The AstraZeneca R&D centre was focussed on tuberculosis, and had a $1 million grant from Wellcome Trust to look at what combination of drugs works best against TB. Although Astra-Zeneca closed down its antibiotics programmes, the ideas they developed in this project emboldened them to start Bugworks, which moved on from TB drugs to tackling infections at a broader level. “I realised that hospital infections are going to get more and more serious,” says Bugworks CEO Anand Anandkumar.
Anandkumar was the founder of another firm called Cellworks, which was the primary partner in the Wellcome Trust programme. Bugworks quickly evolved a platform, from which it developed few possible drug candidates to tackle bacteria that are resistant to a large number of drugs. By April, Bugworks may begin toxicity trials with one of these drug molecules. “It is a fresh approach,” says Anandkumar. “It does not guarantee success, but it guarantees a new look at a serious problem.”
Checking the Vulnerabilty
Around the country, a clutch of startups are finding new ways of tackling antibiotic resistance, a problem that most big companies have given up on. These startups also provide some hope of solving a problem, even if a decade from now, that health experts regard to have assumed serious proportions already.
Bacteria are quickly acquiring resistance to every antibiotic human beings can throw at them. As the death of an American woman who died in September 2016 and hit the headlines last week showed, hospital infections can be fatal no matter what antibiotic we use.
The American woman, who picked up the infection in Delhi, was treated with 26 different antibiotics. But few patients have this luxury in India or elsewhere. “For the vulnerable population,” says Ramanan Laxminarayan, distinguished professor at the Public Health Foundation of India, “it does not matter whether bacteria are resistant to 26 antibiotics. Resistance to just three antibiotics is enough to cause death.” The vulnerable population include the new-born and the old.
Public health experts agree that regulating the use of antibiotics is the first step towards tackling antibiotic resistance. As policy-makers wrestle with regulation, some startups have begun the next step: discovering new antibiotics against drug-resistant bacteria.
Since drug resistance is the main problem, four of these startups — Bugworks and Gangagen in Bengaluru, Vitas Pharma in Hyderabad and Vyome Biosciences in New Delhi — are specifically targeting drug-resistant bacteria.
Drug discovery companies have formidable scientific and business challenges. In India, they have additional challenges to overcome: an unimaginative regulator, lack of funding, and stillmeagre scientific resources. Good ideas get funded at the project level by the government, but it becomes harder and harder as the project increases in sophistication. Barriers become very high once a drug candidate is getting ready to go to clinical trials.
Vitas Pharma, set up in the year 2011, got a `50-lakh Biotech Ignition Grant from the Department of Biotechnology. It got another grant — amount undisclosed – from the Wellcome Trust, and `3 crore from the Indian Angel Network. The company has eight people, two molecules as lead candidates for development, and another molecule at a very early stage, usually called a hit. If everything goes well, Vitas Pharma could get a product to market in five to seven years. If things don’t go well, as is the case in most drug discovery programmes, it could take much longer.
The company’s molecules are supposedly completely novel, and work against the dreaded gram negative bacteria. Bacteria are classified into gram negative and gram positive according to how they stain in a particular method developed by a scientist called Christian Gram. Gram negative bacteria do not retain their stain colour for long. They have an outer membrane that can ward off several chemicals. “It is hard to penetrate this membrane,” says Radha Rangarajan.
In lab studies, Vitas Pharma had found that its candidates kill bacteria resistant to carbapenem, the most powerful antibiotic currently available. The mutation rates are supposedly low, which means that it is difficult for bacteria to acquire resistance. “The compound does more than drugs in the market,” says Rangarajan, “as it overcomes resistance to last line antibiotics.”
Need for Investments
The safety margin also looks good in the lab, but taking two molecules from the lab to market needs money. Even with its lean operation, Vitas Pharma would need about $5 million to take two molecules through toxicology and Phase I clinical trials. How many investors will put in $5 million in a startup developing antimicrobials? And then a few hundred million dollars to take a molecule to market?
Antibiotics are not an attractive market for a pharmaceutical company. Unlike drugs for heart disease or other metabolic diseases, antibiotics are used only for a short time. Unlike anti-cancer drugs, they are generally not priced very high. New antibiotics will not be used widely, as they are a back-up when other antibiotics fail. All these mean that a company cannot get its R&D money back for a long time. Sometimes it could take a few decades for it break even on an antibiotic. If unlucky, it could take a decade or two just to get a product in the market.
Gangagen Biotechnologies has been in existence for 14 years. After 14 years and around $25 million investments, it has one product — a topical application — in Phase II trials and another approaching Phase I trials. It needs to get more investment later this year to continue, a particularly hard task as $25 million has already been invested from multiple investors.
Gangagen is an unusual company, as it is working on an unusual method that has rarely been tried. It started life as a phage therapy company, by developing viruses — called phages — that attack bacteria. It then turned out that the regulators were not prepared for this approach, as very little was understood about how phages would behave in the body. Gangagen then turned to a type of protein called lysin found on the surface of phages, which they use to break into the bacterial cell wall. The company is developing a protein for intravenous use against a deadly class of bacteria called staph. Being in India, money and expertise are hard to find.
Gangagen has one competitor: Contra-Fect Corporation in New York. ContraFect was set up in 2008, but has raised $90 million so far, including a $35 million IPO. It has a lysin molecule, called CF-301, about to enter Phase II clinical trials. It is the first lysin to enter clinical trials. ContraFect has got ahead very quickly, but all is not lost for Gangagen. “From published literature,” says Gangagen CEO TS Balganesh, “we also know the weakness of CF-301.” Balganesh was the head of R&D at AstraZeneca.
Gangagen needs to survive long enough for some of its products to generate revenue. Its original mandate, using phages for killing bacteria, is still not a dead concept. “I am certain phage therapy will come one day,” says Balganesh. But breaking the attitudes of regulators needs protracted effort. Even for conventional drug companies, it is hard these days to get past the US Federal Drug Administration (FDA).
Regulations may not be a serious barrier for Vyome Biosciences, although it is attacking a problem that is no less difficult in scientific terms. Set up in 2011 to develop fungus infections in the scalp, Vyome has now morphed into a company that is developing drugs for drug-resistant skin infections. It has raised $25 million so far. Its first product, for drug-resistant acne, is now in Phase I trials. “We are looking at designing molecules in such a way,” says CEO Venkateswarly Nelabhotla, “that bacteria do not develop resistance.
All new generation antimicrobial companies have this aim, but they use different strategies. Bugworks, for instance, claims to have an Intellectual Property (IP) Platform that lets it design drugs for a large number of bacteria. One of its strategies is to persuade drugs to evade a mechanism — the efflux pump — that lets bacteria throw out invader molecules from inside the cell. “Our central paradigm is to become invisible to the efflux pump,” says V Balasubramanian, president of Bugworks R&D.
In the near future, if these startups end up with a commercial molecule, they will face a challenge that has kept all big companies away from antibiotics. Antibiotics are priced relatively low. The products they develop are likely to be used as a last resort, which reduces their usage. Can the companies price the drugs high, tens of thousands of dollars per course? The price would be lower in India, but still high enough to be outside the reach of the majority. Pharma industry leaders think that high prices are justified, as the costs of prolonged hospitalisation are even higher. Will the Indian society and politicians accept such high prices?