille Scot-Smith on 020 7891 0733