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Uncovered: Safety Issues Linked With Ironwood's Drug, Linzess

Summary

Ironwood’s constipation drug, Linzess, is a primary suspect in at least 7 deaths, 85 hospitalizations, 16 disabilities, all in just 3 years since its launch in 2013.

Linzess is causing previously unknown, unreported and unlabeled severe systemic adverse events, including rapid weight gain, renal failure, blood clots and strokes.

We uncovered new, concerning insights about Linzess’s mechanism of action that are related to a serious, systemic endocrine hormone depletion, which may eventually lead to damage to multiple organs.

Without Linzess there is no Ironwood - its probable removal from the market, or a substantial decrease in its sales due to the exposed safety issues, will spell disaster for.

We submitted our findings to the FDA’s Division of Gastroenterology and Inborn Errors Products. Our findings uncovered a great risk for patients, which the public is not aware of.

The complete report can be found on the Phase V research website

About Linzess

Ironwood Pharmaceuticals' (NASDAQ:IRWD) Linaclotide (marketed under the trade name Linzess in the US and Constella in the EU) is a first-in-class peptide agonist of the receptor Guanylate Cyclase C (GC-C). The FDA approved Linzess in August 2012 for the treatment of chronic idiopathic constipation (CIC) and constipation-predominant Irritable Bowel Syndrome (IBS-C) in adults.

IBS is a group of symptoms, including abdominal pain and changes in the pattern of bowel movements, without any evidence of underlying damage. Since the cause of IBS is poorly understood, most drugs indicated for its treatment target the relief of symptoms. Most commonly, IBS-C is treated with fiber supplements, anticholinergic and antispasmodic medications, antibiotics and specialty-class medications, which include Amitiza (lubiprostone), and Linzess.

CIC is constipation that does not have a physical (anatomical) or physiological (hormonal or other body chemistry) cause. Commonly, CIC is treated with laxatives (osmotic and stimulant) and specialty drugs. Currently, only two drugs are FDA-approved for the treatment of CIC: Linzess and Amitiza.

IRWD retains 50% of the rights to Linzess in the US, sharing the rest with commercial partner Forest Laboratories [acquired by Actavis and subsequently Allergan (NYSE:AGN)]. On Oct 27, 2015, Allergan acquired exclusive rights to Constella in the EU from IRWD's previous EU partner Almirall.

Technically, Linzess is a toxin more than it is a drug since its 14-amino acid peptide sequence is nearly identical to that of heat-stable enterotoxin from Escherichia coli (E. coli toxin). Linzess and the E. coli toxin are agonists of GC-C in the gastrointestinal tract. GC-C has a widespread distribution in all tissues including in the kidneys, brain, heart and reproductive organs. However, according to IRWD, Linzess does not pass through the GI tract and has no systemic circulation in humans.

Catching Linzess and Summary of Findings

We have gathered evidence that IRWD's Linzess poses a real danger to patients by using a software tool that collects and analyzes patient case reports from the FDA Adverse Event Reporting (FAERS) database. We then added the information from a specialized Big Data analysis algorithm which is capable of picking up and processing thousands of patients' and doctors' conversations across the web and in the public domain. Using these tools, we also compared the incidence of adverse events related to Linzess to those of other drugs for the treatment of IBS and CIC.

Having identified the dangers posed by Linzess, we set to explore its mechanism of action, as well as its New Drug Application (NDA) paperwork, in order to identify a possible cause for such widespread systemic side effects seen in patients. We also consulted with an academic researcher well versed in the field, in order to further zero in on the reasons why Linzess seems to pose these dangerous AEs.

We further strengthened our view that Linzess's dangers were not accurately address its clinical development and regulatory pathway, by examining our findings in physicians setting using a survey of 30 gastroenterologists who commonly prescribe Linzess.

Upon the completion of our research, it became apparent that we should imminently warn the FDA about the dangers of Linzess. We subsequently engaged in conversation with the agency's Division of Gastroenterology and Inborn Errors Products and relayed our findings.

Below we present the summary of our findings from the various research approaches:

1. Findings from the Analysis of the FDA Adverse Event Reporting (FAERS) database

FAERS is a database that contains information on adverse event and medication error reports submitted to the FDA by physicians, pharmacists and caregivers. The database is designed to support the FDA's post-marketing safety surveillance program for drugs and therapeutic biologic products.

We utilized data processing & analysis software that scans and analyzes FAERS case reports in order to document the incidence of adverse events in which Linzess was deemed to be a primary suspect by the report filer (overseeing physician, nurse, pharmacist, family member, etc). A drug is defined as a primary suspect if the report filer deemed it to be responsible for the report's subject (death, adverse event).

We compared the incidence of adverse events (NYSE:AES) and serious adverse events (SAEs) contained in FAERS across a range of Linzess's competitor drugs in IBS and CIC. Unsurprisingly, Linzess was deemed the most dangerous drug its peer group (fig. 1), with serious outcome, hospitalization and Important Medical Event (IME) rates that were 10 times higher than those of its major competitor Amitiza (fig. 1&2). Shockingly, Linzess also clearly appeared to be much more dangerous than Lotronex - an IBS drug that has been removed from the market in 2000 due to SAEs and deaths.

In terms of grave outcomes resulting from serious events, Linzess had a significantly higher incidence of deaths, hospitalizations, disabilities, life threatening events and incidents which required intervention than any other drug treating IBS and CIC (figs. 3&4).

Taking all of the outcomes together, Linzess was linked to a serious outcome incidence rate that was 45 times higher than that of its CIC competitor, Amitiza.

Figure 1...


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