Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)

Objective

Multiple inflammatory and neurodegenerative mechanisms drive progression of disability in
fully established multiple sclerosis (MS); therefore, it is unlikely that a single
therapeutic agent will be curative. Analogous to cardiovascular diseases, effective
treatments for evolved MS will likely require individualized combination therapies that
target pathogenic processes active in the particular patient. Ability to reliably measure
such pathogenic processes in living patients is a pre-requisite for a precision-medicine
approach to MS. We identified and validated molecular diagnostic tests of MS and its
progressive stage based on combinatorial cerebrospinal fluid (CSF) biomarkers. These
proteomic tests confirmed results from MS genetic susceptibility studies that selective
dysregulation of adaptive immunity differentiates MS from healthy and other disease states
and that this feature is identical between patients with relapsing-remitting (RRMS) and
progressive (PMS) MS. Instead, PMS subjects have higher central nervous system (CNS) tissue
damage and higher compartmentalization of immune responses to CNS tissue. We observed that
FDA-approved disease modifying therapies (DMTs) only partially normalize biomarkers that
differentiate MS from non-MS, consistent with long-term observations that these therapies are
generally not curative. We also observed that biomarkers of dysregulated adaptive immunity,
whether measured at the untreated stage or after treatment with DMTs, do not predict MS
severity. This is again consistent with genetic data that MS-susceptibility alleles do not
predict MS phenotype. Instead, statistical modeling of CSF biomarkers against measures of MS
disease severity identified alternative processes, such as activation of myeloid lineage,
endothelial cells, astrocytes and remodeling of extracellular matrix in the form of fibrosis
to influence rate of progression of clinical disability. These processes are only marginally
affected by present treatments and cannot be measured by current imaging techniques.
Consequently, the objective of this protocol is: 1. To develop clinical trial methodology
that allows economical screening of prospective therapeutic agents for their efficacy on
biological processes related to MS disease severity using CSF biomarkers; 2. To develop
knowledge base of intrathecal effects of current DMTs and novel treatments targeting varied
mechanisms of MS progression; and 3. To establish and validate framework for development of
effective combination therapies for MS via precision-medicine paradigm.

Study population

Patients with MS who continue to accumulate clinical disability while untreated (e.g. PMS
subjects) or on FDA approved immunomodulatory therapies and are able to travel to NIH every 6
months and undergo serial lumbar punctures (LP).

Design

The protocol has an adaptable workflow that allows simultaneous assessments of multiple
therapeutic agents while maximizing potential therapeutic benefit to the studied subjects and
providing knowledge necessary for rational development of future combination therapies for
MS. To start with, we selected four agents, whose mechanism of action (MOA) have the
potential to inhibit identified processes underlying MS disease severity. Patients will be
assigned to one of the drugs that are not contra-indicated based on existing comorbidities
and to which the patient has a therapeutic target (e.g. treatment that inhibits activation of
myeloid lineage will be assigned only to patients who have elevated CSF biomarkers of myeloid
lineage). Longitudinal measurements of CSF biomarkers will determine if the applied
treatment(s) exert the desired pharmacodynamics (PD) effects in the intrathecal compartment.
While those drugs that do not reproducibly effect CSF biomarkers will be dropped from further
study (or will be tested in higher dose, if possible), drugs with measurable intrathecal PD
activity will be combined to evaluate additive or synergistic effects. Safety, tolerability
and pilot clinical/imaging efficacy data will evaluate surrogacy of the biomarkers and
collect data for power analysis for future definitive trials. The increased understanding of
biomarker biology will be utilized to derive process-specific combinatorial biomarkers and
biomarker signatures predictive of clinical efficacy.

Outcome measures

Primary outcome will be the change in Combinatorial Weight adjusted dIsability ScalE
(CombiWISE) progression at the end of monotherapy + combination therapy period in comparison
to projected baseline disability progression. The acquired longitudinal data will be used for
assessment of biomarker surrogacy, for identification and validation of PD markers for
development of new therapeutic entities and for power analysis of future/definitive clinical
trials.

- INCLUSION CRITERIA:

- Enrolled in 09-I-0032 protocol

- Clinically definite MS

- Age greater than or equal to 18 at time of study enrollment

- Expanded Disability Status Scale (EDSS) 1.0-7.5

- Documented sustained clinical progression of at least 0.5 CombiWISE points/year
(measured by greater than or equal to 4 time-points regression analysis of CombiWISE
values spanning at least 1.5 years in total)

- Subjects of childbearing potential must be willing to use a medically acceptable form
of birth control, which includes abstinence, while being treated on this study

- Patients who desire to continue their current FDA-approved DMTs based on its perceived
(partial) therapeutic benefit will be enrolled with the understanding that the
underlying FDA-approved therapy has to remain stable during this protocol. If patient
desires and/or his/her medical condition requires changing FDA-approved DMT during the
duration of this protocol, the drugs administered under this protocol will be
withdrawn, but the patient will have an option to repeat the entire process: go back
to greater than or equal to 1.5 year baseline period on new DMT to verify that the
rate of progression remains greater than or equal to 0.5 CombiWISE points/year and
then can be matched to the same monotherapy or combination therapy regimen s/he was on
before the immunomodulatory DMT change.

- Willing and able to participate in all aspects of the protocol

- Able and willing to provide informed consent

EXCLUSION CRITERIA:

- Clinically significant medical disorders that, in the judgment of the investigators,
could expose the patient to undue risk of harm or prevent the patient from safely
completing all required elements of the study (such as, but not limited to significant
cerebrovascular disease, ischemic cardiomyopathy, clotting disorder, other
neurodegenerative disorder, substance abuse or significant psychiatric disorder such
as depression with suicidal ideations, unable to perform or tolerate MRI examinations)

- Clinically significant medical disorders, other than MS, that require chronic
treatment with immunosuppressive or immunomodulatory agents

- Pregnancy or Breastfeeding

- Abnormal screening/baseline blood tests exceeding any of the limits defined below:

- Serum alanine transaminase or aspartate transaminase levels which are greater than
three times the upper limit of normal values.

- Total white blood cell count less than 3,000/mm^3

- Platelet count less than 85,000/mm^3

- Serum creatinine level greater than 2.0 mg/dl and eGFR (glomerular filtration rate)
less than 60

- Serological evidence of HIV, HTLV-1 or active hepatitis A, B or C

- Positive pregnancy test

- Breastfeeding

- Following drug-specific exclusion criteria will be applied when assigning one of the 4
tested agents (these are not exclusions from the trial)

- Pioglitazone

- Congestive heart failure

- History of bladder carcinoma

- Type 1 diabetes

- Hypersensitivity to the drug

- Taking teriflunamide (Aubagio) because of risk of hypoglycemia on this
combination

- Montelukast

----Hypersensitivity to the drug

- Hydroxychloroquine

- Retinal disease or retinal changes on OCT; significant vision loss

- Hepatic impairment

- Porphyria

- Hypersensitivity to the drug

- Losartan

- Hypersensitivity to drug

- Renal impairment

- Hepatic impairment

- Congestive heart failure