Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...
Final 2009 m sc thesis oliver vit cv
1. Oral MS therapy
The coming revolution
by
Oliver Vit
A CONFIDENTIAL DISSERTATION SUBMITTED IN PARTIAL FULFILMENT OF THE
REQUIREMENTS FOR A MASTER’S DEGREE IN CLINICAL DRUG DEVELOPMENT
(MSc in Clinical Drug Development)
Queen Mary’s School of Medicine and Dentistry
2009
2.
3. Abstract
This dissertation reviews the oral therapies currently being developed for the treatment of
Multiple Sclerosis based on their strengths, weaknesses, opportunities, relative threats, and
predicts changes to the current market which can be expected upon respective launches.
Methods: A systematic review of publicly available information was initiated in an effort to
identify potential candidates and then to define the Mechanism of Action (MoA), the clinical
development plan (CDP) and the duration of market exclusivity. Where information
concerning the CDP or market exclusivity was found to be lacking, standard assumptions were
used to extrapolate forwards.
Results: No less than 11 candidates were identified across 4 separate MoAs spanning
clinical development phases from Phase I to registration: cladribine, teriflunomide, laquinimod,
fingolimod, BAF312, ACT-128800, CS-0777, ONO 4641, BG-12, Firategrast, CDP-323.
Conclusions: In 2010 Mylinax® (cladribine) and fingolimod will be the first oral therapies
ever launched to treat RRMS. MS therapy will adapt to the coming oral revolution according
to (1) time of approval (2) the risk:benefit profile each MS subtype supports, (3) the degree of
confidence neurologists acquire with these new agents, and (4) direct demands of MS patients
for convenient, efficacious and safe treatment of their disorder. Combination therapy will
i
4. return however restricted to fringe use due to limited expectations and experience. Following
the launch in RRMS, Mylinax® and fingolimod will continue to expand into suspected early
stage MS (CIS) and progressive forms of MS (PPMS/SPMS) respectively. A 2nd wave of orals
consisting of teriflunomide, laquinimod and BG-12 may arrive in the market between 2013-
2014. This will be followed by BAF-312, ACT-128800 and firategrast in a 3rd wave offering a
range of additional differentiation in terms of both efficacy & safety which may arrive by 2017
well in advance of the 1st oral to lose IP protection (fingolimod in 2019).
Clever integration of MRI techniques along with monitoring of biomarkers and potentially
genetic screening may help to change the understanding of MS, its progression and the
therapeutic paradigm. Cost effectiveness as well as patient access will drive further
differentiation between clinically non-differentiated products. Biologics will suffer a dual
pronged assault from lower priced biosimilars and new oral agents as patent expiry and
competition from bio-similars looms; however the market will continue to support innovative
high priced therapy. Continued research into the non-inflammatory component of MS holds
the key to the next revolution.
ii
5. Table of Contents
Figures vi
Tables ix
INTRODUCTION
Etiology 1
Diagnostic tools 7
Current therapy 14
METHODS 19
RESULTS
Oral MS therapies; competitive environment 21
Anti-proliferative/replicant 23
Cladribine 23
Teriflunomide 32
S1P receptor agonists 37
Fingolimod 40
BAF312 55
iii
6. ACT-128800 60
CS-0777 63
ONO 4641 67
Up and coming S1P agonists 67
Nrf2 activation 69
BG-12 69
α4-integrin antagonists 74
Laquinimod 75
Firategrast 80
CDP-323 81
MS biologics; global market
Annual revenues 82
Market capitalization 83
Market exclusivity 84
iv
8. Figures
Figure 1 MS Disease subtypes p.3
Figure 2 Benign MS p.5
Figure 3 MS subtype segmentation p.5
Figure 4 MS subtype segmentation as reported by neurologists (USA) p.6
Figure 5 MS subtype segmentation as reported by patients p.6
Figure 6 MRI scans of T1 & T2 lesions with & without GD+ enhancement p.9
Figure 7 Full EDSS scoring p.11
Figure 8 EDSS scoring as shared with the patient p.12
Figure 9 Pipeline; oral MS agents in Phase II/III p.21
Figure 10 Competitive radar; oral MS agents p.22
Figure 11 Cladribine; chemical structure p.24
Figure 12 Cladribine MS development plan p.24
Figure 13 CLARITY trial design p.26
Figure 14 CLARITY; relapse rates at 2-years p.27
Figure 15 CLARITY; disease progression at 2-years p.27
Figure 16 Cladribine; selective reduction of lymphocytes p.29
Figure 17 Cladribine; registry trial design p.30
Figure 18 Teriflunomide & leflunomide; chemical structures p.32
Figure 19 Teriflunomide MS development plan p.33
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9. Figure 20 HMR1726D-2001 trial design p.34
Figure 21 Teriflunomide; combined unique lesions at 9-months p.35
Figure 22 Ceramide; generic chemical structure p.38
Figure 23 Sphingolipid biosynthetic pathway p.38
Figure 24 Fingolimod; parent and phosporylated metabolite p.40
Figure 25 Fingolimod MS development plan p.41
Figure 26 Fingolimod; SAD on top of Neoral® in renal transplant patients p.42
Figure 27 Fingolimod; SAD lymphocyte reductions p.42
Figure 28 Fingolimod; SAD Bradycardic effects p.43
Figure 29 Fingolimod; Phase IIb trial design p.44
Figure 30 Fingolimod; Phase IIb results at 6-months p.46
Figure 31 Fingolimod; tolerability profile at 6-months p.46
Figure 32 TRANSFORMS trial design p.48
Figure 33 Fingolimod; time to first confirmed relapse in 2-year extension study p.50
Figure 34 FREEDOMS I&II trial design p.52
Figure 35 Fingolimod; relapse rate at 2-years in FREEDOMS p.53
Figure 36 Fingolimod; disease progression at 2-years in FREEDOMS p.53
Figure 37 Fingolimod; Serious Adverse Events reported in FREEDOMS p.54
Figure 38 BAF312 MS development plan p.56
Figure 39 BAF312; BOLD trial design p.57
Figure 40 Mean Ventricular Heart Rate following administration of BAF312 p.58
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10. Figure 41 Absolute lymphocyte count reductions following administration of p.59
BAF312
Figure 42 ACT-128800; SAD pharmacokinetics p.61
Figure 43 ACT-128800; SAD mean lymphocyte count reductions following p.61
single administration
Figure 44 ACT-128800; SAD mean %Δ in lymphocyte count following single p.62
administration
Figure 45 CS-0777P; SAD pharmacokinetics p.64
Figure 46 CS-0777; SAD reduction of lymphocyte sub-populations p.64
Figure 47 CS-0777; SAD peripheral lymphocyte counts p.65
Figure 48 CS-0777; Alanine aminotransferase levels p.65
Figure 49 CS-077-A-U102 trial design p.66
Figure 50 BG-12 MS development plan p.70
Figure 51 BG-12; Phase IIb MS trial design p.71
Figure 52 BG-12; Phase IIb GD+ enhanced lesions at 6-months p.72
Figure 53 Laquinimod; chemical structure p.75
Figure 54 Laquinimod MS development plan p.76
Figure 55 LAQ/5062 trial design p.77
Figure 56 Laquinimod; reduction of T1 GD+ enhanced lesions at 9-months p.78
Figure 57 Firategrast MS development plan p.80
Figure 58 Biologic MS therapy; annual revenues 2006-2008 p.82
Figure 59 Biologic MS therapy; market share 2006-2008 p.83
viii
11. Tables
Table I Biomarkers in Multiple Sclerosis p.13
Table II Properties of sphingosine-1-phosphates p.39
Table III CS-0777P; comparative S1P receptor selectivity p.63
Table IV Phase 0 development of S1P agonists p.68
Table V Protection of MS agents in clinical development (EU) p.85
Table VI Protection of MS agents in clinical development (US) p.85
Table VII Drug development success rates p.97
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12. INTRODUCTION
Etiology
Jean-Martin Charcot was the first physician to discover the lesions in both the brain’s white
matter and spinal cord upon autopsy, and named the disorder Multiple Sclerosis (MS) after
the localized & numerous scars he observed. Since 1868 strides have been made in the
diagnosis and treatment of MS in its varying degrees of severity, however the root cause of
the disorder remains unknown. MS is an autoimmune disorder in which trafficking
lymphocytes gain access to the normally immuno-privileged Central Nervous System (CNS)
following a primary insult to the blood-brain barrier (BBB) and permanent disability
accumulates following increased incidents of demyelination & eventual neuronal loss.
Inflammation plays a role in the earlier stages of the disease hence so it is speculated that as
a precursor to lymphatic attack lymphocytes encounter environmental antigens in the thymus
and incorrectly prime the immune system to falsely identify the myelin sheath as an external
threat to the body. Although not a hereditary disorder, genetic variations may leave certain
individuals more susceptible; likewise it has also been postulated that exposure to foreign
microbes such as the Epstein-Barr virus (EBV) may instigate MS [1][2].
Irrespective of the primary impetus, improperly conditioned T cells cross a compromised
blood-brain barrier (BBB) in the course of immuno-surveillance, attach to the myelin sheath
and release a cytokine cascade recruiting macrophages both from circulating blood and
locally in the form of microglials, inducing an incorrect onslaught against an axon’s
protective myelin sheath. The cytokines released by T cells are also suspect in recruiting and
activating local B cells which then promote an independent B cell attack [3]. Composed
primarily of lipids, the myelin surrounds and insulates a neuron’s elongated axon along
which electric stimuli travel. The brain’s white matter is comprised largely of neurons and
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13. the loss of the myelin sheath often results in the loss of conducting impulses and the
associated function, e.g. loss of gross & fine motor skills, speech, cognitive abilities, etc.
The more progressive subtypes of MS are characterized by a decreased inflammatory
component along with continual mounting neuronal degeneration & loss associated with
increased disability. Although MS is not fatal and does not significantly diminish the
average life-expectancy, progressive accumulation of disability incapacitates the afflicted
slowly stripping them of their cognitive abilities and mobility which eventually renders them
mute, disassociated from society and entirely dependent upon the care of others.
The incidence of MS is known to rise with increasing geographical latitude. Relapsing forms
of the disease most frequently affect young Caucasian females who reside within
industrialized nations. Prevalence has been estimated to be between 2 and 150 cases per
100,000 individuals [4].
The US National Multiple Sclerosis Society (NMSS) defined four distinct subtypes of MS
based on the frequency of relapses driven by repeated inflammatory attacks and the pattern
of accumulation of permanent disability. These are referred to as Relapsing-remitting MS
(RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS) and
Progressive-relapsing (PRMS). Figure 1 depicts these four categories.
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14. Figure 1 – MS Disease subtypes
Source: US National MS Society
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15. Relapsing-remitting MS (RRMS)
By far the most common form of MS accounting for upwards of 80% of new diagnoses,
relapsing-remitting MS is characterized by distinct neurological disturbances followed by
periods of relative calm with potentially a temporal return of lost function alongside an
underlying gradual accumulation of permanent disability over time; patients are usually
women 20-40 years of age.
Progressive-relapsing MS (PRMS)
Patients who suffer repetitive exacerbations of escalating severity & disability separated by
periods of remission are diagnosed with progressive-relapsing MS.
Secondary progressive MS (SPMS)
After 10-20 years a RRMS patient who no longer experiences periods of remission between
symptomatic exacerbations of escalating severity is said to have advanced to secondary
progressive MS.
Primary progressive MS (PPMS)
A continuous and steady loss of function not associated with intermittent exacerbations is
referred to primary progressive MS; patients of both sexes are equally affected and typically
middle aged.
In addition to the MS subtypes categories provided by the US National MS Society, so called
“benign” MS and clinically isolated syndrome (CIS) are frequently used terms.
“Benign” MS
Patients diagnosed with benign MS experience irregular, sporadic attacks of variable
magnitude similar to RRMS which however do not result in the accumulation of disability
over time. See Figure 2.
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16. Figure 2 – Benign MS
Adapted from: www.imaginginformatics.ca
Clinically isolated syndrome (CIS)
A diagnosis of CIS is based on the report of a neurological attack of at least 24 hours in
duration associated with MRI abnormalities suggestive of inflammatory demyelination. A
diagnosis of Clinically Definite MS (CDMS) cannot be ascertained as the occurrence and
location of lesions across both time and space remains uncertain, i.e. in the absence of a
relapse, the risk to subsequently develop CDMS is significantly higher than the general
population. This circumstance is defined as CIS.
Figure 3 illustrates the distribution of MS subtypes as assessed by Net Resources
International. Figure 4 is assembled from a recent market research exercise conducted by
Decision Resources with 102 practicing neurologists in the United States of America.
Figure 5 represents how patients on a popular internet forum supported by <13,000 patients
classify themselves, albeit skewed by the fact that the responders’ condition permits internet
interaction.
Figure 3 – MS subtype segmentation
Source: Drug Development Technology (2007)
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17. MS Population Breakdown By Subtype
20% 19%
CIS
RR-MS
15%
SP-MS
PP-MS
46%
Figure 4 – MS subtype segmentation as reported by neurologists (USA)
Source: Decision Resources (2009)
Figure 5 – MS subtype segmentation as reported by patients
Source: www.patientslikeme.com
It is noteworthy that none of the three exercises used the same nomenclature when
approaching segmentation, and when there is overlap in the classification, e.g. RR MS, SP
MS, PP MS, the reported percentiles vary widely. Most significant is perhaps that 21% of
the patients who being internet active are most likely to have familiarized themselves with
their condition, are in fact unable to identify the MS subtype which afflicts them. Outside of
clinical parameters & measures little else in the MS community appears standard.
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18. Diagnostic tools
The signs and symptoms are varied and include any of the following alone or in
combination: loss of cognitive skills, loss of bladder control, fatigue, nystagmus, restricted or
loss of mobility, optic neuritis, pain, trigeminal neuralgia, Lhermitte’s sign, dysesthesias,
sexual dysfunction, spasticity, transverse myelitis, tremor and alaxia. A patient presenting
with one or more of these first signs symptomatic of MS may indeed be suffering from any
number of peripheral neuropathies, autoimmune disorders, demyelinating disorders, or in
fact nothing at all. The initial diagnosis of MS in any of its forms will be often difficult at
the start due to the vague, mild and transient nature of the symptoms, however no other
disease of the central nervous system (CNS) entirely mimics the debilitating progressive
assault of MS; progressive accumulated disability over time remains the decisive factor in
diagnosing MS.
McDonald criteria
The McDonald criteria were universally accepted by the US NMSS in 2001 and replaced
both Poser and Schumacher diagnostic criteria. Utilizing the knowledge gleaned from
decades of experience with both increasingly sensitive instrumentation and the disease itself,
the McDonald criteria make use of a description & frequency of attacks as reported by the
patient, the total number & dissemination in space and time of lesions detected with
magnetic resonance imaging (MRI) as well as the results from cerebrospinal fluid samples
(CSF) to diagnose the subtype of MS. The presence of multiple oligoclonal bands in CSF
samples is indicative of a recent or ongoing CNS inflammation inclusive of MS.
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19. Magnetic resonance imaging (MRI)
Hydrogen atoms when bound to oxygen produce water; however as the electrons are
unevenly distributed in covalent bonds favoring the oxygen atom and neutrons are not
present in the hydrogen nucleus, the two oxygen-bound hydrogen atoms in a molecule of
H20 behave very much like exposed protons. Aligning the nuclear magnetization of these
protons in the body with a strong magnetic field allows for precise interstitial images to be
taken. These are referred to as MRI scans and have proven invaluable to the diagnosis and
management of MS. MRIs allow practicing neurologists to evaluate the number, size, and
distribution of CNS lesions over time and so determine the extent and severity of the
inflammatory process throughout the lifetime of a MS patient.
The two types of MRI scan commonly used are called T1 and T2 scans. T1 imaging uses
gradient echo to maintain a <90° partial flip angle which allows for faster recovery of NMR
signal with a shorter Repetition time (TR)/ Echo time (TE); images taken within split second
of each other at varying degrees of magnetism can then be taken to produce a composite
image of higher resolution. This allows for better identification of edema and/or sites of
areas of extreme white matter loss otherwise referred to as “black holes”. T2 imaging makes
use of a longer TR/TE via two consecutive pulses prior to detection to refocus the
magnetization by 180° in a process called spin echo; as disturbances in the magnetic field are
lost by spin echo, the MRI resolution is thus enhanced. T2 imaging better identifies
inflammatory sites such as active lesions in the brain. Gadolinium (Gd+) is a contrast agent
which greatly increases MRI resolution of both T1 and T2 images.
Figure 6 illustrates the difference between axial T1 and T2 images with and without Gd+
enhancement.
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20. Figure 6– MRI scans of T1 & T2 lesions with & without GD+ enhancement
Source: Frey et al., 1999. Clinical Application of MRI Image Processing in Neurology, International Journal of Bioelectromagnitism, 1 (1)
Up to 80% of lesions detected on MRI scans may in fact be clinically silent [5]. MRI scans
are unable to detect axonal loss & neural degeneration, or sub-cortical demyelination of the
grey matter. Furthermore the utility as a predictive measure of eventual disability is
questionable as MRI scans are less sensitive to spinal lesions. Irrespective of these
drawbacks MRI scans are currently one of the best diagnostic tools at a neurologist’s
disposal.
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21. Annualized Relapse Rate (ARR)
A relapse is defined as a new neurological symptom or a worsening of a pre-existing
neurological condition whose duration is longer than 24 hours. Often used as a measure of
an agent’s efficacy, the annualized relapse rate (ARR) is simply the mean number of
reported clinical exacerbations over the mean time, hence it can be used for periods of less
than one year.
Expanded Disability Status Score (EDSS)
The Kurzke Expanded Disability Status Score (EDSS) was developed in 1983 to assist the
neurologist in quantifying the degree of disability in a given functional system (FS) for any
given MS patient. It divides the body into the following eight functional systems (FS):
pyramidal, cerebellar, brainstem, sensory, bowel & bladder, visual, cerebral, other. The
neurologist then assesses each FS on a scale from 0 (perfectly functional) to 10 (death) in a
series of 20 half steps. This is a commonly used disability score which in conjunction with
MRI scans helps to determine the progression of MS and the appropriate therapy. Figures 7
& 8 illustrate the full EDSS score from 0-10 and the EDSS score from 0-9 as explained to
patients & their families respectively.
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22. 1.0: No disability, minimal signs on 1 FS
1.5: No disability, minimal signs on 2 of 7 FS
2.0: Minimal disability in 1 of 7 FS
2.5: Minimal disability in 2 FS
3.0: Moderate disability in 1 FS; or mild disability in 3 - 4 FS, though fully ambulatory
3.5: Fully ambulatory but with moderate disability in 1 FS and mild disability in 1 or 2 FS;
or moderate disability in 2 FS; or mild disability in 5 FS
4.0: Fully ambulatory without aid, up and about 12hrs a day despite relatively severe disability.
Able to walk without aid 500 meters
4.5: Fully ambulatory without aid, up and about much of day, able to work a full day,
may otherwise have some limitations of full activity or require minimal assistance.
Relatively severe disability. Able to walk without aid 300 meters
5.0: Ambulatory without aid for about 200 meters. Disability impairs full daily activities
5.5: Ambulatory for 100 meters, disability precludes full daily activities
6.0: Intermittent or unilateral constant assistance (cane, crutch or brace) required to walk
100 meters with or without resting
6.5: Constant bilateral support (cane, crutch or braces) required to walk 20 meters without resting
7.0: Unable to walk beyond 5 meters even with aid, essentially restricted to wheelchair, wheels self,
transfers alone; active in wheelchair about 12 hours a day
7.5: Unable to take more than a few steps, restricted to wheelchair, may need aid to transfer;
wheels self, but may require motorized chair for full day's activities
8.0: Essentially restricted to bed, chair, or wheelchair, but may be out of bed much of the day;
retains self care functions, generally effective use of arms
8.5: Essentially restricted to bed much of the day, some effective use of arms, retains some self care functions
9.0: Helpless bed patient, can communicate and eat
9.5: Unable to communicate effectively or eat/swallow
10.0: Death due to MS
Figure 7 – Full EDSS scoring
Source: http://www.mult-sclerosis.org/expandeddisabilitystatusscale.html.
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23. Figure 8 – EDSS scoring as shared with the patient
Source: https://www.msactivesource.com 0.0: Normal Neurological Exam
Multiple Sclerosis Functional Composite (MSFC)
In 1994 the US NMSS commissioned a task force to standardize the clinical evaluation of
the natural disease progression across meaningful parameters for use in clinical trials. It was
to be multidimensional to reflect the changes an MS patient undergoes over time, scoring of
each parameter was to be independent of any other parameters measured and cognitive
function was to be one of the parameters. In 1995 the results were made public and MSFC
was composed of three components: leg function/ambulation, arm/hand function and
cognitive function. First approved in 1995 the MSFC disability scoring tool has yet to
replace EDSS as a standard clinical endpoint in large registration trials despite favorable
reports from practicing neurologists [5].
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24. Biomarkers
Given the uncertainties associated with the etiology of MS, the genetic & environmental
factors which may predispose individuals to developing MS, the silent debilitating &
variable disease progression, and the ability of the current tools to properly diagnose,
monitor & support proactive treatment regimens, biomarkers are of particular interest. To
date no single biomarker has been successfully coupled with a specific outcome in MS;
however this precludes neither exploratory clinical research with existing biomarkers nor
further investigations in search of novel and predictive biomarkers. Table I summarizes
those biomarkers already identified and their potential significance towards diagnosis &
disease progression. Although more hazardous to procure, biomarkers found in the
cerebrospinal fluid (CSF) are more attractive than those acquired from the blood as the
samples are specifically reflective of the CNS environment.
Table I – Biomarkers in Multiple Sclerosis
Epstein-Barr Virus Significantly higher levels of EBV antibodies found
in MS patients as opposed to the populous at large
(EBV)
Blood serum TOBI Gene encoding transition factor responsible for the
repression of T-cell proliferation; significantly down-
regulated in CIS patients susceptible to rapid
conversion to CDMS
Oligoclonal bands Immunoglobulins associated with active
inflammation; subtraction of oligoclonal bands found
in blood serum from those found in CSF indicates
production within the CNS and along with MRI
outcomes serves as a traditional MS diagnosis
measure
Cytokines Pro & anti-inflammatory
Cerebrospinal fluid
Chemokines Regulate T&B cell recruitment to sites of active
inflammation; not specific to MS
NO/NOS levels Indicative of increased oxidative stress, inflammatory
activity & BBB breakdown
Fetuin-A Immune system regulatory protein; high levels in
CSF are associated directly with demyelination &
active MS
Adapted from: Harris and Sadiq, 2009, Disease Biomarkers in MS, Molecular Diagnosis & Therapy, 13 (4) p.225-244
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25. Current therapy
Intravenous corticosteroids are commonly used to relieve the localized swelling and pain of
acute inflammatory attacks and reduce the potential for accumulating further disability upon
remission. MS patients who have received a 3-5 day course of methylprednisolone often
rapidly regain function; unfortunately this improvement is usually not maintained and there
is no evidence that corticosteroids reduce the long-term risks of eventual relapse. Disease
modifying therapies (DMTs) are largely confined to injectable biologics targeting surface
proteins on lymphocytes which either impede the inflammatory cytokine cascade, adhesion
to endothelium & trafficking through the vascular wall or induce selective lysis of T cells.
All DMTs demonstrate varying degrees of increasing efficacy offset by escalating safety
concerns. Novantrone® is also used in MS patients who fail to respond to treatment with
traditional DMTs.
Betaferon® (interferon β-1b)
Betaferon® was the first non-steroidal DMT developed by Schering AG approved for MS
therapy; it was licensed in July 1993 indicated for use in reducing the frequency of clinical
exacerbations in relapsing forms of MS. Betaferon® is manufactured ex-vivo using
Escherichia coli. It mimics natural cytokines, cell signaling proteins released by
lymphocytes, which have been linked to the enhancement of suppressor T cell activity,
reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation,
and inhibition of lymphocyte trafficking into the central nervous system (CNS) by improving
the integrity of the BBB. The Mechanism of Action (MoA) which provides direct benefit to
MS patients remains unknown. At 2-years, injections every other day with 0.25 mg
Betaferon® yielded a 32% reduction in Annualized Relapse Rate compared to placebo and
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26. no statistically significant reduction in disease progression as measured by EDSS.
Neutralizing antibodies (NABs) do develop over time. Side effects include injection site
reactions/necrosis and flu-like symptoms following administration. The current market
formulation is packaged as pre-filled syringes and commercialized by Novartis.
Copaxone® (glatiramer acetate)
Glatiramer acetate was first licensed by Teva Pharmaceuticals in December 1996 as
Copaxone® for use in reducing the frequency of relapses in RRMS patients. Although the
MoA remains unknown it is likely that the chemical structure of glatiramer acetate mimics
that of myelin and so like a decoy circulating T cells bind to it rather than the protective
myelin. Copaxone® has been shown to have a modest effect of reducing the relapse rate
(~30% reduction) and delaying disease progression at 2-years compared to placebo.
However recent data has demonstrated that there may be significant benefit offered to
interferon-1β monotherapy treatment failures [7]. It is provided as a pre-filled syringe and
delivered via a daily 20 mg subcutaneous injection. NABs are known to develop with
repeated long-term use in almost all patients. The most common adverse events associated
with use are injection site reactions, vasodilatation, chest pain, asthenia, infection, pain,
nausea, arthralgia, anxiety, and hypertonia.
Avonex® (interferon β-1a)
Recombinant DNA techniques using Chinese Hamster Ovarian cells allowed Biogen Idec to
develop the first interferonβ-1a biologic, Avonex®. At 2-years 30 μg Avonex® delivered
once weekly via intramuscular injection demonstrated only an 18% reduction in ARR
compared to placebo; however Avonex® did achieve a relative 37% reduction in disability
progression. In May 1996 it was the first to be granted a license for reducing the frequency
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27. of clinical exacerbations and delay the accumulation of physical disability in relapsing MS
patients. In later clinical trials Avonex® was associated with up to a 38% reduction in ARR;
Avonex®’s increased efficacy is attributed to its ability to greatly improve the integrity of
the BBB as demonstrated in preclinical animal investigations. As with Copaxone® and
Betaseron® NABs develop over time, it is marketed as a pre-filled syringe and injection site
reactions/necrosis & flu-like symptoms upon administration persist along with anemia, fever,
chills, and muscle ache. However unlike all the rest, Avonex® is the market leader
accounting for 25-30% of market capitalization.
Rebif® (interferon β-1a)
Also manufactured using genetically engineered Chinese Hamster Ovarian cells Serono’s
Rebif® was the 3rd biologic developed for use in MS. At 2-years 44 μg delivered 3 times
weekly by subcutaneous injection demonstrated a 32% in annualized relapse rates and a 30%
reduction in disability progression against placebo. Furthermore in a second 6-month
clinical trial against Avonex® an absolute difference in ARR of 12% in Rebif®’s favor
translated into a 32% reduced risk of relapse. In May 1998 it followed Avonex® to be
granted a license for reducing the frequency of clinical exacerbations and delay the
accumulation of physical disability in relapsing MS patients. As with all biologic therapy
NABs specific to Rebif® develop over time. Injection site reactions/necrosis, flu-like
symptoms following administration, leucopenia, and increased liver enzymes are the most
common side effects.
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28. Tysabri® (α4-integrin antagonist)
First developed by Élan and co-developed with Biogen Idec, Tysabri® (natalizumab) was
the first fully humanized monoclonal α4-integrin antibody specifically antagonizing the very
late adhesion-4 (VLA-4) surface protein which enables the T cells to identify & bind to
vascular VCAM-1 and pass through the vessel wall; in effect it hinders lymphocyte
trafficking across the BBB and intestinal wall protecting these organs from potential
autoimmune attack by rogue T cells. Tysabri® is delivered by a 300 mg monthly
intravenous infusion and established a remarkable 69% reduction in ARR and 42% reduced
disease progression as compared to placebo at 2-years in clinical trials. Although
humanization of the antibodies reduced the proportion of patients in whom NABs develop,
NABs indeed develop and reintroduction of Tysabri® in these patients can promote allergic
reactions. This was the first revolution in MS therapy since Avonex®. Tysabri® is
currently penetrating the market at an impressive rate. First licensed in November 2004 it
was briefly removed from the market from 2005 to 2006 due to isolated cases of progressive
multifocal leukoencephalopathy (PML). Tysabri® carries a black box warning regarding
PML and as well as warnings regarding its immunosuppressive effects in the label.
Campath® (anti-CD52)
First developed at Cambridge University’s Pathology department, Campath® (alemtuzumab)
is an anti-CD52 monoclonal antibody licensed for use in the clinical treatment of chronic
lymphocytic leukemia (CLL) and cutaneous T cell lymphoma (CTCL) which is used off-
label in progressive MS patients. Campath® agonizes the surface protein CD-52 present
only on mature T cells and selectively induces lysis. Delivery of Campath® via intravenous
infusion results in an immediate death of circulating T cells and therapy is both complicated
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29. & restricted to hospital use. However in CAMMS223 a Phase IIb RRMS trial, annual
treatment with Campath® achieved a 74% decrease in ARR and a 72% decrease in disability
progression at 3-years compared to traditional Rebif® twice weekly subcutaneous injections.
At present CARE-I & CARE-II two Phase III Rebif®-controlled trials are underway and
scheduled to complete in 2011 and 2012 respectively. However therapy with Campath® is
not without risk; serious and fatal cytopenias, infusion reactions & infections are black-box
warnings in the current CLL label and therefore Campath® is primarily the agent of last
resort currently reserved for off-label use in the progressive forms of MS. Furthermore the
marketing potential of Campath® is in question as the compound loses patent protection in
July 2011 and the use in MS patent filed in 2007 was recently rejected on grounds of lack of
novelty.
Novantrone® (mitoxantrone)
A cytotoxic in the form of a small synthetic antineoplastic anthracenedione, Novantrone® is
typically reserved for cancer therapy, however delivered as a quarterly 12 mg/m2 intravenous
infusion it has proven effective in reducing the ARR and disease progression in both
secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients. As a type
II topoisomerase inhibitor it enters all dividing cells and actively prevents DNA replication
& repair. Novantrone® carries a black box warning as a teratogen with fatal cardiotoxic
potential and requires left ventrical ejection fraction (LVEF) monitoring prior to every
administration.
Page 18
30. METHODS
Given the highly competitive and secretive nature of drug development, retrieving reliable
information regarding potential oral therapies for the use in the treatment of Multiple
Sclerosis (MS) is ridden with misinformation and false leads. To best determine the scope of
this investigation, a thorough review of publically available resources was conducted
inclusive of, but not limited to, listings on the FDA website www.clinicaltrials.gov, annual
reports & press releases of pharmaceutical enterprises, and patent applications & grantings.
Thereafter further efforts were made to elucidate the Mechanism of Action (MoA) and the
clinical development plan of each indentified candidate; the results were eventually compiled
and plotted by MoA & estimated launch date. Where relevant information was not released
the following estimations were applied:
• 6-months between last Phase I trial and the start of a Phase II program
• 1 Phase IIb dose-finding trial assessing MRI and ARR at 6-months at minimum with
1-year of recruitment and 2 months of data cleaning prior to database closure
• 9-months between a dose-finding trial and the start of a Phase III program
• 2 confirmatory registration trials assessing disability at 2-years staggered by 3-months
with 18-months of recruitment and 3 months of data cleaning prior to database closure
• 6-months to submit a Manufacturer’s Authority Application (MAA) from the time of
the last registration trial’s last patient last visit/last data collection point
st
• 1-year review by the 1 Health Authority (HA) to grant Marketing Authorization
(MA), unless an expedited review was granted in which case 6-months was assumed
st
• 3-months between the MA and 1 launch
Page 19
31. The risk:benefit of each candidate was evaluated on the grounds of released efficacy, safety
and tolerability results either in the form of sponsored publications in renowned scientific
journals, e.g. Nature, The Lancet, Neurology, etc., or from presentations given at equally
reputable international conferences, The European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS), The American Academy of Neurology (AAN).
The current market potential was established by extracting the annual revenues of each
product licensed for the treatment of MS as reported in the 2006, 2007, 2008 annual reports
published by the authorized manufacturer. A patent search for each compound was
conducted and finally the extent and duration of intellectual property (IP) protection periods
in the EU were determined based on the known and approximated MA dates.
Page 20
32. RESULTS
Oral MS therapies; competitive environment
In a field crowded with expensive parenterals, oral administration appears wanting, however
the pipelines of many pharmaceutical firms are expanding with a plethora of potential oral
agents promising therapeutic benefit to MS patients across all subtypes. Figure 9 illustrates
the oral compounds in Phase II/III development and the respective corporate sponsors.
Figure 10 depicts all oral compounds in clinical development split by MoA, phase of
clinical development and estimated launch date.
Cladribine, Mylinax (MS), Leustatin® (HCL)
Fingolimod, FTY720
BG-12, BG00012, FAG-102, Panaclar® (psoriasis)
Laquinimod, ABR-215062
Teriflunomide, A-771726
CDP-323
Firategrast, SB-683699, T-0047
BAF312
Figure 9 – Pipeline; oral MS agents in Phase II/III
Page 21
34. Anti-proliferative/replicant
Cladribine
Developed in the late 1970’s at the Scripps Research Institute as a therapeutic agent in the
treatment of lymphomas, cladribine is an adenosine deaminase-resistant purine nucleoside
analogue which is intracellularly phosphorylated to form an active mononucleotide which
then interferes with cell metabolism and DNA repair & replication. As a cytotoxic,
cladribine actively suppresses DNA repair which leads to increased deoxyribonucleotide
levels. This state then signals the activation of polyadenosine diphosphate (ADP) ribose
polymerase which subsequently exhausts cellular nicotinamide adenine dinucleotide (NDA)
levels and leads to eventual apoptosis [8]. Cladribine has demonstrated a good
bioavailability. It has been purported to selectively target only subpopulations of
lymphocytes due to a unique intracellular circumstance in which levels of deoxycytidine
kinase (DCK), an enzyme responsible for phosphorylation of the parent compound, largely
outnumber deoxynucleotide dephosphorylating enzymes in T cells. In nearly all other cells
of the body these enzymes are roughly equal in number which results in a continual
dephosphyrlation of the prodrug and renders it inactive [8]. Cladribine crosses the blood-
brain barrier (BBB) and accumulates with cerebrospinal fluid (CSF) levels exceed plasma
concentrations by up to 25% [9].
Page 23
35. Figure 11 – Cladribine; chemical structure
Source: http://journals.prous.com/journals/dof/20042903/html/df290253/images/113529.gif
Clinical Development
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Biocomparison i.v./tablet
CPMS i.v.
RRMS s.c.
RRMS/SPMS Onward
On top of Rebif
SPMS/PPMS s.c.
Clarity
CIS MS Oracle
MAA MA Launch
Figure 12 – Cladribine MS development plan
Page 24
36. The clinical development of cladribine has spanned decades, indications and corporations. It
debuted as an experimental intravenous infusion therapy for use in lymphomas in the 1980’s.
This was followed by the licensing of a formulation supporting administration via
subcutaneous injection in the treatment of hairy cell leukemia (HCL) by Ortho Biotech in the
early 1990’s. Its lymphopenic properties marked it as a candidate not only for lymphomas
but also for autoimmune disorders where the immune system is suspected of mounting
attacks against otherwise healthy tissues. The Scripps Research Institute conducted 3
moderately sized Phase II clinical trials in chronic progressive Multiple Sclerosis (CPMS),
relapsing-remitting Multiple Sclerosis (RRMS) and Secondary/Primary Progressive Multiple
Sclerosis (SPMS/PPMS) with parenteral cladribine delivered by intravenous infusion or
subcutaneous injection in a total of 229 patients between 1992 and 1997 [9]. Large scale
investigations were not undertaken until the development of an oral tablet formulation which
demonstrated good bioavailability with a t½ of 6-8 hours. Renal excretion accounts for
~50% of systemic clearance with 21-32% of that being unaltered parent compound [9].
However the lymphopenic effects of cladribine last far beyond the 3-4 days it takes for
systemic clearance to be achieved. This supports the dosing schedule of 2-4 cycles of five-
day treatment annually which Merck Serono has implemented in the CLARITY, ONWARD
and ORACLE trials.
Following the favorable results from a short bioequivalence study comparing the
pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new tablet formulation
against the intravenous infusion regimen, differing regimens of oral cladribine were
evaluated in the MS population. In January 2005 Merck Serono’s single registration,
placebo controlled 2-year trial began to recruit 1,326 RRMS patients; recruitment completed
22 months later and preliminary results were released in January 2009. Figure 13 illustrates
the CLARITY trial.
Page 25
37. Jan Nov
Double blind core study Study extension
2005 2009
scr 1 yr 2 yr
Cladribine 3.5 mg/kg x x x x
5.25 mg/kg x x x x x x
Placebo
Rescue therapy 44 μg
(Rebif®)
MRI
EDSS
X = 4/5-day course of administration
Figure 13 – CLARITY trial design
Adapted from: ECTRIMS poster, Sep 2009
Primary endpoint
• qualifying relapse rate at 2 years based on Kurtzke Functional System (KFS) score
Secondary endpoints
• proportion of relapse-free patients
• total number of T1 Gd+ enhanced lesions per patient per scan
• total number of active T2 lesions per patient per scan
• combined unique (CU) lesions per patient per scan
Both the high and the low experimental doses of cladribine met each of these endpoints with
no statistical difference between the two doses. Annualized relapse rates were reduced by
55% and 58% (p<0.001) and progressive disability as measured by EDSS scores was slowed
by 33% and 31% compared to placebo at 2-years respectively. (see Figures 14 & 15)
Furthermore ~80% of the patients treated with either dose of cladribine were relapse-free as
opposed to 61% in the placebo cohort representing a odds ratio of 2.45 (p<0.001) [10].
Page 26
39. In line with expectations, T, B & NK cell counts in exposed patients decreased rapidly upon
administration with either the high or low dose; granulocytes and monocytes levels were
unaffected. Figure 16 depicts the time course of this effect on CD3+ and CD19 count levels.
Merck Serono has yet to release the full safety & tolerability findings inclusive of AEs,
SAEs and SUSARs per dose group; however cladribine appears to be well tolerated with
90% of the enrolled patients completing the trial. Generalized reports of lymphopenia and
leukopenia are in all likelihood attributable to the Mechanism of Action (MoA). In the high
dose group cardiorespiratory arrest in addition to pancytopenia pneumonia led to a fatality in
one patient who was later found to have had an active tuberculosis infection. Four cases of
malignancy including a fatality in the low dose group were reported in four individual
patients exposed to active treatment with cladribine in the CLARITY trial: ovarian,
pancreatic (†) & cervical cancers and a case of melanoma [11]. Individual cases of herpes
zoster, an opportunistic viral infection, were also noted in both active groups [11].
Page 28
41. ONWARDS is a Phase II 2-year trial evaluating the safety of oral cladribine in combination
with interferon-β; RRMS and SPMS patients entering the trial are randomized (1:1) to
receive either 2 short courses of cladribine or placebo annually on top of their current
therapy with either Rebif®, Avonex® or Betaseron®. This trial is not powered to evaluate
the difference in efficacy between these therapies.
Proactively an 8-year pharmacovigilance trial has been launched to survey the incidence of
safety related reports associated with the long term use of cladribine in MS patients. (see
Figure 17)
Figure 17 – Cladribine; registry trial design
Source: ECTRIMS poster, Sep 2009
Primary endpoint
• cumulative incidence of severe and selected infections
• cumulative incidence of malignancies
• cumulative incidence of deaths
• time to resolution of cladribine-induced lymphopenia
• frequency and outcome of pregnancy
• time between seeking pregnancy and becoming pregnant
Page 30
42. Secondary endpoints
• cumulative incidence of myelodysplasic syndromes (MDS)
• cumulative incidence of haematological toxicity
• descriptive analyses of demographic and MS disease characteristics for all
participants
• hazard ratios for severe and selected infections
• hazard ratios for malignancies
• hazard ratios for deaths
• rate of recurrence of study events
• frequency of other clinically relevant events
Although there have been no comparator-controlled trials, Merck Serono issued two press
releases on July 23, 2009 and September 30, 2009 confirming the submission to the EMEA
and the FDA respectively of Manufacturing Authorization Applications (MAA) requesting
licensing for use of cladribine in RRMS. The FDA announced in 2006 that cladribine had
been awarded the status of “Fast Track” which designates an accelerated approval process
with a priority review of the dossier. If approved, cladribine will be the first highly effective
oral medication to meet the high and as of yet unmet medical need in MS.
Merck Serono is further establishing itself within the field of MS with the Phase III
ORACLE trial in which 200 newly diagnosed CIS patients at risk of progressing to
Clinically Definite MS (CDMS) will be randomized to receive either placebo or 1 or 2
courses of cladribine annually until conversion to CDMS.
Page 31
43. Teriflunomide
As a disease-modifying antirheumatic drug (DMARD) Arava® (leflunomide) inhibits the de-
novo pyramidine synthesis by hampering dihydro-orotate dehydrogenase (DHODH) and in
parallel exhibits anti-inflammatory properties. Arava® is licensed for use in Rheumatoid
Arthritis (RA) & psoriatic arthritis (PsA), and recently received orphan drug status for
transplant rejection from the FDA. Teriflunomide is the active metabolite of leflunomide;
both compounds belong to Sanofi-Aventis. The pro-inflammatory, activated T&B cells
which propagate brain lesions in MS are rapidly dividing and therefore targeting an enzyme
such as DHODH makes intuitive sense; teriflunomide arrests the division of the T&B cells
and renders them cytostatic. Resting lymphocytes are spared the effects of teriflunomide
through salvage pathways and continue with vital immuno-surveillance activities. Due to
the fact that teriflunomide’s target is an intracellular enzyme, it breaches the cell wall and
discontinuation of therapy is problematic requiring treatment with either cholestyramine or
activated charcoal.
Teriflunomide Leflunomide
Figure 18 – Teriflunomide & leflunomide; chemical structures
Source: http://journals.prous.com/journals/dof/20073211/html/df321007/images/fig13.gif
Page 32
44. Clinical Development
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
HMR1726D-2001
HMR1726D-2002
PoC HMR1726D-2004
On top of Copaxone
PoC TENERE
On top of interferon-β
TEMSO
EFC6049
TOWER
TOPIC (CIS MS)
MAA MA Launch
Figure 19 – Teriflunomide MS development plan
In 2006 O’Connor et al. published the findings from the 9-month placebo-controlled dose-
finding Phase IIb trial with teriflunomide in 177 RR/SPMS patients recruited over 14 months
at 16 sites in France and Canada [11]. Patients were randomized to receive either daily doses
7 mg or 14 mg of experimental teriflunomide or placebo and MRIs were taken every 6
weeks. Figure 20 outlines the trial design.
Page 33
45. Apr Mar Nov
Double blind core study Study extension
2001 2003 2011
scr x 1.5 3 4.5 6 7.5 9 mon 1 yr 2 yr 3 yr* 9 yr
Teriflunomide 7 mg //
14 mg //
Placebo
First week MRI
loading dose
EDSS
* safety and efficacy readout
Figure 20 – HMR1726D-2001 trial design
Adapted from: O’Connor et al., 2006. , A Phase II Study of the Safety and Efficacy of Teriflunomide in Multiple Sclerosis with Relapses,
Neurology, 66, p. 894-900
Primary endpoint
• total number of new and persisting combined unique (CU) lesions at 9 months
Secondary endpoints
• total number of lesions on T1 Gd+ enhancing MRI images
• total number of new & enlarging lesions on T2 Gd+ enhancing MRI images
• total number of patients with CU active, T1 and T2 Gd+ enhancing active lesions
• % change from baseline to endpoint in the burden of disease measured by T2 lesion
volume
Clinical endpoints
• number of patients experiencing a relapse
• annualized relapse rate
• number of relapsing patients requiring a course of steroids
• disability progression EDSS
Page 34
46. In this exploratory study in relapsing MS patients, doses of 7 mg OD and 14 mg OD
teriflunomide met the primary endpoint by reducing CU lesions by 60% (p<0.03) and 40%
(p<0.01) respectively compared to placebo. Treatment with teriflunomide significantly
reduced the number of T1 lesions per scan, new & enlarging T2 lesions per scan and new T2
lesions. Once daily 14 mg teriflunomide demonstrated statistically non-significant trends
towards lower ARRs, fewer relapsing patients, and the slowing of disability progression.
Figure 21 depicts the effect of teriflunomide on CU lesions over 9 months. The 14 mg OD
dose was associated with a non-statistically significant reduction in ARR of 32% and a 69%
reduction in the number of patients with a worsened disability state. The safety and
tolerability profile at 9-months was comparable between all groups.
Figure 21 – Teriflunomide; combined unique lesions at 9-months
Source: O’Connor et al., 2006. , A Phase II Study of the Safety and Efficacy of Teriflunomide in Multiple Sclerosis with Relapses,
Neurology, 66, p. 897
Following these encouraging results Sanofi-Aventis advanced teriflunomide into an
aggressive MS program encompassing monotherapy & combination therapy in relapsing MS
and the effects of monotherapy in early stage MS (CIS). The first RMS registration 2-year
placebo-controlled trial TEMSO began in September 2004 and has completed the
Page 35
47. recruitment of 1080 RR/SP/PPMS patients in 21 countries and is scheduled to report in
October 2010. TOWER is a 1-year placebo-controlled confirmatory trial in RMS patients
which began recruiting the targeted 1110 RR/SP/PPMS patients in August 2008 in 19
countries and is projected to complete by September 2011. In parallel to these registration
trials, Sanofi-Aventis launched TENERE a Proof-of-Concept (PoC) trial evaluating the
safety and efficacy of combination therapy with Rebif® (interferonβ-1a) in 300 RMS
patients and a second PoC trial comparing the safety of combination treatment with
Copaxone® (glatiramer acetate) at 6-months in 120 MS patients. TENERE is currently
recruiting whereas the 6-month combination trial with Copaxone® has completed
recruitment. Both PoC trials are expected to form a part of the Manufacturing Authority
Application (MAA).
Additionally TOPIC the 2-year placebo-controlled Phase III trial in an early stage/at risk
population began recruiting 780 CIS patients at 133 sites within 20 countries in February
2008.
Administration of either 7 mg OD or 14 mg OD teriflunomide is common to all of the above
mentioned trials.
Page 36
48. S1P receptor agonists
G protein-coupled receptors (GPCR) have come to the forefront of pharmacological research
as they transverse the cell wall and mediate intracellular signaling through the release of
specific messenger molecules. As a result a pharmacological agent need only interact with
the GPCR on the cell’s outer surface and need not necessarily penetrate the cell to induce or
exclude an intracellular response. Relying on the cell membrane’s innate protective
properties, undesired intracellular responses can thus be greatly reduced. Depending on the
conformational structure of and affinity between both target receptor & pharmacological
agent, a higher degree of specificity for the target receptor over other structurally similar yet
functionally different receptors can also potentially reduce many undesirable side effects.
Ceramides, a family of bioactive lipids present in the cell membrane of many cells, are
found predominantly in the skin; accounting for up to 50% of the lipid count in the stratum
corneum and in trace amounts throughout the rest of the body. Although ceramides are not
G protein-coupled receptors, following extensive research it was determined that similar to
GPCRs, they could also mediate intracellular responses inclusive of cell differentiation,
transformation, proliferation, and programmed cell death, i.e. apoptosis. The mechanism by
which these activities are achieved is still uncertain. Although de novo synthesis in animals
is possible, it is significantly faster for cells under stress to produce ceramide via the
hydrolyzing enzyme sphingomyelin phosphodiesterase (SMase).
Ceramides are composed of a fatty acid bound to sphingosine via an amide bond as shown in
Figure 22 beneath. The terminal hydroxyl group can be further conjugated to produce a
multitude of unique sphingolipids.
Page 37
49. Sphingosine
Fatty acid
Figure 22 – Ceramide; generic chemical structure
Adapted from: http://www.lipidlibrary.co.uk/Lipids/ceramide/index.htm
The process by which catabolism of ceramide yields sphingosine-1-phosphate (S1P), an
endogenous signaling sphingolipid found predominantly in the circulating blood supply, is
shown in Figure 23.
Figure 23 – Sphingolipid biosynthetic pathway
Source: Rosen et al., 2009. Sphingosine 1-Phosphate Receptor Signaling, Annual Review of Biochemistry, 78, p. 745
S1P was shown to be an extracellular ligand released by both mast cells and platelets among
other cells which binds to S1P1-5, a family of lysophospholipid GCPRs. The known activity
of all known S1Px receptors, as determined by experiments with knock-out mice, in-vitro
assays or a combination of both, is listed beneath in Table I.
Page 38
50. Table II – Properties of sphingosine-1-phosphates
Distribution Cellular function and consequences
S1P1 brain Astrocyte: migration
heart B-cell: blockade of egress, chemotaxis
spleen Cardiomyocyte: increased β-AR positive inotropy
liver Endothelial cell: early vascular system development, adherens
lung junction assembly, APC-mediated increased barrier integrity
thymus Neural stem cell: increased migration
kidney Pericyte: early vascular system development (VSMC)
skeletal muscle T-cell: blockade of egress, chemotaxis, decreased late-stage
lymphoid maturation
VSMC
S1P2 brain Cardiomyocyte: survival to ischemia-reperfusion
heart Epithelial cell (stria vascularis): integrity/development
spleen Epithelial hair cells (cochlea): integrity/development
liver Endothelial cell (retina): pathological angiogenesis, adherens
lung junction disruption
thymus Hepatocyte: proliferation/matrix remodeling
kidney Fibroblast (MEF)
skeletal muscle Mast cell: degranulation
VSMC: decreased PDGF-induced migration
S1P3 brain Cardiomyocyte: survival to ischemia-reperfusion
heart Dendritic cell (hematopoietic): worsening experimental sepsis
spleen lethality/inflammation/coagulation
liver
lung
thymus
kidney
skeletal muscle
testis
S1P4 lung T-cell: migration/cytokine secretion
lymphoid
S1P5 brain NK cell: trafficking
skin Oligodendrocyte: survival
spleen OPC: glial process retraction; inhibition of migration
Source: Rosen et al., 2009. Sphingosine 1-Phosphate Receptor Signaling, Annual Review of Biochemistry, 78, p. 749
This sequestration of peripheral blood lymphocytes via S1P1 agonism is thought to offer
primary therapeutic benefit in MS, effectively reducing the chances of further immunological
attacks on myelinated brain tissue.
Page 39
51. Fingolimod
The discovery of these 5 lysophospholipids and the elucidation of their expression &
function has presented the pharmaceutical industry with an entirely new and novel set of
target receptors. The first and most well known non-selective S1P1,3-5 agonist to reach
clinical trials was Novartis’ fingolimod, also known as FTY720. Fingolimod is an analogue
to a naturally occurring Myriocin metabolite ISP-1 produced by the fungus Isaria sinclairii
which has been used for centuries in traditional Chinese medicine [13]. Fingolimod was first
synthesized in 1992 by Kunitomo Adachi & Kenji Chiba, two Japanese medicinal chemists.
Long after its entry in the 1990’s into clinical testing as a novel immunomodulator,
fingolimod was found to be a sphingosine-like prodrug in 2002. Fingolimod-phosphate
(fingolimid-P), the active metabolite produced via phosphorylation by sphingosine kinase, is
a potent agonist at all S1P receptors with the exception of S1P2 and selectively reduces both
peripheral T&B cell counts in the blood [14]. There is also evidence that fingolimod-P acts
as a cannabinoid antagonist, cPLA2 inhibitor, and ceramide synthase inhibitor [15][16][17].
Figure 24 depicts the structure of both the parent compound fingolimod and its prodrug
fingolimod-P.
Sphingosine
kinase
fingolimod fingolimod-P
Figure 24 – Fingolimod; parent and phosporylated metabolite
Adapted from: http://journals.prous.com/journals/dof/20073211/html/df321007/images/fig12.gif
Page 40
52. Lymphocytes naturally migrate from secondary lymphoid tissues and the thymus, where the
concentration of sphingosine-1 phosphate (S1P) is low, to the blood where the aggregation is
significantly higher. It has been postulated that the immunosuppressive effect witnessed
with fingolimod-P is due its ability as a “functional antagonist” to internalize the S1P1
receptors on the surface of the T&B cells and so by desensitize them to the gradient of S1P
leaving them sequestered in the lymphatic system [18]. Fingolimod-P does not affect the
activation, proliferation or effector functions of these lymphocytes nor does it affect levels of
natural killer cells, monocytes or granulocytes in the blood.
Clinical Development
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
199X SAD
1998 MAD
RRMS/SPMS
Ethnic sensitivity
Asthma
Freedoms I
Freedoms II end
2011
Transforms
Avonex controlled
Informs (PPMS) 2013
MAA MA Launch
Figure 25 – Fingolimod MS development plan
The 1st administration of fingolimod in single ascending doses on top of Neoral® in human
renal transplant patients was reported in 2002 by Budde et al. [19]. Figure 26 depicts the
study design.
Page 41
53. -21d -2d -1d -1hr x 0.5 1 2 6 12 24 48 72 96hr
FTY720 0.25 mg
0.5 mg
0.75 mg
1.0 mg
2.0 mg
3.5 mg
Placebo
administration
undisclosed timepoints
FEV1, FVC, DLCO, exercise
Figure 26 – Fingolimod; SAD on top of Neoral® in renal transplant patients
Adapted from: Budde et al., 2002. First human trial of FTY720 a novel immunomodulator in stable renal transplant patients, Journal of the
American Society of Nephrology, 13(4), p.1073-83
All doses showed a reversible transient lymphopenia as shown in Figure 27. Whereas the
variability in response to the 0.25 – 2.0 mg doses failed to yield clear dose-dependent
relationship, 3.5 mg fingolimod demonstrated a dramatic mean decrease of 73% from
baseline values within 8 hours of administration.
Figure 27 – Fingolimod; SAD lymphocyte reductions
Source: Budde et al., 2002. First human trial of FTY720 a novel immunomodulator in stable renal transplant patients, Journal of the
American Society of Nephrology, 13(4), p.1077
Page 42
54. Single administration was considered to be safe and well tolerated with no serious adverse
effects. However the most common adverse event was dose-dependent transient
asymptomatic bradycardia. As the treatment arms contained few and occasionally shared the
same subjects, the pulse rate data was combined to produce a low dose group of 0.25 & 0.5
mg and a high dose group of 0.75, 1, 2 & 3.5 mg. A more pronounced effect is associated
with the higher dose groups. Figure 28 clearly illustrates this effect.
Figure 28 – Fingolimod; SAD Bradycardic effects
Source: Budde et al., 2002. First human trial of FTY720 a novel immunomodulator stable renal transplant patients, Journal of the American
Society of Nephrology, 13(4), p.1077
Encouraged by these results, Novartis engaged in further development of fingolimod
culminating in the decision to enter full scale development in two indications where the
sequestration of lymphocytes could plausibly provide therapeutic promise: renal transplant
and Multiple Sclerosis.
In 2006 Salvadori et al. reported on a 1-year Phase III registration trial in renal transplant
which began in May 2003 and recruited 668 patients in 42 sites worldwide [20]. This trial
established no benefit for either a course of 2.5 mg fingolimod plus a full-dose of
cyclosporine or 5 mg fingolimod plus a reduced-dose of cyclosporine over the standard care:
mycophenolate mofetil plus a full-dose of cyclosporine. The safety findings of note
Page 43
55. consisted of the expected transient first dose bradycardia as well as lower creatinine
clearance levels and a dose-dependent, increased incidence of macular edema.
Also in 2006 Kappos et al. reported on the placebo controlled 6-month Phase IIb dose
finding study in MS which began in May 2003 and recruited 281 patients in 26 sites ex-US
[21]. This study explored the efficacy of fingolimod doses 5 mg and 1.25 mg against
placebo at 6-months in patients which presented with either relapsing-remitting MS (RRMS)
or secondary progressive MS (SPMS); thereafter an open label extension was offered to all
patients who desired to continue on treatment with fingolimod until either the eventual
registration or termination of the clinical development program. Figure 29 illustrates the
study design.
May October April May
Double blind core study Study extension
2003 2004 2005 2010
scr x 1d 7d 1 mon 2 3 4 5 6 mon 9 mon 1 yr
FTY720 1.25 mg //
5 mg
5 mg dose shows no more
Placebo efficacy than 1.25 mg and
all remaining patients are
switched to 1.25 mg @
MRI month 15
x = 24hr Holter
x x ECG x at select sites
FEV1, FVC, DLCO
EDSS, MSFC
Figure 29 – Fingolimod; Phase IIb trial design
Adapted from: Kappos et al., 2006. Oral fingolimod (FTY720) for relapsing Multiple Sclerosis, New England Journal of Medicine, 335),
p.1124-41
Following the heart rate disturbances and reports of dyspnea witnessed in the SAD trial,
monitoring measures, i.e. electrocardiogram (ECG), Holter monitoring, forced expiratory
volume in 1 second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung
for carbon monoxide (DLCO), were implemented in the protocol to ensure the patient’s
Page 44
56. safety as well as to better describe the occurrence, course & severity of these events. The
endpoints were:
Primary endpoint
• reduction in the number of Gd+ enhanced lesions/patient at 6 months on T1-weighted
MRI images
Secondary endpoints
• total volume of Gd+ enhanced lesions per patient
• proportion of patients with Gd+ enhanced lesions
• total number of new lesions/patient on T2-weighted MRI images
• brain volume from baseline to month 6
Clinical endpoints
• number of patients remaining free of relapse
• annualized relapse rate
• time to first relapse
• Expanded Disability Status Score (EDSS) at 12 months
Both experimental doses of fingolimod met all of the endpoints above with the exception of
brain volume from baseline to month 6 and EDSS at 12 months. As shown in Figure 30 the
higher dose of 5 mg failed to differentiate itself from the effects witnessed with 1.25 mg at 6-
months. After the 5 mg dose continued to provide no increased clinical benefit compared to
the 1.25 mg dose at 12-months, it was discontinued as an experimental dose in subsequent
MS trials.
Page 45
57. Proportions of patients who were free of
Gd-enhanced lesions on T1 weighted MRI
at month 0 and 6 Estimated time to a first confirmed relapse
Figure 30 –Fingolimod; Phase IIb results at 6-months
Source: Kappos et al., 2006. Oral fingolimod (FTY720) for relapsing Multiple Sclerosis, New England Journal of Medicine, 335), p.1132
Both experimental doses of fingolimod were judged to be well tolerated in the patient
population. The majority of the SAEs were associated with the 5 mg dose. Figure 31 lists
the most common reported SAEs and AEs associated with both doses at 6-months. Raised
levels of liver enzyme levels (>3 x ULN) of both alanine transaminase (ALT) and aspartate
transaminase (AST) were noted at 6-months. No clinical symptoms were observed and the
levels normalized equally either over time without a down-titration or upon discontinuation
of treatment altogether.
Figure 31– Fingolimod; tolerability profile at 6-months
Adapted from: Kappos et al., 2006. Oral fingolimod (FTY720) for relapsing Multiple Sclerosis, New England Journal of Medicine, (335),
p.1134-37
Page 46
58. This Phase IIb dose-finding study established neither a full dose response curve nor any
improvement on the disability score observed with either dose at 6-months; however the
45% reduction in Annualized Relapse Rate (ARR) against placebo was already a tremendous
improvement on the ~ 30% ARR reductions achieved with currently marketed biologics.
Furthermore it could be argued that 6-months was far too short a period to measure the delay
to disease progression in an indication whose time course spans more than a decade on
average - and fingolimod held the promise of convenient oral once daily administration.
Novartis abandoned the renal transplant program and invested in a substantial MS Phase III
program which began with two registration trials TRANSFORMS & FREEDOMS and
eventually expanded to include FREEDOMS II. TRANSFORMS was a 1-year trial with 2
doses of 1.25 mg and 0.5 mg against Avonex® the market leading interferon β-1a which
began in May 2006 and recruited 1,292 patients with 141 clinical sites in 18 countries.
Figure 32 depicts the trial design as disclosed at the World Congress on Treatment and
Research in Multiple Sclerosis. Holter monitoring was dropped as a requirement. Many of
the remaining safety monitoring measures were the same, i.e. MRI, ECG, FEV1, FVC and
DLCO. New monitoring requirements included ophthalmological exams, chest x-ray and
high resolution CT scan (HRCT). Ophthalmological exams could be warranted given the
increased incidence of macular edema in the renal transplant program. Chest x-rays might
have been used to exclude patients with latent tuberculosis infections which could be
reactivated under therapy. HRCT was introduced presumably to determine the etiology of
the dyspnea reported in the Phase IIb study. Given the 1-year duration of this trial and the
decrease in FEV1 observed in the Phase IIb trial, it is possible that the use of HRCT scans
was used to detect potential fibrotic changes which could result in constriction of the
bronchial passages and eventually lead to difficulty in breathing.
Page 47
59. May Sep Apr
Double blind core study Study extension
2006 2008 2011
scr x 1 yr
FTY720 0.5 mg
1.25 mg
Avonex® 30 μg
??
MRI
??
ECG
??
FEV1, FVC, DLCO
??
EDSS, MSFC
??
Chest X-ray or HRCT
??
Ophthalmological exam
Figure 32 – TRANSFORMS trial design
Adapted from: WCTRIMS poster, Sep 2008
This trial was conducted in the patients with relapsing-remitting MS (RRMS). The
endpoints were as follows:
Primary endpoints
• monthly MRI lesion parameters
• safety & tolerability at 6-months
Secondary endpoints
• time to first relapse at 6-months
• proportion of relapse-free patients at 6-months
Page 48
60. On December12, 2008 Novartis issued a press release disclosing the initial results from the
TRANSFORMS trial. Strikingly the lower dose of 0.5 mg demonstrated a better clinical
response than the higher 1.25 mg dose; 52% reduction in ARR as opposed to 38%
respectively (p<0.001). Fingolimod was once more considered to be well tolerated as 87%
of the patients completed the study. Also of note was the ARR of 0.33 relapses/year
determined from the 431 Avonex® treated patients. The registration trial as reported in the
Avonex® Manufacturing Authorization Application (MAA) submitted to the FDA did not
report a clinical benefit to patients in the first year of administration; it reported an ARR of
1.03 in the active 65 patient arm against 0.8 reported in the 45 patient placebo arm at 1-year
with a therapeutic benefit manifesting itself only at the 2-year timepoint. In the
TRANSFORMS data Avonex® appears to already have an effect at 6-months. This
however may be due to the change in clinical practice since 1996 when the MAA was
submitted. Curiously enough Novartis decided against releasing data pertaining to disease
progression as measured by EDSS.
The astounding efficacy was off-set by the long term safety profile however. Transient
bradycardia remained a common safety finding, AST & ALT levels ≥ 3 x ULN were
reported in some patients, along with 7 cases of macular edema. New findings included
increased blood pressure (BP), 7 cases of skin cancer and 2 fatal viral infections: primary
disseminated varicella (†) and herpes encephalitis (†). Malignancies and opportunistic
infections are two well known risks associated with long term immunosuppression.
Shortly after the December 2008 press release, O’Connor et al. published the results of the
Phase IIb 2-year extension study [22]. 250 (89%) of the patients from the core study entered
the optional open-label extension study where those patients initially receiving placebo
therapy were re-randomized to receive long term treatment with either 1.25 mg or 5 mg
fingolimod. O’Connor et al. reported on the outcomes from the remaining 189 (75.6%)
patients as they completed 2-years of continuous treatment. As previously mentioned within
3 months of the study start the 5 mg dose group was discontinued due to an increased safety
Page 49
61. burden combined with a lack of increased efficacy compared to 1.25 mg at 6-months.
Patients re-randomized to either dose of fingolimod exhibited a similar reduction on
inflammatory markers as detected by MRI, i.e. T2 weighted Gd+ enhanced images, as
previously witnessed in the active groups in the core study. Those patients continuing with
either 1.25 mg treatment or down-titrating from 5 to 1.25 mg improved or remained stable
and these groups demonstrated a 55% or 53% relative reduction in ARR respectively after 1-
year of continuous treatment including the core study exposure. Figure 33 illustrates the
proportion of patients remaining relapse-free over time.
Figure 33 – Fingolimod; time to first confirmed relapse in 2-year extension study
Source: O’Connor et al., 2009. Oral fingolimod (FTY720) in Multiple Sclerosis, Neurology (72), p.76
AEs and withdrawal of consent were the two most common reasons for treatment
discontinuation. The majority of the AEs were mild to moderate in nature with
nasopharyngitis, headache, influenza and lymphopenia being the most prevalent. 10% of the
patients experienced at least one SAE: unconfirmed macular edema, peripheral edema,
hepatitis, jaundice, MS relapse, hirsutism, flushing, neutropenia, adrenal mass, acute
abdomen, inguinal hernia, salpingitis, drug exposure during pregnancy and hypertension.
ALT elevations >3 x ULN were reported in 12-16% of the patient population.
Page 50
62. As expected peripheral lymphocyte counts decreased by up to 75% from baseline and
remained between 500 - 600 cells/m3. Furthermore there were no reported instances of
opportunistic infections or malignancies as one might expect with the continuous use of a
compound which so effectively reduces circulating lymphocytes.
Transient bradycardia continued to be witnessed in naïve patients switching from placebo to
active treatment within the first hour of dosing and resolved without further medical
intervention after a maximal 4-5 hours. Comparison with pre-treatment values at 2-years
revealed no further instances of bradycardia.
A decrease in systolic blood pressure was observed in the first 6 hours of dosing which
returned to baseline values by Day 7 without intervention. At 2-years a mean increase of 4.1
- 6.3 mm Hg in sitting BP from the baseline values measured in the core study was noted.
Pulmonary function was not explicitly monitored in the long term extension study; however
reports of asthma and dyspnea were associated with both dose groups.
In contrast to the core study and TRANSFORMS, there were no instances of confirmed
macular edema.
The FREEDOMS trials are two identical 2-year placebo-controlled studies investigating the
doses of 1.25 mg and 0.5 mg fingolimod. FREEDOMS I began in January 2006 and
recruited 1,272 RRMS patients with 115 clinical sites in 19 countries ex-US. FREEDOMS
II began later in June 2006 and recruited 1,080 RRMS patients with 107 clinical sites
predominantly in the US but also included sites from another 7 countries. Figure 34 depicts
the FREEDOMS I&II trial design as disclosed at the World Congress on Treatment &
Research in Multiple Sclerosis and an independent press release in September 2009.
Page 51
63. Jan Aug Apr
Double blind core study Study extension
2006 2009 2011
scr x 6 mon 1 yr 2 yr
FTY720
FTY720 0.5 mg
1.25 mg
Placebo
MRI
??
ECG
??
FEV1, FVC, DLCO
??
EDSS, MSFC
x x = MSFC
??
Chest X-ray
??
Ophthalmological exam
Figure 34 – FREEDOMS I&II trial design
Adapted from: WCTRIMS poster, Sep 2008 / FREEDOMS press release, Sep 2009
Both of these trials were conducted in the patients with relapsing-remitting MS (RRMS).
The endpoints were as follows:
Primary endpoint
• Annualized relapse rate at 2-years
Secondary endpoints
• Proportion of relapse-free patients treated at 2-years
• Safety & tolerability of fingolimod at 2-years
• Burden of disease and inflammatory activity as measured by MRI lesion parameters
at 2-years
On September 30, 2009 Novartis released the first results from the FREEDOMS trial.
Compared to placebo daily oral dosing with 0.5 and 1.25 mg led to a reduction in
Annualized Relapse Rates (ARR) by 54% and 60% (p<0.001) and slowing of disease
Page 52
64. progression as measured by EDSS scores of 30% and 32% respectively at 2-years. (see
Figures 35 & 36)
The 0.5 mg dose appears to have been safer and better tolerated than the 1.25 mg dose. In
contrast to placebo and 1.25 mg groups, no cases of heart rhythm disorders, macular edema,
melanoma, breast cancer or deaths were reported with this dose. Figure 37 provides the
SAE listings.
Figure 35– Fingolimod; relapse rate at 2-years in FREEDOMS
Source: FREEDOMS press release, Sep 2009
Figure 36 – Fingolimod; disease progression at 2-years in FREEDOMS
Source: FREEDOMS press release, Sep 2009
Page 53
65. Figure 37 – Fingolimod; Serious Adverse Events reported in FREEDOMS
Source: FREEDOMS press release, Sep 2009
Novartis plans to submit a Manufacturer’s Authorization Application (MAA) to the EU and
a New Drug Application (NDA) to the FDA by the end of 2009; the FDA has not granted
Fast Track status to fingolimod.
Novartis has initiated INFORMS, a 3-year study comparing the effects of 1.25 mg
fingolimod against placebo in 654 patients with primary progressive MS (PPMS). There is
no licensed treatment for PPMS. Currently there are no on-going trials exploring the
efficacy and safety of combination therapy with other licensed products in RRMS. Neither
clinically isolated syndrome (CIS) nor secondary progressive MS (SPMS) are presently
under investigation with fingolimod.
Page 54
66. BAF312
The natural process of remyelination begins with the migration of oligodendrocyte precursor
cells (OPC) to sites of axonal trauma and ends with the development of mature
oligodendrocyte cells which re-sheath the damaged neurons with myelin. As S1P5 is
predominantly expressed in oligodendrocytes and the white matter tracts of the brain, it
presented itself as an interesting target to researchers investigating demyelinating disorders.
Novgorodov et al. published work which links the inhibition of OPC migration to agonism of
S1P5 using S1P in cultured cells from neonatal rat cortices; however other studies show an
increased survival rate of mature oligodendrocytes in cytotoxic environments [23][24].
Although fingolimod, a non-selective S1P1,3-5 agonist, demonstrated a high degree of clinical
efficacy as measured by reduced GD+ enhanced lesions, ARR & disability progression,
differentiation between the therapeutic benefits derived from remyelination as a direct result
of S1P5 agonism or otherwise, and lymphocyte sequestration will remain highly speculative;
comparative outcomes from clinical trials in patients suffering demyelinating disorders are
the sole means to investigate this mechanism and even then the conclusions will not be
decisive.
In 2004, during the conduct of the fingolimod Phase IIb program, Germana Sanna et al.
published an article which linked S1P3 agonism with bradycardia using S1P3 knock-out mice
[25]. Novartis developed a dual S1P1/5 agonist BAF312 which was >1,000 fold more
selective for S1P1 than S1P3 and began the first pharmacological study with 63 human
subjects in October 2006.
Page 55
67. Clinical Development
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
CBAF312A2101 SAD
?
CBAF312A210X MAD
CBAF312A2201 IIb X
LPLV
MAA MA Launch
Figure 38 – BAF312 MS development plan
In December 2008 Novartis disclosed the initiation of the BOLD Phase IIb trial in RRMS
patients. The experimental dosing range of 0.5 to 10 mg against placebo was constructed
based on the PK/PD data from the BAF312 SAD trial and the mean lymphocyte count
reductions associated with a clinical improvement in the previous fingolimod MS Phase IIb
trial. An interim analysis at 3-months will allow the introduction of up to 2 additional doses
for the remainder of the 6-month treatment period in an effort to hone in on the doses most
likely to be efficacious in the Phase III program. The BOLD trial is currently recruiting 275
RRMS patients at 82 investigational sites in 12 countries and is scheduled to conclude
treatment in October 2010. This was an apparent leap-frogging of the standard MAD trial in
human subjects. Figure 39 depicts the study design of the BOLD trial.
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68. Figure 39 – BAF312; BOLD trial design
Source: ECTRIMS, Sep 2009
BOLD is conducted exclusively in relapsing-remitting MS (RRMS) patients. The endpoints
are as follows:
Primary endpoint
• Dose dependent relationship among five doses of BAF312 and placebo as measured
by the number of combined unique active MRI lesions at 3-months
Secondary endpoints
• Safety & tolerability of BAF312 at 3 & 6 months
• Number of relapses, annualized relapse rate (ARR), and proportion of relapse-free
patients
• Correlation between the course of lymphocyte count with MRI activity & clinical
outcomes
• Additional MRI parameters
• Steady state plasma concentrations
Page 57
