8 August 2019
Intermittent or chronic nausea. Bloating. Burning, shearing or gnawing abdominal pain. A feeling of fullness after eating just a few bites. Poor appetite and weight loss. These symptoms add up to the distressing condition known as gastroparesis – a chronic, life-limiting disorder that leads to weight loss and potentially life-threatening complications. Gastroparesis is characterised by delayed gastric emptying and, while it is often associated with type 1 diabetes, most cases are idiopathic. There are no cures, only treatments, and some of those are less than satisfactory – posing risks of serious side effects and losing potency over time.
Gastroparesis appears to associate with aberrant regulation of gastrointestinal function through neuropeptides binding to the neurokinin receptors, namely NK-1, -2 and -3. There are signs of a possible step forward with tradipitant, a second generation NK-1 receptor antagonist. There is evidence that this drug is well tolerated by humans, with only mild side-effects, and that it has benefited patients with gastroparesis.
Unfortunately, recent actions by the Food and Drug Administration (FDA) have halted this drug from moving forward in the approval process, with the agency requiring that a fatal study on dogs be carried out before allowing a human clinical trial to continue. This study would involve force-feeding the drug to healthy, young dogs every day for 9 months, in vastly greater amounts than the clinical trial participants have been taking. The maker of the drug, Vanda Pharmaceuticals, however, is refusing to carry out this test without evidence that the dog study is, in fact, justified, and has filed a lawsuit against the FDA.
Tradipitant developed from the observation that NK-1 antagonists may be effective analgesics, but would require chemical modification to address issues of poor bioavailability and metabolic degradation. The expression profile of the neurokinin receptors throughout the central and peripheral nervous system puts these receptors at the centre of many vital physiological processes, including hormone and gland secretion, pain, blood vessel dilation and immune responses. Thus, modulating neurokinin receptor activity presents an exciting opportunity to address several disparate conditions. The location of NK-1 receptors in the region of the brain that controls vomiting suggests that NK-1 antagonists would be effective as anti-emetics and may be particularly helpful in controlling some of the symptoms of gastroparesis.
There has been intense research interest in neurokinin receptors since the 1990s; over 400 patents relating to NK-1 antagonists have been filed, 250 clinical trials registered and countless volumes of data collected and analysed, with over 900 research papers published in the last 10 years alone, offering vital information regarding compound safety and efficacy.
This prior evidence of safety in humans, together with the poor translation rates that continue to demonstrate the failure of animal models to accurately predict human efficacy and safety, indicate that further testing on dogs is unnecessary. Tradipitant has a positive safety record in clinical trials for pruritus in atopic dermatitis and alcoholism as well as in Vanda Pharmaceutical’s four-week trial for gastroparesis. Also, structurally-related compounds, such as apepritant, have been successfully used to treat chemotherapy-induced emesis for many years. Instead of the FDA insisting on more and more animals studies, the agency should conduct retrospective analyses of data pertaining to previous nine-month dog studies, compared to other animal data for the same compounds. This will make it possible to evaluate whether submitting dogs to chronic testing regimes adds any relevant information beyond what is already known from existing preclinical trials, the in vitro data, activity data and clinical trials.
This is not just about improving science and saving dogs. It is also about providing the best treatments — and a big dose of hope — to those who are living with gastroparesis. The people who took tradipitant for four weeks and felt relief from their symptoms can no longer benefit from the drug due to the FDA’s requirements.
We urge the agency to continue following the initiative of former FDA Commissioner Scott Gottlieb, who pledged to reduce the reliance on animals used in testing conducted by both the agency and industry. Dr. Gottlieb specifically stated “… [animal testing] needs to be done with great care and with a very clear understanding that there’s an overwhelming public health purpose to the experimentation.” It is clear that for tradipitant there isn’t a rational need for conducting yet another animal study.