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Vol 20, No. 03, March 2016   |   Issue PDF view/purchase
Cennerv Pharma: A Company that Fights Along with Mental Illnesses
Cennerv Pharma (“Cennerv”) is a pharmaceutical development company started by Dr. Anil K. Ratty in year 2014, focusing on developing novel therapies for mental dysfunction in the ‘Big 5’ central nervous system disorders. Cennerv’s effective solutions improve quality of life for patients and restore their dignity. With a total market value of US$77 billion and growing, these diseases together represent the pharmaceutical industry’s second largest therapeutic category. Rising global urbanization coupled with increasing human longevity is creating an expanding incidence of mental illnesses.

Cennerv's 'Big 5' central nervous system disorders are:

  • Depression
  • Insomnia
  • Dementia (includes Alzheimer’s)
  • Schizophrenia
  • Autism

Dr. Anil K. Ratty (R) is the Chairman and CEO for Cennerv Pharma. He is a Singaporean with a Biochemistry Ph.D. from NUS. He spent part of this Ph.D. period in Nagasaki University, Japan. He has more than 25 years in R&D in neurosciences starting in the U.S.A. with Buffalo General Hospital and Roswell Park Cancer Institute. He returned to Singapore to work in IMCB (Institute of Molecular and Cell Biology), and DMRI (Defence Medical Research Institute, MINDEF). He shifted his career from research to commercial aspects as the Vice President of Fisher Scientific (SEA) to build a biotech business unit providing products and services to customers from India to China, including Australia. He set up a company called Chakra Biotech in 2001. The drug candidates being developed by Cennerv were derived from Chakra Biotech. He spun out Cerca Insights in Malaysia (a provider of animal behaviour phenotyping services) and this was sold to Psychogenics Inc., USA, in 2014.

Dr. Michael Entzeroth (E) is the Chief Scientific Officer/Chief Operating Officer for Cennerv Pharma. He joined the company in 2014. As a chemistry-trained scientist, he has more than 30 years of experience in drug discovery and development industry. He was involved in the development of Micardis, a blockbuster antihypertensive at Boehringer Ingelheim, Germany. He joined CEREP, France, in 1999 before becoming the CSO of a Singapore biotech company, S*BIO in 2003. In 2007, he joined A*STAR and built up the Experimental Therapeutics Center with Dr. David Lane, which is now managed by Dr Alex Matter, as a centre of excellence to advance and accelerate drug discovery in Singapore.

Dr. Ratty patented a mouse model for psychosis, which was the second patent for a transgenic mouse to be awarded in the United States in 1995. The transgenic mouse, called the chakragati mouse, exhibited several pathologies, including behavioural responses, which map to the psychosis conditions in humans. “These mice exhibited an abnormal circling phenotype when presented with environmental stress cues. This repetitive circling behaviour was coupled with hyperactivity. These mice were validated as a screening model for psychosis in a study with a number of antipsychotics being prescribed to patients. Besides the behavioural and pharmacological aspects, these mice also had anatomical patterns that mapped to schizophrenia in humans.” Said Dr. Ratty. “In fact, one of our drug candidates was identified through screening in this mouse model.” Dr. Ratty added.

“In Cennerv Pharma, we identify drug candidates that have shown efficacy in either human studies or in animal models of disease. This mitigates the risk of efficacy in development.” mentioned Dr. Entzeroth.

Why are you still looking for depression drug when there are so many depression drugs? Dr. Ratty said, “There is no one drug that works on all depression patients. About 30% of these patients do not respond to treatment after 2, and sometimes 3 different phases of drug administration. Cennerv’s drug candidate for the depression treatment has a unique mechanism of action and has the potential to make a difference to the patients suffering from this disease.”

Business Model of Cennerv Pharma

“Cennerv Pharma’s business strategy is to develop our drug candidates to be Phase 3-ready. Before any drug candidate can be tested on humans, it must have data showing its safety in animals. This is the pre-clinical development stage. With this data in hand, we will need to conduct safety studies in humans. This is termed as Phase 1 study and is conducted in adult volunteers. The next stage is Phase 2 where a small group of patients is involved. The final stage is Phase 3 that is conducted in a much larger cohort of patients after which a New Drug Application is made to market and sell the drug to patients. We are a small company. Our business model is to develop our candidates through Phase 2 and then license them out to bigger pharmaceutical companies. Licensing revenue comprises upfront, milestone and royalty payments.” Dr. Entzeroth explained.

Cennerv has 5 drug candidates in its pipeline. (Refer to Figure 1). The company is carrying out Phase 2 trials for its two most advanced compounds (CB2202 and CB2810) and completing the pre-clinical development for its earlier stage compounds (CB2233, CB8411 and CB0306).

“Cennerv Pharma has two drugs in Phase 2, i.e. the insomnia drug and anti-depression drug. The others need to complete pre-clinical toxicology studies. The clinical trials will take about 2-3 years while the preclinical studies will take 1-2 years,” explained Dr. Entzeroth.

Cennerv’s CB2810 is a repurposed drug candidate. It has been used in Japan for more than 25 years as an anti-depressant, and after generating some animal data, it is re-purposed for insomnia by Cennerv. There is also some old human data indicating the effect of CB2810 on human sleep architecture. The other drug candidates in Cennerv’s pipeline are new chemical entities (NCEs) and have patents around them.

In short, Cennerv’s development strategy is to leverage through collaborations and/or partnerships with the diverse specialty contract research providers in the region and beyond to move its pipeline along the development pathway and to provide the best return of investment for the shareholders and more importantly provide safe and effective medicines to patients suffering from mental illnesses.

Which of the “Big 5” central nervous system disorders is the most serious disease?

R: All central nervous system disorders are serious. Mental illness is the leading cause of disability in the world, higher than cancer or heart disease. The economic healthcare burden of these diseases is huge. And at the centre of this burden are the care-givers, who have to bear the huge economic and emotional costs. We are living longer because of the many advances in medical science. However, we must also have a good quality of life, a life without disabilities to bog us down. Suffering from dementia or depression or schizophrenia is not conducive to a good quality of life. Children suffering from ADHD or autism present a huge emotional burden to parents. Cennerv is working hard to help patients suffering from any of these “Big 5” illnesses.

E: I think one of the most important points during the early onset of mental disease is the support from family. The family has to understand the patient, support and tolerate them. Then it is important that the family encourages the patient to talk to a psychiatrist and get the right treatment and/or medication.

What are some of the challenges you faced in the journey of drug development?

R: Capital. Drug development is a high capital investment. However, the returns are disproportionately immense. Convincing the local investment community that development is a value creation exercise is the greatest challenge. On top of that we have to convince the investors, who realize that such medicines are required, of the financial risk. Our challenge is then to mitigate the development risk and enhance the chances of financial success. In other words, convince the investors that besides helping fellow humans by alleviating their suffering, they can also make some money.

Phases of Pre-Clinical & Clinical Development

During the interview, Dr. Entzeroth also shared with us the phases of bringing drug to the market. “The research phase is where you do everything to explain the mechanism of molecules and their mode of actions. Then comes the pre-clinical development, during which you get your drug candidate ready for the clinics. This means that you need to show your drug is safe to be given to a human being following guidelines set up by the regulatory authorities.

If you have all the documentation showing that your drug is safe and shows biological activity, it is now time for an Investigational of New Drug Filing (IND). In the subsequent Phase 1 clinical trial is where you give the drug for the first time to a human being. Normally phase 1 trials are performed in healthy adult volunteers; you don’t give a drug that you don’t know how it works yet to a sick person, because his condition might be worsened. Once you have established the safety window of the drug, you look at its effect on the patients in a Phase 2 clinical trial. Here you are looking at: Do my drugs help the patients? If yes, wonderful; you have reached the second level of clinical success. Phase 3 clinical trials are more complicated, as there are multicenter studies to examine the drug effect in a larger population and a wider medical background. If all the filed data are accepted, then we speak of the approval of new drug application (NDA), which is after the end of Phase 3 trials. You will obtain market approval and might now sell the drug. The pharmaceutical industry is the most regulated industry. In every country nowadays, whatever you put into your mouth in the form of drugs is regulated by the Health Authorities.”

From your point of view as a drug developer, how do you minimise side effects while increasing the drug efficacy?

E: Firstly, in principle, you have to know the mechanism and how the drug works. With the knowledge of the mechanism, you are able to optimize potency, selectivity and the duration of the drug to be present in the organism. The most important part comes, to selecting the right candidate. All our candidates have shown efficacy in man or a relevant animal model. With respect to side effects, you require thorough testing.Even though you have gone through Phase 3, you will not be able to completely predict all the side effects of the drug. Despite that you may have tested the drug on probably 2000-3000 patients in Phase 3, you will give the drug to hundreds of thousands or millions of patients with different background when it goes to the market. You might not see problems that only have a probability of less than one in ten thousand to show up in a Phase 3 trial. This is why, after the marketing of the drug, there is the post-marketing monitoring, where the doctors in the field report back to the company and to the health authorities if any kind of unexpected side effects appear. That is a very difficult phase. Companies need to take proper actions and not be guided by money-related issues. If the company acts on ethical grounds, then it should have follow-ups for each aspect, and if needed, the drug must be taken out from the market even though it has been a multi-million dollar investment. In general, the occurrence of side effects seen with registered drugs is rather low and not frequent. What we have to make sure is that we push forward our drug candidates only after having scientifically confirmed that they are safe. We will not go out to the patients if we see any adverse effect during any phase of clinical development. Ethics is one of the biggest aspects in drug development.

R: We need safer and effective drugs that meet the unmet critical needs of patients. Cennerv’s pipeline tries to meet those criteria. We identified our drugs from previous data associated with the chemical entities. These have shown efficacy in humans or animal models of disease. For those that had clinical data, they must have shown good safety profiles. It is a lot of work to get to this point.

It is tough to address unmet needs in mental disorder problems. What inspires you to tap into this niche market?

R: I like the brain… and the brain is the most complex organ of the human body…the final frontier. In the 1990s, US, Europe and Japan declared it as the Decade of the Brain. A lot of knowledge on the brain stems from that decade. The brain is a fascinating organ. It governs so many systems in the human being. It is even the seat of the mind. It ultimately governs our behaviour as well.

E: There is part of the Big Brain Project ongoing in Switzerland, sponsored by ETH and the government, trying to monitor by computer how the brain works. It has been ongoing for close to 10 years but they have not come to a point where they can explain the complexity of the human brain yet. In the meantime, we have to be looking at what we can do to help people with mental disorders. About 30-50% of depression people have resistance and don’t respond to any of the medicines they are receiving, which we called treatment-resistant depression (TRD). Our drugs have novel mechanisms of action. Specifically with respect to our depression drug candidate, similar drugs were non-selective, therefore had a lot of side effects, and some of them irreversibly bound to the target enzyme. We now have products in our development, which soon will go into Phase 2 clinical studies, moving to proof-of-concept to human beings. We will prove the drug works in patients and, as it has completely different mechanism compared to the current ones, we think we have certain gauge filling an unmet medical need. With a different mechanism of action, we think the drug has the opportunity to help the patients who have failed to respond to other drug medications. For our new antidepressant, we are now conceiving a Phase 2 trial. We have finished the synopsis of the Phase 2 trial and by next year we will send in the final protocol and all the data needed for approval to move the drug forward.

Personal Drive and Passion in Neuroscience Industry

“When I was a student at Columbia University, I had to work in the lab each part of my time, even during my vacation. Then one day I found myself developing new molecules, but I wasn’t sure what this molecule was good for.” Therefore he decided to dropout from organic into biochemistry in his last special academia, in order to see what his molecules might be able to do. He was interested in what he was pursuing and knew that he wanted to go into the pharmaceutical industry. "When you watch movies on people's disability, you feel that you can do something about it. If you can do something about it, why don't you do it? That's actually what we are up to. We want to change things for the betterment of the patients. - (Dr. Entzeroth)

In contrast, Dr. Ratty never considered commercializing science. He enjoyed uncovering the mysteries or nature through his research, humbled by the great unknown in Nature. Over time, he began to develop an interest in how all this scientific knowledge can be applied. He became more enamoured with the prospect of doing science that could reach out to people. In other words, science that becomes technology and is brought to help people through commercial practice.

This interview was conducted by
Carmen Loh Jia Wen & Clarrie Ng Si Qian on 16th Dec. 2015.

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