Understandably, many young biotech companies are eager to announce promising Phase I results.  Simply-stated, a Phase I clinical trial is a preliminary test to determine whether a drug candidate is safe and can be tolerated by humans.  This usually involves testing various doses in order to see if there are any adverse effects.  It usually involves healthy volunteers, but in a few cases, such as this one, the trial can be done in patients who actually have a disease. Phase I trials are not designed to test if the drug is efficacious to treat a disease.  This means that “positive results” do not necessarily mean that the drug will work against the disease.

We’re relying here on a press release from ImmusanT (ref. 1), and on a YouTube video posted by the company’s Chief Scientific Officer, Bob Anderson, Ph.D. (Ref. 2). Pharmaceutical companies often do not release full details of their clinical trials so that they can be subjected to critical peer-review. Clinical trial data is commonly maintained as confidential information between the company and the FDA, so we don’t have a lot to go on at this point. The study was performed at two clinical centers in Australia.

Twenty-five celiac patients were given three, weekly doses of Nexvax2, which is a mixture of small peptides, or fragments, of the gluten protein. There were a further 9 patients who received a placebo, for comparison.  All the patients had the HLA-DR2 haplotype, and were on a gluten-free diet prior to the study. Four different doses of Nexvax2 were tested. At the higher doses, 7 of 19 patients reported nausea, and two vomited. One patient had to withdraw from the trial because of severe gastrointestinal symptoms.

What is safe and tolerable? Ultimately, this is a somewhat subjective judgment, but the bottom line is that the FDA (or other regulatory body for clinical trials outside the US) needs to be convinced that the drug is safe enough to continue to Phase II clinical trials. With any drug, if you use a high enough dose you will observe toxicity—this is not surprising since all drugs are designed to change the function of the body. While a number of unpleasant side-effects were observed, especially at higher doses, we expect that lower doses will actually be used in later studies to see if the patients can be desensitized to gluten.

We don’t know yet if the company has been approved to proceed to the next phase of clinical studies—ultimately it will be the regulatory agencies who determine if the drug is sufficiently safe and well-tolerated.

While the authors of this study refer to “bioactivity”, what they really mean is that they saw a change in the blood profile of the patients in this trial. However, many kinds of response count as bioactivity: this is completely different from saying that the drug was efficacious for treating a disease. We will have to wait for future clinical trials to see if the drug actually helps to treat celiac disease.

Most people think of vaccines as a way of protecting against an infectious disease. In this case, material based on the infectious agent (such as bacterium or virus) is administered in order to provoke an immune reaction to that material. Later, if a person is exposed to the bacterium or virus, the body is primed and ready to attack the foreign material vigorously and rapidly.

The “vaccine” described in this clinical study is the exact opposite, an approach called immunotherapy. Instead of trying to provoke a strong response to a foreign substance, such as gluten, the idea is give small amounts of the foreign substance repeatedly, so that the immune system is effectively tricked into thinking that the substance is not foreign at all. In other words, it’s a vaccine designed to reduce the reaction to a foreign substance.

Immunotherapy has been used effectively for some allergic diseases, typically by administering small amounts of the foreign protein (or “antigen”). The use of small peptide fragments of an antigen for immunotherapy has been proposed and tried for decades, but the field is still in its infancy (Refs.  3-5). While this area of research is exciting and intriguing, we have not been able to find any examples of where such an approach has resulted in an approved therapy, so far.

An allergy results from the body recognizing a foreign substance (such as pollen) by the IgE antibody, causing inflammation (such as hives, or even shock). In contrast, in celiac disease, the body’s reaction to gluten involves IgA or IgG antibodies, and allergy to gluten is relatively uncommon. Attempting immunotherapy for this kind of reaction is very interesting, but it also means that we are in largely uncharted waters (Refs.  3-5).

Celiac disease is considered an autoimmune disease, meaning that the body attacks its own proteins, “thinking” that they are foreign. It is not certain, however, what portion of the symptoms of celiac disease can be attributed to antibodies against gluten. Unfortunately, this means that even if Nexvax2 is able to block the body’s immune response to gluten, it doesn’t necessarily mean that it will block the autoimmunity.

ImmusanT has designed its drug candidate based on the peptide fragments of gluten that are most likely to provoke an immune reaction (adaptive immunity). However, gluten toxicity is actually more complicated, since there are different peptide fragments that can cause inflammation directly, activating the “innate” immune system (Refs.  6-8). This means that blocking the production of antibodies to gluten may not be sufficient to alleviate inflammation in the intestine. In addition, while celiac disease is the greatest concern, there is also increasing evidence of non-celiac gluten sensitivity in a substantial fraction of the population, and it’s not obvious that a vaccine would affect this condition.

A gluten-free diet works to alleviate some or all of the damage and side effects seen in celiac disease, and has no known side effects (other than inconvenience, cost and social stigma). For a drug to be successful, it should be at least as safe as the existing therapies, and ideally should offer some improvement above and beyond current therapy (Ref. 9,10). This is especially true since the full risk profile of a drug does not become clear until after the drug is launched on the market.  It would be a shame for people to abandon their gluten-free diet in the hopes that a pill or vaccination would take care of the problem. On the other hand, our hunch is that if an immunotherapy is developed that has even a partial activity, it might be used in addition to a gluten-free diet, especially since the recovery of many celiac patients is often slow. This might be especially relevant to the small fraction of “refractory” patients who do not respond to a gluten-free diet (ref. 10).

We’re not trying to be pessimistic or negative here, but just offering a strong voice of caution that we are a long way from a cure for celiac disease, and that Phase I clinical trials are a preliminary stage of the drug development process. Indeed, it is a sad truth that the majority of drug candidates which pass Phase I are ultimately not sufficiently safe or efficacious to be taken to the market. We want to stress that we find the scientific research done by Dr. Anderson and his colleagues elegant and exciting, and wish ImmusanT the best of luck in developing this drug! There is definitely a need for treatment options beyond just a gluten-free diet, because about half of the people with celiac disease still have some intestinal damage after 5 years on a gluten-free diet. We will definitely follow up with further posts as we learn more about this important research.

References:

Ref 1:  ImmusanT reports positive resutls from Nexvax1 Phase 1 study in celiac disease

Ref 2:  A Phase I study to determine safety, tolerability and bioactivity of Nexvax2 in HLA DQ2+ volunteers with celiac disease following a long-term, strict gluten-free diet

Ref 3:  Future forms of immunotherapy J. Allergy Clin Immunol 2011 Jan;127(1):8-15 doi:10:1016.jaci.2010.10.034  Casale, TB & Stokes, JR

Ref. 4: Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nature Medicine Supplement 2005 11:4  Larche, M & Wraith, DC

Ref. 5:  An update on immunotherapy for food allergy Curr Opin Allergy Clin Immunol. 2010 10(6):587-93.  Skurlock, AM & Jones, SM.

Ref. 6:  Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease Gut 2007 56(4):480-8.  doi:10/1136/gut2005.086637 Barone, VM et al.

Ref. 7: Gliadin Peptide P31-43 Localises to Endocytic Vesicles and Interferes with Their Maturation. PLoS One 2010; 5(8):e12246.  Barone, MV et al.

Ref. 8:  Gliadin-Mediated Proliferation and Innate Immune Activation in Celiac Disease Are Due to Alterations in Vesicular Trafficking PLoS One. 2011; 6(2):e17039.  Barone, MV et al.

Ref. 9:  Celiac disease: pathogenesis of a model immunogenetic disease J Clin Invest 117:41-49.  Kagnoff, MF

Ref. 10:  The Spectrum of Celiac Disease: Epidemiology, Clinical Aspects and Treatment Nat Rev Gastroenterol Hepatol. 2010;7(4):204-213. Tack, JG et al.