Inflammatory Bowel Disease (IBD)
Inflammatory Bowel Disease (IBD) is an umbrella term used to describe disorders that involve chronic inflammation of the digestive tract. The two major types of IBD include Ulcerative colitis and Crohn’s disease characterized by inflammation of the lining of the digestive tract, are characterized by persistent or recurrent bloody diarrhea, abdominal pain, frequent bowel movements. fatigue and weight loss.
Curative medical therapy for IBD patients does not currently exist. Optimal management is an early induction of remission followed by a sustained and durable period of steroid-free remission and long-term maintenance to prevent relapse. For active CD the treatment algorithm starts with steroids, enteral nutrition, 5-ASA therapy, and can evolve to anti-TNFa agents such as infliximab, adalimumab or vedolizumab, alone, or in some combination. Unfortunately, not all patients respond to these therapies and over time, IBD patient responses become more refractory. Importantly, 30-50% of IBD patients with severe disease who are begun on biologic therapy, such as anti-TNFa, fail to achieve remission due to lack of drug response, loss of response, drug intolerance, or severe side effects that require cessation of therapy.
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, causes chronic inflammation in the gastrointestinal tract. In 2015 and 2016, an estimated 3.1 million (1.2%) U.S. adults reported having received a diagnosis of IBD. The prevalence of Crohn’s disease individually is approximately 319 per 100,000 adults and for UC it was approximately 249 per 100,000 adults. While IBD is generally nonfatal, people with IBD are often heavy users of the health care system. IBD patients often take medications and visit doctors frequently to achieve and maintain remission, and severe cases or those not responding to medications may require hospitalizations and surgeries. To correctly determine the severity of IBD, clinicians need to consider the clinical symptoms, the impact of the disease on the patient, the patient’s quality of life, the inflammatory burden, the extent of bowel involvement, and the location of the problem. Clinicians then need to consider the patient’s history. The current symptoms need to be understood in the context of the course of the disease since diagnosis. When biologic agents are typically prescribed to treat moderate-to-severe CD and ulcerative colitis (UC), they are licensed according to the definitions used in clinical trials. Namely, the Crohn’s Disease Activity Index (CDAI) assigns a score for CD, and the Mayo Score is used for UC. Severity also depends on the extent of structural damage, if any. There are numerous test that lead to a more accurate diagnosis of IBD including lab tests, stool studies, colonoscopy, flexible sigmoidoscopy, upper endoscopy, capsule endoscopy, Computerized tomography (CT) scan, and magnetic resonance imaging (MRI).
In summary, when diagnosing for severity, clinicians typically look at the following: for CD, these measures are rectal symptoms (more than 10 loose stools per week or not, abdominal pain); anorectal symptoms (pain, urgency, incontinence, discharge, tenesmus, active fistula); impact on daily activities; serum biomarkers (anemia, elevated CRP level, albumin level); mucosal lesions (active or not); whether the patient has complicated disease (presence or absence of a fistula, abscess, stricture, stoma, and/or intestinal resection); whether the patient has responded to corticosteroids, biologic agents, and/or immunomodulators within the past 12 months; and whether the disease is extensive (the degree of ileal involvement and/or pancolitis). For UC, these measures are the frequency of loose stools; anorectal symptoms; impact on daily activities; serum biomarkers; mucosal lesions; response to medication; whether the patient has extensive colitis; and whether the patient has been hospitalized within the past 12 months (with the same subcategories as above, when applicable
ALT-100 Benefits
We speculate the eNAMPT-neutralizing ALT-100 mAb to be a strategy to address the unmet need for therapies that limit inflammatory bowel injury/fibrosis and improve remission & survival in severe IBD. Published and unpublished data strongly support involvement of eNAMPT in human IBD pathobiology. First, NAMPT RNA and protein expression are significantly increased in intestinal tissues from IBD patients and are highly upregulated by IBD-relevant stimuli including growth factors and cytokines. Second, plasma/serum eNAMPT levels are elevated in IBD subjects and correlate with disease severity and responses to anti-TNFa therapies. Thirdly, NAMPT polymorphisms (SNPs), previously linked to inflammatory disease severity in ARDS and pulmonary hypertension (PH), associate with IBD severity in GWAS studies. Lastly, compellingly published data demonstrate eNAMPT is a highly druggable target, with ALT-100 mAb profoundly attenuating multiple preclinical systemic inflammation/organ injuries (ARDS, PH, radiation-induced fibrosis, cancer). Importantly, ALT-100 mAb reduces colon fibrosis/severity in preclinical IBD.
Anti-TNF agents fail in 20% of IBD patients, and an additional 10%–15% may lose response every year despite an initial benefit. There are multiple factors that may contribute to primary nonresponse or secondary loss of response, including concurrent intestinal infection, overlapping functional bowel symptoms, and, importantly, inadequate therapeutic drug concentrations. There are several reasons for low serum levels of drug, including increased clearance due to increased inflammatory burden, protein loss from a permeable inflamed mucosa, the development of neutralizing antidrug antibodies, or other patient-related factors such as increased body mass index or male sex. In patients who have nonresponse or loss of response to an anti-TNF therapy, and in whom there is an adequate serum level of anti-TNF, cycling within the class to another anti-TNF therapy is not likely to be of benefit. In these situations, pivoting to a different mechanism of inflammatory control may be preferred.