Drug shows promise for painful sensory neuropathy

Off-label use, safety trials provide hope

Nerve growth factor (NGF), a naturally occurring molecule that encourages nerve fiber growth, is being tested as a treatment for sensory neuropathy, a debilitating condition that affects about 30% of those with HIV infection.

A multicenter study funded by the AIDS Clinical Trials Group at the National Institutes of Health and led by researchers at Johns Hopkins University in Baltimore has demonstrated that NGF can reduce pain caused by this common disorder.1

The drug, produced by Genentech Inc. in South San Francisco, CA, is being tested in a phase III trial for a similar condition called diabetic retinopathy. Genentech hopes to obtain fast-track FDA approval as early as spring 1999.

HIV sensory neuropathy, a condition in which tiny nerves in the feet, legs, and hands become damaged, generally occurs fairly late in the disease process when an individual’s CD4 count is 200 or 300, explains Justin McArthur, MBBS, MPH, deputy director of neurology at Johns Hopkins. In addition to pain, patients may experience numbness as well as burning and tingling sensations, and often require narcotics for relief.

"It’s not life-threatening, but it does affect quality of life and basic functioning," says McArthur. "Patients often can’t walk, can’t stand, not because they are weak but because they are in so much pain," he adds.

Researchers speculate that the nerve damage may be caused by the infection or by HIV medications and antiretroviral drugs used to treat it. When neuropathy develops, patients may have to quit using certain drugs — even if they are effective in controlling HIV — in hopes of allowing the condition to reverse itself. The drugs include nucleoside analogs that can inhibit enzymes in HIV’s life cycle, specifically didanosine (DDI), stavudine (D14), and zalcitabine (DDC).

However, there has been no specific treatment for sensory neuropathy, and no treatment that would generate new nerve fibers to lessen the pain. Physicians have relied on tricyclic antidepressants, anticonvulsants, and pain killers to treat pain symptoms.

A promising preliminary study

At this year’s 12th World AIDS Conference in Geneva, Switzerland, McArthur and his research team reported on the phase II placebo-controlled randomized trial of 271 patients that was initiated in mid-1996. Patients at Johns Hopkins and several other academic centers received either placebo injections, lower-dose NGF, or higher-dose NGF. They self-injected the dose twice a week for a total of 18 weeks. All patients continued with their regular medication regimens.

At four-week intervals, researchers asked patients about their degree of discomfort, had them rate their pain, and took other neurological measures. "A significant number of people saw their symptoms — their pain — improve," says McArthur. The group receiving the placebo did not see improvements. Also, there was no difference between those who received the lower or higher doses, McArthur adds. Patients tolerated the drug well and had no significant side effects, although 40% of patients had some aching and soreness at the injection site.

Using "punch biopsy," a technique used by dermatologists for many years, researchers were able to investigate layers of skin where myriad nerve fibers had deteriorated. "This is a very neat way of easily quantifying the number of nerve fibers in the skin. It’s the first time [this adaptation of the technique] has been used in a clinical trial," says McArthur.

Biopsies at week 18 did not show regrowth of the nerves, leading researchers to decide to continue observing patients until week 70. "Patients at week 70 had received at least one year’s worth of NGF," says McArthur. "I would say 18 weeks is not long enough to regenerate nerve fibers in the skin. The team plans to follow the trial group for a full year beyond week 70. Patients who received NGF in the preliminary study will continue receiving the drug."

Off-label use the only option

Genentech has been pleased with the drug’s effectiveness in the diabetes clinical trials. "The drug has been well-tolerated," says Michelle Truelson, a company spokeswoman. "We have encouraging news concerning its effects in reducing the severity of neuropathy symptoms in diabetics." However, Genentech has decided not to sponsor further studies of NGF in HIV-related sensory neuropathy.

Genentech’s decision to forgo HIV studies is "unfortunate," says Mike Donnelly, a member of the Community Constituency Group, which advocated strongly for the trial. However, the company has agreed to continue supplying the drug to participants in the sensory neuropathy trial. "This may at least provide long-term safety data for the drug in the HIV-related sensory neuropathy trial," says Donnelly.

While overseeing the care of 12 patients enrolled in New York City-based Mount Sinai Hospital’s arm of the NGF trial, David Simpson, MD, has seen the drug’s effects first-hand. "It’s very exciting. Neuromuscular and neuropathy problems can be devastating in terms of patients’ quality of life. Until now, there’s been very little that we could do for them," says Simpson, who is co-chair of the AIDS Clinical Trials Group at NIH and director of the Neuro-AIDS Research Program at Mount Sinai.

While he is pleased that NGF may soon be available for off-label use, he cautions that even if the drug gets FDA approval for diabetes, HIV patients’ insurance companies may balk at providing coverage. "Coverage is not linked to FDA approval, but FDA approval helps," Simpson says.

McArthur and Simpson remain committed to pursuing NGF in HIV treatment and plan to design further trials, even if Genentech does not sponsor them. "If the drug is going to be used off-label for HIV, we want to know the best way to use it. The issue is still very much alive," says Simpson.

Reference

1. McArthur J, Yiannoutsos C, Clifford D. Trial of recombinant human nerve growth factor for HIV-associated sensory neuropathy. Presented at the 12th World AIDS Conference. Geneva, Switzerland; 1998.