Crohn’s caused by a bacterium
RDHL has patent license to use the only known test to detect said bacterium in humans
RDHL also has RHB-104, a treatment to eradicate this bacterium
Almost no coverage of this, therefore RDHL is undervalued
Israeli biotech ﬁrm
Trades on TASE and NASDAQ as ADS
1 ADS == 10 shares
Small cap - $101.7M
No analyst coverage (at least none public)
Only Institutional owner is GS with .45% stake
in the company
Importance of RHB-104
Others — Rehashings - 50-50 approval
Suesskind (Board) - Fmr CFO of Teva Pharma — grew
the company through acquisitions from market cap of $37M
Ben-Asher (CEO) — Fmr manager at ProSeed Capital,
Fulbright at Harvard who studied pharma & markets
good because it’s not mainly doctors, yet has a
few doctors on the board.
• E.g. Thomas
Borody — Developed 3x therapy for H Pylori
As of December 31
(U.S. dollars in thousands)
Balance Sheet Data:
Cash and short term investments
$3M spent on R&D for RHB-104, more than double
any other drug
Coronado Biosciences - Helminths
Only direct competitor
Similar market cap (98.1M)
But treatment not effective in other studies
And in studies where it was shown effective, it
wasn’t signiﬁcantly more effective than current
500,000 Americans have Crohn’s
Main theory: Immune system attacks lining of intestines and causes inﬂammation. Causes pain,
diarrhea, nausea, vomiting, fevers. Can cause ulcers, ﬁstulas, perforations, strictures.
Discovered by Scottish surgeon Kennedy Dalziel in 1913.
1895 H.A. Johne - similar disease in cattle - MAP
Dalziel: “So similar as to justify a proposition that the diseases may be the same”
MAP also causes disease in other primates (e.g. baboons)
Problem.. in Johne’s it’s easy to see
MAP with a microscope
Most mycobacteriums’ cell walls
retain acid stains…
Rodrick Chiodini - microbiologist at
Brown cultured live MAP from
children with Crohn’s disease
MAP spheroblast. Implications of
shedding cell wall
Can reform cell wall up to years
later, which is how Chiodini cultured
it in his lab.
New way to culture by detecting presence of MAP DNA. Anywhere from 65% to 100% of
crohn’s patients have MAP vs. 4% of those with UC (e.g. probably not an opportunistic
Due to the fact that 20% of patients w/ crohn’s are misdiagnosed, the actual numbers could be
1997 London — Rifabutin + clarithromycin — 94% remission rate
Done 5 more times in U.S. and Australia — similar ﬁndings
Not large studies, no control groups
Hard to do studies on treatment ideas like this (same w/ H Pylori in the 80s)
(Many of these antibiotics are generic now & if successful would eliminate the multibillion dollar
industry of maintaining Crohn’s with anti-TNF inhibitors.)
Market cap Crohn’s treatment $1.4 billion 2008, $2.1 billion 2015 estimate
RDHL ﬁrst real large phase III trial
Patent protected combo of 3 antibiotics
Clarithromycin, clofazimine, and rifabutin — only drug to treat cause not symptoms
Few side effects
Current drugs don’t work well, e.g. inﬂiximab (Remicade) 28% in remission @ 54 wks.
Expensive (18-30K)/year vs antibiotics (e.g. RHB-104) <$5000 per year
Too low dosages ~60% of required — issue of synergies not working out, prior trials didn’t do this
52 wks 40% remission (2007 myoconda/giaconda phase 3)
Already has orphan drug status from FDA (easier approval process, R&D tax breaks)
New trial has appropriate dosages of antibiotics — Phase III set to end March 2015 in US + Israel.
Phase III will begin mid 2014 for Europe — 52 week study, double blind w/ placebo controls
No safety issues (already existing drugs)
Lead investigator — David Graham, MD - fmr Pres. of American College of Gastroenterology
“I believe that RHB-104 holds the potential to change the current treatment paradigm and offer
patients suffering from Crohn's disease a new and safe therapeutic alternative, targeting the
potential cause of the disease rather than the symptoms alone.”
3 Migraine PDUFA (not important to thesis)
2015 — Study results
theory — doesn’t always work out in practice
• Estimate: 50-50
could have bad trial results
• Estimate: stock
could drop anywhere from 20-50%
lower end of this scale, 5 other drugs in pipeline
3. Issue (will discuss in conclusions)
Crohn’s likely caused by MAP
Drug combo already known to be more effective than current standard of care in
Phase III trials before acquisition (likely positive result from FDA)
Company has only patent for MAP detection in humans
RDHL undervalued due to revolutionary unorthodox ideas, slowness of medicine,
no analyst coverage, superior management compared to most biotech ﬁrms (both
on the R&D and ﬁnancial sides), and its relative obscureness in the U.S.
Recommendation: Buy 2298 shares RDHL now to avoid paying a premium after
likely price jump on Feb. 3 if FDA approves RHB-103* Reevaluate around March
2015 (expected results of Phase III RHB-104 trial)
*”The trial met its speciﬁed endpoints and FDA's criteria, in all parameters for bioequivalence, between RedHill's
RHB-103 oral thin-ﬁlm, and Merck & Co.'s Maxalt-MLTR, a leading, approved, migraine treatment, based on Rizatriptan,
a 5-HT1 receptor agonist drug.”
Why doesn’t everyone get Crohn’s?
Criteria for causality of a disease by an infection — Koch’s postulates - studies w/ chickens +
1. The microorganism must be found in abundance in all organisms suffering from the disease, but should
not be found in healthy organisms.!
! 2.! The microorganism must be isolated from a diseased organism and grown in pure culture !
! 3.! The cultured microorganism should cause disease when introduced into a healthy organism.!
! 4.! The microorganism must be reisolated from the inoculated, diseased experimental host and identiﬁed as
being identical to the original speciﬁc causative agent.
Tried before in Crohn’s & didn’t work — why should RDHL’s work then?
Prior studies used monotherapy, however mycobacteria develop resistance easily and take
months or even years to completely get rid of.
1992 - Clarithromycin very effective in vitro along with rifabutin. — block protein synthesis
Most antibiotics don’t work — block cell wall synthesis (MAP = no cell wall)
WHY IMMUNOSUPPRESSANTS WORK
NOD2 & Crohn’s
NOD2 & Johne’s + MAP
6MP and Azathioprine —- mechanisms unknown, kill MAP in vitro
Immunosuppressants issue (6mp/remicade) & anti-MAP activity
SPREAD OF MAP
Spreads through milk and meat, primarily from cattle.
May explain why Crohn’s is only seen in milk drinking places (e.g. Europe, U.S., Canada,
etc.), but not in India (where milk is usually boiled ﬁrst) or in Japan
Japanese farmers/gov’t rewards
English milk — 25% contains MAP
USDA claims pasteurization kills all bacteria in milk, so researchers decided to take milk
off the shelves and try to culture MAP. Success in ~20% of milk jugs.
MAP takes 10 min. of pasteurization or boiling temp to kill, US milk 15s/161F.
Thompson DE. "The Role of Mycobacteria in Crohn's Disease." Journal of Medical Microbiology
Hermon-Taylor, J. "The Causation of Crohn's Disease and Treatment with Antimicrobial Drugs."
Italian Journal of Gastroenterology-Hepatology. 1998 Dec;30(6):607-10.
NAID. "Crohn's Disease - Is There a Microbial Etiology? Recommendations for a Research Agenda."
Conference was held in the Natcher Conference Center on the NIH campus in Bethesda, Maryland on
December 14th, 1998.
Paratuberculosis And Crohn's Disease by Michael Greger, MD