Oral MS therapy         The coming revolution                                  by                           Oliver Vit    ...
AbstractThis dissertation reviews the oral therapies currently being developed for the treatment ofMultiple Sclerosis base...
return however restricted to fringe use due to limited expectations and experience. Followingthe launch in RRMS, Mylinax® ...
Table of ContentsFigures                                           viTables                                            ixI...
ACT-128800                   60              CS-0777                      63              ONO 4641                     67 ...
DISCUSSION         (Mylinax®) Cladribine   86         Teriflunomide           88         Fingolimod              89       ...
FiguresFigure 1    MS Disease subtypes                                           p.3Figure 2    Benign MS                 ...
Figure 20   HMR1726D-2001 trial design                                              p.34Figure 21   Teriflunomide; combine...
Figure 41   Absolute lymphocyte count reductions following administration of   p.59            BAF312Figure 42   ACT-12880...
TablesTable I     Biomarkers in Multiple Sclerosis                       p.13Table II    Properties of sphingosine-1-phosp...
INTRODUCTIONEtiologyJean-Martin Charcot was the first physician to discover the lesions in both the brain’s whitematter an...
the loss of the myelin sheath often results in the loss of conducting impulses and theassociated function, e.g. loss of gr...
Figure 1 – MS Disease subtypesSource: US National MS Society                                 Page 3
Relapsing-remitting MS (RRMS)By far the most common form of MS accounting for upwards of 80% of new diagnoses,relapsing-re...
Figure 2 – Benign MSAdapted from: www.imaginginformatics.caClinically isolated syndrome (CIS)A diagnosis of CIS is based o...
MS Population Breakdown By Subtype                                      20%       19%                                     ...
Diagnostic toolsThe signs and symptoms are varied and include any of the following alone or incombination: loss of cogniti...
Magnetic resonance imaging (MRI)Hydrogen atoms when bound to oxygen produce water; however as the electrons areunevenly di...
Figure 6– MRI scans of T1 & T2 lesions with & without GD+ enhancementSource: Frey et al., 1999. Clinical Application of MR...
Annualized Relapse Rate (ARR)A relapse is defined as a new neurological symptom or a worsening of a pre-existingneurologic...
1.0: No disability, minimal signs on 1 FS     1.5: No disability, minimal signs on 2 of 7 FS     2.0: Minimal disability i...
Figure 8 – EDSS scoring as shared with the patientSource: https://www.msactivesource.com 0.0: Normal Neurological ExamMult...
BiomarkersGiven the uncertainties associated with the etiology of MS, the genetic & environmentalfactors which may predisp...
Current therapyIntravenous corticosteroids are commonly used to relieve the localized swelling and pain ofacute inflammato...
no statistically significant reduction in disease progression as measured by EDSS.Neutralizing antibodies (NABs) do develo...
of clinical exacerbations and delay the accumulation of physical disability in relapsing MSpatients. In later clinical tri...
Tysabri® (α4-integrin antagonist)First developed by Élan and co-developed with Biogen Idec, Tysabri® (natalizumab) wasthe ...
& restricted to hospital use. However in CAMMS223 a Phase IIb RRMS trial, annualtreatment with Campath® achieved a 74% dec...
METHODSGiven the highly competitive and secretive nature of drug development, retrieving reliableinformation regarding pot...
The risk:benefit of each candidate was evaluated on the grounds of released efficacy, safetyand tolerability results eithe...
RESULTSOral MS therapies; competitive environmentIn a field crowded with expensive parenterals, oral administration appear...
Figure 10 – Competitive radar; oral MS agents                                                Page 22
Anti-proliferative/replicantCladribineDeveloped in the late 1970’s at the Scripps Research Institute as a therapeutic agen...
Figure 11 – Cladribine; chemical structureSource: http://journals.prous.com/journals/dof/20042903/html/df290253/images/113...
The clinical development of cladribine has spanned decades, indications and corporations. Itdebuted as an experimental int...
Jan                                                   Nov                                              Double blind core s...
Figure 14 – CLARITY; relapse rates at 2-yearsSource: ECTRIMS poster, Sep 2009Figure 15 – CLARITY; disease progression at 2...
In line with expectations, T, B & NK cell counts in exposed patients decreased rapidly uponadministration with either the ...
Figure 16 – Cladribine; selective reduction of lymphocytesSource: ECTRIMS poster, Sep 2009                                ...
ONWARDS is a Phase II 2-year trial evaluating the safety of oral cladribine in combinationwith interferon-β; RRMS and SPMS...
Secondary endpoints   •   cumulative incidence of myelodysplasic syndromes (MDS)   •   cumulative incidence of haematologi...
TeriflunomideAs a disease-modifying antirheumatic drug (DMARD) Arava® (leflunomide) inhibits the de-novo pyramidine synthe...
Clinical Development2002   2003     2004    2005      2006         2007       2008   2009   2010   2011   2012    2013   2...
Apr                                                      Mar                                                Nov           ...
In this exploratory study in relapsing MS patients, doses of 7 mg OD and 14 mg ODteriflunomide met the primary endpoint by...
recruitment of 1080 RR/SP/PPMS patients in 21 countries and is scheduled to report inOctober 2010. TOWER is a 1-year place...
S1P receptor agonistsG protein-coupled receptors (GPCR) have come to the forefront of pharmacological researchas they tran...
Sphingosine                                   Fatty acidFigure 22 – Ceramide; generic chemical structureAdapted from: http...
Table II – Properties of sphingosine-1-phosphates             Distribution                Cellular function and consequenc...
FingolimodThe discovery of these 5 lysophospholipids and the elucidation of their expression &function has presented the p...
Lymphocytes naturally migrate from secondary lymphoid tissues and the thymus, where theconcentration of sphingosine-1 phos...
-21d   -2d   -1d -1hr x 0.5 1   2    6      12      24            48            72             96hr FTY720             0.2...
Single administration was considered to be safe and well tolerated with no serious adverseeffects.        However the most...
consisted of the expected transient first dose bradycardia as well as lower creatinine clearance levels and a dose-depende...
safety as well as to better describe the occurrence, course & severity of these events. Theendpoints were:Primary endpoint...
Proportions of patients who were free of Gd-enhanced lesions on T1 weighted MRI at month 0 and 6                          ...
This Phase IIb dose-finding study established neither a full dose response curve nor anyimprovement on the disability scor...
May                                         Sep                      Apr                                  Double blind cor...
On December12, 2008 Novartis issued a press release disclosing the initial results from theTRANSFORMS trial. Strikingly th...
burden combined with a lack of increased efficacy compared to 1.25 mg at 6-months.Patients re-randomized to either dose of...
As expected peripheral lymphocyte counts decreased by up to 75% from baseline andremained between 500 - 600 cells/m3. Furt...
Jan                                                 Aug                       Apr                                         ...
progression as measured by EDSS scores of 30% and 32% respectively at 2-years. (seeFigures 35 & 36)The 0.5 mg dose appears...
Figure 37 – Fingolimod; Serious Adverse Events reported in FREEDOMSSource: FREEDOMS press release, Sep 2009Novartis plans ...
BAF312The natural process of remyelination begins with the migration of oligodendrocyte precursorcells (OPC) to sites of a...
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Final 2009 m sc thesis oliver vit cv
Upcoming SlideShare
Loading in …5
×

Final 2009 m sc thesis oliver vit cv

702 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
702
On SlideShare
0
From Embeds
0
Number of Embeds
26
Actions
Shares
0
Downloads
7
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Final 2009 m sc thesis oliver vit cv

  1. 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. 2. AbstractThis dissertation reviews the oral therapies currently being developed for the treatment ofMultiple Sclerosis based on their strengths, weaknesses, opportunities, relative threats, andpredicts 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 toidentify potential candidates and then to define the Mechanism of Action (MoA), the clinicaldevelopment plan (CDP) and the duration of market exclusivity. Where informationconcerning the CDP or market exclusivity was found to be lacking, standard assumptions wereused to extrapolate forwards.Results: No less than 11 candidates were identified across 4 separate MoAs spanningclinical 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 therapiesever launched to treat RRMS. MS therapy will adapt to the coming oral revolution accordingto (1) time of approval (2) the risk:benefit profile each MS subtype supports, (3) the degree ofconfidence neurologists acquire with these new agents, and (4) direct demands of MS patientsfor convenient, efficacious and safe treatment of their disorder. Combination therapy will i
  3. 3. return however restricted to fringe use due to limited expectations and experience. Followingthe launch in RRMS, Mylinax® and fingolimod will continue to expand into suspected earlystage MS (CIS) and progressive forms of MS (PPMS/SPMS) respectively. A 2nd wave of oralsconsisting 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 arange of additional differentiation in terms of both efficacy & safety which may arrive by 2017well in advance of the 1st oral to lose IP protection (fingolimod in 2019).Clever integration of MRI techniques along with monitoring of biomarkers and potentiallygenetic screening may help to change the understanding of MS, its progression and thetherapeutic paradigm. Cost effectiveness as well as patient access will drive furtherdifferentiation between clinically non-differentiated products. Biologics will suffer a dualpronged assault from lower priced biosimilars and new oral agents as patent expiry andcompetition from bio-similars looms; however the market will continue to support innovativehigh priced therapy. Continued research into the non-inflammatory component of MS holdsthe key to the next revolution. ii
  4. 4. Table of ContentsFigures viTables ixINTRODUCTION Etiology 1 Diagnostic tools 7 Current therapy 14METHODS 19RESULTS Oral MS therapies; competitive environment 21 Anti-proliferative/replicant 23 Cladribine 23 Teriflunomide 32 S1P receptor agonists 37 Fingolimod 40 BAF312 55 iii
  5. 5. 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 81MS biologics; global market Annual revenues 82 Market capitalization 83Market exclusivity 84 iv
  6. 6. DISCUSSION (Mylinax®) Cladribine 86 Teriflunomide 88 Fingolimod 89 BAF312 90 ACT-128800 91 CS-0777 91 BG-12 92 Laquinimod 93 Firategrast 93CONCLUSION 94REFERENCES 99 v
  7. 7. FiguresFigure 1 MS Disease subtypes p.3Figure 2 Benign MS p.5Figure 3 MS subtype segmentation p.5Figure 4 MS subtype segmentation as reported by neurologists (USA) p.6Figure 5 MS subtype segmentation as reported by patients p.6Figure 6 MRI scans of T1 & T2 lesions with & without GD+ enhancement p.9Figure 7 Full EDSS scoring p.11Figure 8 EDSS scoring as shared with the patient p.12Figure 9 Pipeline; oral MS agents in Phase II/III p.21Figure 10 Competitive radar; oral MS agents p.22Figure 11 Cladribine; chemical structure p.24Figure 12 Cladribine MS development plan p.24Figure 13 CLARITY trial design p.26Figure 14 CLARITY; relapse rates at 2-years p.27Figure 15 CLARITY; disease progression at 2-years p.27Figure 16 Cladribine; selective reduction of lymphocytes p.29Figure 17 Cladribine; registry trial design p.30Figure 18 Teriflunomide & leflunomide; chemical structures p.32Figure 19 Teriflunomide MS development plan p.33 vi
  8. 8. Figure 20 HMR1726D-2001 trial design p.34Figure 21 Teriflunomide; combined unique lesions at 9-months p.35Figure 22 Ceramide; generic chemical structure p.38Figure 23 Sphingolipid biosynthetic pathway p.38Figure 24 Fingolimod; parent and phosporylated metabolite p.40Figure 25 Fingolimod MS development plan p.41Figure 26 Fingolimod; SAD on top of Neoral® in renal transplant patients p.42Figure 27 Fingolimod; SAD lymphocyte reductions p.42Figure 28 Fingolimod; SAD Bradycardic effects p.43Figure 29 Fingolimod; Phase IIb trial design p.44Figure 30 Fingolimod; Phase IIb results at 6-months p.46Figure 31 Fingolimod; tolerability profile at 6-months p.46Figure 32 TRANSFORMS trial design p.48Figure 33 Fingolimod; time to first confirmed relapse in 2-year extension study p.50Figure 34 FREEDOMS I&II trial design p.52Figure 35 Fingolimod; relapse rate at 2-years in FREEDOMS p.53Figure 36 Fingolimod; disease progression at 2-years in FREEDOMS p.53Figure 37 Fingolimod; Serious Adverse Events reported in FREEDOMS p.54Figure 38 BAF312 MS development plan p.56Figure 39 BAF312; BOLD trial design p.57Figure 40 Mean Ventricular Heart Rate following administration of BAF312 p.58 vii
  9. 9. Figure 41 Absolute lymphocyte count reductions following administration of p.59 BAF312Figure 42 ACT-128800; SAD pharmacokinetics p.61Figure 43 ACT-128800; SAD mean lymphocyte count reductions following p.61 single administrationFigure 44 ACT-128800; SAD mean %Δ in lymphocyte count following single p.62 administrationFigure 45 CS-0777P; SAD pharmacokinetics p.64Figure 46 CS-0777; SAD reduction of lymphocyte sub-populations p.64Figure 47 CS-0777; SAD peripheral lymphocyte counts p.65Figure 48 CS-0777; Alanine aminotransferase levels p.65Figure 49 CS-077-A-U102 trial design p.66Figure 50 BG-12 MS development plan p.70Figure 51 BG-12; Phase IIb MS trial design p.71Figure 52 BG-12; Phase IIb GD+ enhanced lesions at 6-months p.72Figure 53 Laquinimod; chemical structure p.75Figure 54 Laquinimod MS development plan p.76Figure 55 LAQ/5062 trial design p.77Figure 56 Laquinimod; reduction of T1 GD+ enhanced lesions at 9-months p.78Figure 57 Firategrast MS development plan p.80Figure 58 Biologic MS therapy; annual revenues 2006-2008 p.82Figure 59 Biologic MS therapy; market share 2006-2008 p.83 viii
  10. 10. TablesTable I Biomarkers in Multiple Sclerosis p.13Table II Properties of sphingosine-1-phosphates p.39Table III CS-0777P; comparative S1P receptor selectivity p.63Table IV Phase 0 development of S1P agonists p.68Table V Protection of MS agents in clinical development (EU) p.85Table VI Protection of MS agents in clinical development (US) p.85Table VII Drug development success rates p.97 ix
  11. 11. INTRODUCTIONEtiologyJean-Martin Charcot was the first physician to discover the lesions in both the brain’s whitematter and spinal cord upon autopsy, and named the disorder Multiple Sclerosis (MS) afterthe localized & numerous scars he observed. Since 1868 strides have been made in thediagnosis and treatment of MS in its varying degrees of severity, however the root cause ofthe disorder remains unknown. MS is an autoimmune disorder in which traffickinglymphocytes gain access to the normally immuno-privileged Central Nervous System (CNS)following a primary insult to the blood-brain barrier (BBB) and permanent disabilityaccumulates 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 asa precursor to lymphatic attack lymphocytes encounter environmental antigens in the thymusand incorrectly prime the immune system to falsely identify the myelin sheath as an externalthreat to the body. Although not a hereditary disorder, genetic variations may leave certainindividuals more susceptible; likewise it has also been postulated that exposure to foreignmicrobes such as the Epstein-Barr virus (EBV) may instigate MS [1][2].Irrespective of the primary impetus, improperly conditioned T cells cross a compromisedblood-brain barrier (BBB) in the course of immuno-surveillance, attach to the myelin sheathand release a cytokine cascade recruiting macrophages both from circulating blood andlocally in the form of microglials, inducing an incorrect onslaught against an axon’sprotective myelin sheath. The cytokines released by T cells are also suspect in recruiting andactivating local B cells which then promote an independent B cell attack [3]. Composedprimarily of lipids, the myelin surrounds and insulates a neuron’s elongated axon alongwhich electric stimuli travel. The brain’s white matter is comprised largely of neurons and Page 1
  12. 12. the loss of the myelin sheath often results in the loss of conducting impulses and theassociated function, e.g. loss of gross & fine motor skills, speech, cognitive abilities, etc.The more progressive subtypes of MS are characterized by a decreased inflammatorycomponent along with continual mounting neuronal degeneration & loss associated withincreased disability. Although MS is not fatal and does not significantly diminish theaverage life-expectancy, progressive accumulation of disability incapacitates the afflictedslowly stripping them of their cognitive abilities and mobility which eventually renders themmute, disassociated from society and entirely dependent upon the care of others.The incidence of MS is known to rise with increasing geographical latitude. Relapsing formsof the disease most frequently affect young Caucasian females who reside withinindustrialized nations. Prevalence has been estimated to be between 2 and 150 cases per100,000 individuals [4].The US National Multiple Sclerosis Society (NMSS) defined four distinct subtypes of MSbased on the frequency of relapses driven by repeated inflammatory attacks and the patternof accumulation of permanent disability. These are referred to as Relapsing-remitting MS(RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS) andProgressive-relapsing (PRMS). Figure 1 depicts these four categories. Page 2
  13. 13. Figure 1 – MS Disease subtypesSource: US National MS Society Page 3
  14. 14. 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 byperiods of relative calm with potentially a temporal return of lost function alongside anunderlying gradual accumulation of permanent disability over time; patients are usuallywomen 20-40 years of age.Progressive-relapsing MS (PRMS)Patients who suffer repetitive exacerbations of escalating severity & disability separated byperiods 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 betweensymptomatic exacerbations of escalating severity is said to have advanced to secondaryprogressive MS.Primary progressive MS (PPMS)A continuous and steady loss of function not associated with intermittent exacerbations isreferred to primary progressive MS; patients of both sexes are equally affected and typicallymiddle 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” MSPatients diagnosed with benign MS experience irregular, sporadic attacks of variablemagnitude similar to RRMS which however do not result in the accumulation of disabilityover time. See Figure 2. Page 4
  15. 15. Figure 2 – Benign MSAdapted from: www.imaginginformatics.caClinically isolated syndrome (CIS)A diagnosis of CIS is based on the report of a neurological attack of at least 24 hours induration associated with MRI abnormalities suggestive of inflammatory demyelination. Adiagnosis of Clinically Definite MS (CDMS) cannot be ascertained as the occurrence andlocation of lesions across both time and space remains uncertain, i.e. in the absence of arelapse, the risk to subsequently develop CDMS is significantly higher than the generalpopulation. This circumstance is defined as CIS.Figure 3 illustrates the distribution of MS subtypes as assessed by Net ResourcesInternational. Figure 4 is assembled from a recent market research exercise conducted byDecision 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 patientsclassify themselves, albeit skewed by the fact that the responders’ condition permits internetinteraction.Figure 3 – MS subtype segmentationSource: Drug Development Technology (2007) Page 5
  16. 16. 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 patientsSource: www.patientslikeme.comIt is noteworthy that none of the three exercises used the same nomenclature whenapproaching segmentation, and when there is overlap in the classification, e.g. RR MS, SPMS, PP MS, the reported percentiles vary widely. Most significant is perhaps that 21% ofthe patients who being internet active are most likely to have familiarized themselves withtheir condition, are in fact unable to identify the MS subtype which afflicts them. Outside ofclinical parameters & measures little else in the MS community appears standard. Page 6
  17. 17. Diagnostic toolsThe signs and symptoms are varied and include any of the following alone or incombination: loss of cognitive skills, loss of bladder control, fatigue, nystagmus, restricted orloss of mobility, optic neuritis, pain, trigeminal neuralgia, Lhermitte’s sign, dysesthesias,sexual dysfunction, spasticity, transverse myelitis, tremor and alaxia. A patient presentingwith one or more of these first signs symptomatic of MS may indeed be suffering from anynumber of peripheral neuropathies, autoimmune disorders, demyelinating disorders, or infact nothing at all. The initial diagnosis of MS in any of its forms will be often difficult atthe start due to the vague, mild and transient nature of the symptoms, however no otherdisease of the central nervous system (CNS) entirely mimics the debilitating progressiveassault of MS; progressive accumulated disability over time remains the decisive factor indiagnosing MS.McDonald criteriaThe McDonald criteria were universally accepted by the US NMSS in 2001 and replacedboth Poser and Schumacher diagnostic criteria. Utilizing the knowledge gleaned fromdecades 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 thepatient, the total number & dissemination in space and time of lesions detected withmagnetic 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 CSFsamples is indicative of a recent or ongoing CNS inflammation inclusive of MS. Page 7
  18. 18. Magnetic resonance imaging (MRI)Hydrogen atoms when bound to oxygen produce water; however as the electrons areunevenly distributed in covalent bonds favoring the oxygen atom and neutrons are notpresent in the hydrogen nucleus, the two oxygen-bound hydrogen atoms in a molecule ofH20 behave very much like exposed protons. Aligning the nuclear magnetization of theseprotons in the body with a strong magnetic field allows for precise interstitial images to betaken. These are referred to as MRI scans and have proven invaluable to the diagnosis andmanagement of MS. MRIs allow practicing neurologists to evaluate the number, size, anddistribution of CNS lesions over time and so determine the extent and severity of theinflammatory process throughout the lifetime of a MS patient.The two types of MRI scan commonly used are called T1 and T2 scans. T1 imaging usesgradient echo to maintain a <90° partial flip angle which allows for faster recovery of NMRsignal with a shorter Repetition time (TR)/ Echo time (TE); images taken within split secondof each other at varying degrees of magnetism can then be taken to produce a compositeimage of higher resolution. This allows for better identification of edema and/or sites ofareas of extreme white matter loss otherwise referred to as “black holes”. T2 imaging makesuse of a longer TR/TE via two consecutive pulses prior to detection to refocus themagnetization by 180° in a process called spin echo; as disturbances in the magnetic field arelost by spin echo, the MRI resolution is thus enhanced. T2 imaging better identifiesinflammatory sites such as active lesions in the brain. Gadolinium (Gd+) is a contrast agentwhich 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. Page 8
  19. 19. Figure 6– MRI scans of T1 & T2 lesions with & without GD+ enhancementSource: 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 scansare unable to detect axonal loss & neural degeneration, or sub-cortical demyelination of thegrey matter. Furthermore the utility as a predictive measure of eventual disability isquestionable as MRI scans are less sensitive to spinal lesions. Irrespective of thesedrawbacks MRI scans are currently one of the best diagnostic tools at a neurologist’sdisposal. Page 9
  20. 20. Annualized Relapse Rate (ARR)A relapse is defined as a new neurological symptom or a worsening of a pre-existingneurological condition whose duration is longer than 24 hours. Often used as a measure ofan agent’s efficacy, the annualized relapse rate (ARR) is simply the mean number ofreported clinical exacerbations over the mean time, hence it can be used for periods of lessthan one year.Expanded Disability Status Score (EDSS)The Kurzke Expanded Disability Status Score (EDSS) was developed in 1983 to assist theneurologist in quantifying the degree of disability in a given functional system (FS) for anygiven MS patient. It divides the body into the following eight functional systems (FS):pyramidal, cerebellar, brainstem, sensory, bowel & bladder, visual, cerebral, other. Theneurologist then assesses each FS on a scale from 0 (perfectly functional) to 10 (death) in aseries of 20 half steps. This is a commonly used disability score which in conjunction withMRI 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 topatients & their families respectively. Page 10
  21. 21. 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 days 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 MSFigure 7 – Full EDSS scoringSource: http://www.mult-sclerosis.org/expandeddisabilitystatusscale.html. Page 11
  22. 22. Figure 8 – EDSS scoring as shared with the patientSource: https://www.msactivesource.com 0.0: Normal Neurological ExamMultiple Sclerosis Functional Composite (MSFC)In 1994 the US NMSS commissioned a task force to standardize the clinical evaluation ofthe natural disease progression across meaningful parameters for use in clinical trials. It wasto be multidimensional to reflect the changes an MS patient undergoes over time, scoring ofeach parameter was to be independent of any other parameters measured and cognitivefunction was to be one of the parameters. In 1995 the results were made public and MSFCwas composed of three components: leg function/ambulation, arm/hand function andcognitive function. First approved in 1995 the MSFC disability scoring tool has yet toreplace EDSS as a standard clinical endpoint in large registration trials despite favorablereports from practicing neurologists [5]. Page 12
  23. 23. BiomarkersGiven the uncertainties associated with the etiology of MS, the genetic & environmentalfactors 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. Todate no single biomarker has been successfully coupled with a specific outcome in MS;however this precludes neither exploratory clinical research with existing biomarkers norfurther investigations in search of novel and predictive biomarkers. Table I summarizesthose biomarkers already identified and their potential significance towards diagnosis &disease progression. Although more hazardous to procure, biomarkers found in thecerebrospinal fluid (CSF) are more attractive than those acquired from the blood as thesamples 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 MSAdapted from: Harris and Sadiq, 2009, Disease Biomarkers in MS, Molecular Diagnosis & Therapy, 13 (4) p.225-244 Page 13
  24. 24. Current therapyIntravenous corticosteroids are commonly used to relieve the localized swelling and pain ofacute inflammatory attacks and reduce the potential for accumulating further disability uponremission. MS patients who have received a 3-5 day course of methylprednisolone oftenrapidly regain function; unfortunately this improvement is usually not maintained and thereis no evidence that corticosteroids reduce the long-term risks of eventual relapse. Diseasemodifying therapies (DMTs) are largely confined to injectable biologics targeting surfaceproteins on lymphocytes which either impede the inflammatory cytokine cascade, adhesionto endothelium & trafficking through the vascular wall or induce selective lysis of T cells.All DMTs demonstrate varying degrees of increasing efficacy offset by escalating safetyconcerns. Novantrone® is also used in MS patients who fail to respond to treatment withtraditional DMTs.Betaferon® (interferon β-1b)Betaferon® was the first non-steroidal DMT developed by Schering AG approved for MStherapy; it was licensed in July 1993 indicated for use in reducing the frequency of clinicalexacerbations in relapsing forms of MS. Betaferon® is manufactured ex-vivo usingEscherichia coli. It mimics natural cytokines, cell signaling proteins released bylymphocytes, 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 improvingthe integrity of the BBB. The Mechanism of Action (MoA) which provides direct benefit toMS patients remains unknown. At 2-years, injections every other day with 0.25 mgBetaferon® yielded a 32% reduction in Annualized Relapse Rate compared to placebo and Page 14
  25. 25. no statistically significant reduction in disease progression as measured by EDSS.Neutralizing antibodies (NABs) do develop over time. Side effects include injection sitereactions/necrosis and flu-like symptoms following administration. The current marketformulation is packaged as pre-filled syringes and commercialized by Novartis.Copaxone® (glatiramer acetate)Glatiramer acetate was first licensed by Teva Pharmaceuticals in December 1996 asCopaxone® for use in reducing the frequency of relapses in RRMS patients. Although theMoA remains unknown it is likely that the chemical structure of glatiramer acetate mimicsthat of myelin and so like a decoy circulating T cells bind to it rather than the protectivemyelin. 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 tointerferon-1β monotherapy treatment failures [7]. It is provided as a pre-filled syringe anddelivered via a daily 20 mg subcutaneous injection. NABs are known to develop withrepeated long-term use in almost all patients. The most common adverse events associatedwith 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 todevelop the first interferonβ-1a biologic, Avonex®. At 2-years 30 μg Avonex® deliveredonce weekly via intramuscular injection demonstrated only an 18% reduction in ARRcompared to placebo; however Avonex® did achieve a relative 37% reduction in disabilityprogression. In May 1996 it was the first to be granted a license for reducing the frequency Page 15
  26. 26. of clinical exacerbations and delay the accumulation of physical disability in relapsing MSpatients. 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 ofthe BBB as demonstrated in preclinical animal investigations. As with Copaxone® andBetaseron® NABs develop over time, it is marketed as a pre-filled syringe and injection sitereactions/necrosis & flu-like symptoms upon administration persist along with anemia, fever,chills, and muscle ache. However unlike all the rest, Avonex® is the market leaderaccounting for 25-30% of market capitalization.Rebif® (interferon β-1a)Also manufactured using genetically engineered Chinese Hamster Ovarian cells Serono’sRebif® was the 3rd biologic developed for use in MS. At 2-years 44 μg delivered 3 timesweekly by subcutaneous injection demonstrated a 32% in annualized relapse rates and a 30%reduction in disability progression against placebo. Furthermore in a second 6-monthclinical trial against Avonex® an absolute difference in ARR of 12% in Rebif®’s favortranslated into a 32% reduced risk of relapse. In May 1998 it followed Avonex® to begranted a license for reducing the frequency of clinical exacerbations and delay theaccumulation of physical disability in relapsing MS patients. As with all biologic therapyNABs specific to Rebif® develop over time. Injection site reactions/necrosis, flu-likesymptoms following administration, leucopenia, and increased liver enzymes are the mostcommon side effects. Page 16
  27. 27. Tysabri® (α4-integrin antagonist)First developed by Élan and co-developed with Biogen Idec, Tysabri® (natalizumab) wasthe first fully humanized monoclonal α4-integrin antibody specifically antagonizing the verylate adhesion-4 (VLA-4) surface protein which enables the T cells to identify & bind tovascular VCAM-1 and pass through the vessel wall; in effect it hinders lymphocytetrafficking across the BBB and intestinal wall protecting these organs from potentialautoimmune attack by rogue T cells. Tysabri® is delivered by a 300 mg monthlyintravenous infusion and established a remarkable 69% reduction in ARR and 42% reduceddisease progression as compared to placebo at 2-years in clinical trials. Althoughhumanization of the antibodies reduced the proportion of patients in whom NABs develop,NABs indeed develop and reintroduction of Tysabri® in these patients can promote allergicreactions. This was the first revolution in MS therapy since Avonex®. Tysabri® iscurrently penetrating the market at an impressive rate. First licensed in November 2004 itwas briefly removed from the market from 2005 to 2006 due to isolated cases of progressivemultifocal leukoencephalopathy (PML). Tysabri® carries a black box warning regardingPML 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 chroniclymphocytic leukemia (CLL) and cutaneous T cell lymphoma (CTCL) which is used off-label in progressive MS patients. Campath® agonizes the surface protein CD-52 presentonly on mature T cells and selectively induces lysis. Delivery of Campath® via intravenousinfusion results in an immediate death of circulating T cells and therapy is both complicated Page 17
  28. 28. & restricted to hospital use. However in CAMMS223 a Phase IIb RRMS trial, annualtreatment with Campath® achieved a 74% decrease in ARR and a 72% decrease in disabilityprogression 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 andscheduled to complete in 2011 and 2012 respectively. However therapy with Campath® isnot without risk; serious and fatal cytopenias, infusion reactions & infections are black-boxwarnings in the current CLL label and therefore Campath® is primarily the agent of lastresort currently reserved for off-label use in the progressive forms of MS. Furthermore themarketing potential of Campath® is in question as the compound loses patent protection inJuly 2011 and the use in MS patent filed in 2007 was recently rejected on grounds of lack ofnovelty.Novantrone® (mitoxantrone)A cytotoxic in the form of a small synthetic antineoplastic anthracenedione, Novantrone® istypically reserved for cancer therapy, however delivered as a quarterly 12 mg/m2 intravenousinfusion it has proven effective in reducing the ARR and disease progression in bothsecondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients. As a typeII topoisomerase inhibitor it enters all dividing cells and actively prevents DNA replication& repair. Novantrone® carries a black box warning as a teratogen with fatal cardiotoxicpotential and requires left ventrical ejection fraction (LVEF) monitoring prior to everyadministration. Page 18
  29. 29. METHODSGiven the highly competitive and secretive nature of drug development, retrieving reliableinformation regarding potential oral therapies for the use in the treatment of MultipleSclerosis (MS) is ridden with misinformation and false leads. To best determine the scope ofthis investigation, a thorough review of publically available resources was conductedinclusive of, but not limited to, listings on the FDA website www.clinicaltrials.gov, annualreports & press releases of pharmaceutical enterprises, and patent applications & grantings.Thereafter further efforts were made to elucidate the Mechanism of Action (MoA) and theclinical development plan of each indentified candidate; the results were eventually compiledand plotted by MoA & estimated launch date. Where relevant information was not releasedthe 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
  30. 30. The risk:benefit of each candidate was evaluated on the grounds of released efficacy, safetyand tolerability results either in the form of sponsored publications in renowned scientificjournals, e.g. Nature, The Lancet, Neurology, etc., or from presentations given at equallyreputable international conferences, The European Committee for Treatment and Research inMultiple Sclerosis (ECTRIMS), The American Academy of Neurology (AAN).The current market potential was established by extracting the annual revenues of eachproduct licensed for the treatment of MS as reported in the 2006, 2007, 2008 annual reportspublished by the authorized manufacturer. A patent search for each compound wasconducted and finally the extent and duration of intellectual property (IP) protection periodsin the EU were determined based on the known and approximated MA dates. Page 20
  31. 31. RESULTSOral MS therapies; competitive environmentIn a field crowded with expensive parenterals, oral administration appears wanting, howeverthe pipelines of many pharmaceutical firms are expanding with a plethora of potential oralagents promising therapeutic benefit to MS patients across all subtypes. Figure 9 illustratesthe 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 ofclinical 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 BAF312Figure 9 – Pipeline; oral MS agents in Phase II/III Page 21
  32. 32. Figure 10 – Competitive radar; oral MS agents Page 22
  33. 33. Anti-proliferative/replicantCladribineDeveloped in the late 1970’s at the Scripps Research Institute as a therapeutic agent in thetreatment of lymphomas, cladribine is an adenosine deaminase-resistant purine nucleosideanalogue which is intracellularly phosphorylated to form an active mononucleotide whichthen interferes with cell metabolism and DNA repair & replication. As a cytotoxic,cladribine actively suppresses DNA repair which leads to increased deoxyribonucleotidelevels. This state then signals the activation of polyadenosine diphosphate (ADP) ribosepolymerase which subsequently exhausts cellular nicotinamide adenine dinucleotide (NDA)levels and leads to eventual apoptosis [8]. Cladribine has demonstrated a goodbioavailability. It has been purported to selectively target only subpopulations oflymphocytes due to a unique intracellular circumstance in which levels of deoxycytidinekinase (DCK), an enzyme responsible for phosphorylation of the parent compound, largelyoutnumber deoxynucleotide dephosphorylating enzymes in T cells. In nearly all other cellsof the body these enzymes are roughly equal in number which results in a continualdephosphyrlation of the prodrug and renders it inactive [8]. Cladribine crosses the blood-brain barrier (BBB) and accumulates with cerebrospinal fluid (CSF) levels exceed plasmaconcentrations by up to 25% [9]. Page 23
  34. 34. Figure 11 – Cladribine; chemical structureSource: http://journals.prous.com/journals/dof/20042903/html/df290253/images/113529.gifClinical 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 LaunchFigure 12 – Cladribine MS development plan Page 24
  35. 35. The clinical development of cladribine has spanned decades, indications and corporations. Itdebuted 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 viasubcutaneous injection in the treatment of hairy cell leukemia (HCL) by Ortho Biotech in theearly 1990’s. Its lymphopenic properties marked it as a candidate not only for lymphomasbut also for autoimmune disorders where the immune system is suspected of mountingattacks against otherwise healthy tissues. The Scripps Research Institute conducted 3moderately sized Phase II clinical trials in chronic progressive Multiple Sclerosis (CPMS),relapsing-remitting Multiple Sclerosis (RRMS) and Secondary/Primary Progressive MultipleSclerosis (SPMS/PPMS) with parenteral cladribine delivered by intravenous infusion orsubcutaneous injection in a total of 229 patients between 1992 and 1997 [9]. Large scaleinvestigations were not undertaken until the development of an oral tablet formulation whichdemonstrated 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 forsystemic 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, ONWARDand ORACLE trials.Following the favorable results from a short bioequivalence study comparing thepharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new tablet formulationagainst the intravenous infusion regimen, differing regimens of oral cladribine wereevaluated 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 completed22 months later and preliminary results were released in January 2009. Figure 13 illustratesthe CLARITY trial. Page 25
  36. 36. 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 administrationFigure 13 – CLARITY trial designAdapted from: ECTRIMS poster, Sep 2009Primary endpoint • qualifying relapse rate at 2 years based on Kurtzke Functional System (KFS) scoreSecondary 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 scanBoth the high and the low experimental doses of cladribine met each of these endpoints withno statistical difference between the two doses. Annualized relapse rates were reduced by55% and 58% (p<0.001) and progressive disability as measured by EDSS scores was slowedby 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 asopposed to 61% in the placebo cohort representing a odds ratio of 2.45 (p<0.001) [10]. Page 26
  37. 37. Figure 14 – CLARITY; relapse rates at 2-yearsSource: ECTRIMS poster, Sep 2009Figure 15 – CLARITY; disease progression at 2-yearsSource: ECTRIMS poster, Sep 2009 Page 27
  38. 38. In line with expectations, T, B & NK cell counts in exposed patients decreased rapidly uponadministration with either the high or low dose; granulocytes and monocytes levels wereunaffected. 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 with90% of the enrolled patients completing the trial. Generalized reports of lymphopenia andleukopenia are in all likelihood attributable to the Mechanism of Action (MoA). In the highdose group cardiorespiratory arrest in addition to pancytopenia pneumonia led to a fatality inone patient who was later found to have had an active tuberculosis infection. Four cases ofmalignancy including a fatality in the low dose group were reported in four individualpatients exposed to active treatment with cladribine in the CLARITY trial: ovarian,pancreatic (†) & cervical cancers and a case of melanoma [11]. Individual cases of herpeszoster, an opportunistic viral infection, were also noted in both active groups [11]. Page 28
  39. 39. Figure 16 – Cladribine; selective reduction of lymphocytesSource: ECTRIMS poster, Sep 2009 Page 29
  40. 40. ONWARDS is a Phase II 2-year trial evaluating the safety of oral cladribine in combinationwith interferon-β; RRMS and SPMS patients entering the trial are randomized (1:1) toreceive either 2 short courses of cladribine or placebo annually on top of their currenttherapy with either Rebif®, Avonex® or Betaseron®. This trial is not powered to evaluatethe difference in efficacy between these therapies.Proactively an 8-year pharmacovigilance trial has been launched to survey the incidence ofsafety related reports associated with the long term use of cladribine in MS patients. (seeFigure 17)Figure 17 – Cladribine; registry trial designSource: ECTRIMS poster, Sep 2009Primary 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
  41. 41. 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 eventsAlthough there have been no comparator-controlled trials, Merck Serono issued two pressreleases on July 23, 2009 and September 30, 2009 confirming the submission to the EMEAand the FDA respectively of Manufacturing Authorization Applications (MAA) requestinglicensing for use of cladribine in RRMS. The FDA announced in 2006 that cladribine hadbeen awarded the status of “Fast Track” which designates an accelerated approval processwith a priority review of the dossier. If approved, cladribine will be the first highly effectiveoral 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 IIIORACLE trial in which 200 newly diagnosed CIS patients at risk of progressing toClinically Definite MS (CDMS) will be randomized to receive either placebo or 1 or 2courses of cladribine annually until conversion to CDMS. Page 31
  42. 42. TeriflunomideAs a disease-modifying antirheumatic drug (DMARD) Arava® (leflunomide) inhibits the de-novo pyramidine synthesis by hampering dihydro-orotate dehydrogenase (DHODH) and inparallel exhibits anti-inflammatory properties. Arava® is licensed for use in RheumatoidArthritis (RA) & psoriatic arthritis (PsA), and recently received orphan drug status fortransplant rejection from the FDA. Teriflunomide is the active metabolite of leflunomide;both compounds belong to Sanofi-Aventis. The pro-inflammatory, activated T&B cellswhich propagate brain lesions in MS are rapidly dividing and therefore targeting an enzymesuch as DHODH makes intuitive sense; teriflunomide arrests the division of the T&B cellsand renders them cytostatic. Resting lymphocytes are spared the effects of teriflunomidethrough salvage pathways and continue with vital immuno-surveillance activities. Due tothe fact that teriflunomide’s target is an intracellular enzyme, it breaches the cell wall anddiscontinuation of therapy is problematic requiring treatment with either cholestyramine oractivated charcoal. Teriflunomide LeflunomideFigure 18 – Teriflunomide & leflunomide; chemical structuresSource: http://journals.prous.com/journals/dof/20073211/html/df321007/images/fig13.gif Page 32
  43. 43. Clinical Development2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014HMR1726D-2001HMR1726D-2002 PoC HMR1726D-2004 On top of Copaxone PoC TENERE On top of interferon-β TEMSO EFC6049 TOWER TOPIC (CIS MS) MAA MA LaunchFigure 19 – Teriflunomide MS development planIn 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 monthsat 16 sites in France and Canada [11]. Patients were randomized to receive either daily doses7 mg or 14 mg of experimental teriflunomide or placebo and MRIs were taken every 6weeks. Figure 20 outlines the trial design. Page 33
  44. 44. 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 readoutFigure 20 – HMR1726D-2001 trial designAdapted 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. 894-900Primary endpoint • total number of new and persisting combined unique (CU) lesions at 9 monthsSecondary 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 volumeClinical endpoints • number of patients experiencing a relapse • annualized relapse rate • number of relapsing patients requiring a course of steroids • disability progression EDSS Page 34
  45. 45. In this exploratory study in relapsing MS patients, doses of 7 mg OD and 14 mg ODteriflunomide 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 significantlyreduced the number of T1 lesions per scan, new & enlarging T2 lesions per scan and new T2lesions. Once daily 14 mg teriflunomide demonstrated statistically non-significant trendstowards 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 ODdose 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 andtolerability profile at 9-months was comparable between all groups.Figure 21 – Teriflunomide; combined unique lesions at 9-monthsSource: O’Connor et al., 2006. , A Phase II Study of the Safety and Efficacy of Teriflunomide in Multiple Sclerosis with Relapses, Neurology, 66, p. 897Following these encouraging results Sanofi-Aventis advanced teriflunomide into anaggressive MS program encompassing monotherapy & combination therapy in relapsing MSand the effects of monotherapy in early stage MS (CIS). The first RMS registration 2-yearplacebo-controlled trial TEMSO began in September 2004 and has completed the Page 35
  46. 46. recruitment of 1080 RR/SP/PPMS patients in 21 countries and is scheduled to report inOctober 2010. TOWER is a 1-year placebo-controlled confirmatory trial in RMS patientswhich began recruiting the targeted 1110 RR/SP/PPMS patients in August 2008 in 19countries and is projected to complete by September 2011. In parallel to these registrationtrials, Sanofi-Aventis launched TENERE a Proof-of-Concept (PoC) trial evaluating thesafety and efficacy of combination therapy with Rebif® (interferonβ-1a) in 300 RMSpatients and a second PoC trial comparing the safety of combination treatment withCopaxone® (glatiramer acetate) at 6-months in 120 MS patients. TENERE is currentlyrecruiting whereas the 6-month combination trial with Copaxone® has completedrecruitment. Both PoC trials are expected to form a part of the Manufacturing AuthorityApplication (MAA).Additionally TOPIC the 2-year placebo-controlled Phase III trial in an early stage/at riskpopulation began recruiting 780 CIS patients at 133 sites within 20 countries in February2008.Administration of either 7 mg OD or 14 mg OD teriflunomide is common to all of the abovementioned trials. Page 36
  47. 47. S1P receptor agonistsG protein-coupled receptors (GPCR) have come to the forefront of pharmacological researchas they transverse the cell wall and mediate intracellular signaling through the release ofspecific messenger molecules. As a result a pharmacological agent need only interact withthe GPCR on the cell’s outer surface and need not necessarily penetrate the cell to induce orexclude an intracellular response. Relying on the cell membrane’s innate protectiveproperties, undesired intracellular responses can thus be greatly reduced. Depending on theconformational structure of and affinity between both target receptor & pharmacologicalagent, a higher degree of specificity for the target receptor over other structurally similar yetfunctionally different receptors can also potentially reduce many undesirable side effects.Ceramides, a family of bioactive lipids present in the cell membrane of many cells, arefound predominantly in the skin; accounting for up to 50% of the lipid count in the stratumcorneum and in trace amounts throughout the rest of the body. Although ceramides are notG protein-coupled receptors, following extensive research it was determined that similar toGPCRs, they could also mediate intracellular responses inclusive of cell differentiation,transformation, proliferation, and programmed cell death, i.e. apoptosis. The mechanism bywhich these activities are achieved is still uncertain. Although de novo synthesis in animalsis possible, it is significantly faster for cells under stress to produce ceramide via thehydrolyzing enzyme sphingomyelin phosphodiesterase (SMase).Ceramides are composed of a fatty acid bound to sphingosine via an amide bond as shown inFigure 22 beneath. The terminal hydroxyl group can be further conjugated to produce amultitude of unique sphingolipids. Page 37
  48. 48. Sphingosine Fatty acidFigure 22 – Ceramide; generic chemical structureAdapted from: http://www.lipidlibrary.co.uk/Lipids/ceramide/index.htmThe process by which catabolism of ceramide yields sphingosine-1-phosphate (S1P), anendogenous signaling sphingolipid found predominantly in the circulating blood supply, isshown in Figure 23.Figure 23 – Sphingolipid biosynthetic pathwaySource: Rosen et al., 2009. Sphingosine 1-Phosphate Receptor Signaling, Annual Review of Biochemistry, 78, p. 745S1P was shown to be an extracellular ligand released by both mast cells and platelets amongother cells which binds to S1P1-5, a family of lysophospholipid GCPRs. The known activityof all known S1Px receptors, as determined by experiments with knock-out mice, in-vitroassays or a combination of both, is listed beneath in Table I. Page 38
  49. 49. Table II – Properties of sphingosine-1-phosphates Distribution Cellular function and consequencesS1P1 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 VSMCS1P2 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 migrationS1P3 brain Cardiomyocyte: survival to ischemia-reperfusion heart Dendritic cell (hematopoietic): worsening experimental sepsis spleen lethality/inflammation/coagulation liver lung thymus kidney skeletal muscle testisS1P4 lung T-cell: migration/cytokine secretion lymphoidS1P5 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
  50. 50. FingolimodThe discovery of these 5 lysophospholipids and the elucidation of their expression &function has presented the pharmaceutical industry with an entirely new and novel set oftarget receptors. The first and most well known non-selective S1P1,3-5 agonist to reachclinical trials was Novartis’ fingolimod, also known as FTY720. Fingolimod is an analogueto a naturally occurring Myriocin metabolite ISP-1 produced by the fungus Isaria sinclairiiwhich has been used for centuries in traditional Chinese medicine [13]. Fingolimod was firstsynthesized 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, isa potent agonist at all S1P receptors with the exception of S1P2 and selectively reduces bothperipheral T&B cell counts in the blood [14]. There is also evidence that fingolimod-P actsas 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 prodrugfingolimod-P. Sphingosine kinase fingolimod fingolimod-PFigure 24 – Fingolimod; parent and phosporylated metaboliteAdapted from: http://journals.prous.com/journals/dof/20073211/html/df321007/images/fig12.gif Page 40
  51. 51. Lymphocytes naturally migrate from secondary lymphoid tissues and the thymus, where theconcentration of sphingosine-1 phosphate (S1P) is low, to the blood where the aggregation issignificantly higher. It has been postulated that the immunosuppressive effect witnessedwith fingolimod-P is due its ability as a “functional antagonist” to internalize the S1P1receptors on the surface of the T&B cells and so by desensitize them to the gradient of S1Pleaving them sequestered in the lymphatic system [18]. Fingolimod-P does not affect theactivation, proliferation or effector functions of these lymphocytes nor does it affect levels ofnatural 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 LaunchFigure 25 – Fingolimod MS development planThe 1st administration of fingolimod in single ascending doses on top of Neoral® in humanrenal transplant patients was reported in 2002 by Budde et al. [19]. Figure 26 depicts thestudy design. Page 41
  52. 52. -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, exerciseFigure 26 – Fingolimod; SAD on top of Neoral® in renal transplant patientsAdapted 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.1073-83All doses showed a reversible transient lymphopenia as shown in Figure 27. Whereas thevariability in response to the 0.25 – 2.0 mg doses failed to yield clear dose-dependentrelationship, 3.5 mg fingolimod demonstrated a dramatic mean decrease of 73% frombaseline values within 8 hours of administration.Figure 27 – Fingolimod; SAD lymphocyte reductionsSource: 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
  53. 53. Single administration was considered to be safe and well tolerated with no serious adverseeffects. However the most common adverse event was dose-dependent transientasymptomatic bradycardia. As the treatment arms contained few and occasionally shared thesame subjects, the pulse rate data was combined to produce a low dose group of 0.25 & 0.5mg and a high dose group of 0.75, 1, 2 & 3.5 mg. A more pronounced effect is associatedwith the higher dose groups. Figure 28 clearly illustrates this effect.Figure 28 – Fingolimod; SAD Bradycardic effectsSource: 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.1077Encouraged by these results, Novartis engaged in further development of fingolimodculminating in the decision to enter full scale development in two indications where thesequestration of lymphocytes could plausibly provide therapeutic promise: renal transplantand Multiple Sclerosis.In 2006 Salvadori et al. reported on a 1-year Phase III registration trial in renal transplantwhich began in May 2003 and recruited 668 patients in 42 sites worldwide [20]. This trialestablished no benefit for either a course of 2.5 mg fingolimod plus a full-dose ofcyclosporine 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
  54. 54. 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 yrFTY720 1.25 mg // 5 mg 5 mg dose shows no morePlacebo 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
  55. 55. safety as well as to better describe the occurrence, course & severity of these events. Theendpoints were:Primary endpoint • reduction in the number of Gd+ enhanced lesions/patient at 6 months on T1-weighted MRI imagesSecondary 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 6Clinical endpoints • number of patients remaining free of relapse • annualized relapse rate • time to first relapse • Expanded Disability Status Score (EDSS) at 12 monthsBoth experimental doses of fingolimod met all of the endpoints above with the exception ofbrain volume from baseline to month 6 and EDSS at 12 months. As shown in Figure 30 thehigher 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 tothe 1.25 mg dose at 12-months, it was discontinued as an experimental dose in subsequentMS trials. Page 45
  56. 56. 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 relapseFigure 30 –Fingolimod; Phase IIb results at 6-monthsSource: Kappos et al., 2006. Oral fingolimod (FTY720) for relapsing Multiple Sclerosis, New England Journal of Medicine, 335), p.1132Both experimental doses of fingolimod were judged to be well tolerated in the patientpopulation. The majority of the SAEs were associated with the 5 mg dose. Figure 31 liststhe most common reported SAEs and AEs associated with both doses at 6-months. Raisedlevels of liver enzyme levels (>3 x ULN) of both alanine transaminase (ALT) and aspartatetransaminase (AST) were noted at 6-months. No clinical symptoms were observed and thelevels normalized equally either over time without a down-titration or upon discontinuationof treatment altogether.Figure 31– Fingolimod; tolerability profile at 6-monthsAdapted from: Kappos et al., 2006. Oral fingolimod (FTY720) for relapsing Multiple Sclerosis, New England Journal of Medicine, (335), p.1134-37 Page 46
  57. 57. This Phase IIb dose-finding study established neither a full dose response curve nor anyimprovement on the disability score observed with either dose at 6-months; however the45% reduction in Annualized Relapse Rate (ARR) against placebo was already a tremendousimprovement 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 delayto disease progression in an indication whose time course spans more than a decade onaverage - and fingolimod held the promise of convenient oral once daily administration.Novartis abandoned the renal transplant program and invested in a substantial MS Phase IIIprogram which began with two registration trials TRANSFORMS & FREEDOMS andeventually expanded to include FREEDOMS II. TRANSFORMS was a 1-year trial with 2doses of 1.25 mg and 0.5 mg against Avonex® the market leading interferon β-1a whichbegan 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 andResearch in Multiple Sclerosis. Holter monitoring was dropped as a requirement. Many ofthe remaining safety monitoring measures were the same, i.e. MRI, ECG, FEV1, FVC andDLCO. New monitoring requirements included ophthalmological exams, chest x-ray andhigh resolution CT scan (HRCT). Ophthalmological exams could be warranted given theincreased incidence of macular edema in the renal transplant program. Chest x-rays mighthave been used to exclude patients with latent tuberculosis infections which could bereactivated under therapy. HRCT was introduced presumably to determine the etiology ofthe dyspnea reported in the Phase IIb study. Given the 1-year duration of this trial and thedecrease in FEV1 observed in the Phase IIb trial, it is possible that the use of HRCT scanswas used to detect potential fibrotic changes which could result in constriction of thebronchial passages and eventually lead to difficulty in breathing. Page 47
  58. 58. 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 examFigure 32 – TRANSFORMS trial designAdapted from: WCTRIMS poster, Sep 2008This trial was conducted in the patients with relapsing-remitting MS (RRMS). Theendpoints 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
  59. 59. On December12, 2008 Novartis issued a press release disclosing the initial results from theTRANSFORMS trial. Strikingly the lower dose of 0.5 mg demonstrated a better clinicalresponse 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/yeardetermined from the 431 Avonex® treated patients. The registration trial as reported in theAvonex® Manufacturing Authorization Application (MAA) submitted to the FDA did notreport a clinical benefit to patients in the first year of administration; it reported an ARR of1.03 in the active 65 patient arm against 0.8 reported in the 45 patient placebo arm at 1-yearwith a therapeutic benefit manifesting itself only at the 2-year timepoint. In theTRANSFORMS data Avonex® appears to already have an effect at 6-months. Thishowever may be due to the change in clinical practice since 1996 when the MAA wassubmitted. Curiously enough Novartis decided against releasing data pertaining to diseaseprogression as measured by EDSS.The astounding efficacy was off-set by the long term safety profile however. Transientbradycardia remained a common safety finding, AST & ALT levels ≥ 3 x ULN werereported in some patients, along with 7 cases of macular edema. New findings includedincreased blood pressure (BP), 7 cases of skin cancer and 2 fatal viral infections: primarydisseminated varicella (†) and herpes encephalitis (†). Malignancies and opportunisticinfections 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 thePhase IIb 2-year extension study [22]. 250 (89%) of the patients from the core study enteredthe optional open-label extension study where those patients initially receiving placebotherapy were re-randomized to receive long term treatment with either 1.25 mg or 5 mgfingolimod. 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 within3 months of the study start the 5 mg dose group was discontinued due to an increased safety Page 49
  60. 60. 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 oninflammatory markers as detected by MRI, i.e. T2 weighted Gd+ enhanced images, aspreviously witnessed in the active groups in the core study. Those patients continuing witheither 1.25 mg treatment or down-titrating from 5 to 1.25 mg improved or remained stableand 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 theproportion of patients remaining relapse-free over time.Figure 33 – Fingolimod; time to first confirmed relapse in 2-year extension studySource: O’Connor et al., 2009. Oral fingolimod (FTY720) in Multiple Sclerosis, Neurology (72), p.76AEs and withdrawal of consent were the two most common reasons for treatmentdiscontinuation. The majority of the AEs were mild to moderate in nature withnasopharyngitis, headache, influenza and lymphopenia being the most prevalent. 10% of thepatients experienced at least one SAE: unconfirmed macular edema, peripheral edema,hepatitis, jaundice, MS relapse, hirsutism, flushing, neutropenia, adrenal mass, acuteabdomen, 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
  61. 61. As expected peripheral lymphocyte counts decreased by up to 75% from baseline andremained between 500 - 600 cells/m3. Furthermore there were no reported instances ofopportunistic infections or malignancies as one might expect with the continuous use of acompound which so effectively reduces circulating lymphocytes.Transient bradycardia continued to be witnessed in naïve patients switching from placebo toactive treatment within the first hour of dosing and resolved without further medicalintervention after a maximal 4-5 hours. Comparison with pre-treatment values at 2-yearsrevealed no further instances of bradycardia.A decrease in systolic blood pressure was observed in the first 6 hours of dosing whichreturned 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; howeverreports of asthma and dyspnea were associated with both dose groups.In contrast to the core study and TRANSFORMS, there were no instances of confirmedmacular edema.The FREEDOMS trials are two identical 2-year placebo-controlled studies investigating thedoses of 1.25 mg and 0.5 mg fingolimod. FREEDOMS I began in January 2006 andrecruited 1,272 RRMS patients with 115 clinical sites in 19 countries ex-US. FREEDOMSII began later in June 2006 and recruited 1,080 RRMS patients with 107 clinical sitespredominantly in the US but also included sites from another 7 countries. Figure 34 depictsthe 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
  62. 62. 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 examFigure 34 – FREEDOMS I&II trial designAdapted from: WCTRIMS poster, Sep 2008 / FREEDOMS press release, Sep 2009Both 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-yearsOn 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 inAnnualized Relapse Rates (ARR) by 54% and 60% (p<0.001) and slowing of disease Page 52
  63. 63. progression as measured by EDSS scores of 30% and 32% respectively at 2-years. (seeFigures 35 & 36)The 0.5 mg dose appears to have been safer and better tolerated than the 1.25 mg dose. Incontrast 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 theSAE listings.Figure 35– Fingolimod; relapse rate at 2-years in FREEDOMSSource: FREEDOMS press release, Sep 2009Figure 36 – Fingolimod; disease progression at 2-years in FREEDOMSSource: FREEDOMS press release, Sep 2009 Page 53
  64. 64. Figure 37 – Fingolimod; Serious Adverse Events reported in FREEDOMSSource: FREEDOMS press release, Sep 2009Novartis plans to submit a Manufacturer’s Authorization Application (MAA) to the EU anda New Drug Application (NDA) to the FDA by the end of 2009; the FDA has not grantedFast Track status to fingolimod.Novartis has initiated INFORMS, a 3-year study comparing the effects of 1.25 mgfingolimod against placebo in 654 patients with primary progressive MS (PPMS). There isno licensed treatment for PPMS. Currently there are no on-going trials exploring theefficacy and safety of combination therapy with other licensed products in RRMS. Neitherclinically isolated syndrome (CIS) nor secondary progressive MS (SPMS) are presentlyunder investigation with fingolimod. Page 54
  65. 65. BAF312The natural process of remyelination begins with the migration of oligodendrocyte precursorcells (OPC) to sites of axonal trauma and ends with the development of matureoligodendrocyte cells which re-sheath the damaged neurons with myelin. As S1P5 ispredominantly expressed in oligodendrocytes and the white matter tracts of the brain, itpresented itself as an interesting target to researchers investigating demyelinating disorders.Novgorodov et al. published work which links the inhibition of OPC migration to agonism ofS1P5 using S1P in cultured cells from neonatal rat cortices; however other studies show anincreased survival rate of mature oligodendrocytes in cytotoxic environments [23][24].Although fingolimod, a non-selective S1P1,3-5 agonist, demonstrated a high degree of clinicalefficacy as measured by reduced GD+ enhanced lesions, ARR & disability progression,differentiation between the therapeutic benefits derived from remyelination as a direct resultof S1P5 agonism or otherwise, and lymphocyte sequestration will remain highly speculative;comparative outcomes from clinical trials in patients suffering demyelinating disorders arethe sole means to investigate this mechanism and even then the conclusions will not bedecisive.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 moreselective for S1P1 than S1P3 and began the first pharmacological study with 63 humansubjects in October 2006. Page 55

×