clinical trial trends by tr

Developments in CliniCal trialsA PHARMA MATTERS REPORT

expert analysis of key elements and current trends shaping the clinical landscape.

publisheD maY 2014

reuters/Yuriko nakao

in this issue

I. INTRODUCTION................................................................................3

II. BIgDaTawhaTsINITfORClINICalTRIals?...........................4

III. aNeweRaINRIsk-BaseDMONITORINg......................................5

IV. laTesTINDeRMaTOlOgYClINICalReseaRCh:whaTwas RePORTeDDURINgTheaNNUalMeeTINgOfTheaMeRICaN aCaDeMYOfDeRMaTOlOgYINMaRCh2014...............................7

Fast onset oF aCtion oF seCukinumab CompareD to etanerCept in the treatment oF moDerate to severe psoriasis ......................................................................... 7

Goselkumab, an eFFeCtive anD well tolerateD therapY For psoriasis aCCorDinG to a phase ii stuDY ........................8

noninFerioritY oF oral toFaCitinib to injeCtable etanerCept For psoriasis DemonstrateD in a phase iii trial .....................................................................................9

antipruritiC eFFiCaCY oF Ct-327 in psoriasis ConFirmeD in a new phase ii trial. phase iii trials announCeD ...........10

siGniFiCant improvements in qualitY oF liFe in aDult patients with atopiC Dermatitis treateD with Dupilumab ................................................................................11

For more information on thomson reuters Cortellis Clinical trials intelligence visit lifesciences.thomsonreuters.com

AlvAro ArjonA, PhDEditorial dirEctor of drug dEvElopmEnt at thomson rEutErs

after exploring the circadian regulation of innate immunity during his time at rutgers university and the Yale school

of medicine, alvaro joined thomson reuters in 2009. he has been managing scientific and clinical information and currently oversees the drug development editorial teams, who contribute to several life sciences information solutions and platforms. alvaro has authored several book chapters and over 25 peer-reviewed articles in journals such as nature immunology, immunity, the journal of Clinical investigation and pnas.

Beth nuskeypharmacEutical rEsEarch analyst clinical trials at thomson rEutErs

in this role, beth is responsible for collecting and validating the intelligence contained within Cortellis

Clinical trial intelligence, focusing on global clinical trial developments. prior to joining thomson reuters in 2013, beth worked as a research scientist and teaching assistant in the field of molecular biology and genetics. she holds a degree in biology from rutgers university.

XAvier rABAsseDA, MDmEdical dirEctor, pharma sErvicEs

Xavier rabasseda studied medicine in barcelona, Geneva and paris. after working as a researcher in cellular and molecular neurobiology in the

hpital Cantonal, Geneva; Centre national pour la recherche scientifique, Gif-sur-Yvette, paris; and universitat de barcelona, he joined prous science (now part of thomson reuters) as medical Director. his direct responsibilities include reporting from medical conferences and reviewing medical information from across business units, while also supporting marketing and sales build new projects that include a medical edge.

elsA AriAs, PhDEditorial & contEnt managEr clinical

elsa joined thomson reuters in 2009, when she started working in the scientific Content Group within the publications Department. she worked

on several products and content sets and also participated in some interesting projects, such as acting as editorial representative on a collaboration with the european society of medical oncology. Currently she manages clinical information, providing content to Cortellis Clinical trials intelligence and integrity. she has a phD in molecular biology and experience in metabolic disease research.

DEvElOPMEnTS in CliniCAl TRiAlS 3

i. introDuCtion

as the pharmaceutical industry strives to meet the ever-increasing complexity of drug development, new technology in clinical trials has become a beacon of hope. with big data comes the promise of accelerated patient recruitment, real-time monitoring of clinical trials, bioinformatics empowerment of quicker phase progression, and the overwhelming benefits of precision medicine for select trials. risk-based monitoring stands to benefit as well. with a strengthening focus on centralized data by the FDa and industrys transformative initiative, transcelerate, a new era in trial risk mitigation has begun. the traditional method of intensive on-site monitoring is becoming a thing of the past as statistical, real-time analysis of site and trial-wide data provides the means to monitor with greater efficiency and effectiveness from afar. however, when it comes to big data, there are challenges that lie ahead. patient privacy, commercial investment protection, technology woes, and data variability are all limitations to be met with considerable thought.

at the annual meeting of the american academy of Dermatology this year, clinical trials on psoriasis, atopic dermatitis, and other skin diseases were discussed in detail. this review of clinical research reports on novel therapies for psoriasis and atopic dermatitis reveals the impact of these diseases and the drug candidates that have been successful in phase ii and iii studies.

Data-focused highlights of novel dermatological trials, as well as real-life big data approaches and an insight on the new methodology of risk-based monitoring, are all discussed in this edition of Developments in Clinical trials.

3

DEvElOPMEnTS in CliniCAl TRiAlS4

allowing real-time monitoring could unleash invaluable real world information and outcomes for the assessment of therapeutic interventions and for disease understanding (e.g. health eheart study.) these technologies may play a direct role in research as subjects contribute, for example, genomic data and side effects information to large databases. in the e-patient era, higher connectivity with medical care providers poses a big data challenge, but it could expedite clinical development and advance disease understanding if tackled appropriately.

known drugs can move quickly to later phases of clinical development as big data approaches and bioinformatics provide the necessary quantitative and statistical power to create meaningful associations between large sets of biological and medical data. this repurposing tactic has for example triggered a phase iia trial of desipramine (an antidepressant first launched in 1962) in small cell lung cancer. Currently, one of the biggest biomedical data challenges is being posed by the rapid increase of disparate molecular data repositories and large-scale proteomic and genomic readouts from clinical studies. big data tools certainly hold promise to make clinical sense of this overload of molecular information, better enabling precision medicine.

these are just some examples of how big data plays a role in clinical trials. Clearly, not all therapeutic areas, study types or development programs would benefit equally from big data tools, and there are still technology and statistical hurdles that need to be overcome. Concerns around patient privacy and restrictions on data sharing need to be addressed as well. while its difficult to envisage that information derived from big data methodologies will ever substitute well-controlled clinical trials, there are sufficient indications nowadays to conclude that these approaches have a lot to offer in terms of clinical trial planning, design, and execution. moreover, big data solutions could be highly valuable for drug repurposing and for the acceleration of translational research. as big data analytics and visualizations are poised to uncover hidden patterns in the data, it will be interesting to observe what unforeseen clinical insight is generated by these strategies.

ii. biG Data whats in it For CliniCal trials?

some argue that the big data challenge has been around for quite some time, and its only more recently, as data has grown at a substantially accelerated pace in a much less structured manner, that big data has become, well, bigger. that seemingly spurious augment orders huge changes in volume, velocity and variety that make the process of transmuting data into actionable insight substantially more complex.

lets look into the clinical space. Clinical trial databases and clinical study results and associated publications continue to grow year by year not only in volume but also (and more importantly) in variety and disparity. at the patient level, the explosion of biologic data mediated by technological breakthroughs - the omics revolution - is rapidly adding an unprecedented degree of depth and complexity to biomedical information. if we also consider the wealth of self-generated demographic, epidemiologic, health, and lifestyle information in social media and other online settings, then one could envisage clinical data going from big to bigger. but, regardless of the label we choose, where the big data opportunities and challenges lie in the clinical development arena?

patient recruitment may be accelerated via mining of consumer data and lifestyle analytics, allowing faster identification of subjects that meet eligibility criteria. this approach allowed orexigen therapeutics to initiate randomization of almost 9,000 subjects with cardiovascular risk factors one year earlier than expected for the light study. Clinical site selection may also benefit from the geographical juxtaposition and visualization of medical and online patient data.

similarly, big data approaches can be applied to integrate and standardize disparate repositories of medical records and clinical trials across multiple organizations to facilitate the identification of patients that may qualify for inclusion in trials. networks of health care providers and research institutions such as the total Cancer Caretm Consortium and the pinnaCle registry research alliance for cardiovascular research are being created for this purpose.

health-related information and habits measured through online activity as well as via mobile apps


historically, a feet-on-the-street approach has been the gold standard for risk-based monitoring (rbm) of clinical trials. sponsors have relied heavily on intensive source data verification (sDv) and on-site monitoring, however, as the cost of drug development rises, this method is beginning to lose its luster. soaring technology and the draw of big data have given industry food for thought why not benefit from real time electronic data capture by routing clinical trial information to a centralized repository and conduct monitoring from there? the advantages of off-site monitoring are compelling - a reduction in travel costs and carbon footprint, the ability to assess and prioritize risks for maximum safety and data quality, and source data errors caught before they sully the trial. that is not to say that centralized statistical monitoring (Csm) is without its limitations industry experts agree that the best approach is a personalized one, and will likely include a comprehensive methodology.

in retrospective analyses, transCelerate biopharma inc., the Food and Drug administration (FDa), and the society for Clinical trials (sCt) have all identified the traditional method of trial monitoring as inefficient and costly. not only does an on-site-monitoring-only approach comprise upwards of 30% the cost of global clinical trials, but it has high environmental impact and falls short on error discovery. in an analysis of the second european stroke prevention study (esps2), it was discovered through statistical off-site monitoring that plasma concentration distribution data from one research site differed considerably from the rest of the sites. this analysis was completed after two on-site monitoring attempts failed to detect what had been marked early in the trial as a high-risk center for fraud or misconduct. in this case, the inadequacy of on-site monitoring resulted in the exclusion of data from 438 patients who had completed the clinical trial. in addition to identifying risks and data errors that on-site monitoring cannot pick up, the sCt indicates that integrating statistical targeted monitoring in rbm plans results in approximately 25% less site visits during a clinical trial, reducing burden

while improving monitoring practices. human error, too, contributes to the drawbacks of on-site monitoring. iCon plc, a global contract research organization (Cro), asserts that the balance of on-site monitoring rests with the Clinical research associate (Cra). relying solely on Cras for risk-based clinical trial monitoring comes with specific limitations. site and data quality are viewed through the narrow scope of the Cras previous experience, not encompassing a cross-trial or even trial-wide view. this is not to say that those in favor of centralized monitoring dismiss the value of clinical specialists and a trained human eye. both iCon and transCelerate, a preeminent pro-transformative group focused on rbm and drug development acceleration, agree that a professional with a comprehensive understanding of the trial, and perhaps even the clinical landscape surrounding the indication, is required to effectively evaluate the analytics and put them in context. iCon boasts an automated system that they use in accordance with analytical and visualization tools, human intelligence, and established courses of action involving targeted on-site monitoring by Cras. in combination, their method has detected and corrected site-level failures in a timely and effective manner.

the Clinical trials transformative initiative (Ctti), a partnership dedicated to increasing clinical trial quality and efficiency, suggests a ground-up approach to risk-based monitoring by employing their quality by Design (qbD) method during the entire research process. they contend that from protocol design onwards, quality can be ensured by designing a study that is inherently mindful of safety and data quality risks, as well as amendable to maintaining a focus on Critical processes and Critical Data. the transCelerate rbm methodology incorporates this qbD approach in their quality risk management approach. in their position paper, risk-based monitoring methodology, the initiative has also recommended that source data review (sDr) should be favored over sDv. this allows for a more holistic assessment of protocol compliance as well as site and processes quality, rather than data transcription verification, which transCelerate argues is negligible in terms of trial error

iii. a new era in risk-baseD monitorinG


detection. sDr focuses on-site monitoring efforts, targeting critical data and processes that are identified early on in rbm plan development using what they call a risk-assessment Categorization tool (raCt). risk-driven, targeted monitoring can cut down on costs and increase safety and data validation. at the 2013 Global Clinical trials (GCt) conference in boston, many industry experts agreed that an industry-wide set of standards and tools for risk-evaluation is needed. panelists advocated transCelerates model as the standard to be implemented.

transCelerates methodology follows a step-by-step process that begins with a program-level and protocol-level risk assessment, filters through the raCt to develop an integrated quality risk management plan (iqrmp), assigns a risk level to each study, defines critical data and processes, and finally creates potential risk indicators with accompanying thresholds. off-site monitors will follow trial-specific monitoring plans (mps) within the iqrmp to adequately mitigate risks. their plan is adaptable and can be tailored to the technology available to the each study and, they argue, will become more and more pertinent as all clinical trial data goes digital. transCelerates initial position paper has been revisited in their risk-based monitoring update volume i to address concerns over sDv invalidation. the group will be releasing results from a retrospective analysis to further evaluate the importance of sDv as a measure of quality control in may 2014. the FDa has reviewed pilot study monitoring plans from transCelerate and has provided feedback for revision and an updated rbm guidance and revised raCt will be released sometime in the first quarter of 2014. training materials for those who wish to implement transcelerates risk-based monitoring methodology are available on their website.

limitations to off-site and statistical monitoring are implicit and there are several challenges to keep in mind when developing rbm plans that veer off of the beaten path. in large-scale global trials there is always the possibility that research centers, particularly those in rural areas, may lack the technology to participate in off-site monitoring. in centers that do the possibility of unclean data, low volume of data (particularly in rare diseases),

variable availability of data, and systematic differences between sites all become limitations. accounting for these, one can detect a range of errors in clinical trial data through statistical analysis including unintentional and careless data errors as well as fabricated and falsified data. the sCt provides examples of such using retrospective analysis of actual trial datasets. experts at GCt 2013 agreed that Data privacy officers will be required because of the inherently sensitive nature of the data particularly as informed consent forms and raw patient data become entirely digital and shared between Cros via a Clinical trial management system (Ctms).

as we move forward in the digital age, the pharmaceutical industry is empowering statistical inference to target risks in clinical trials. reliance on 100% sDv and on-site monitoring creates a taxing and ineffectual method to monitoring clinical trials, leading to undiscovered errors and high economic impact. instead, industry proposes that a risk-based, critical data focus with centralized off-site monitoring and targeted on-site monitoring should become the gold standard. with a focus on centralized monitoring in the oversight of Clinical investigations a risk-based approach to monitoring guidance document, the FDa clearly agrees, though they provide only a general framework. transCelerate and other future-focused groups have developed their own detailed risk-based monitoring plans, taking full advantage of the FDas green light. other countries are following suit in order to increase transparency and perhaps set rbm plan precedence for indications in clinical trials, the european medicines agency (ema) has vowed to publish risk-based monitoring plan summaries for all medicines authorized in 2014 and beyond. earlier in 2012, they finalized their reflection paper on risk based quality management in clinical trials which touted the benefits of Csm. bettering risk-based monitoring through technology is a topic that is not up for debate in the pharmaceutical industry. as the complexity and cost of drug development rises, the need to streamline is ever-present and industry can agree - adaptive, targeted monitoring is the superhighway to quality clinical trial data.


iv. latest in DermatoloGY CliniCal researCh: what was reporteD DurinG the annual meetinG oF the ameriCan aCaDemY oF DermatoloGY in marCh 2014

a major highlight during this years annual meeting of the american academy of Dermatology was the latest in Dermatology research symposium on saturday march 22, which included four major clinical research reports on investigational putative novel therapies for psoriasis as well as a novel candidate therapeutic for atopic dermatitis, two very common skin diseases that have a dramatic impact on the quality of life of the sufferers and, particularly in the case of atopic dermatitis, which affects mostly young children, their families. the evolution of cases of psoriasis worldwide, which can be graphically seen in Fig. 1, clearly supports the need for active, safe, well-tolerated treatments and the corresponding need for intensive research for identifying such treatments.

psoriasis endangers the life of sufferers through severe symptoms such as pruritus, and also has a marked impact in the patients self-consciousness because of the visible skin lesions. their quality of life is severely impaired, with implications on mental wellbeing, physical wellbeing, sleep and general functioning. atopic dermatitis has a similar impact, with the addition of parents worries about their childrens welfare and the added increased risk for infections resulting from a damaged skin barrier at an age where children want to play and have an active life. although emollients and skincare products can in fact transiently improve signs and symptoms of both psoriasis and atopic dermatitis, active therapies that act on the pathophysiological phenomena that give rise to the two conditions are sought to offer a better control of the whole cohort of signs and symptoms resulting from the corresponding etiopathogenic situations. hope in the form of favorable results from clinical trials with selected therapies with a specific, targeted mechanism of action arose during the latest in Dermatology research symposiums presentations and discussion in Denver, Colorado.

Fast onset oF aCtion oF seCukinumab CompareD to etanerCept in the treatment oF moDerate to severe psoriasisData from the FiXture and other clinical trials of secukinumab in psoriasis and additional information were also presented during the meeting of the american academy of Dermatology in Denver in march 2014. however, as rapid relief from symptoms of psoriasis is important for patients, the results of the FiXture study comparing secukinumab to etanercept in patients with moderate to severe plaque-type psoriasis were revised in a post-hoc analysis to comparatively assess the onset of action of the two therapies. in the trial, cohorts of 327, 327, 326 and 326 patients were randomized to the interleukin-17-blocking antibody secukinumab (150 or 300 mg), the tumor necrosis factor antagonist etanercept (50 mg twice weekly) or placebo through week 8, and, from week 12 onwards, patients initially treated with placebo were rerandomized to any of the three active treatment regimens. as depicted in Fig. 2, the median time

0

20

40

60

80

100

120

140

160

180

2000 2005 2010 2015 2020 2025

Trial records

with

resu

lts

Year of trial completion

figurE 1. projEctEd worldwidE prEvalEncE of psoriasis basEd on data through yEar 2010 according to thomson rEutErs incidEncE and prEvalEncE databasE (ipd).


to achieve a 50% decrease in the psoriasis area and severity index (pasi) scores was shorter with secukinumab 300 mg (3.0 weeks) than with secukinumab 150 mg (3.9 weeks). etanercept showed a slower onset of action, with a mean time to reach this endpoint of 7.9 weeks. symptoms continued to improve after rapid clinical benefit, reaching a peak by week 16, at which time pasi75 response rates were higher in patients treated with secukinumab than etanercept, which was still effective with response rates greater than placebo. the proportion of patients with an investigator global assessment of clear or almost clear (iGa scores 0 or 1) at week 16 were again higher in patients receiving secukinumab than etanercept or placebo. the high response rates obtained with secukinumab were largely maintained through week 52 in the maintenance phase of the study.

secukinumab was well tolerated compared to etanercept. at mean exposure time of 317.5, 320.7, 331.9 and 95.2 days in the secukinumab 150 mg, secukinumab 300 mg, etanercept and placebo cohorts, the incidences of adverse events were 77.6, 80.5, 73.3 and 51.4%. overall, the results of this analysis added to other reports on the clinical effectiveness of secukinumab in the treatment of psoriasis by reporting faster therapeutic benefits than other forms of therapy, which, given the patients need for relieving symptoms, represents a valuable additional advantage.

Guselkumab, an eFFeCtive anD well tolerateD therapY For psoriasis aCCorDinG to a phase ii stuDYConfirmation of the effectiveness of guselkumab, an anti-interleukin-23 antibody, in the treatment of moderate to severe psoriasis was obtained in the phase ii X-plore trial, which was a randomized, placebo- and active-controlled trial in which cohorts of 41-43 patients each received subcutaneous guselkumab at doses of 5, 50 or 200 mg every 12 weeks or 15 or 100 mg every 8 weeks, adalimumab at the approved doses, or placebo. treatment was administered for 40 weeks, but the main endpoint of the trial was response at 16 weeks. as shown in Fig. 4, by that moment up 85.7 and 83.3% of patients receiving 100 and 200 mg of guselkumab exhibited an investigators Global assessment rating of clear or almost clear (scores of 0 or 1), compared to significantly lower rates of response in patients receiving adalimumab, despite the efficacy of the latter compared to placebo. the corresponding pasi75 response rates also demonstrated a superiority of guselkumab over adalimumab (Fig. 5), which like etanercept in the previous trial concerning secukinumab, is a tumor necrosis factor--blocking agent. the greater responses to guselkumab at the higher doses were maintained when considering the proportions of patients with a Dermatology life quality index score of 0 or 1 (Fig. 6), indicating a benefit on the patients quality of life that reflects the improvement in signs and symptoms, including self-perception of health and appearance, brought about by guselkumab. as in the case of the investigators Global assessment, guselkumab 100 and 200 mg was more effective than adalimumab, which exhibited rates of efficacy comparable to guselkumab 15 or 50 mg. this overall benefit of guselkumab on signs and

0

1

2

3

4

5

6

7

8

9

Time (w

eeks)

Secukinumab 150 mg Secukinumab 300 mg Etanercept 50 mg 2x/wk

figurE 2. mEdian timE to rEach a 50% dEcrEasE in thE psoriasis arEa and sEvErity indEx scorEs in patiEnts with modEratE to sEvErE psoriasis initiating trEatmEnt with sEcukinumab 150 or 300 mg, or EtanErcEpt 50 mg twicE wEEkly in thE fixturE trial.

0

10

20

30

40

50

60

70

80

90

Patie

nts (%

)

Secukinumab 150 mg Secukinumab 300 mgEtanercept 50 mg 2x/wk Placebo

PASI75 PGA 0/1

figurE 3. proportion of patiEnts with a psoriasis arEa and sEvErity indEx 75% rEsponsE or an invEstigators global assEssmEnt of 0/1 (lEsions clEarEd or almost clEarEd) by wEEk 16 of trEatmEnt with sEcukinumab 150 or 300 mg, EtanErcEpt 50 mg twicE wEEkly, or placEbo in thE fixturE trial.


injectable etanercept. as apparent from Fig. 7, in both cases tofacitinib 5 mg showed reduced efficacy, but was still significantly more effective than placebo. overall, the results demonstrated the noninferiority of oral tofacitinib 10 mg twice daily versus subcutaneous etanercept 50 mg twice weekly in terms of efficacy in controlling signs and symptoms of psoriasis. all treatments were well tolerated, with serious adverse events reported in 2.1 and 1.8% of tofacitinib recipients, 2.1% of etanercept recipients and 4.7% of placebo recipients. Few discontinuations due to adverse events were required, demonstrating the favorable safety and tolerability of all study treatments.

symptoms of psoriasis was maintained through week 40, at which time the doses of 50, 100 and 200 mg showed statistical significance compared to adalimumab. Furthermore, patients initiated on placebo and switched to guselkumab 100 mg every 8 weeks also showed high response rates at week 40. the agent was well tolerated throughout the study period, with a low frequency of serious adverse events, no malignancies or major adverse cardiovascular events and an overall incidence of adverse events comparable across groups. notably, the incidence of injection-site reactions through week 16 was 0.6% in both the guselkumab (combined) and placebo groups compared to 6.6% in the adalimumab arm, whereas the overall frequency of adverse events throughout the study was 63.4% with guselkumab versus 72.1% with adalimumab.

noninFerioritY oF oral toFaCitinib to injeCtable etanerCept For psoriasis DemonstrateD in a phase iii trialsecukinumab, a monoclonal antibody, and etanercept, a fused protein, are large compounds that need to be delivered by injection. small molecules that can be administered orally have a clear advantage in therapeutics, and research into targeted orally bioavailable therapies targeted against the pathophysiological mechanisms that result in psoriasis was part of the new clinical trials discussed during the latest in Dermatology research symposium at the annual meeting of the american academy of Dermatology. a phase iii trial demonstrating noninferiority of tofacitinib, an oral small molecule, compared to etanercept, an injectable biological, was indeed discussed, which emphasized the advantages a small molecular oral drug could have for patient acceptance as well as risks of immunogenicity. tofacitinib 5 and 10 mg twice daily was compared to etanercept 50 mg by subcutaneous injection twice weekly and a matching placebo in cohorts of 329, 335, 330 and 107 patients with mild to moderate plaque-type psoriasis, respectively. by week 12 (main endpoint of the trial), a pasi75 response had been attained by at least as many patients with the higher dose of the oral medication as patients receiving injectable therapy. a physician global assessment of clear or almost clear from all cutaneous lesions was also reported by as many patients receiving 10 mg of tofacitinib orally as those receiving

0

20

40

60

80

100

Patie

nts (%

)

Guselkumab 5 mg 1x/12 wks



Guselkumab 100 mg 1x/8 wks Placebo


Adalimumab

figurE 4. proportion of patiEnts with an invEstigators global assEssmEnt of 0/1 (lEsions clEarEd or almost clEarEd) by wEEk 16 of trEatmEnt with gusElkumab, adalimumab or placEbo in thE x-plorE trial.

0

20

40

60

80

100

Patie

nts (%

)






Adalimumab

figurE 5. proportion of patiEnts with a psoriasis arEa and sEvErity indEx 75% rEsponsE by wEEk 16 of trEatmEnt with gusElkumab, adalimumab or placEbo in thE x-plorE trial.


antipruritiC eFFiCaCY oF Ct-327 in psoriasis ConFirmeD in a new phase ii trial. phase iii trials announCeDChronic pruritus has a tremendous impact on the quality of life of patients with chronic skin diseases such as psoriasis and atopic dermatitis, but its severity does not correlate with disease activity, suggesting potential for therapies targeting pruritus. as nerve growth factor and the trka kinase mediate the sensorial and neuromediator pathways related with pruritus, the antipruritic activity of Ct-327, a selective trka kinase inhibitor, was tested in a phase iib trial that included 160 patients with mild psoriasis. three strengths of Ct-327 (0.05, 0.1 and 0.5%) and the corresponding vehicle were applied twice daily for 8 weeks. pruritus visual analogue scores decreased by a maximum of 60% compared to 20% with placebo, with a marginal additional benefit on the modified psoriasis area and severity index scores but without local reactions or systemic absorption. in consequence, Ct-327 was associated with fewer adverse events and fewer discontinuations due to pruritus than the vehicle. with these favorable results, an ongoing phase iii trial in patients with psoriasis is currently ongoing, while a phase iib trial is also under way to test the efficacy of the investigational agent in patients with pruritus associated to atopic dermatitis. Details for phase ii clinical trials of Ct-327 in patients with psoriasis or atopic dermatitis are available in Cortellis Competitive intelligence.

0

10

20

30

40

50

60

70

80

Patie

nts (%

)

Tofacitinib 5 mg Etanercept 50 mg 2x/wkTofacitinib 10 mg Placebo

PASI75 PGA 0/1

0

20

40

60

80

Patie

nts (%

)






Adalimumab

figurE 6. proportion of patiEnts with a dErmatology lifE Quality indEx scorE of 0 or 1 by wEEk 16 of trEatmEnt with gusElkumab, adalimumab or placEbo in thE x-plorE trial.

figurE 7. proportion of patiEnts with a psoriasis arEa and sEvErity indEx 75% rEsponsE or an invEstigators global assEssmEnt of 0/1 (lEsions clEarEd or almost clEarEd) by wEEk 12 of trEatmEnt with tofacitinib 5 or 10 mg p.o., EtanErcEpt 50 mg s.c. twicE wEEkly, or placEbo.


for atopic dermatitis. Furthermore, changes in qoliaD scores correlated with changes in pruritus scores using the visual analog scale as well as the standardized 5-D scale. Dupilumab was well tolerated, with an overall incidence of adverse events of 89.1% compared to 83.3% in the placebo arm, but a very low frequency of serious adverse events (1.8% vs. 20.4%). the frequency of skin infections was remarkably lower in dupilumab compared to placebo recipients (5.5 vs. 24.1%). with favorable safety and tolerability, the results revealed meaningful improvements in the quality of life in adults with atopic dermatitis treated with dupilumab, supporting the use of targeted therapies, in this case with a large biological product, a monoclonal antibody.

During the four-day conference, many additional clinical trials were discussed on psoriasis, atopic dermatitis and other diseases affecting the skin and skin structures.

siGniFiCant improvements in qualitY oF liFe in aDult patients with atopiC Dermatitis treateD with Dupilumabadditional clinical trials with additional monoclonal antibodies and small molecules in patients with psoriasis were discussed during other oral and electronic poster sessions in the major conference, but the latest in Dermatology research symposium included also a presentation on a clinical trial testing a novel putative targeted therapy for atopic dermatitis. atopic dermatitis is a very frequent disease of the skin in young children. however, clinical trials in children are a major concern for safey, so that dupilumab, a fully human monoclonal antibody targeting interleukin-4 recepor , was tested in a phase ii randomized, double-blind study in adult patients with moderate to severe atopic dermatitis. the study included 109 subjects, randomized to dupilumab 300 mg s.c. or a matching placebo during 12 weeks, with safety assessments up to 16 weeks later. the quality of life index for atopic Dermatitis (qoliaD) scale was applied to a subset of 64 patients, 32 from each arm, and analyses were performed in this subset of patients. by week 12, the eczema area and severity index (easi) scores had decreased by a significantly higher extent in patients receiving dupilumab compared to those receiving placebo. as reflected in Fig. 8, the corresponding decreases in the qoliaD scores as well as numerical ratings of pruritus in a visual analog scale also revealed a significant advantage of dupilumab. easi 50 and 75% responses were attained by 90.6 and 68.8% of patients in the active treatment arm compared to 40.6 and 12.5% in the control arm, further confirming the clinical effectiveness of dupilumab as a treatment

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

Chan

ge (%

)

PlaceboDupilumab

EASI QoLIAD VAS

figurE 8. pErcEnt changE in thE EczEma arEa and sEvErity indEx, Quality of lifE indEx for atopic dErmatitis and pruritus visual analog scalE scorEs by wEEk 12 of trEatmEnt with dupilumab or placEbo.


notes

2014 thomson reuters. all rights reserved. thomson reuters and the kinesis logo are trademarks of thomson reuters.

reuters/leonhard Foeger

the ones to watCh

an examination of the strategic data and insights of thomson reuters Cortellis Competitive intelligence. read expert reviews of the most promising drugs changing clinical phase, receiving approval and launching. every quarter. orphan drugs exploration of unmet medical need significant pharmaceutical milestones and much more!

DisCover the unDisCovereD with Cortellis Competitive intelliGenCe.

subscribe today: go.thomsonreuters.com/totw

2014 thomson reuters. all rights reserved. thomson reuters and the kinesis logo are trademarks of thomson reuters.

accelerateyourstrategicclinicaldevelopmentdecisionsandadvancepersonalizedmedicineandpatientcare.

access global clinical trials information covering biomarkers, devices, biologics and drugs. integrated with extensive scientific information and competitive intelligence from thomson reuters.

explore Cortellis Clinical trials intelligence the most effective resource for fast clinical trial development and strategic portfolio decisions.

sign up for a free demo on go.thomsonreuters.com/cti

cortellis clinicAl triAls intelligence

ClearlY CORTElliS

about CliniCal solutions From thomson reuters

thomson reuters life sciences offers a range of information, tools, and services relating to clinical trials.

Cortellis CliniCal trials intelliGenCe

the most powerful resource to accelerate a wide variety of strategic clinical development decisions. Covering drugs, medical devices and biomarkers, Cortellis Clinical trials intelligence is built on globally focused technology, including: robust searching, alerting, exporting, analytics/ visualizations, customer information integration and an application programming interface (api). Cortellis Clinical trials intelligence also integrates with other best in class content from thomson reuters.

proFessional serviCes CliniCal

our life sciences professional services team provide customized solutions that leverage our unique blend of content, technology, and expertise

Clinical trial design - patient stratification techniques, recommended endpoints

Clinical trial planning site selection and future disease landscaping and epidemiology

strategic decision making entering or exiting disease area decision support, r&D organizational consulting

Custom analytics & visualizations to drive strategic decision making around drug safety, trial timelines, and competitive trials

note to press:

to request further information or permission to reproduce content from this report, please contact:

laura Gazephone: +1 203 868 3340email: [email protected]

For more information on thomson reuters Cortellis visit: lifesciences.thomsonreuters.com or email [email protected]

to sign up to our pharma matters range of publications visit:go.thomsonreuters.com/pharmamatters

spotliGht onan exciting review of the key market players and deals highlights for leading areas of industry investment and development.

the ones to watCh Focuses on the latest phase changes in the pharmaceutical pipeline.

movers anD shakers unravels the most significant game-play in the us generics market.

the CuttinG eDGe oF ChemistrYinsights into the chemistry advances transforming drug discovery and development.

ThOMsONReUTeRsRegIONalOffICes

north Americaphiladelphia +1 800 336 4474 +1 215 386 0100

latin Americabrazil +55 11 8370 9845other countries +1 215 823 5674

europe, Middle east and Africa london +44 20 7433 4000

Asia Pacific singapore +65 6775 5088tokyo +81 3 5218 6500

For a complete office list visit: ip-science.thomsonreuters.com/contact

10019643 Copyright 2014 thomson reuters

QuiCkly gAin A bETTER unDERSTAnDing Of DRug SAfETy. finD OuT HOw.

visit lifesciences.thomsonreuters.com

lifE SCiEnCES COnnECT blOgDelivering industry insights, commentary, and thought leadership pieces derived from our life sciences solutions and experts.

visit lsconnect.thomsonreuters.com

clinical trial trends by tr

Documents

clinical information

clinical landscape

medical information

thomson reutersin

thomson reutersafter

new phase

medical conferences

medical edge