[Ip-health] The Economist: "Repurposing" off-patent drugs offers big hopes of new treatments

Thiru Balasubramaniam thiru at keionline.org
Mon Mar 4 05:23:09 PST 2019


Cross purposes
“Repurposing” off-patent drugs offers big hopes of new treatments
But governments need to give companies incentives to invest in them

Feb 28th 2019

Towards the end of 2014 a 66-year-old British man named Alistair had a
seizure. A scan revealed shocking news. He had an inoperable brain tumour—a
glioblastoma—that was likely to kill him in a few years. Soon afterwards,
he read a newspaper article suggesting that a cocktail of cheap, everyday
drugs, chosen for their anti-cancer effects, had helped a patient with the
same disease. His doctors were unimpressed but said: “We can’t stop you.”

Four years on Alistair is still taking this drug regimen alongside the
“standard-of-care” treatment. The drug cocktail is prescribed by Care
Oncology, a private clinic in London, which recommends a statin (a
cholesterol-lowering drug), metformin (used to treat type-2 diabetes),
doxycycline (an antibiotic) and mebendazole (an anti-worming agent). These
may sound radical, but are actually safe, cheap, generic medicines with
evidence of some anti-cancer effects. Nonetheless, their labels do not say
they treat glioblastoma—nor any other cancer for that matter.

This lack of clinical interest is not unusual. There is a huge untapped
medicine chest of generic drugs with unexploited uses. Originally approved
for one disease, these drugs went off-patent and now show promise in other
diseases. Thalidomide, a morning-sickness drug forever linked with scandal
and disaster, found new uses in leprosy and a blood cancer. An acne
medicine is now part of an effective treatment for a form of leukaemia.
Viagra, famously, came from failed work in angina.

The scale of the opportunity for “drug repurposing” is vast. Bruce Bloom,
boss of Cures Within Reach, an American repurposing charity, says 9,000
generic drugs have been approved. Pan Pantziarka, of the Anticancer Fund,
another charity, says his group has found evidence in almost 260 non-cancer
drugs of anti-cancer activity. Most have lost patent protection. The
science that has piqued interest in these drugs comes from pre-clinical lab
work in animals, case reports, small clinical trials and large-scale
observational studies.

Increasingly, large-scale screening studies are plucking options from
oblivion. After screening thousands of approved drugs, the National
Institutes of Health (NIH), an American research agency, identified 25
molecules that might fight drug-resistant bacteria, half of which are
already approved drugs. The California Institute for Biomedical Research in
San Diego has a library of 12,000 drug compounds it is testing against
disease-causing pathogens. Two drugs are in trials as a result: an
anti-rheumatic treatment called auranofin for tuberculosis; and
clofazimine, a leprosy drug, to treat the parasite Cryptosporidium.

Drugs like these—off-patent, cheap and already approved—are relatively
quick to develop to treat new diseases. New molecular entities can cost
hundreds of millions of dollars to test, and safety and toxicity problems
mean that 45% of drugs fail clinical trials. Repurposed drugs, with
well-established safety profiles, can save about five to seven years in
development time. Approval rates are higher, and some think overall costs
are 60% of those of new drugs.

Multiple choice

Interest in drug repurposing has been rising, particularly for medicines
that could treat neglected diseases in poor countries, and rare diseases,
cancer and mental health. A recent study in JAMA Psychiatry said that
statins, metformin and blood-pressure drugs had potential for treating
mental illnesses such as schizophrenia and bipolar disorder. Minocycline,
an antibiotic, is already being tested as a treatment for autism. Ammar
Al-Chalabi, a neurologist at Kings College, London, wants to repurpose
Triumeq, an hiv drug, to fight motor neurone disease.

There is a problem, however. Katherine Arline of Shepherd Therapeutics, a
biotech firm that works in rare cancers, says that, because the costs are
high and may not be recouped, firms have little incentive to run clinical
trials on generic drugs. Once the costs of testing and registering have
been paid, the lack of patent protection means that any firm can make the
drug. Some describe generics as “financial orphans”.

One approach is to change the generic drug to create something patentable.
This is how the American drug firm, Johnson & Johnson (J&J), approached
ketamine, an anaesthetic with a stack of evidence to support its use in
treatment-resistant depression. J&J tweaked the molecule to create a
variant that could also be inhaled. Reformulation is costly and risks
reducing the efficacy of the drug. But J&J seems likely to receive approval
from the Food and Drug Administration, the FDA.

For years, like many off-label medicines, ketamine has been a valuable but
hard-to-obtain therapy. This has driven the growth of ketamine clinics in
America and Europe. In Britain Oxford Health, a unit within the National
Health Service (NHS), will provide it. But the NHS as a whole does not
cover it because it is not approved for this use, so patients must pay £795
($1,058) for three infusions; J&J’s esketamine is likely to be far more

Several issues dog reusing generic medicines in new indications. Mr Bloom
says that, in his experience, between one-third and a half of patients are
loth to use drugs outside the current standard of care—even if they have a
disease they know is going to kill them. And even if doctors might be
willing in principle to prescribe an off-label drug, many feel unable to do
so because of worries about their legal liability should something go
wrong. Or there may be disputes over whether public health services or
insurers will pay for drugs that have not been approved for that disease.

Nonetheless, many non-profit groups see promise in supporting trials into
drug repurposing. Epidemiological data can offer enticing leads. An
insurance database in Taiwan shows a 76% reduction in the risk of
tuberculosis among diabetic patients on metformin, and progressively larger
protective effects with higher cumulative doses. However, Udai Banerji, a
researcher at the Institute of Cancer Research in London, warns that
randomised clinical trials are necessary to prove definitively the value of
a drug to treat a new disease.

Trials are costly, but the benefits can be huge. The Drugs for Neglected
Diseases Initiative, a Swiss non-profit research group, supported R&R into
fexinidazole, which was abandoned by a pharma firm at an early stage but
was then found to show anti-parasitic qualities. This January, after years
of work, it was approved for sleeping sickness in the Democratic Republic
of Congo. It is the first oral medicine for the disease, and works for all
stages of it.

When it comes to cancer, some of the most promising generic pills are
already well-known. Cancer Research UK, a charity, is testing aspirin to
see if it can stop cancer recurring; metformin in a large prostate-cancer
trial; and an anti-fungal medication to treat bowel cancer. The Anticancer
Fund in Brussels has high hopes for propranolol in treating
angiosarcoma—cancers of the inner lining of blood vessels—and for
pancreatic cancer. Propranolol is a generic 1960s beta-blocker used for a
wide range of ailments such as hypertension, anxiety and migraine. If
approved for cancer, its price would be negligible compared with the tens
of thousands of dollars a month normally charged for cancer medicines. Mr
Banerji estimates that one cancer drug in five that goes off-patent is
likely to have uses in treating other cancers. It is “almost free money”,
he says.

The Anticancer Fund believes that the path to wider uptake of repurposed
drugs is through approval and relabelling by drug regulators for new
treatments. Although difficult and expensive, Mr Pantziarka says it
unleashes a cascade of important events. When a regulator licenses a drug,
clinical guidelines are updated, drug formularies are changed,
reimbursement should follow more smoothly and clinicians gain experience
using it. In America Mr Bloom agrees that relabelling will encourage the
usage of repurposed drugs.

Money, though, is a crucial constraint. Even governments keen to pump cash
into drug development prioritise drugs with patents. Mr Pantziarka says
many official funding schemes, such as the EU’s Horizon 2020 programme,
want projects that hold intellectual property. In America the National
Centre for Advancing Translational Sciences will support research to help
drug companies repurpose molecules for which they hold patents.

Finance is not the only obstacle. Only the makers or original developers of
a drug are permitted to adjust its label. Sanofi, based in Paris, was the
firm that requested regulatory review of fexinidazole for sleeping
sickness—although the r&d was a charitable effort. But drug firms are not
obliged to support non-commercial efforts to repurpose drugs. And outside
the industry it is hard to find the legal expertise to manage the necessary

Some of these concerns are under review by an expert group on repurposing
within the European Commission. It is looking at how regulatory changes, as
well as legal and financial support, could support repurposing by third
parties such as charities and foundations. The Anticancer Fund wants the
regulator to be able to evaluate evidence on drugs that has been submitted
by third parties such as itself.

As non-profits make headway in repurposing, corporate interest may be
rising. Mr Bloom says that ten years ago not a single pharma company would
have anything to do with his charity. Today he receives calls from at least
two or three small- to mid-sized firms every month saying they are
interested. In terms of achieving new treatment options, this is good news.
But it will not bring cheaper medicines in areas traditionally neglected by
the drug industry. Firms will focus on finding ways to patent the new
uses—through reformulation or new combinations of substances—and charge
high prices for the finished product.

If governments want cheaper drugs, non-profits will need financial
incentives and a helpful regulatory framework. Would-be repurposers have
come up with some suggestions. They include making regulators give free
advice and waive approval fees, and a public fund to support repurposing.
Another idea is a “social-impact bond”—backed by private investors funding
a range of drug trials for diseases that cost public-health services a lot
of money to treat. When drugs are approved, investors are paid back by the
public health service, which makes savings by using the newly approved
generic drugs.

Patiently waiting

The slow pace of change leaves patients like Alistair stranded. Care
Oncology says it will publish results from its glioblastoma patients this
spring. Though welcome, this will fall short of the gold-standard trial
evidence needed to register a drug. The treatment will be left in limbo.
And patients will be left to wonder why governments fail to see the purpose
of repurposing drugs.

This article appeared in the International section of the print edition
under the headline "A higher purpose"

Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org

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