Transcript Therapeutics for Respiratory viruses

Therapeutics for Respiratory
viruses
Yasir Waheed, PhD
• Respiratory virus infections occur commonly and are
responsible for a great deal of morbidity worldwide.
• In the developed world respiratory viruses are responsible
for a considerable amount of morbidity which has a
significant economic impact. Mortality rates however are
low.
• In contrast, in developing countries, these viruses are
responsible for approximately 20 to 30% of respiratory
deaths in children.
• The spectrum of disease ranges from upper respiratory
tract infections such as common colds to infections of the
lower respiratory tract manifesting as bronchiolitis or
pneumonia.
Adenoviruses
• Adenovirus infections in humans were originally
associated with respiratory disease, however it was
recognized that they could also be responsible for
gastrointestinal and eye infections.
• Adenoviruses not only account for a significant
proportion of viral respiratory infections in the general
population, but they are also an important cause of
morbidity and mortality in patients who are
immunocompromised, particularly children, neonates
and those undergoing bone marrow transplantation.
• Upper respiratory tract infections (URIs) generally
resolve within one week and antiviral therapy is not
required. Adenovirus pneumonia can be sufficiently
severe, with possible long-term health risks.
• Patients are treated with either ribavirin or cidofovir.
• Cidofovir has shown benefit in several settings.
Cidofovir has delayed onset of adenovirus disease in an
animal model setting, but could not fully suppress viral
replication.
• There are several reports of successful cidofovir
therapy for adenovirus infections of BMT or HSCT
patients.
Respiratory Syncytial Virus (RSV)
Respiratory Syncytial Virus (RSV)
• Respiratory syncytial virus (RSV) is a common cold agent
and the chief worldwide viral cause of moderate-to-severe
acute upper and lower respiratory tract illness in infancy.
• Almost all children are infected by 3 years of age, most
suffering only mild symptoms with rhinorrhea, cough and
fever.
• However, 25 – 40% of children develop lower respiratory
signs. In temperate regions, indicative of a viral
bronchiolitis or pneumonia ~1 in 40 infants is hospitalised
because of RSV infection.
• In the US, in 2000, it was estimated that there were
~86,000 RSV-related hospitalizations in a year, ~98% of
which occurred in children < 5 years old.
• In elderly persons, RSV causes pneumonia and
exacerbations
of
chronic
obstructive
pulmonary disease (COPD).
• In the US, there are an estimated 14,000–
60,000 RSV-related hospitalizations and 1,500
– 7,000 deaths in people >65 years owing to
RSV infection each year.
Fusion inhibitors
• BMS-433771 inhibits the entry of the virus into cells
through direct interaction with the F protein. It works
by disruption of the conformation within the fusion
hairpin structure, which is absolutely critical for the
fusion. In vitro, BMS-433771 inhibited both RSV-A and B replication, and had an ED50 of 20 nM.
• RFI-641 is a specific inhibitor of RSV fusion. It both
blocks viral fusion to the cell membrane and prevents
syncytium formation by binding to protein F.
• In murine models of RSV infection, RFI-641
administered nasally 2 h before infection reduced viral
titers in the lung by 0.63 – 1.53 log.
• JNJ-2408068 is a benzimidazole derivative and has a very potent
anti-RSV activity. It inhibits both virus–cell fusion and cell–cell
fusion of human RSV-A and -B as well as bovine RSV but it does not
work against other Paramyxoviridae.
• In vitro cytotoxicity and antiviral effects are seen in the cotton rats,
where selective anti-viral activity is evident. Significant drug levels
occur in the lung and a concentration of 10 nM reduces RSV load
1,000-fold. Outside the lung, only low levels of JNJ-2408068 are
found.
• TMC353121, the new morpholinopropylaminobenzimidazole
derivative of JNJ-2408068, has recently been synthesised as a result
of molecular modelling in a lead optimisation program. TMC353121
is under active preclinical evaluation by Tibotec.
Attachment inhibitor
• MBX-300 (Microbiotix, US) is the compound
that targets the viral attachment protein.
• It underwent in vivo efficacy studies and
toxicology trials including testing in monkeys
and showed anti-RSV activity and a good
safety profile.
IMPDH inhibitors
• EICAR is a nucleoside analogue with anti-viral
properties.
• In vitro, it inhibits replication of paramyxoviruses
(parainfluenza, mumps, measles and RSV) and
orthomyxovirus (influenza) with EC50s of 0.06 –
2.3 μg/ml.
• In HeLa, Vero, MDCK and LLCMK2 cells, even
doses of 200 μg/ml are non-cytotoxic. In
replicating cells, 5.6 – 12 μg/ml inhibits growth. It
works by inhibiting IMPDH, leading to depletion
of intracellular GTP.
IMPDH: Inosine monophosphate dehydrogenase
Antisense anti-RSV agents: ALNRSV01
• There have been several recent reports
describing a number of antiviral siRNAs tested in
vitro and in vivo.
• ALN-RSV01 (Alnylam Pharmaceuticals) is the first
siRNA targeting a microbial pathogen tested in
humans and the first siRNA administered to the
human respiratory tract.
• ALN-RSV01 is designed to inhibit the replication
of RSV by interrupting the synthesis of the viral
nucleocapsid protein (N-protein).
• Studies in mice showed that ALN-RSV01 (2 mg/kg, single dose)
protected against subsequent RSV infection, and could also be used
to treat an existing RSV infection, thereby decreasing viral load >
10,000-fold.
• The results of the first two placebo-controlled healthy volunteer
studies demonstrated the drug is safe over a wide range after nasal
delivery.
• Phase II trials with an inhaled nebuliser formulation are continuing.
These studies may provide validation of the general strategy of
siRNA delivery to the respiratory tract.
• Antisense strategies, therefore, show great promise, but may
require further improvement before they can be used clinically.
Reduced cost, increased in vivo stability, increased expression levels
and delivery to relevant cell populations may all represent
significant hurdles for the development of this technology.
N protein inhibitors: RSV-604
• RSV-604 is an oral benzodiazepine under development
by Novartis.
• Found by screening libraries of small molecules, it
inhibits viral replication and the inhibitory activity is in
the submicromolar range for both RSV-A and RSV-B.
• Promising preclinical data have enabled the study of
the drug in Phase I trials, where volunteers have been
exposed to increasing quantities of it.
• These studies showed that the drug was well absorbed
in humans, and that one dose a day was sufficient to
achieve antiviral EC90 levels.
Rhinoviruses
• Most cold and flu–like illnesses are caused by
human rhinoviruses (HRVs). HRV has also been
associated with more serious illness, such as
exacerbation of asthma, wheezing illnesses in
children, and chronic obstructive pulmonary
disease (COPD).
• HRV is a major cause of acute viral respiratory
tract infections in hospitalized children and is
among the leading causes of childhood mortality.
• Many potentially promising antiviral compounds have been
investigated in healthy adults with self-limited rhinovirus
URIs, but so far none have met the requirement of a low
risk –to-benefit ratio.
• The candidate drugs include interferon, capsid binding
agents (pleconaril and pirodavir), protease inhibitors
(Rupintrivir), and receptor blockade (soluble ICAM-1).
• Interferon
has
received
extensive
evaluation.
Unfortunately, treatment trials have been disappointing.
When intranasal IFN is started after rhinovirus challenge or
after the first cold symptoms, it has only a modest effect on
symptoms in spite of a reduction in viral titer.
• Another treatment approach is to combine intranasal
interferon (commercially available IFN-a2b), intranasal
ipratropium, and oral naproxen.
• Four days of treatment with this combination reduced
viral load as well as symptoms in volunteers with
induced rhinovirus URIs.
• Treatment of natural colds with intranasal IFN-a2b plus
oral chlorpheniramine and ibuprofen for 4.5 days
significantly reduced the total symptoms but only the
viral titer on Day 3 during rhinovirus infection when
compared with the placebo group.
Ipratropium used to prevent shortness of breath, coughing and chest tightness.
Naproxen used to treat pain or inflamation.
Hlorpheniramine is a cough, cold and allergy drug.
• Oral pleconaril has been another promising drug for treatment of
rhinovirus infection. Oral pleconaril significantly reduced the time
to a 50% reduction in total symptoms when treatment was initiated
within 36 hours of the first symptom. Unfortunately, during a
prevention study with long-term use of pleconaril for 6 weeks, it
was discovered that pleconaril induced cytochrome P-450 3A
enzyme, which metabolizes a variety of drugs.
• There is a great need for the development of antiviral treatment
medications for rhinovirus URIs in children with serial rhinovirus
infections, in the elderly with more severe symptomatology to
rhinovirus URIs, and in patients with frequent involvement of ears,
sinuses, or lower airways.
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