Biocon's Eureka Moment

1. Biocon’s Eureka Moment
Vidya Krishnan, Bangalore, Sept 13, 2013
Mint
In early 2010, a 35-year-old woman suffering from psoriasis volunteered for clinical trials
of Alzumab, an antibody then under development by Bangalore-based Biocon Ltd to
treat the chronic skin condition.
Having spent 11 years trying various treatment regimens unsuccessfully, the patient
found to her surprise that the new drug produced results within eight weeks of starting
to use it, with a 97% recovery rate, measured against a score called the psoriasis area
severity index that’s compiled before the drug testing starts.

2. A further 28 weeks later, the patient, who didn’t want to be named, had hope of relief
and a better quality of life with use of Alzumab and Biocon realized it had struck a
potential jackpot.
Psoriasis is a lifelong, auto-immune disease, which occurs when the immune system
sends out faulty signals that speed up the growth cycle of skin cells. The disease is
caused by abnormal lymphocytes (a type of white blood cells) which result in
overproduction of new skin cells that merge together into plaques of thickened, scaling
skin. There is no known cure for the ailment at present.
Psoriasis can occur on any part of the body and is associated with other serious health
conditions, such as diabetes, heart disease and depression, according to the US National
Foundation of Psoriasis.
The disease affects 2-3% of the world’s population and 1-2% of Indian people, and the
global market for psoriasis therapies is estimated to cross $8 billion by 2016, according
to Biocon.
Lymphocytes are agents of the immune system that produce proteins called antibodies
to defend the human body when it is attacked by bacteria and viruses. Sometimes,
instead of protecting the body from infection or disease, the immune system attacks
and destroys the body’s healthy tissues. This is called auto-immunity.
The novel “mechanism of action” of Alzumab can be applied to a spectrum of auto-
immune diseases, basically changing the course of treatment of such ailments.
On 10 August, Biocon announced the launch in India of Alzumab for treatment of
psoriasis, saying it would come with a less aggressive dosing regimen and a longer
treatment-free period, promising a better quality of life to the patient. It claimed for the
drug an “excellent safety and efficacy profile with very low opportunistic infection rates
and longer remission period”.
At Rs.7,950 for a 24-week course, the drug will be 50% cheaper than similar drugs in the
market.

3. The biologic drug, which will soon be tested on patients with rheumatoid arthritis, can
be applied to over 100 different types of auto-immune diseases including Type 1
diabetes and multiple sclerosis. Biocon’s chairperson and managing director Kiran
Mazumdar-Shaw calls this molecule a “pipeline in a product”.
The beginnings
Alzumab may just be the breakthrough Biocon has been seeking for the past decade.
After decades of dabbling with enzymes and me-too drugs—which were low
investment, low risk and also delivered very few returns for the company—Biocon
started scouting for potential molecules in university laboratories that could be
developed into novel drugs.
Mazumdar-Shaw set up Biocon in 1978 when she was 25 years old and the
biotechnology industry had just started in India. She started the company in a rented
garage in Bangalore with a seed capital of Rs.10,000.
“The first 20 years of my career were about enzyme innovation. Over the past decade,
we have transformed our business from enzymes to biopharmaceuticals but the
fundamental of focusing on innovation has remained. Now we are focusing on drug
innovation,” she said in an interview on 23 August.
“When I started Biocon, even though we focused on enzymes, we ensured some level of
innovation went into the process. We developed novel application for enzymes. So,
from the very beginning, Biocon had an innovative business approach. For me, it is
about the business of science and not the other way,” she added.
In the hour-long interview, Mazumdar-Shaw spoke at length about the decade-long
process of innovation that led to this path-breaking Alzumab research. The word
“serendipity”—which means happy accident—was used often, both by Mazumdar-Shaw
and the scientists at Biocon who worked on the drug.
In early 2001, Mazumdar-Shaw travelled to Havana, on the northeastern coast of Cuba,
visiting university laboratories for possible drug candidates in early stage of
development. At the Centre of Molecular Immunology (CIM), she got interested in a
molecule which, at that time, was code named “Th1”.

4. “It was an anti-CD6 antibody and I was told by Cuban researchers that the molecule had
some potential in auto-immune diseases like RA (rheumatoid arthritis) and psoriasis,”
she said. The CD6 is a gene attached to lymphocytes that fights chronic infection.
Lasting effect
In diseases where the immune system has launched an attack on the body, the Th17
pathway only attacks the rogue cells and not the healthy cells, leading to longer
remission. Th17 pathway is a subset of a type of white blood cells discovered only in
2007 and is now understood to play a key role in auto-immune diseases.
When someone has psoriasis, for example, an antigen (bacteria, virus, parasite, etc.,) is
presented to a “T cell”. The principle function of the T cells (Th1, Th2, Th17) is to launch
a response against this antigen or foreign body attacking the immune system.
What ends up happening is that when the T cell is presented with this foreign threat, it
releases cytokines (molecules that act as messengers between cells). The cytokines kill
the infection using the Th1 pathway or Th17 pathway.
The drug not only works, its effect lasts.
“As we started developing this molecule, we realized that the Cubans had very little
understanding of the molecule. They were going down the “Th1” path so our initial
focus was along Cuban understanding. As we were developing the product, during
Phase 1 and 2 studies (for RA and psoriasis), we got good indicative results,” Mazumdar-
Shaw said.
“We decided on a Phase 3 study for psoriasis because it was the easiest and had visible
end points. When we looked at all things we were measuring, we realized that certain
results were unexpected. That was our serendipity moment,” she added.
The researchers soon realized that the molecule appeared to be treating cells that were
not even being monitored.
“We suddenly found that certain types of cytokines which were never even factored
were being regulated by this anti-CD6. We realised that this actually works in the Th17
pathway.”

5. Auto-immunity
When the immunity works flawlessly, these cytokines kill the antigen and go back to a
nascent stage until another threat is presented. But in auto-immune diseases, the body
launches a response against its own healthy cells.
“In auto-immune diseases, the cycle of attack does not stop and constantly the body is
attacking itself. Earlier, the Th17 pathway was not unknown. Now, the scientific
community knows that using the Th17 pathway, it can fix the immune system-stop the
body from attacking itself—instead of treating or mopping up symptoms that are
presented as the body constantly attacks itself,” said Abhijit Barve, head of research and
development at Biocon.
The Th17 pathway was discovered in 2007, but “clinical transformation” of this
discovery was yet to be elucidated.
Biocon’s Eureka moment coincided with a global movement in which the value of the
new science in auto-immune diseases was being crystallized. The new approach has
caused a shift in cell-mediated immunity with increasing evidence suggesting that it may
play an important role in the pathology of immune-mediated diseases.
Only, unlike other researchers across the world, Biocon had data coming from Phase 3
of psoriasis trials to support an otherwise heavily theoretical research.
According to experts, many companies are now looking to develop drugs using the Th17
pathway. “World over, a lot of work is being done to understand this pathway and its
role in auto-immune diseases,” said S.P. Byotra, head of the department of internal
medicine at New Delhi’s Sir Ganga Ram Hospital.
Unraveling the pathway
“This new science is fascinating and gives hope in treating diseases like cancers and even
HIV/AIDS if it is understood why the immune system acts the way it does,” Byotra said.
“Earlier, diseases like tuberculosis and plague were also considered untreatable mass
killers. the Th17 pathway will be crucial for over 200 auto-immune diseases so obviously
all companies are looking at ways to develop drugs along this method. The process will
be long-drawn but it could prevent a lot of diseases considered untreatable now,” he
said.

6. Unlike Alzumab, most drugs mop up nasty cytokines. Simply put, the older drugs
addressed symptoms of psoriasis such as dryness and red patches instead of tackling the
cause of the disease. Prior to Alzumab, patients were relapsing within 8-10 weeks.
“Suddenly, we were the most advanced players in their field,” added Barve. “This
pathway is still being unravelled. The disease quickly comes back with the older drugs
whereas our drug actually starts regulating the Th17 pathway and stops disease from
developing. This new pathway stops the nasty cells. Our drug basically fixes the problem
with the immune system and not cleaning up skin, hence the long remission.” he said.
As things stand now, Biocon is perhaps the only company in the world—certainly the
only company in Asia—to have clinical data to support work in this area. Following the
success in treatment of psoriasis, Biocon has already received approvals from the Drug
Controller General of India to conduct trials on rheumatoid arthritis. Animal model
studies on multiple sclerosis have shown promising results.
While the same “mechanism of action” could be applied to a spectrum of auto-immune
diseases, the combined market for therapies to treat psoriasis, rheumatoid arthritis and
multiple sclerosis is worth over $20 billion.
Biocon will have patent coverage for the technology till 2030. The company is currently
looking for partners to expand commercialization of the therapy around the globe.
“It will depend on who we partner with and how we choose to commercialize this. One
thing is certain—we have a blockbuster on our hands,” said Mazumdar-Shaw.