PERSPECTIVE
Power of Rare Diseases: Found in Translation
Mark C. Fishman
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Aside from established genetic evidence, the best proof of a model for disease pathogenesis rests on predicted perturbation via targeted medicines in clinical trials. Here,
I discuss the strategy of performing exploratory frst-in-human clinical studies on
mechanistically homogeneous populations (often small groups of patients with rare
diseases) as a routine entrance to full-registration clinical trials. Over the past decade,
this approach has proved some pathogenic theories, disproved others, and guided
investigators in new scientifc directions. The immediate advantages have been smaller
trials and provision of new treatments for rare diseases. Later, indications often can be
expanded to subsets of more common diseases.
begins afer a positive response has been observed in a PoC trial and is continued in PoC
extension cohorts while preparing to initiate
a formal dose range–fnding phase 2b study.
In some cases, candidate drugs that achieve
successful PoCs have been designated as
breakthrough therapies by the U.S. Food
and Drug Administration (FDA) (1).
Over the past decade, small PoC clinical
trials that focused on homogeneous patient
populations have provided insights into disease pathogenesis, facilitated provision of
new medicines for patients with rare diseases, and refned extension into larger trials.
Here, I describe some of the lessons learned
from the 175 PoC trials conducted at NIBR.
Using a two-by-two chart, consultants have trials. Te goal of our PoC trials is to show FROM RARE TO SUBSETS OF
been known to defne “strategy” as whatever whether a drug is efective in a defned set of COMMON DISEASES
puts a client in the upper right corner. Defne patients. Tis moves beyond fnding a safe Muckle-Wells and IL-1. One guiding
the ordinate as “unmet medical need” and drug dose in healthy volunteers (classical premise is that fundamental pathways disthe abscissa as “scientifc tractability” and, phase 1) or proving that the drug target is rupted in rare disorders are the same as
voilà, you have a strategy for drug discovery engaged in the patient (pharmacodynam- those in subsets of patients with common
and development (Fig. 1A). If patients need ics). Te patient must show a defned clini- diseases (Fig. 1B). In evaluating ACZ885, a
a drug (unmet need), and there is a shot at cal response for a PoC trial to be considered monoclonal antibody (mAb) to interleukindeveloping one (tractability), that’s a logical successful. Te clinical response is fre- 1β (IL-1β), we focused on the Muckle-Wells
starting point.
quently assessed using one dose, the highest syndrome. Tis rare autosomal-dominant
A main corollary to this strategy is a focus tolerable one, which ofen was determined cryopyrin-associated periodic syndrome
on rare diseases, which are ofen neglected in a typical phase 1 study of healthy vol- (CAPS) is caused by gain-of-function mufrom a drug discovery vantage point be- unteers or subjects with a disease. PoC tri- tations in the NALP3 gene, which encodes
cause of the small potential market. But rare als are smaller than full phase 2 trials—the a component of the infammasome. Te
diseases—especially those
genetic defect results in
A
B
with a genetic basis—
constitutive activation of
Subset of broader
Homogeneous
ofen have well-defned
caspase-1, which generpopulation
population
Best
biological mechanisms.
ates excess IL-1β cytostrategy
Because of the homogekine (2). Patients sufer
Unmet
medical
neity of rare genetic disorfrom rash, fevers, and
need
ders and (hopefully) prearthralgias; preventing
cise molecular targeting
IL-1β from activating
of medicines made posits receptor with an ILUnderstanding of
disease mechanism
sible by strong underly1β mAb has been shown
ing science, small clinical
previously to improve
trials can reveal whether Fig. 1. Human biology drives drug discovery. (A) The strategy depicted is defined by a symptoms (3). Tradiwe are correct about the focus on diseases with the most severe unmet medical needs and in which mechanistic tional market research
pathogenesis of a disease understanding of the biology is strong. (B) A PoC trial focuses on a population of would not pinpoint such
patients in which the disease mechanism is as homogeneous as possible, often those
and the efectiveness of a with a rare genetic disease. When possible, we then extend findings to subsets of pa- a rare disease as a sensipotential new medicine.
ble indication over more
tients with more common disorders.
At Novartis Institutes
prevalent infammatory
for BioMedical Research
disorders such as rheu(NIBR), we refer to such small, precisely standard frst registration efcacy and side- matoid arthritis (RA). But RA is a far more
targeted frst-in-human clinical studies as efect trials. To make PoC trials meaningful heterogeneous disease, and the mechanistic
proof-of-concept (PoC) trials. Because the with few patients, we have found it critical link to IL-1β is far more tenuous. Testing
term “proof-of-concept” is used as broadly to focus on as homogeneous a patient popu- treatments for such conditions necessitates
and vaguely as “translational medicine,” lation as possible. One or more such trials large and long clinical trials.
let me be specifc about how our defnition can be carried out in parallel in discrete paTe frst Muckle-Wells patient treatof PoC trials difers from standard clinical tient populations, and the most robust indi- ed with the IL-1β mAb (ACZ885) was a
cation (that is, the population that shows the 33-year-old woman who had sufered daily
Novartis Institutes for BioMedical Research, Cambridge,
greatest beneft) is then selected for the frst urticarial rash, malaise, arthralgias, and faMA 02139, USA.
E-mail: [email protected]
full-registration trials. Dose fnding usually tigue since childhood. Hours afer a single
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DRUG DISCOVERY
PERSPECTIVE
injection her infammatory markers normalized, and within 48 hours she experienced a complete clinical remission that
lasted 169 days. Afer treating three patients,
all with similarly robust responses, we declared the PoC trial a success and moved
on to registration trials for CAPS (including Muckle-Wells syndrome and familial
cold autoinfammatory syndrome), which
became the frst approved indication for the
drug (termed Ilaris).
Rather than the standard approach of
pursuing regulatory approval of a drug in a
large-market indication and returning later
for testing in rare diseases—the results of
which are ofen reported only as case reports
in small trials from academic institutions—
the PoC approach quickly provides approved
therapies to patients sufering from rare diseases. Can such fndings be expanded to subsets of patients with more common diseases
(Fig. 1B)? During the registration trials for
the drug ACZ885 in Muckle-Wells patients,
evidence appeared that the cryopyrin pathway is activated by uric acid crystals and thus
may function in the development of gout, the
most common infammatory arthritis in the
developed world (4).
Tere is a medical need for better gout
therapies, especially for the subset of patients for whom standard therapies—
colchicine, steroids, and nonsteroidal antiinfammatory drugs—are contraindicated.
Hence, we explored the efect of the IL-1β
mAb in a PoC trial of six patients with acute
gout fares, three who received the mAb and
three controls who received corticosteroids.
All three patients responded well to mAb
therapy, confrming the pathogenic role of
this pathway and indicating that the drug
may be efective in treating gout. Tus, we
proceeded to full registration trials for gout,
which led to the drug’s approval in Europe
for this indication. We are now investigating
additional indications in which stimulation
of the cryopyrin infammasome pathway is
implicated, such as systemic juvenile idiopathic arthritis.
Tuberous sclerosis and mTOR. Conserved from yeast to humans, the mammalian target of rapamycin (mTOR) pathway
is an essential growth-regulatory pathway
that responds to nutrients and growth factors. Te tuberous sclerosis genes TSC1
and TSC2 encode tumor growth suppressors that negatively regulate the mTOR
pathway; mutations in these genes activate
mTOR and lead to tissue overgrowth. In humans, mutations in TSC1 or TSC2 cause the
rare autosomal-dominant disorder tuberous sclerosis, which is marked by benign,
tumorlike growths in many tissues, including skin, kidney, heart, and brain (ofen
causing seizures). Twenty-eight patients
with tuberous sclerosis were enrolled in a
PoC trial in Cincinnati, Ohio, to examine
the efect of RAD001, a rapamycin derivative that inhibits mTOR. Te study focused
on subependymal giant cell astrocytomas
(SEGA), which are benign brain ventricular
tumors that occur in 5 to 20% of patients
with tuberous sclerosis and require surgical
removal. %e efect of RAD001 was clear:
None of the treated patients developed
new lesions or required surgery, many had
a decline in seizure frequency, and 21 had
a reduction of 30% or more in their tumor
size (5). %ese fndings confrmed the role
of mTOR in SEGA development and suggested that RAD001 might be used to prevent seizures. Although the medicine has
side efects, notably stomatitis, the patients’
quality of life improved. %e drug was approved for the treatment of astrocytomas
in tuberous sclerosis patients, and investigational studies are under way to examine
efects on other aspects of the disease, such
as renal tumors (6), epilepsy, and cognitive
impairment.
Expansion of investigational studies to
malignant cancers is a logical step, as aberrations in the mTOR pathway are associated
with a variety of tumor types. For example,
combination with an aromatase inhibitor
has been observed to improve progressionfree survival in postmenopausal women
with hormone-positive advanced breast
cancer (7).
as joint infammation. IL-17 concentrations
are increased in the vicinity of infammation,
and some patients with Crohn’s disease carry
polymorphisms in genes that encode components of the IL-17 infammatory pathway.
However, in a PoC trial, AIN457 did not
reduce the Crohn’s disease activity index in
patients with Crohn’s disease (and the incidence of infections was higher than placebo)
(10). %ese results suggest that Crohn’s disease pathology is less dependent on IL-17
than are other autoimmune disorders.
CHALLENGING HYPOTHESES
Not all PoC trials are successful, no matter
how apparently airtight the underlying scientifc hypothesis is. Strong experimental
evidence suggests that many autoimmune
disorders depend on the cytokine IL-17,
which is released from the %17 population
of efector T lymphocytes (8). One way to
test the IL-17 hypothesis is with the use of
targeted medicines. In a series of PoC trials, patients were treated with AIN457, an
inhibitory mAb to IL-17, which was found
to ameliorate psoriasis, psoriatic arthritis,
ankylosing spondylitis, and rheumatoid
arthritis (9). Crohn’s disease is a relapsing remitting infammatory disease of the
gastrointestinal (GI) tract characterized by
pain, diarrhea, and, in some patients, GI obstruction and extraintestinal pathology such
REFINING TARGET POPULATIONS
Genetic uniformity does not guarantee
consistency of response because epigenetic
modifcations may alter gene expression.
Fragile X syndrome is caused by a singlegene defect, an expansion of a CGG repeat
in the 5′-untranslated region of the FMR1
gene. %is defect is associated with autism
and other behavioral and intellectual disorders. %e pathogenesis of fragile X syndrome is under debate but is speculated to
result from up-regulation of proteins normally kept under control by the fragile X
gene product, including the metabotropic
glutaminergic receptor mGluR5 (11). A PoC
trial with an mGluR5 blocker, AFQ056, was
conducted in 30 patients with the fragile X
syndrome. Initially, no statistically signifcant evidence of a response was detected.
CHANGING INDICATIONS
PoC trials can also quickly redirect use
of a new lead compound. For example, in
seeking an antihypertensive drug for patients with primary hyperaldosteronism,
we designed the small molecule LCI699
to reduce aldosterone levels by blocking
11-β-hydroxylase, an enzyme in the adrenal cortex that converts 11-deoxycortisol to
cortisol. LCI699 reduced blood pressure in
a PoC trial but also reduced adrenocorticotropic hormone–stimulated cortisol release,
which could make it less attractive for the
treatment of hyperaldosteronism. However, another endocrine disorder, Cushing’s
disease, results from excess cortisol release
triggered by ACTH-secreting tumors of the
pituitary. %e excess cortisol causes diabetes, dyslipidemia, obesity, and depression.
%ere are no approved medications for
Cushing’s disease, and surgery is required
for relief. In another PoC trial, LCI699 consistently reduced urinary free cortisol in all
nine patients; hence, we have redirected the
drug toward further investigational studies
on Cushing’s disease.
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PERSPECTIVE
However, we knew that the FMR1 gene is
not silenced directly by the CGG repeat, but
rather by epigenetic suppression of gene expression, and epigenetic modifcations are
not equally evident in all individuals who
bear the CGG repeat expansion. When we
analyzed the response of a subset of seven
patients with full methylation of the fragile X gene, there was evidence of a positive
behavioral response to AFQ056 in all (12).
Further investigational trials are being conducted to examine both genetic and epigenetic characteristics of the fragile X gene so
as to defne a precise responder population.
INTERPRETATION OF POC TRIALS
Statistical analyses of small clinical trials
may be facilitated by a variety of trial designs (13), including an adaptive trial design
and Bayesian approaches (14), but we ofen
fnd that the robustness of response in a few
patients is to be convincing with respect to
the clinical hypothesis. Certainly, many important felds have been launched by trials
with dramatic responses in just a few patients. James Lind’s 1753 trial of nutritional
therapies for scurvy included only two patients in the oranges and lemons arm (15).
%e frst intracoronary thrombolytic therapy included two patients with one success
(16). Cancer chemotherapy began in 1942
with Goodman, Gilman, and Lindskog’s administration of nitrogen mustard to a single
patient with refractory lymphosarcoma. %e
results could not be published until World
War II ended (17) because of concerns
about the chemical warfare implications of
nitrogen mustard, but the success quickly
led to exploration of this agent at Yale University and other institutions.
In the oncology feld, PoC trials are becoming more standard, even if not so designated. Drugs are tested early in patients
rather than in healthy volunteers because
of the low therapeutic ratio of many cancer therapies, and patient populations are
rendered more homogeneous with genetic
characterization of tumors.
POCS AND R&D
Drug discovery and development has been
described as an inefcient and fawed process, with an average of 20 to 30 new medicines approved each year by FDA, only a
handful of which are novel with respect to
target and clinical need (18, 19). %ere are
many reasons for this paucity, and a lack of
well-validated drug targets is high on the
list. %erefore, when evaluating agents that
are truly new in terms of target or medical
need, or when disease pathogenesis is not
well understood or has not been manipulated in human patients, clinical trials that
yield negative results can readily redirect
R&D eforts before deeper resource investments are committed. %e traditional graveyard of new medicines is early discovery
through phase 2 clinical trials, where success rates have declined now to 7% across
the industry (20). Since instituting successful PoC as a routine entry criterion to
a larger clinical development program and
registration trials, Novartis has seen a 50%
increase in early-development success rates
(now 21%). We believe this is at least in part
because of the PoC approach. More precise
genomic stratifcation of common disorders
should further increase our opportunities to
use PoC trials to probe disease pathogenesis
in homogeneous populations and deliver effective targeted medicines to patients with
rare and common diseases.
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Acknowledgments: I thank T. Wright, E. Beckman, B. Weber,
and J. Spector for helpful commentary on the manuscript.
Competing interests: The author is president of the NIBR.
The opinions are those of the author and not those of any of
the Novartis Group of companies. All statements regarding
any indications for or use of compounds for which regulatory
approval has not been granted are investigational only (safety
and efficacy have not been established).
10.1126/scitranslmed.3006800
Citation: M. C. Fishman, Power of rare diseases: Found in
translation. Sci. Transl. Med. 5, 201ps11 (2013).
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