From Clinical Trials to Treatments: 0 → → 9 and Counting…

From Clinical Trials to Treatments:

0 → → 9 and Counting…

Outline for today

• The clinical trial process• How clinical trials are changing• Progress to date: from 0 options to 9 and counting…• A closer look at Aubagio and BG-12• Thumbs up and thumbs down examples from clinical trials• Introducing a valuable resource• Questions – comments – concerns

Why large-scale, multicenter, placebo-controlled trials are the gold-standard

• MS is a highly variable disease Symptoms/disease course vary Responses to treatment vary Outcomes may differ from one center to another Large-group data overcome variability

• The placebo response is powerful 70% of people with MS who are treated with a placebo

will demonstrate improvement – at least for a while A new treatment must show sustained benefit beyond

that placebo effect

The clinical trial process

• Pre-clinical phase – animal studies• Phase I (evaluating safety in humans)

small, unblinded, open-label studies• Phase II (evaluating efficacy + safety in humans)

small, double-blind• Phase III (required for FDA approval)

large, multi-center, randomized, double-blind, placebo-controlled /comparator studies

• Phase IV – Post-Marketing Real-world experience after a drug comes to market

The benefits and challenges of Phase IV

• The benefits gained from post-marketing data We learn how drugs “behave” in the real world

• Patients are more heterogeneous

• Prescribers are more heterogeneous

• Patients are not as carefully screened

• Treatment is not as carefully monitored We broaden our knowledge of short- and long-term

benefits and risks

• Trials are short; real-life has no time limit

– Gilenya and cardiac issues

– Tysabri and PML

– Novantrone and leukemia

.

The benefits and challenges of Phase IV, cont’d

• The challenges of post-marketing data Phase IV data are uncontrolled and anecdotal

• Events reported by patients and doctors may or may not be related to the medication – and without a randomized, control group comparison, there is no way to tell

• Different people report the same experience differently; people report different experiences in the same way

• It can take time for important patterns to emerge

How clinical trials are changing

• Placebo-controlled trials pose ethical issues Can we deprive people with MS of the established

standard of care?• Comparator trials are becoming more common

FDA may require comparison with existing standard of care

Declaration of Helsinki – 2000

The risks, benefits, burdens and effectiveness of a new method should be tested against those of the best current

prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic

method exists.

International Advisory Committee on Clinical Trials of New Agents in MS (National MS Society 2006)

Placebo-controlled trials may be considered:•In forms of the disease for which there is no effective treatment (PPMS and PPMS without relapses)•For subjects who are unwilling/unable to take an available medication•For subjects who have not benefited from available medications•For subjects in areas where effective treatments are not available•When every effort has been made to ensure that patients have access to effective treatments and are fully aware of their options outside of the trial

How clinical trials are changing, cont’d

• Almost all trials are international Increasing the pool of untreated subjects Larger pool of subjects without access to existing

treatments• Trials need greater diversity

Disease course variation between racial groups• Medication trials are needed in pediatric MS patients

How clinical trials are changing, cont’d

• FDA: Patient-focused drug development To assess a drug’s benefits and risks we must:

• Understand the severity of condition • Review the available treatment options

Patients who live with a disease;• Have a direct stake in the drug review process • Have a unique perspective on disease severity and unmet

medical needs– Impact on activities of daily living– Impact on quality of life

The Role of PDUFA V

• 1993 – Prescription Drug User Fee Act (PDUFA) Required drug manufacturers to help pay the cost of the drug

review process As of 2011, these fees made up 62% of drug review budget Reduced the waiting time for drug review/approval from two

years to one.• PDUFA V (2013-2017) – provides resources for including patients in

the review process Patient Focused Drug Development Process is underway Patient-reported outcomes to be evaluated for inclusion with

traditional types of outcome measures

Where have clinical trials gotten us so far?

A long way in a relatively short period of time

• Prior to 1993 – “Diagnose and Adios” is the norm For the fortunate few:

• Relapse management• Symptom management• Rehabilitation• Emotional support

• 1993 to 2005 – five DMT options interferon beta medications (Avonex, Betaseron, Rebif) glatiramer acetate (Copaxone) mitoxantrone (Novantrone)

Still looking at the big picture

• 2006 to 2010 – three additional DMT options natalizumab (Tysabri) interferon beta-1b (Extavia) fingolimod (Gilenya)

• 2010 to 2011 – three new sx management medications dalfampridine (Ampyra) – walking dextromethorphan/quinidine (Nuedexta) – PBA* onabotulinumtoxinA (Botox) – upper limb spasticity;

urinary incontinence

*pseudobulbar affect

And the even bigger picture

• 2012 – one new oral teriflunomide (Aubagio)

• 2013 and beyond – the sky’s the limit BG00012 (dimethyl fumarate) expected in March alemtuzumab (Lemtrada) – submitted to the FDA ocrelizumab – RRMS trial; PPMS trial recruiting; comparison

trial recruiting natalizumab – phase II PPMS/SPMS trial – completed rituximab – phase II/III PPMS – completed daclizumab – phase II RRMS trial -- completed ponesimod -- phase II trial completed simvastatin (Zocor) – phase II completed in

progressive MS

And more…

A closer look at our newest option

• Teriflunomide (Aubagio) Approved in 2012 to treat relapsing forms of MS Taken orally once per day – 7 mg or 14 mg dose Reduces the spread of T and B immune cells; stops the

production of immune messenger chemicals by T cells. Benefits demonstrated in clinical trials:

• Reduction of relapses in both doses vs. placebo• Slowed disability progression vs. placebo;

statistically significant only at the higher dose• Greater benefit on all MRI measures in both groups

vs. placebo; but greater in higher dose group• Fewer side effects in the lower dose group

Teriflunomide, cont’d

Most common side effects• Abnormal liver functions, hair thinning (alopecia), diarrhea,

influenza, nausea and unusual numbness or tingling in the hands or feet (paresthesias)

“Black box warnings”• Liver damage• Birth defects [Category X rating – the medication must be

completely out of a man’s or woman’s body prior to conception]

For more detailed information, go to www.ms-coalition.org/EmergingTherapies

FDA- Defined Pregnancy ratings

• A – controlled studies show no risk• B – no evidence of risk in humans but remains a possibility [GA]• C – evidence suggests chance of fetal harm but the benefits

may outweigh the risks [all interferons and natalizumab]• D – positive evidence of risk from studies or post-marketing

data but benefits may outweigh the risks [mitoxantrone]• X – positive evidence of animal or human fetal abnormalities

from studies or post-marketing data with risks outweighing any possible benefit [teriflunomide]

A closer look at the next probable option

• BG-12 (dimethyl fumarate) FDA decision expected in 1st quarter of 2013 Capsule taken orally – 240 mg taken 2 or 3 times daily Benefits reported in DEFINE trial: both doses vs. placebo:

• 49% and 50% reduction in risk of relapse • 48% and 53% relative reduction of annualized relapse rate• 38% and 34% reduction in risk of disability progression• Fewer new, enlarging or active lesions on MRI

BG-12, cont’d

Benefits reported in CONFIRM trial: both doses vs. placebo:• Lower annualized relapse rate• Reduced disease activity on MRI• Smaller proportion of people experienced relapses• No benefit on disease progression vs. placebo

Most common side effects of BG-12 in both trials:• Flushing and gastrointestinal events• Reduced white blood cell counts but no reports of

opportunistic infections • Liver enzymes elevated in the DEFINE study, but no reports

of significant liver injury or liver failure.

And one more…

• Alemtuzumab (Campath) Humanized monoclonal antibody: reduces or eliminates

selective lymphocytes (T cells and/or B cells) Intravenous infusion for 5 days; 3 days one year later In phase III trials compared to Rebif® [Care I: treatment-

naïve patients; Care II; patients who experienced relapses on Rebif]

• Significantly reduced relapse rate • May significantly reduce worsening of disability• More likely to be relapse-free for two years

Alemtuzumab, cont’d

Infusion side effects: headache, rash, nausea, fever Complications:

• Mild-moderate infections• Up to 1% developed immune thrombocytopenic

purpura (ITP) – detected early through safety monitoring program and treated with conventional treatments.

• Less than 20% had autoimmune thyroid problems that were managed with conventional treatments

Other trials that have given us a thumbs up

• Complementary therapies that are entering the mainstream through careful, controlled research: Exercise Cooling Vitamin D

Trials that have given us a “thumbs down”

Ginkgo biloba – did not improve cognition in a randomized controlled trial

Donepezil (Aricept) – did not improve memory in a randomized controlled trial

St. Johns wort – was not effective with serious depression; may be helpful in milder depression

Bee sting therapy – shown not be effective in treating MS

A variety of DMT wanna-be’s

Some reasons why trials fail

The cause of MS is still unknown so the treatment target may be incorrect

Benefits in animals may not translate into benefits for humans

Some possible candidates actually worsen MS Some possible candidates cause major side effects Some short-term benefits may disappear over time Some trials aren’t designed correctly to see benefit

Every negative trial has something valuable to teach us

The good news is…

• People with MS have 9 treatment options and more on the way• More clinical trials are in process than ever before.• Progressive forms of MS are getting the international attention

they deserve. The International Collaborative on Progressive MS has set

the following priorities:• Identification of experimental models for progressive MS• Identification and validation of therapeutic targets • Strategies for proof of-concept clinical trials • Clinical outcome measures• Symptom management and rehabilitation

Clinical Trial Resources

• National MS Society http://nationalmssociety.org/research/clinical-trials/index.aspx

• U.S. National Institutes of Health www.ClinicalTrials.gov

• NARCOMS www.mscare.org/cmsc/CMSC-NARCOMS-Information.html

• The Center for Information and Study on Clinical Research www.searchclinicaltrials.org/

• NIH Clinical Trials and You www.nih.gov/health/clinicaltrials/index.htm• CenterWatch

www.centerwatch.com/

Emerging Therapies Collaborative – www.ms-coalition.org/EmergingTherapies

• Unique partnership “to promote optimal, individualized treatment …by facilitating effective communication and medical decision-making” Multiple Sclerosis Coalition* American Academy of Neurology Multiple Sclerosis VA Centers of Excellence East/West Americas Committee for Treatment & Research in MS

• Downloadable information for professional and lay readers: Developed by members of the Collaborative Approved by all participating organizations Evidence-based

*Multiple Sclerosis Coalition

• Accelerated Cure Project for Multiple Sclerosis• Can Do Multiple Sclerosis• Consortium of Multiple Sclerosis Centers• International Organization of Multiple Sclerosis Nurses• Multiple Sclerosis Association of America• Multiple Sclerosis Foundation• National Multiple Sclerosis Society• United Spinal Association

S.E.A.R.C.H.™ Model from MSAA

• Developed by Multiple Sclerosis Association of America (MSAA) to help people evaluate treatment options:

S. = SafetyE. = EffectivenessA. = AffordabilityR. = RisksC. = ConvenienceH. = Health Outcomes (overall wellness/quality of life)

• Information and toolkit available at www.MSAssociation.org/programs/Search