Efficacy and Safety of SYN-010 in IBS-C
Efficacy and Safety of SYN-010 in IBS-C
Irritable bowel syndrome (IBS) is a gastrointestinal (GI) syndrome characterized by chronic
 abdominal pain and altered bowel habits in the absence of any organic cause. The symptoms of
 IBS not only adversely affect a patient's health-related quality of life (QoL), but also
 place a significant financial burden on society due to reduced work productivity and
 increased use of healthcare-related resources. Patients with IBS frequently complain of
 abdominal bloating and increased gas production in the form of flatulence or belching. The
 prevalence in North America and Europe is approximately 10-15%. Irritable bowel syndrome
 affects all ages and genders however there is a 2:1 female predominance in North America.
 Irritable bowel syndrome is classified into 4 subtypes based on stool pattern: IBS with
 constipation (IBS-C), IBS with diarrhea, mixed IBS, and un-subtyped IBS. Irritable bowel
 syndrome with constipation is defined as the presence of hard or lumpy stools with ≥ 25
 percent of bowel movements and loose or watery stools with < 25% of bowel movements.

 SYN-010 is a modified release, oral formulation of lovastatin being developed for the
 treatment of IBS-C. The SYN-010 program is based predominantly on research by Dr. Mark
 Pimentel and collaborators hypothesizing that reduction in intestinal methane (methane)
 production can reverse constipation and improve global symptoms in IBS-C. Methane production
 in humans is due to methanogenic archaea in the intestine, predominantly Methanobrevibacter
 smithii (M. smithii). Methane, the key product of anaerobic respiration of methanogens, had
 been perceived to produce no ill effects in humans aside from gaseous distention. However,
 several research groups worldwide have shown that a significant percentage of patients with
 IBS-C excrete methane, and elevated methane production by methanogens correlates with
 constipation and related symptoms in both IBS-C and chronic idiopathic constipation. A direct
 causative role for methane in IBS-C was demonstrated in a recent case report, wherein a woman
 undergoing fecal microbiota transplantation (FMT) for C. difficile infection unknowingly
 received stool containing a high concentration of methanogens. The FMT recipient rapidly
 developed severe symptoms of IBS-C that were subsequently reversed by ablation of methane
 production.
SYN-010 has previously been evaluated in consecutive Phase 2a clinical trials. Sixty-three
 (63) IBS-C patients with high breath methane (>10 ppm) at screening were enrolled in a
 multicenter, randomized, controlled, double-blinded clinical trial (RCT) in which they
 received SYN-010 21 mg, SYN-010 42 mg or Placebo once daily for 4 weeks. Fifty-four (54)
 subjects who completed the RCT continued into an open-label extension (EXT) in which all
 subjects received SYN-010 42 mg once daily for an additional 8 weeks.

 The SYN-010 Phase 2a studies were intentionally designed as mechanistic proof-of-concept
 studies, wherein reductions in breath methane were employed as a rapid and cost-effective
 means by which to determine if SYN-010 could be effective in treating an underlying cause of
 symptoms in IBS-C. Breath methane was reduced relative to baseline in SYN-010 treatment
 groups, and lower breath methane levels correlated with an increased number of complete
 spontaneous bowel movements (CSBMs) at week 12, consistent with the proposed
 methane-inhibiting action of lovastatin lactone.

 Since lovastatin has not previously been used to treat IBS-C patients, the SYN-010 Phase 2a
 studies were also focused on the safety of the SYN-010 dosage form. Daily doses of SYN-010
 were well-tolerated by IBS-C patients over the 12-week treatment period (at least 8 weeks of
 SYN-010 42 mg). SYN-010 did not cause clinically meaningful or persistent changes in serum
 liver and muscle markers in IBS-C patients at daily doses of 21 mg and 42 mg. Modest
 decreases from baseline in lipid parameters observed after 7 days of SYN-010 21 mg or 42 mg
 had largely faded by 28 days and were not evident after 12 weeks of dosing. Very few adverse
 events were reported over 12 weeks of SYN-010 treatment and all were of mild or moderate
 intensity. No serious adverse events were reported and there were no incidences of
 drug-related diarrhea, which is an important potential benefit of SYN-010 as an IBS-C
 therapy.

 Although the Phase 2a studies were not prospectively powered for formal statistical
 evaluation of clinical endpoints, compelling improvements in CSBMs, abdominal pain, and
 bloating were observed in SYN-010 treatment groups. These clinical findings have been
 presented in multiple public forums and a panel of clinical advisors affirmed that the Phase
 2a data validate the need to evaluate optimal dosing of SYN-010 in a larger patient
 population over a longer dosing period.

 Based on the potential clinical benefit observed in Phase 2a, this Phase 2b clinical study
 will evaluate in more detail the clinical effects of two dose strengths of SYN-010
 administered over a longer treatment period (12 weeks per FDA guidelines) to a larger number
 of IBS-C patients. The study will seek more definitive evidence regarding potential symptom
 improvements and safety in IBS-C patients. The study also seeks to provide new information of
 relevance to both efficacy and safety by measuring changes to the microbiome in patient stool
 samples; serum level of cytokine markers of inflammation; and expanded breath gas
 measurements.

 SYN-010 is a hydroxypropyl methylcellulose (HPMC) capsule filled with enteric-coated tablets
 from which lovastatin is released at different intestinal pH values. The tablets are designed
 to pass through the stomach unchanged then release a small amount of lovastatin into the
 duodenum and the majority of the lovastatin dose into the ileocecal junction and colon. The
 amount of lovastatin to be released into the small and large intestine is anticipated to be
 consistent with the relative levels of methane-producing archaea in each location of the
 intestine.

 Methane production (methanogenesis) is a ubiquitous process in the human intestine, disposing
 of hydrogen and other by-products formed during bacterial fermentation. Methane production in
 humans is almost entirely due to the archeon M. smithii. Elevated intestinal methane
 production reduces intestinal motility and is a cause of constipation, pain and bloating in
 IBS-C.

 Interest in lovastatin as a potential inhibitor of methanogenesis originated with recognition
 that the rate-limiting step in the synthesis of archaeal lipid membranes is catalyzed by
 HMG-CoA reductase (HMGR) which is the target enzyme for cholesterol-lowering statins.
 Subsequent in vitro studies (described above) and computational studies have since determined
 that HMGR is not the target for lovastatin anti-methanogenic activity; rather, lovastatin
 lactone appears to exert a direct effect on methanogenesis enzymes. The mechanism by which
 lovastatin lactone inhibits methane production by M. smithii has not been conclusively
 determined; however, detailed computational studies showed that lovastatin lactone may
 competitively inhibit F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), an
 enzyme that is integral to the M. smithii methanogenesis pathway.

 Methanogenic archaea reside predominantly in the human colon, with lower methanogen levels
 measured in the small intestine of some patients. Methane production at both sites
 contributes to reduced gastrointestinal motility and rat studies suggest that the ileocecal
 region may be of particular significance. SYN-010 utilizes a dual-pulse release profile to
 deliver a portion of the lovastatin dose to the small intestine and the majority of the dose
 to the ileocecal junction and colon where the most methane-producing organisms are found; the
 relative amounts of lovastatin released into the small and large intestine are consistent
 with the anticipated relative levels of methanogens in each location.

 Lovastatin lactone exerts its methane-reducing effect in the intestinal lumen and systemic
 absorption of lovastatin is not required for its therapeutic effect in IBS-C.
Inclusion Criteria:

 -  Male or female participants aged between 18 and 65 years inclusive.

 -  Patient must be willing and able to participate in the study for the required
 duration, understand and sign the informed consent (ICF), and be willing to comply
 with all protocol-related visits and procedures.

 -  Patient has had IBS-C symptoms (as defined by Rome III diagnostic criteria) for at
 least 6 months prior to diagnosis.

 -  Patient has an average score of ≥ 3.0 for daily abdominal pain at its worst (11-point
 numerical rating scale [NRS]) during and up to the 17 days immediately before
 randomization (i.e. Pre-treatment Period).

 -  Patient has an average of ≤ 3 CSBMs per week or ≤ 5 SBMs per week during the 17 days
 immediately before randomization (i.e. Pre-treatment Period).

 -  Patient has a breath methane level ≥ 10 ppm on a lactulose breath test administered at
 Screening.

 -  Patient may be on a stable, continuous regimen of fiber or probiotics one month before
 the Screening Visit; however, they must maintain a stable dose regimen through Week
 12.

 -  Patient must agree to refrain from starting a new diet, changing stable dose of
 supplemental fiber, or changing exercise pattern that may affect IBS-C symptoms from
 the time of Screening through the end of the study. If the patient takes food products
 that are strong inhibitors of cytochrome P450 3A (CYP3A) (e.g. grapefruit juice,
 Seville orange juice, St. John's Wort), he/she must agree to refrain from taking these
 from the time of Screening through the end of the study.

 -  Patient must agree to use an acceptable method of contraception from the time of
 signing the ICF to 30 days after the final dose of study drug if the patient is a
 sexually active female of child-bearing potential (defined as any female who has
 experienced menarche and who is NOT permanently sterile or postmenopausal.
 Postmenopausal is defined as 12 consecutive months with no menses without an
 alternative medical cause). Adequate contraceptive measures include: oral
 contraceptives (stable use for two or more cycles before Screening); intrauterine
 device; Depo-Provera®; Norplant® System implants; partner with a vasectomy;
 double-barrier birth control (e.g. use of a condom plus diaphragm or condom plus
 either contraceptive sponge, foam, or jelly); or abstinence. According to drug
 research standards, male patient must agree to use an acceptable method of
 contraception and refrain from donating sperm from the time of signing the ICF to 90
 days after the final dose of study drug.

 -  A female patient of child-bearing potential must be non-pregnant and non-lactating and
 have negative pregnancy tests at the Screening Visit and on Day 1 prior to dosing with
 study drug.

 -  Patients must be able to understand and be willing to sign the written informed
 consent form. A signed informed consent form must be appropriately obtained prior to
 the conduct of any trial-specific procedure.

 -  Willing and able to comply with the protocol, including follow-up visits and
 examinations.

 Exclusion Criteria:

 -  Patient has loose (mushy) or watery stools for > 25% of their bowel movements (BMs)
 during the 12 weeks before Screening or during the Screening and Pre-treatment
 Periods.

 -  Patient has a history of cathartic colon, laxative, or enema abuse.

 -  Patient has a history of ischemic colitis.

 -  Patient has a history of pelvic floor dysfunction.

 -  Patient has a history of bariatric surgery for the treatment of obesity.

 -  Patient has a history of surgery to remove a segment of the gastrointestinal (GI)
 tract at any time before the Screening Visit.

 -  Patient has any history of myopathy, rhabdomyolysis, chronic myalgia, or familial
 history of hereditary muscular disorders.

 -  Patient has been diagnosed with or has a family history of familial adenomatous
 polyposis, hereditary nonpolyposis colorectal cancer, or any other form of familial
 colorectal cancer.

 -  Patient currently has any structural abnormality of the GI tract or a disease or
 condition that can affect GI motility, or any unexplained and clinically significant
 symptoms such as lower GI bleeding, rectal bleeding, heme-positive stool,
 iron-deficiency anemia, weight loss, or systemic signs of infection.

 -  Patient has had any previous surgery involving the abdomen, pelvis, or retroperitoneal
 region during the last 12 months prior to Screening, with the exclusion of
 laparoscopic gallbladder surgery or appendix removal.

 -  Patient has a history of diverticulitis or any chronic condition that could be
 associated with abdominal pain or discomfort and could confound the assessments in the
 study (e.g. inflammatory bowel disease, chronic pancreatitis, polycystic kidney
 disease, ovarian cysts, endometriosis, or lactose intolerance).

 -  Patient has history of severe renal insufficiency defined as an actual or estimated
 glomerular filtration rate of < 30 mL/min/1.73 m2 within the 6 months prior to
 Screening Visit.

 -  Patient has any history of a medical condition or a concomitant medical condition
 that, in the opinion of the investigator, would compromise the patient's ability to
 complete the study safely or could confound the assessments in this study (e.g.
 uncontrolled hypothyroidism).

 -  Patient is known to have elevated liver enzyme levels (aspartate aminotransferase
 [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP]) or creatine kinase
 levels that are ≥ 1.5 times the upper limit of normal (ULN) that have not been
 resolved within the 4 weeks prior to consent and/or these elevated levels are present
 at the Screening Visit laboratory assessment.

 -  Patient has any abnormal laboratory results, electrocardiogram (ECG) findings, or
 physical examination findings deemed clinically significant by the investigator during
 the Screening Period.

 -  Within 14 days prior to the Screening Visit, patient has used concomitant medications
 that are: (1) moderate-to-strong inhibitors of cytochrome P450 3A (CYP3A) and/or organ
 anion transporting polypeptide (OATP)1B1 (e.g. cyclosporine, verapamil, dronedarone,
 diltiazem, amiodarone, itraconazole, ketoconazole, posaconazole, voriconazole,
 clarithromycin, telithromycin, human immunodeficiency virus protease inhibitors,
 boceprevir, telaprevir, nefazodone, erythromycin, cobicistat-containing products); (2)
 other concomitant medications that are excluded from the lovastatin label (e.g.
 rifampin, colchicine, ranolazine); or (3) metformin or GLP-1 agonists. Patients should
 not take any of these concomitant medications during the treatment phase of the study
 without contacting the investigator.

 -  Patient has hypersensitivity to statins; or has used any statins, fibrates, > 1 g/day
 of niacin, or gemfibrozil within the 3 months prior to the Screening Visit.

 -  Patient reports current chronic or frequent use of drugs known to cause constipation
 (e.g. narcotics) for the 3 months prior to Screening.

 -  Patient has taken over-the-counter IBS treatments (e.g. laxatives) or proton pump
 inhibitors within 3 days prior to the Screening Visit.

 -  Certain drugs used for the treatment of IBS (e.g. low dose tricyclic antidepressants)
 may be allowed at the discretion of the Medical Monitor provided the patient remains
 on a stable dose for one month prior to the Screening Visit and throughout the study
 with the exception of tegaserod, lubiprostone, linaclotide, metoclopramide,
 prucalopride, domperidone, or antibiotics within 2 months prior to the Screening
 Visit. Certain drugs used for the treatment of IBS (e.g. low dose tricyclic
 antidepressants) may be allowed at the discretion of the Medical Monitor provided the
 patient remains on a stable dose for one month prior to the Screening Visit and
 throughout the study with the exception of tegaserod, lubiprostone, linaclotide,
 metoclopramide, prucalopride, domperidone, CandiBactin, Atrantil, Allimax/Allimed
 within 2 weeks prior to the Screening Visit or antibiotics within 2 months prior to
 the Screening Visit.

 -  Patient has used an opioid chronically or frequently within the 3 months prior to the
 Screening Visit and for the duration of the study.

 -  Patient is currently enrolled in, or plans to enroll in, another clinical study or has
 used any investigational drug or device within 1 month before signing the ICF through
 the completion of the study.

 -  Patient has previously participated in a SYN-010 study.

 -  Patient has a history of alcohol or drug abuse within the 12 months prior to the
 Screening Visit.