Pretomanid is promising, especially since, unlike the last two drugs—Bedaquiline and Delamanid—it is developed by the non-profit TB Alliance rather than a traditional pharma company. As The Ken has reported earlier, pharma companies prefer to control supply. TB Alliance, meanwhile, is all about access. US-based Mylan N.V. will bring Pretomanid to India after November 2020. While this is reason enough to hope that the drug will be available to those in need, the story is not the same for the second breakthrough that also came about in August.
On 8 August, six-year-old Bengaluru-based genomics company MedGenome announced it had developed India’s first Whole Genome Sequencing (WGS)-based test. Called ‘SPIT SEQ’, it provides a detailed analysis of every single mutation present in tuberculosis bacteria directly from a phlegm sample. Sequencing of the bacteria’s DNA can show the entire resistance profile of the patient, allowing doctors to determine every drug they are resistant to in one go.
SPIT SEQ is a marked improvement from the conventional culture growth test. Not only does it test for antibiotic resistance across a wider range of drugs—13 as opposed to 4—but it also brings down diagnosis time. Currently, patients must wait until testing on all possible drugs is done. With a long turnaround diagnosis time, repeated testing leads to multiple changes in the course of treatment. The whole process can take upwards of eight weeks—a criminal delay when time isn’t a luxury. Finally, after much trial and error, doctors settle on the right cocktail of drugs necessary for treatment. ‘SPIT SEQ’ cuts through this, enabling doctors to quickly prescribe the most effective drug to a tuberculosis patient within days.
SPIT SEQ is special because while WGS itself is common the world over, most of it is done using culture. This isn’t ideal because the TB bacteria (mycobacterium tuberculosis) takes upto eight weeks for culture growth. MedGenome, however, uses a microbacterial bait to isolate and extract the TB DNA directly from phlegm samples, speeding up the process while remaining accurate. At present, SPIT SEQ allows for diagnosis in less than 10 days, and has been validated with over 100 samples where it recorded 100% sensitivity and 98.04% specificity when compared with German company Hain Lifescience’s Line Probe Assay.
However, this leap in TB diagnostics has a catch. While conventional tests for screening are available locally, only around six large government reference labs nationwide, can host sequencers. The new test is accurate and fast, but it is not yet accessible by those who need it.
As per the Global TB report 2017, the estimated incidence of TB in India was approximately 2.8 million, accounting for about a quarter of the world’s TB cases. Under the national TB programme, 46,000 suffering from MDR TB and 2,700 from XDR TB, in 2018, were registered for treatment. If MedGenome is to be of help to diagnose drug resistance in tens of thousands of more TB sufferers like these, it needs to travel beyond a referral lab.
MedGenome, which is funded by the likes of Sequoia Capital and Emerge Ventures, has begun the process of mainstreaming SPIT SEQ. Already, it has submitted its test results to the Indian Council of Medical Research (ICMR). Next, its tech will have to go through an extensive in-country validation to get the apex research body’s stamp. If successful, and if it gets a World Health Organization (WHO) approval, it would be eligible for incorporation in the national TB programme. Even to go beyond India, it would need a WHO approval.
India has a strategic plan to tackle TB, with a goal to eradicate the disease by 2025—five years ahead of the world target of 2030 as enshrined in the Sustainable Development Goals. Bringing diagnostic tech like SPIT SEQ closer to the patient could help India meet its goal.
Approval is undoubtedly MedGenome’s most major hurdle today. Without the approval of either ICMR or WHO, SPIT SEQ will remain limited in scope. ICMR approval on its own would be pivotal, given that India has the highest TB burden in the world. As a part of the national TB programme, the tech would effectively be mainstreamed in the country, reaching those who need it most and can afford it the least.
WHO approval, meanwhile, could see the tech adopted in other high TB burden countries. China, India and South Africa have the highest number of TB cases globally and, together with Brazil, account for 46% of all new cases. Without WHO approval, MedGenome’s tech stands little chance of being deployed in any of these countries, regardless of its promise.
Today, the complete battery of tests from a phlegm sample, including culture, costs Rs 17,000 ($237). A SPIT SEQ along with a set of basic tests costs just over two-thirds of that—Rs 12,000 ($168). But MedGenome knows it can and needs to do better. But it will struggle without access to the mass market.
At present, the cost of one test is fixed at Rs 7,500 ($105), with a diagnosis taking around 10 days. However, with an increase in the number of samples, the whole process can be radically optimised. Not only can the cost be brought down by 20% to Rs 6,000 ($84), but diagnosis turnaround time can also be brought down to two or three days as the company needn’t wait to collect a minimum number of samples. Today, MedGenome waits for three days to collect a minimum number of 24 samples.
MedGenome, which has launched the tech commercially on a business-to-business level (B2B), has received an order to process 2,000 samples. Some African countries have also shown an interest, says VL Ramprasad, COO of MedGenome. To cater to this interest, he adds, MedGenome is thinking about doing something locally in these countries since shipping the samples isn’t feasible and could affect the viability of samples.
Even as SPIT SEQ dreams of the mass market, another Bengaluru-based company has already made considerable progress in this regard. Molbio Diagnostics Pvt Ltd, which has operated in the TB space for 18 years, is celebrating the Government of India’s call to purchase 1,512 of the company’s TrueNat machines. These perform point-of-care molecular tests that can diagnose TB as well as test for resistance to the anti-TB drug rifampicin (part of the first line of TB treatment) in one hour.
TrueNat will replace the first drug resistance test available in India—Cartridge-Based Nucleic Acid Amplification Test (CBNAAT).
CBNAAT is done using a machine called GeneXpert—developed by US-headquartered Cepheid—which has 1,300 installations across India. A large number of these were purchased by India’s national TB programme and are used at the district hospital level. In December 2010, the WHO also recommended that countries incorporate the test into their programmes. CBNAAT, like TrueNat, detects TB and resistance to rifampicin.
GeneXpert, however, has found itself overtaken by TrueNat as the latter is not just cheaper but faster as well. While GeneXpert costs $17,000 (Rs 12 lakh), TrueNat costs only half of that—Rs 6 lakh ($8381). And while TrueNat spits out results in an hour, GeneXpert takes twice as long. MedGenome is some way off both these tests. While it tests for a greater range of drug resistance, the estimated minimum cost of instrument needed for conducting SPIT SEQ is $19,000 (Rs 13.5 lakh).
MedGenome would do well to learn from TrueNat’s story if it wants to get to the mass market. In addition to just cost, the fact that TrueNat is battery-operated (unlike GeneXpert which needs uninterrupted power supply) and didn’t need air-conditioning to function helped it reach the primary health centre (PHC) level. This is the first point of care for a TB patient. Today, 225 PHCs in the southern Indian state of Andhra Pradesh use TrueNat.
It took MolBio 18 years to reach where it has. “TrueNat’s operational feasibility was first established through a study at 100 microscopy centres across 50 districts in India between 2016 and 2017,” said Chandrasekhar Nair, Molbio’s chief technology officer. It was only in October 2017 that ICMR recommended the substitution of conventional tests like smear microscopy and GeneXpert with TrueNat.
However, despite TrueNat slowly taking over the Indian TB diagnosis market, it still doesn’t have the requisite approvals to capture the global market. Currently, Geneva-based FIND (Foundation for Innovative New Diagnostics), a global health non-profit, is evaluating TrueNat on behalf of the WHO.
Sanjay Sarin, head of FIND India, explained that all new technologies need to go through an extensive in-country validation exercise. Through this, they are assessed on their performance and compared with the existing technologies for sensitivity and specificity. This will essentially certify the technology to enter the WHO supply chain. At present, TrueNat is being tested in four countries—India, Peru, Ethiopia and Papua New Guinea.
If TrueNat passes the WHO test, India would have developed a TB diagnostic test for the world.
TrueNat’s rise is testament to the importance of access in diagnostics. An expert microbiologist on the TB diagnostics committee of the ICMR, who requested anonymity, says as much. Diagnostics must be available at the point of care. This is what made CBNAAT a big revolution as well—it was available close to the patient, avoiding delays, so one can know if a patient has TB or rifampicin resistance with an easy technology, the expert said.
MedGenome’s technology, however, fails on these parameters. Not only is the tech more expensive and restricted to a handful of large reference labs, but there are also training costs involved to use the equipment and a waiting period to gather enough samples. The importance of SPIT SEQ, however, is becoming more pronounced by the day.
Recently, Indian scientists discovered several mutations in the genes of TB bacteria which are causing drug resistance. The results of this four-year-long research were published in the latest issue of Frontiers in Microbiology, a scientific journal. According to the research, the TB bacteria may soon become resistant even to recent drugs such as Bedaquiline. What’s worse, the diagnostic kits used in India for drug-resistant TB cannot spot this.
This is where WGS, the tech on which SPIT SEQ is based, becomes extremely critical. “We can look at all known mutations on the genome. It’s a step towards understanding transmission. Also, some strains are more virulent than others. WGS gives them a lineage. It gives them a name and a family,” the expert microbiologist said. This allows scientists to track transmission of TB as well, the expert added.
It isn’t that MedGenome is the only WGS-based TB diagnostic tool. Five government reference labs also use WGS to understand drug resistance and track TB transmission. However, SPIT SEQ is a lot faster because it doesn’t rely on TB culture.
Leena Menghaney, regional head (South Asia) at the Access Campaign at Médecins Sans Frontières (MSF), believes that Next-generation sequencing (NGS) tools (like SPIT SEQ) have great potential in settings with clinical reference labs. Like Mumbai, for example. However, she adds that operational/translation research projects are needed to see how they can be adapted to the needs of the TB programme.
In an ideal scenario, the government would expand access to both conventional tests that may be slow but diagnose drug resistance as well as NGS for rapid diagnoses in high burden settings like Mumbai. This sort of multi-pronged approach would go a long way to meeting India’s target of eliminating TB by 2025.
The government, too, has upped its spending on TB care. According to WHO’s Global Tuberculosis Report 2018, domestic funding for India’s national TB programme quadrupled between 2016 and 2018. It shot from $110 million (Rs 790 crore) in 2016 to $458 million (Rs 3,320 crore) in 2018, accounting for 79% of India’s national TB budget.
Has this translated to increased spending on TB diagnostics though? It has, said an RNTCP official. Out of the Rs 3,000 crore- odd RNTCP budget, around Rs 500 crore is spent on TB diagnostics. This figure has almost doubled from the previous year as the number of installations of GeneXpert machines has increased, said the official.
The government’s increased expenditure on TB diagnostic machines and kits offers hope that there is a willingness to invest in newer diagnostic technologies like SPIT SEQ. For that to become a reality, though, SPIT SEQ and MedGenome must first jump the approval hurdles that the likes of TrueNat and GeneXpert have so arduously crossed.