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November 29th, 2016 SUBSCRIBE TO INSIGHTS

Celiac Disease (CD)is an immune-mediated disorder of the small intestine caused by a permanent sensitivity to gluten in genetically susceptible individuals. Gluten is a general name for the proteins found in wheat (wheatberries, durum, emmer, semolina, spelt, farina, farro, graham), rye, barley, and triticale. Gliadin, one of the two principal protein groups comprising gluten, plays a critical role. The prevalence of CeD is currently estimated at 1% in both Europe and the USA (three million each). Furthermore, the incidence of CeD is increasing among certain populations in Africa (Saharawui), Asia (India), and the Middle East.

Celiac disease is a multisystem, immune based disorder triggered by the ingestion of gluten in genetically susceptible individuals. The western population has witnessed an increased prevalence of 1% in the past few decades.

In contrast to other autoimmune diseases, the gluten protein is a well-defined environmental trigger for the development of CeD clinical manifestations. Predisposition is predominantly linked to human leukocyte antigen (HLA) class II alleles, specifically in the HLA-DQ region. Around 95% of CeD patients have the HLA-DQ2 heterodimer and close to 5% have the HLA-DQ8 heterodimer. Tissue transglutaminase (tTG) is a calcium dependent ubiquitous enzyme that catalyzes post-translational modification of proteins and is released from cells during inflammation. This enzyme exerts at least two critical roles in the pathogeny of CeD: first, as a protein-deamidating enzyme that enhances gluten’s immune-stimulatory effect, and second, by producing autoantibodies (anti-tTG, detectable by ELISA) that further contribute to autoimmunity. Glutamine-rich gliadin peptides are substrates for tTG and the resulting deamidated, negatively charged peptides have a much higher affinity for HLA-DQ2 and HLA-DQ8. Thus, tTG is believed to play a key role in the pathogenesis of CeD.

CeD results from a complex interplay of genetics and environment, leading to the dysregulation of the immune system and consequent autoimmune attack. CeD patients present with diarrhea (45-80%), abdominal pain, anemia, short stature, weight loss. and fatigue. In addition, a very high unmet need for treatment exists because of early diagnosis difficulties and no approved pharmacological therapies. The atypical presentation of CeD is the most difficult to diagnose as clinical symptoms are generally extra-gastrointestinal, for example, debilitating migraines, disabling severe joint pain, chronic fatigue, arthritis, and headache. Diagnosis of CeD is confirmed by histological evaluation of duodenal biopsy and management is primarily by a gluten free diet (GFD)

By 2012, gluten-free products were creating waves in grocery stores around the US -- Time Magazine named it the second most popular food trend in 2012 and once again in 2015. Perceived by the masses as “healthy,” sales of gluten-free products soared in 2015 totaling US $1.5 billion. Although a GFD is a medical necessity for patients with gluten sensitivity, it has also been adopted by many people, especially women, with no gastrointestinal abnormalities. The trending GFD market is thus projected to reach US $4.89 billion by 2021, expanding at a 7.7% compound annual growth rate (2015 to 2021). Unfortunately, outcome analysis from clinical studies has proven that 50-60% of CeD patients experience relapse even after following a strict GFD.

Multiple research studies have shown a strong association between the concurrent prevalence of celiac disease and depression. The risk for developing depression is 1.8 times more likely for people with CeD in comparison to the general population.

Movers & Shakers

Despite the fact that 50-60% of GFD patients relapse, the active clinical pipeline is small compared to other gastroenterological indications, e.g., Crohn’s disease and ulcerative colitis. The pressure is on for both pharma and academia to introduce non-dietary therapies for CeD patients. Ideally, the target product profile should lessen the reliance on GFD and decrease symptoms due to accidental gluten ingestion.

The clinical pipeline for CeD includes ten candidates split equally between phase 1 and phase 2. The following molecules have shown positive results in clinical studies:

  • Larazotide acetate is an 8-amino acid, tight junction modulator not systemically absorbed. It is a first-in-class oral peptide acquired by Innovate Biopharmaceuticals from Alba Therapeutics (February 2016). In May 2014, Alba announced that it met its primary endpoint in a 342-patient phase 2b trial with statistical significance (P=0.022; NCT01396213). Larazotide acetate has received Fast Track designation by the US FDA for the treatment of CeD and will enter registration phase 3 trials in 2017.

  • Latiglutenase is a mixture of two gluten-specific recombinant proteases that degrade gluten proteins into small, physiologically irrelevant fragments. It is administered as an add-on to GFD for the treatment of CeD. In 2012, latiglutenase received Fast Track designation by the U.S. FDA for the treatment of CeD and in Q1 2016, ImmunogenX completed the acquisition of Alvine Pharmaceuticals including latiglutenase. Unfortunately, results from a Phase 2b trial (NCT01917630) revealed no difference between latiglutenase and placebo groups in several related parameters, i.e., change from baseline for ratio of length of villous to crypt, number of intraepithelial lymphocytes (IEL), or serologic markers of CeD.

  • BL-7010, developed by BioLineRx, is a gliadin sequestrant, having a high affinity for the immunogenic glutin peptides that result in CeD pathology. Positive phase I/2 clinical results were recently announced where the study met its primary endpoints. BioLineRx has received confirmation regarding the classification of BL-7010 as a Class IIb medical device in the European Union.
  • Nexvax2®, developed by ImmusanT, is a therapeutic vaccine intended to protect against the effects of gluten exposure in HLA-DQ2.5+ patients with CeD. Data from Phase 1 demonstrate that, when compared to placebo, three weekly doses of Nexvax2® modulated proinflammatory cytokine release following a 3-day gluten challenge. These observations suggest that Nexvax2 may be more effective with longer or more intensive dosing schedules and this hypothesis is being tested in ongoing studies.

Interestingly, Takeda’s Entyvio® (vedolizumab), marketed for Crohn’s disease and ulcerative colitis, is also being investigated to prevent CeD in established celiac patients undergoing histological remission (Study ID: NCT02929316).
Once recognized as a “rare disorder of children,” it is now universally acknowledged by physicians and academia that CeD can be diagnosed among any age group. Individuals who are genetically susceptible and later exposed to various environmental triggers develop CeD. Although it is a highly prevalent gastrointestinal condition affecting 1 in a 100 globally and at least3 million and 530,000in United States and England respectively, CeD faces an acute lack of awareness both at the patient and physician level. Alarmingly, 83% of Americans who have CeD remain undiagnosed or misdiagnosed with other conditions. Patients with CeD present with symptoms that most often mimic other gastrointestinal disorders (including neurological conditions), thus compounding this statistic. Fortunately, community awareness campaigns have been instrumental in educating people about CeD-linked symptoms. A gluten free diet, currently the only treatment available, remains exorbitantly costly averaging 17% more for basic staples, 316 % more for gluten-free wraps, and 574 % more for flour.
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