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& 2014 International Society of Nephrology

Emerging treatments for amyloidosis

Rabya H. Sayed1,2, Philip N. Hawkins1 and Helen J. Lachmann1,2

National Amyloidosis Centre, UCL Medical School, Royal Free Hospital, London, UK and 2UCL Centre for Nephrology, UCL Medical
School, Royal Free Hospital, London, UK

Amyloidosis results from protein misfolding, and ongoing

amyloid deposition can ultimately lead to organ failure and
death. Historically, this is a group of diseases with limited
treatment options and frequently poor prognosis. However,
there are now targeted therapeutics emerging in the form
of stabilizers of the precursor protein, inhibitors of
fibrillogenesis, fibril disruptors, and blockers of protein
translation, transcription, and immunotherapy. We review
many of these approaches that are currently being assessed
in clinical trials.
Kidney International advance online publication, 3 December 2014;
KEYWORDS: amyloidosis; chemotherapy; diflunisal; eprodisate;
immunotherapy; oligonucleotides

The term amyloidosis encompasses a group of diseases

caused by the pathogenic misfolding of specific proteins that
differ substantially with respect to organ involvement, management, and prognosis. Recent diagnostic developments have
improved disease recognition, and the incidence of systemic
amyloidosis is estimated to be at least c. 8 per million per
year, although likely to be higher.1 Immunoglobulin lightchain associated (AL) and secondary (amyloid A (AA))
amyloidoses are by far the most prevalent subtypes with renal
involvement present in two-thirds and 490% of patients,
respectively.2,3 Renal presentation mainly reflects glomerular
deposits with proteinuria, often overt nephrotic syndrome,
and varying renal insufficiency.4,5 However, where tubulointerstitial involvement predominates, particularly in some
types of hereditary apolipoprotein A-1 amyloidosis, a gradual
decline in renal excretory function, without significant proteinuria, occurs.6 Untreated, median survival with AL amyloidosis is only 12 months; however, survival after treatment
now exceeds 3 years,7 and it remains critically important that
we strive to further ameliorate both the morbidity and
mortality burden associated with systemic amyloidosis. This
review specifically focuses on the novel therapies that have
lately entered the clinical testing arena or that loom on the

Correspondence: Helen J. Lachmann, National Amyloidosis Centre, UCL

Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF,
UK. E-mail:
Received 28 February 2014; revised 22 April 2014; accepted 24 April
Kidney International

The amyloidoses are the consequence of protein misfolding

and aggregation, subsequent insoluble fibril formation, and
accumulation in the extracellular space, ultimately causing
organ dysfunction and death.8 More than 30 different
amyloid fibril precursor proteins are known in humans, but
all fibril types essentially share a similar ultrastructure.9 The
acquired highly characteristic b-pleated conformation of amyloid
fibrils is associated with specific biophysical properties,
including the ability to bind Congo red dye in a spatially
ordered manner that produces diagnostic green birefringence
when viewed under cross-polarized light10,11 (Figure 1). Under
electron microscopy, amyloid deposits appear as randomly
arranged, rigid nonbranching fibrils of B10 nm in diameter
and of indeterminate length.12
The mechanisms by which amyloid deposits cause tissue
damage have not yet been fully elucidated. The presence
of large amounts of amyloid material can disrupt tissue
architecture and mechanically interfere with the physiologic
function of affected organs.13 Prefibrillar oligomeric species


RH Sayed et al.: Emerging treatments for amyloidosis

Figure 1 | Sections of a renal biopsy sample were stained with Congo red dye and viewed at 200 magnification. (a) Amorphous
deposits of eosinophilic material are visible within the glomerulus. (b) Pathognomonic green birefringence of amyloid deposits is visible when
viewed under cross-polarized light. (c) Immunostaining of the amyloid deposits with anti-k antibodies was strongly positive (brown stain).

Table 1 | The major amyloid subtypes

Amyloid subtype

Fibril precursor


Clinical involvement


immunoglobulin light chains


Serum amyloid A protein

Renal (5080%), cardiac, liver,

spleen, bones, GI, autonomic and
peripheral neuropathy, soft tissue
Renal (495%), liver, spleen,
adrenals, autonomic neuropathy

ATTR: wild-type

Wild-type transthyretin
Variant transthyretin


b2-Microglobulin (associated
with chronic dialysis)

AFib (hereditary)

Variant fibrinogen Aa

AI (hereditary)
AII (hereditary)
Lysozyme (hereditary)

Variant apolipoprotein AI

Chemotherapy directed at the underlying

plasma cell dyscrasia
Potentially novel agents
Treatment aimed at the specific underlying
inflammatory condition
Potentially eprodisate
Mainly supportive with optimization of fluid status
Cardiac transplantation
Potentially novel agents
Livercardiacrenal transplantation
Potentially novel agents
Mainly supportive, for example, splints, braces, collars.
High-flux dialyzer membranes, frequent hemodialysis,
b2M adsorption columns to reduce formation
Renal transplantation
Renalliver transplantation
Potentially novel agents
Renal /  liver transplantation
Potentially novel agents
Renal transplantation
Potentially novel agents
Renal transplantation
Potentially novel agents

Variant apolipoprotein AII

Variant lysozyme

Cardiac, soft tissue

Dominant neurologicalcardiac
involvement (dependent upon
specific TTR variant)

Osteoarticular, bone cysts, soft

tissue. Late visceral deposition
including cardiac, GI, and spleen
Renal (mainly medullary),
liver, heart, skin, larynx
Renal, liver, GI, spleen, lymph
nodes, lung, thyroid, salivary glands

Abbreviations: AA, amyloid A; AFib, fibrinogen Aa-chain; AL, immunoglobulin light chain amyloidosis; ATTR, amyoidogenic transthyretin; b2M, b2-microglobulin; GI,
gastrointestinal; TTR, transthyretin.

may also be toxic and contribute to organ dysfunction;

cytotoxicity, in these cases, seems to be related to structural
flexibility and exposure of hydrophobic residues.14
The major types of systemic amyloidosis are described in
Table 1. Ideally, immunofluorescence on fresh tissue or,
failing that, immunohistochemistry on fixed sections should
be used to distinguish between the different types.12 Sometimes
a characteristic distribution of deposits on light microscopy
alone can provide diagnostic pointersfor example, isolated
heavy glomerular involvement in fibrinogen Aa amyloidosis.15 Genetic testing is invaluable in diagnosing and
excluding the known hereditary forms of amyloidosis, and
fibril typing by mass spectrometry is increasingly used when
immunostaining fails to provide definitive results.16

Transthyretin (TTR) is a 55-kDa homotetrameric plasma

protein that transports thyroxine and Vitamin A and is associated in its wild-type (wt) form with acquired amyloidosis,

termed wild-type TTR (wtTTR) amyloidosis and formerly

known as senile systemic amyloidosis.17,18 More than 100
genetic variants of TTR are associated with autosomal dominant
hereditary amyloidosis, and these usually involve the peripheral
and autonomic nervous system and/or the heart.19,20 Notable
variants include TTR Val30Met, which is the most common
cause of familial amyloid polyneuropathy (FAP), and Val122Ile,
which occurs in B4% of African Americans and is associated
with late-onset familial amyloid cardiomyopathy, although with
quite low penetrance.2125 Untreated FAP is a progressive disease
resulting in death within 715 years;26 although renal amyloid
deposits occur, only 34.6% develop chronic kidney disease and
10% progress to end-stage renal failure.27
The conversion of circulating TTR protein into amyloid
requires dissociation of the normal tetrameric protein into
monomers, conformational change, and assembly to form
the fibrils.19,21 The propensity to form amyloid is influenced
by specific amino-acid substitutions and environmental
factors such as pH and oxidative stress.28
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RH Sayed et al.: Emerging treatments for amyloidosis

WtTTR amyloidosis is very likely to be an underdiagnosed condition that commonly presents in the older
population with symptoms predominantly of right-sided
heart failure and often a history of the carpal tunnel
syndrome.29 Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where
supraventricular arrhythmias are present, and an avoidance
of digoxin and calcium channel blockers. Antihypertensives
are usually poorly tolerated as these patients can be profoundly hypotensive.30,31
Circulating TTR protein is almost exclusively liver derived,32
and the surgical gene therapy with liver transplantation
has been undertaken in more than 2000 FAP patients since
1990.33,34 Liver transplantation, when performed early,
prolongs life, particularly in patients with the TTR Met30
variant, but neurological impairment and a poor quality of
life remain problematic.35 In other mutations, and in older
patients, outcomes are less favorable, and may reflect
postoperative amyloid cardiomyopathy.36 This is thought to
be due to the deposition of wt TTR on a template of
preexisting cardiac amyloid derived from variant proteins.37
The need for better therapies has resulted in the development
of a number of novel strategies, and some of these have been
assessed in clinical trials.

Diflunisal is a nonsteroidal anti-inflammatory drug that

stabilizes tetrameric TTR in vitro by binding via the thyroid
hormone receptor sites.38,39 Berk et al.40 recently completed
an international, multicenter, placebo-controlled study of 130
FAP patients, with neurological outcome as the primary end
point. The exclusion criteria included patients 475 years
of age, a history of gastrointestinal bleeding, estimated
glomerular filtration rate o30 ml/min, and NYHA (New
York Heart Association) Class IV heart failure. Sixty-three
patients with a median age of 59.7 years, of whom 54.6% had
TTR Met30, completed the study, having taken either 250 mg
diflunisal or placebo daily over a 2-year period. The authors
reported a significant reduction in the rate of progression of
neurological impairment and an improved quality of life in
the diflunisal-treated group, with 29.7% of the diflunisal and
9.4% of the placebo group displaying a stable neurological
score by Neuropathy Impairment Score plus 7 nerve tests
(NIS 7) at 2 years. Drug-related adverse events, including
gastrointestinal bleeding and renal dysfunction, did not differ
between the two groups.40

undertook a randomized phase II/III double-blinded trial

that assigned either 20 mg oral tafamadis or placebo to 128
FAP patients (mean age 39 years) with the V30M TTR
mutation and early neuropathy for a period of 18 months.
Plasma TTR stabilization was seen in 98% of tafamadistreated patients and none of the placebo arm. The study did
not show a significant change in the predefined primary end
point but suggested a slowed deterioration in small fiber
neuropathy in the tafamadis arm at 18 months, with 45.3%
of the evaluable diflunisal and 29.5% of the placebo group
displaying a stable neurological score by NIS of the lower
limb at 18 months. The most common side effects included
urinary tract infections and diarrhea. There has been no
evidence that Tafamadis affects thyroid function tests;
however, routine monitoring is advised. Notably, Coelhos
study excluded patients with an estimated glomerular filtration rate of o30 ml/min, and there currently remains no
evidence of efficacy in cardiac TTR amyloidosis.
This study has split the drug regulatory authorities with
the European Medicine Agency granting approval for Tafamadis
use in FAP for TTR Met30 patients with early disease who
can still walk independently. It has not yet been approved by
the US Food and Drug Administration.
These two studies highlight some of the difficulties in
conducting drug trials in amyloidosis and amyloid neuropathy
in particular. These include problems with patient selection
(the study populations were very different) and quantifying
the amyloid deposits; there are no imaging techniques that can
accurately identify let alone quantify neural amyloid deposits,
and biopsies are subject to sampling error. In addition, nerve
biopsies can only be used very sparingly, and it is not clear that
assessment of amyloid by serial fat aspirates (a safe and easily
obtained source of tissue) provides a reliable insight into
changes in amyloid load. The assessment of neurological
function is currently onerous and dependent on clinical
experience and subjective interpretation. The widely used
measures reported in these two studies are taken from the
diabetic literature and may not be entirely appropriate; the rate
of deterioration of neurological function in FAP is much more
rapid than that seen in diabetes, and there have been no
prospective observational studies to validate these methodologies in amyloid neuropathy. The numerical scores that are
generated give the impression that any particular change in
score has similar clinical weight regardless of baseline function,
and this seems inherently unlikely.
Ongoing questions relating to whether either of these
agents will be beneficial in cardiac amyloidosis are being
addressed at present.


(2-(3,5dichlorophenyl)-benzox-azole-6-carboxylic acid) is an orally administered drug that acts to
stabilize the TTR tetramer through its affinity for the T4binding site, and it does not carry the risks associated with
nonsteroidal anti-inflammatory drug use.41 It is protein
bound, metabolically stable, and X94% is excreted
unchanged from the digestive tract. Coelho et al.42
Kidney International


Recent in vitro experiments show that 50 mmol/l epigallocatechin-3-gallate, the most abundant catechin in green tea
(GT), efficiently inhibits fibril formation from amyloid
b-protein, a-synucleine, and TTR and converts existing
fibrils into nonfibril conformers.43,44 TTR tetramer stabilization is observed when epigallocathechin-3-gallate binds to


RH Sayed et al.: Emerging treatments for amyloidosis

recombinant wt and variant TTR tetramers at three sites

different from the thyroxine-binding site.45 Kristen et al.46
undertook a prospective study of 19 patients with cardiac
TTR amyloidosis consuming either standardized GT extract
in the form of capsules or 1.22 l of GT/day over a year. Ten
patients had hereditary ATTR amyloidosis and 9 patients had
wtTTR amyloidosis. Five patients did not complete the
study (2 died, 2 discontinued GT/GT extract, and one
underwent heart transplantation). In the subgroup of
patients evaluated by cardiac magnetic resonance imaging,
a mean decrease in 12.5% left ventricular mass was detected.
There were no serious adverse effects reported by any of the



The discovery of RNA interference by Fire and

which they were awarded the Nobel Prize in Physiology in
2006, demonstrated how the transfer of genetic information
from DNA to protein can be blocked. Oligonucleotide-based
therapies, including small interfering RNAs (siRNAs) and
antisense RNAs, have the ability to cause changes at the
translational level without becoming integrated into the
human genome.48
The siRNAs are noncoding, double-stranded molecules
that are components of the endogenous RNA interference
pathway that serves to control gene expression. They vary in
length from 18 to 30 base pairs and are chemically modified
for drug delivery to increase stability and limit immunogenicity.49 Lipid nanoparticles have been used to deliver
siRNAs to hepatocytes parenterally; these have resulted in a
robust and durable reduction in genetic expression across a
variety of species.50 Antisense oligonucleotides (ASOs) are
1325 nucleotide single-stranded DNA molecules that hybridize to a specific messenger RNA (mRNA) sequence and
prevent transcription.51,52 The mechanisms through which
both types of oligonucleotide work are illustrated in Figure 2.
Oligonucleotide therapies for ATTR have shown great
promise in preclinical models, and both siRNAs and
antisense RNAs are being investigated in clinical studies
( NCT01960348 and NCT01737398).
Coelho et al.53 undertook a single-dose, randomized,
placebo-controlled phase I trial using ALN-TTR01 and
nanoparticles); these contain an identical siRNA that binds
to an mRNA segment common to both wt and mutant TTR.
There was a rapid, dose-dependent, and durable reduction
in transthyretin levels in the 32 patients with TTR
amyloidosis.53 Alnylam Pharmaceuticals (Massachusetts)
have developed an RNA interference therapeutic that has
been chemically modified by conjugation to an Nacetylgalactosamine moiety, thereby refining hepatocyte
targeting and allowing subcutaneous administration;49,54,55
this is currently in phase II trials for cardiac ATTR
ASOs have already been tested clinically in the treatment of viral diseases, cancer, and metabolic disease.5658


of DNA


3 Promoter

of DNA



Oligonucleotide-based therapies






Figure 2 | Hepatocyte schematic demonstrating the mechanism

by which small interfering RNAs (siRNAs) block the transcription
process and antisense oligonucleotides interfere with the
translation process, ultimately preventing transthyretin (TTR)
formation. (1) The siRNAs bind to the RNA-inducing silencing
complex (RISC) in an adenosine triphosphate (ATP)dependent
manner. (2) This multisubunit protein complex migrates toward
messenger RNA (mRNA). At some point, the siRNA unwinds and the
antisense strand remains bound to the RISC and blocks transcription
by the direct degradation of the target mRNA sequence through the
use of both endo- and exonucleases.37, 42 (3) The mRNA migrates into
the cytoplasm where (4) hybridization with the antisense
oligonucleotide prevents protein translocation (5).

ISIS-TTRRX is a second-generation chimeric antisense

inhibitor of TTR. It binds selectively and with high affinity
to the nontranslated portion of the human TTR mRNA and
results in its degradation, preventing production of both wt
and variant TTR protein. ISIS-TTRRX twice-weekly
subcutaneous injections have been well tolerated in both
TTR transgenic mouse models and monkeys with a reduction
in hepatic TTR mRNA and plasma wt TTR protein levels by
B80%, and it is currently under evaluation in a phase I
clinical trial in normal healthy volunteers.26,59 It will initially
be developed for patients with FAP, and a randomized,
double-blind, placebo-controlled study to assess the longterm safety and efficacy of ISIS-TTRRx in patients with FAP
was initiated in 2013.
The mechanism by which ASOs mediate their effect could
be beneficial in other types of amyloidosis. Kluve-Beckerman
et al.60 used ASOs to suppress serum amyloid A protein
(SAA) production in mice and demonstrated that SAA levels
in ASO-treated mice were 63% lower than those in controls,
resulting in reduced AA amyloid deposition.
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RH Sayed et al.: Emerging treatments for amyloidosis


Systemic AA amyloidosis results in organ dysfunction due to

extracellular deposition of N-terminal fragments of SAA in
the form of insoluble amyloid fibrils. These deposits have a
predilection for the kidneys, spleen, liver, and intestines, with
the kidney being the most commonly affected organ. Patients
typically present with progressive proteinuria, nephrotic
syndrome, and renal insufficiency.5,61 SAA is a hepatic acutephase response protein, and synthesis can be upregulated by
1000-fold in response to inflammatory cytokines, particularly
interleukins 6 and 1, and, to a lesser extent, tumor necrosis
factor-a.6264 A persistent inflammatory response can arise
from any variety of causes, the more common ones being
rheumatoid arthritis, seronegative arthritides, inflammatory
bowel disease, and long-standing infections such as osteomyelitis, decubitis ulcers, and bronchiectasis.61 It is not yet
known what predisposes certain patients to develop systemic
AA amyloidosis; there has been no one specific gene or allele
identified, and it may be that the frequency and severity of
inflammatory episodes and thus the degree and duration of
elevated SAA levels is the primary risk factor. Other identified
risk factors include the SAA1 isotype and perhaps variants in
Renal transplantation

Renal involvement is the most frequent and serious complication of AA amyloidosis,66 necessitating the need for renal
replacement therapy including renal transplantation. Pinney
et al.67 described 43 patients with AA amyloidosis with renal
transplants and a median follow-up of 5.1 years. Graft loss
due to recurrent amyloid occurred in only 4.6% of cases and
predicted median graft survival was 10.3 years. Lower SAA
levels were associated with an improved outcome, with graft
survival, noncensored for death, of 14.5 years in patients with
a median SAA value of o10 mg/l and 7.8 years in those with
a median SAA value of 410 mg/l. Furthermore, the median
SAA concentration was significantly higher among those with
graft amyloid recurrence. Of the patients, 37% died, with
approximately two-fifths of deaths being due to infection.
Kofman et al.68 showed that their cohort of 59 transplanted
AA patients had a 5-year patient survival of 83.1% and graft
survival (censored for death) of 83.1%. Patient survival was
less good compared with the outcome of 179 age-matched
renal transplant recipients, although graft survival was not
statistically different.68 A total of 72.3% developed at least
one infection, and 43% of patient deaths were due to severe
sepsis. They postulated that this risk arose from both preand post-transplant immunosuppression.
Current drug treatment

Current treatment is aimed at reducing SAA production to

healthy normal levels (3 mg/l) through control of the respective underlying inflammatory disease. Sustained suppression
of SAA production results in amyloid regression.69 Lachmann
et al.61 reported an improvement in renal functions in
patients with a median SAA concentration of 6 mg/l and
Kidney International

deterioration in patients with a median SAA concentration of

28 mg/l. Proteinuria may diminish substantially, although
gradually over months and even years, in patients with AA
amyloidosis when the underlying inflammatory disease
remains quiescent.61

Glycosaminoglycans, such as heparin sulfate, promote fibril

assembly by acting as chaperones during early stages of
protein refolding and amyloid formation. Eprodisate (Kiacta,
Neurochem) is a negatively charged, sulfonated molecule that
is structurally similar to heparin sulfate and works by competitively inhibiting the interaction between SAA and glycosaminoglycans. It has inhibited AA amyloid development
in experimental mouse models. A multicenter, randomized,
double-blind, placebo-controlled trial in 180 patients with
AA amyloidosisassociated nephropathy was completed.70 As
eprodisate is renally cleared, the dosage of daily drug prescribed was dependent upon creatinine clearance. Study
medication was continued for 24 months, unless the patient
progressed to end-stage renal disease, had a significant adverse
event, withdrew from the study, or required rescue medication such as cytotoxic agents, colchicine, or anti-tumor necrosis
factor agents. Rheumatoid arthritis (49% of the patients) and
familial Mediterranean fever (19%) were the most common
underlying inflammatory diseases. Treatment with eprodisate
was associated with a 42% reduction in the risk of worsening
renal disease (as measured by creatinine clearance) or death
(0.370.93 P 0.02). More specifically, compared with placebo,
eprodisate significantly reduced the risk of doubling of serum
creatinine, the risk of a 50% reduction in creatinine clearance,
and the slope of decline in creatinine clearance. The decline in
creatinine clearance was 4.7 ml per min per 1.73 m2 per year
greater in the placebo group than in the eprosidate group, a
relative difference of 30%.70 Perhaps surprisingly, there was no
significant difference in terms of the overall changes in proteinuria. Despite these encouraging results, there was some
concern that some of the apparent drug benefit reflected a
poor outcome in the subgroup of placebo patients who had
nephrotic-range proteinuria at baseline, and the US and
European regulatory bodies requested a confirmatory second
phase III trial that is ongoing.71

Systemic AL amyloidosis is by far the most frequently

recognized type of amyloidosis with potentially significant
multiorgan involvement. Fibrils are derived from monoclonal
immunoglobulin light chains, and AL amyloidosis most
commonly occurs in patients with otherwise asymptomatic
and low-grade clonal plasma cell dyscrasias, although 1015%
of patients have multiple myeloma.12,72 Current treatment
centers on suppressing clonal B cells, and hence reducing the
supply of the amyloidogenic fibril precursor protein. This
may facilitate gradual regression of amyloid deposits and
stabilization or improvement in vital organ function
(Figure 3). There is convincing evidence that more complete


RH Sayed et al.: Emerging treatments for amyloidosis

Table 2 | Mayo cardiac amyloid staging system

Median survival (months)

Stage I

Stage II

Stage III

o0.035 mg/l

X0.035 mg/l
X332 ng/l

X0.035 mg/l

o332 ng/l

X332 ng/l

Abbreviations: cTNT cardiac troponin T; NT-proBNP, N-terminal pro-brain natriuretic

This staging system is widely used in studies when evaluating therapeutic efficacy.
Higher stages correlate with a worse prognosis.64

Figure 3 | Iodine-123 (123I)-labeled serum amyloid P (SAP)

component scintigraphy. Anterior-posterior view of an SAP scan,
demonstrating (a) a large total body amyloid load with hepatic
and splenic involvement (b) with regression after nine cycles of
chemotherapy, resulting in a small total body amyloid load.

clonal responses are associated with both longer treatmentfree survival and a greater chance of improvement in organ
function. In low-risk patients, autologous stem cell transplantation is widely regarded as the treatment of choice,
although this was not supported by the only randomized
study to be performed,73 and outcomes depend heavily on
patient selection and center experience.
The prognosis of untreated AL patients remains 1215
months,74 and just a few months for patients with significant
cardiac involvement, highlighting the need for novel, more
effective regimens. The pathological light chains may have a
direct cardiotoxic effect and, although renal failure clearly
adds to disease burden, it is actually cardiac damage that is
the major prognostic marker.75 This is assessed by the Mayo
staging system (Table 2) and improvement after treatment
directly affects prognosis.76 However, one should bear in
mind the effect of a diminishing renal excretory function on
the widely used prognostic markers: serum cardiac troponin
T and the NT-proBNP (N-terminal fragment of pro-brain
natriuretic peptide). Importantly, as organ response can often
be delayed, treatment efficacy is monitored through the
measurement of hematological parameters, specifically
serum-free light-chain measurements (Table 3).77
Current treatment

The agents currently used include the newer immunomodulatory drugs and the proteasome inhibitor, bortezomib, as
well as the more traditional regimes (Table 4). Current
regimes have been modified from multiple myeloma protocols,
and treatment choice depends upon the type and severity of
organ involvementfor example, cardiac involvement, peripheral neuropathy, or significant hypotension may preclude
particular agents. These drugs are commonly combined with

dexamethasone and are often used in conjunction with a

myelosuppressive agent, such as cyclophosphamide.
Melphalan and dexamethasone have been used to reduce
the production of aberrant light chains, and although 33% of
intermediate-risk patients achieved complete response (CR)
with high-dose dexamethasone and a median survival of 5.1
years, CRs were halved in patients with significant cardiac AL
(who could only tolerate low-dose dexamethasone), 26% of
whom died during the period of treatment.78,79 Furthermore,
there is significant myelosuppression associated with intermediate-dose melphalan.80 The potential advantage of
autologous stem cell transplantation (ASCT) in delivering a
longer remission-free period and a relatively quick CR)
means that patients should be considered for this procedure
from the onset. The depth of hematological response is
associated with the degree of organ response, emphasizing
the importance of trying to achieve CR either through
chemotherapy alone or with ASCT.
Autologous stem cell transplantation

This was first reported as a major breakthrough in AL

amyloidosis by Comenzo et al.81 in 1998. Recently, Cibeira
et al.82 showed that a CR, after ASCT, confers an overall
survival of 86% at 5 years and an event-free survival of 8.3
years compared with 2 years for patients not in CR. However,
treatment-related mortality has been reported as being as
high as 40% in 1999, and since then efforts have been made
to risk stratify patients more rigorously.83 Gertz et al.84
undertook the largest study of patients receiving ASCT
and have recently refined their eligibility criteria, as
analysis showed that higher levels of cardiac biomarkers
were the sole predictors of early mortality after ASCT, and
treatment-related mortality was o1% if the NT-proBNP was
o5000 pg/ml and troponin was o0.06 ng/ml. In selected
lowintermediate-risk AL patients, ASCT is well established
as a first-line treatment, but the use of stringent criteria,
designed to reduce treatment-related mortality, means that
only 14% of newly diagnosed cases seen in the UK national
center have been considered for ASCT.
Immunomodulatory drugs

Thalidomide is most commonly combined with cyclophosphamide and dexamethasone.85,86 Of the patients, 33% have
been reported to have achieved a complete or very good
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RH Sayed et al.: Emerging treatments for amyloidosis

Table 3 | Current international criteria for monitoring hematological response

Response category


Complete response
Very good partial response
Partial response
No response

Normalization of FLC levels and ratio, negative serum and urine immunofixation
Reduction in the dFLC to o40 mg/l
450% reduction in the dFLC
o50% response in dFLC

Abbreviations: dFLC, difference between the involved FLC and the uninvolved FLC; FLC, free light chains.66

Table 4 | Current chemotherapy regimens for AL amyloidosis


Primary agent plus adjunctive





Thalidomide (with
and dexamethasone)

(second generation)

(with dexamethasone)

(third generation)

(with dexamethasone)

Alkylator and
purine analog
Proteasome inhibitor

(and dexamethasone)
Bortezomib (and
cyclophosphamide or with
dexamethasone and melphalan)

Main side effects


Hematological toxicity
Peripheral edema
GI side effects
Fluid retention
Fatigue and postural hypotension
Peripheral neuropathy
Increase in cardiac biomarkers
Skin rash
Skin rashes
Increase in cardiac biomarkers
Renal dysfunction
Fluid retention
Fatigue and postural hypotension
Peripheral neuropathy
Increase in cardiac biomarkers
Skin rash

Good choice for intermediate-risk and frail patients

without significant cardiac involvement. IV MDex too
toxic for routine use but used if poor GI absorption

Peripheral neuropathy
GI disturbance
Peripheral edema

Useful in disease refractory to alkylators and bortezomib.

Response is not achieved rapidly. Addition of
cyclophosphamide or melphalan has improved the CR
rate but two-thirds of patients develop side effects

Useful where disease is relapsed/refractory to

lenalidomide and thalidomide including cardiac patients

Useful for relapsed/refractory disease

Advised upfront in those with a poor prognosis
where a rapid response is required

Abbreviations: AL, immunoglobulin light chain amyloidosis; CR, complete response; GI, gastrointestinal; IV MDex, intravenous melphalan-dexamethasone.

partial response, after a median of 7 months, but 29% of

patients died and 50% of treated patients had to be
hospitalized for treatment toxicities, mainly fluid retention,
lethargy, infection, hypotension, and neuropathy.87
Lenalidomide has a hematological response rate ranging
from 41 to 47%, including relapsed and thalidomide
refractory cases. Doses higher than 15 mg are poorly tolerated
with side effects including cytopenias, fatigue, and fluid
retention. In a retrospective analysis from the Boston group,
66% of patients exposed to lenalidomide developed renal
dysfunction, which was reversible in 44% of cases.88
However, it was reasonably well tolerated in patients with
end-stage renal failure. There has also been an observed
increase in NT-proBNP and other cardiac biomarkers with
the use of immunomodulatory agents, and this has been
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correlated with mortality.89 Time to hematological response

is longer than that observed with bortezomib, but CRs have
been seen.90

This thalidomide analog was reported by Dispenzieri et al.91

to induce a 48% hematological response rate with 3% CRs in
33 heavily pretreated patients. The 1-year progression-free
survival and overall survival rates were 59% and 76%,
respectively. Of the 33 patients, 12 had renal involvement,
and 2 of these patients demonstrated organ improvement.91
Proteasome inhibitors

Bortezomib induces a rapid decrease in serum-free lightchain concentration in patients with myeloma.92 Purified


plasma cells from amyloid patients are twice as vulnerable to

bortezomib inhibition as those from myeloma patients.93
This is thought to be because amyloidogenic light chains have
a greater propensity to misfold, thus overloading the proteasome. Its efficacy in achieving both a high hematological
and organ response rate has led to it being adopted as a frontline therapy in AL amyloidosis,94 and it is being increasingly
used in those with severe cardiac involvement whose outlook
is extremely poor.95,96 Venner et al.97 reported a hematological response of 81.4% using biweekly bortezomib, cyclophosphamide, and dexamethasone, superseding that achieved
by other combinations including 71% with bortezomib/
dexamethasone,98 67% with bortezomib/ melphalan/dexamethasone,99 and 69% with bortezomib alone.100 Other
novel proteasome inhibitors currently undergoing trials
include ixazomib and carfilzomib.94,101

Although known treatments such as chemotherapy in AL

type and anti-inflammatory drugs in AA type can halt and/or
slow down the production of amyloid fibrils, these do not
work to promote the clearance of existing deposits that can
be a cause of considerable morbidity and, in some instances,
organ and patient death.

Using passive immunotherapy to produce a regulated immune

response against amyloid deposits is an attractive approach to
increase amyloid clearance. Such antibodies could be directed
against specific amyloid proteins such as immunoglobulin light
chains or SAA or against constituents that are common to all
types of amyloidosis such as serum amyloid P component (SAP).
Wall et al.102 have generated fibril-specific monoclonal
antibodies that have been shown to opsonize and promote
clearance of AL and AA amyloid in mice models. Building on
this work, a company called Prothena has been granted
orphan drug status for their monoclonal antibody NEOD001
that has been designed to specifically target AL amyloidosis.
A phase I clinical trial investigating safety and tolerability in
patients with systemic AL in 2013 is now open for recruitment in seven US centers ( Identifier:
CPHPC and anti-human SAP antibodies

SAP, a normal nonfibrillar plasma glycoprotein synthesized

by hepatocytes, is a constituent of all amyloid deposits and
can comprise up to 14% of the dry mass of amyloid. SAP
binding both physically stabilizes amyloid fibrils103 and protects
them from proteolysis and degradation by phagocytic cells.
R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC) is a competitive inhibitor of
SAP binding to amyloid fibrils. It consists of two D-proline
residues joined by a six-carbon aliphatic linker. The palindromic
structure of this drug crosslinks pairs of SAP molecules in the
plasma that triggers their complete clearance by the liver,
eventually gradually depleting SAP from the amyloid depos8

RH Sayed et al.: Emerging treatments for amyloidosis

its.104,105 It also rapidly depletes SAP from the CSF. Gillmore

et al.74 undertook a prospective study in 31 patients with
advanced systemic amyloidosis of AL, fibrinogen Aa-chain,
ATTR, Gelsolin, ApoA1, AA, and Ab2M types. The patients
received CPHPC by twice-daily subcutaneous injection, and six
subjects continued to receive CPHPC for another year. This
treatment produced a sustained and profound depletion of
circulating SAP in all cases, and in the two patients in whom
amyloidotic material became available for analysis there was also
substantial SAP depletion from the amyloid deposits. In four of
the five dialysis-independent patients with fibrinogen Aa-chain
proteinuria increased and renal survival was shorter in five of six
matched untreated historical controls. Among 13 patients with
advanced AL amyloidosis, organ function improved in 2 cases
and was stable in 7 cases. In two AL cases with refractory clones and a third case with a modest clonal response, organ
function deteriorated. The only adverse events attributable to CPHPC were transient minor local stinging at the
injection site for two patients. There were five expected deaths
associated with advanced amyloid cardiomyopathy.74
Administration of anti-human SAP antibodies to mice
with amyloid deposits containing human SAP triggers a
potent, complement-dependent, macrophage-derived giant
cell reaction that swiftly removes massive visceral amyloid
deposits without adverse effects. As short-term treatment
with CPHPC almost completely depletes SAP from the
circulation but not from amyloid deposits, passively
administered anti-SAP antibodies can specifically target
amyloid deposits. A study with amyloidotic human SAP
transgenic mice was undertaken comprising pretreatment
with CPHPC for 5 days followed by intraperitoneal injection
of either an IgG fraction of monospecific polyclonal sheep
anti-human SAP serum or a control sheep IgG or no
injection. The visceral amyloid load was scored histologically
28 days later. The amyloid deposits in mice treated with
CPHPC and anti-SAP antibodies were massively reduced
compared with those having received CPHPC alone or with
control antibodies. There was no disruption to the normal
structure of the affected viscera, and there were no clinical or
biochemical adverse effects. Histological analyses at 24 h after
anti-SAP antibody administration showed that all deposits
were densely infiltrated with mononuclear inflammatory cells
and some granulocytes. On day 2, macrophages fused to
form giant cells and demonstrated phagocytic endocytotic
activity. By day 16, amyloid clearance was largely complete.
This process depends critically on macrophage activity, and
ablation of macrophage activity using liposomal clodronate
resulted in no reduction in amyloid load.106
Currently, a phase I/II trial is in progress to evaluate the
effects and safety of co-administrating CPHPC with anti-SAP
antibodies ( Identifier: NCT01777243).
Fibril disruptors

Physical disruption of the structure of amyloid fibrils by

small intercalating molecules may sufficiently destabilize the
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RH Sayed et al.: Emerging treatments for amyloidosis

fibrils, hence increasing their degradation. Gianni et al.107 in

1995 made the serendipitous observation that the administration of the anticancer drug 4iodo-4deoxyrubicin
(I-DOX) to a patient with AL amyloidosis and multiple
myeloma was associated with a rapid and impressive clinical
improvement; this prompted further evaluation in eight
patients with refractory AL amyloid. There was clinical
improvement in five of the patients, and in two patients the
improvement was immediate. I-DOX induced amyloid
reabsorption in three patients with a measurable reduction
in the interventricular septal thickness, massive urinary
excretion of amyloid fragments, and substantial reduction
in a large amyloidoma and in splenic and hepatic deposits. A
further study by Merlini et al.108 found that I-DOX binds to
amyloid fibrils, irrespective of amyloid subtype, and it does
so in vitro and in vivo, possibly by inhibiting further growth
of the amyloid fibrils and by promoting amyloid reabsorption. It has been proposed that I-DOX disrupts the fibrillar
structure of the native fibrils, hence producing an intermediate structure that may be more readily available for
enzymatic degradation.109
The resemblance of the polycyclic conjugated structure of
the tetracyclines with a glycone moiety of iododoxorubicin,
believed responsible for the antiamyloidogenic effect, has
prompted further investigation into the less toxic tetracyclines. A phase II, open-label study is underway to investigate
the effects of 100 mg b.d. of p.o. doxycycline and 250 mg t.d.s.
of taurodesoxycholic acid in 20 patients with hereditary
TTR, wtTTR amyloidosis, and a domino recipient. Two
patients stopped treatment because of gastrointestinal side
effects. The study so far has demonstrated stabilization of
cardiac and neuropathic involvement in the remaining
patients, although final results are awaited.110

Currently, treatment options in amyloidosis rely on reducing

the supply of the precursor protein and thus depend
absolutely upon accurate typing of the amyloid. There is no
doubt that comprehensive disease staging and a tailored
individualized approach improve patient outcomes, but
treatment-related morbidity is a significant problem. This is
especially so in AL amyloidosis where advanced cardiac
disease is uniquely challenging. A further point in AL
amyloidosis is that the underlying clonal disorder may be or
become refractory, thereby requiring a number of lines of
therapy from a chemotherapeutic armamentarium.
Advances in the understanding of protein misfolding and
its pathogenic consequences have led to an unprecedented
number of novel treatment approaches. Stabilization of the
protein precursor by agents that bind and lock them into
their normal configuration such as Tafamadis and Diflunisal
have emerged as agents to slow down the deterioration in
TTR amyloid, a disease that previously could only be addressed
by liver transplantation. Even more radically, siRNA and
antisense oligonucleotides can target specific genes to
switch off amyloid protein production. Eprodisate, through
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interference with early mechanisms in fibril formation, has

shown promise in patients with renal AA amyloidosis. Once
mature fibrils have been deposited, physical disruption by
intercalating agents such as doxycycline may destabilize the
amyloid, and early clinical studies suggest this may in turn
stabilize organ function.
An exciting new development has been the emergence of
immunotherapies that have the unique potential to promote
clearance of amyloid deposits. Human studies, currently
being undertaken with both monoclonal anti-AL antibodies
and anti-SAP antibodies, hope to replicate the promising
results achieved in mouse models.
This review of potential therapeutic options demonstrates
how research in amyloidosis has embraced advances in
molecular biology and has entered an exciting era where basic
science has now been translated into human trials.

All the authors declared no competing interests.


We thank Janet Gilbertson for providing the histology images and

David Hutt for providing the SAP scintigraphy images.







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