NEW YORK – Seven years after a splashy — if somewhat eerie — debut at the American Association for Clinical Chemistry annual meeting, Cepheid has apparently backed away from its GeneXpert Omni, a rugged, rapid, and sensitive point-of-care diagnostics platform that some expected to change the way active TB and HIV would be tested in underserved communities.
Without much fanfare, the Danaher subsidiary has apparently pulled the plug on further developing the system, with the only public disclosure of the news a short reference last fall on a website associated with the Vatican.
While Cepheid pulled out all the stops in 2015 announcing the new system, it shows no interest now in discussing its decision and why it stopped development of the Omni. Neither Cepheid nor its parent company Danaher responded to repeated requests for comment.
Beyond just one diagnostic device, the development of the platform may be representative of the challenges faced by diagnostic developers trying to create new technology aimed at communities where lifesaving diagnoses are a challenge. Even if Cepheid had all the right intentions, the realities of the market may have been too difficult for the Sunnyvale, California-based company to overcome, some said.
And although the business decision to cancel Omni seems like a retreat on a global promise to so-called high-burden developing countries (HBDCs), some sources interviewed for this story also pointed out that at least Cepheid has been attempting to address the diagnostics needs of areas with high rates of disease but not much money — an objective not many other companies have even attempted.
Cepheid's former CEO, John Bishop, spearheaded Omni's development and championed the system from its AACC debut in 2015 until the firm was acquired by Danaher in 2018. But when told about its apparent cancellation, Bishop, who had not heard the news, recently said, "It is extremely disappointing," particularly given that Omni was "a major step ahead of anything in the market."
Dx for underserved communities
Omni was developed as an easy to use 2-pound, 9-inch-tall, smartphone-controlled molecular diagnostics system that performed point-of-care, sample-to-answer PCR testing using Cepheid's existing cartridges.
With a battery life of up to 12 hours and ruggedized for use in dusty or humid places, the Omni was described by Cepheid at AACC 2015 as having the potential to bring desperately needed TB and HIV testing to underserved communities in remote places. The price quoted for the system in 2015 was $2,895, well below other point-of-care molecular diagnostics instruments.
Bishop said stakeholder communities he met with were very excited about Omni. For example, he personally took an Omni prototype to South Africa — a country experiencing a high burden of HIV and TB — and even visited a remote Zulu village to gauge the desirability and utility of Omni's TB and HIV testing.
"They were blown away," Bishop said in an interview. With Omni, "They had the ability right there in the village to do the test, and they could also do a variety of tests" from Cepheid's diagnostics menu, for example HIV testing.
Back then, Cepheid had long-term, undisclosed strategies to outfit mobile test vans with Omnis, Bishop said. The tiny footprint of the instrument meant many systems could fit in a small space, essentially increasing capacity and enabling high-throughput PCR anywhere a vehicle could go. This strategy could be mixed and matched with other Cepheid systems to offer high- and low-volume testing and incorporate the firm's technology that enables it to safely send data from remote locations.
Cepheid entered a strategic collaboration on Omni with FIND, the Switzerland-based diagnostics non-profit, in late 2015 to support global trials of the platform.
The system was delayed in 2018, but Omni was still in development in July 2020 when the firm's chief medical and technology officer said Cepheid was "100 percent committed" to it and planned to incorporate its new 10-color detection chemistries into Omni.
In November of 2020, the firm also made a commitment to the Vatican's Rome Action Plan — an international effort meant to overcome bottlenecks to HIV and TB services for children — to release the GeneXpert Omni in 2021 in a limited set of countries, with a broader market release in 2022. Other firms that made TB-specific commitments to the Rome Action Plan in 2020 included Abbott, Hologic, MolBio, Roche, Hain, and FujiFilm.
In December 2020, Cepheid even obtained an Emergency Use Authorization for a SARS-CoV-2 test on the Omni from the US Food and Drug Administration, and by late 2021, Omni's point-of-care promise had also apparently been realized.
A team led by FIND published an evaluation of Omni's performance last December in collaboration with a reference lab in Milan, Italy demonstrating Omni's TB detection was equivalent to the legacy Cepheid GeneXpert system and even effective under challenging environmental conditions.
But even before that evaluation, in October 2021, word began to leak out that Cepheid would no longer continue developing Omni.
The news came in the form of a small update note on the Rome Plan website, as the global TB community was reeling from the pandemic-related reversal of progress in decreasing TB infections.
"After many years of investment in the GeneXpert Omni platform, Cepheid made the decision that this was not a sustainable technology and decided to stop the development," the page documenting Cepheid's commitments said.
The update noted that this "is the reality for both Cepheid's HBDC and commercial markets."
Then last December, Cepheid requested FDA revoke its Omni COVID test EUA, saying the company's other tests were meeting public testing needs. The system is also currently listed as "discontinued" in a chemical, biological, radiological, nuclear and explosive (CBRNE) technology index from contract research organization MRIGlobal.
Although it appears only one trial site was ever given an Omni to field test, this team was also told the system was discontinued, even though it had good results using it to test people in their homes in South Africa.
Andrew Medina-Marino, the lead investigator on that trial and a researcher at the University of Cape Town's Desmond Tutu HIV Foundation, confirmed in an interview that the Omni worked "fantastically well" in his team's hands for an acceptability and feasibility study of home-based TB testing which compared sputum and oral swab specimens.
The Omni, he said, was a lightweight single unit that was easy to use and handle, and could be readily carried around. In the trial — which was funded by FIND and the US National Institutes of Health — the Omni provided excellent utility in the field and had "near perfect" results in comparison with lab-based GeneXpert testing.
But in January 2022 Medina-Marino and his team encountered trouble when some of the TB test cartridges they were using expired. Other Cepheid systems allow an override, he said, provided they are being used for research, but Omni did not seem to have this capability. He contacted the company to get more test cartridges, and a few days later was told that the Omni was being discontinued, and that he would be provided access to the firm's Edge device to complete his study.
Now using the Edge system, the team has found that the requirement for an external battery and a laptop for operation make it less portable, although the test results are also comparable to lab-based assays, Medina-Marino said.
At this point, the full scope of Omni's cancellation, or how it relates the firm's Edge system, is unclear.
In 2020, Cepheid was granted an expansion of its contract with the US Army to develop Omni. Overseen by the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) and totaling $86.6 million, the contract also encompassed the development of four panel assays to run on the Omni system — for hemorrhagic and tropical fevers, bacterial pathogens, and bacterial versus virus host response.
"The JPEO-CBRND continues to work with Cepheid on a man-portable diagnostic system," a spokesperson at the organization said. He explicitly declined, however, to specify whether the system being developed is the Omni.
For both children and adults with suspected TB, a molecular diagnostic TB assay should be the first test used, according to the World Health Organization's 2021 guidelines.
For young children — who are the focus of the Rome Action Plan — TB is dire. According to WHO, 1 million new cases of childhood TB in 2016 resulted in 250,000 deaths.
Rapid molecular diagnostic tests, like the Cepheid Xpert MTB/RIF Ultra, are considered the best way to diagnose pediatric cases, in part because kids can't produce much of the sputum needed for so-called smear testing or microbial culturing.
In HBDCs, TB is also more prevalent in communities, so children living with HIV acquired via mother-to-child transmission are especially vulnerable to TB infection.
Without a diagnosis, sick kids typically are not given drug therapies that are lifesaving but also toxic. Médecins Sans Frontières (MSF), also known as Doctors Without Borders, estimates 60 percent of kids with TB will never be diagnosed. Nearly all of the children who die from TB have never been treated, and four-fifths of these children are under the age of five.
In adults, TB in the context of an HIV co-infection is also challenging, as HIV infection makes sputum production difficult. This is true globally, but it is particularly challenging in countries like Eswatini, formerly known as Swaziland, where data suggests that one-third of the adult population is living with HIV and roughly 66 percent of people with TB have HIV co-infections.
Against this backdrop, global health donors and diagnostics activists have attempted to persuade Cepheid to reduce the price of its TB test and other tests on the legacy GeneXpert systems in HBDCs starting as early as 2012, in order to increase access and save move lives.
Activists at MSF began collaborating with the Treatment Action Group (TAG), a spinout of HIV activist group ACT-UP, to focus on improving TB and other diagnostics access, particularly for children and adults with HIV co-infection.
Even with subsidies for HBDCs, Cepheid's four-module legacy GeneXpert instruments cost approximately $17,000, with cartridges costing an additional $9.98 each. Some of the concerns that activists had about the cost of the legacy GeneXpert also centered around the platform's required warranty and maintenance contracts. And, since Cepheid fully transitioned from 6-color to 10-color technology in its systems, the access pricing of a four-module GX IV instrument and laptop to operate it has increased to $19,500.
Dubbing themselves the "Time for $5 coalition," TAG and MSF, together with more than 100 civil society organizations globally, advocated in a 2019 technical brief that Cepheid reduce the price of its TB test cartridges to $5 in low- and middle-income countries, in part citing public investment in development of the GeneXpert technology.
Last year, TAG and MSF published a financial analysis in PLOS One estimating that Cepheid had been supported with $252 million in public funds to develop its GeneXpert systems and cartridges.
Specifically, the analysis calculated that the public investments in the development of GeneXpert included more than "$11 million in funding for work in public laboratories leading to the first commercial product, $56 million in grants from the [US] National Institutes of Health, $73 million from other US government departments, $67 million in R&D tax credits, $38 million in funding from non-profit and philanthropic organizations, and $9.6 million in small business 'springboard' grants."
Cepheid's response to the Time for $5 Coalition, the brief noted, was that the firm had no plans to reduce prices, but that it hoped for "breakthroughs" to enable affordable pricing in the future.
After the Rome Action Plan update popped up in October, the Time for $5 Coalition quickly applied public pressure — in the form of an open letter — to try to persuade Cepheid to reinstate the Omni project.
"Cepheid’s decision to cancel the launch of the point-of-care Omni instrument will leave many people with TB, HIV, [hepatitis B and C], and COVID-19 without access to diagnosis and proper care, and carelessly squander the public resources and time that have supported the development and evaluation of the Omni technology between 2015 and today," the coalition wrote.
The letter, which was copied to numerous international aid groups, demanded that Cepheid respond by close of business on Oct. 28, 2021.
Cepheid never responded, according to David Branigan, the TB project officer at TAG, and Stijn Deborggraeve, a diagnostics advisor for infectious diseases at MSF Access Campaign.
Cepheid claims an installed base of more than 40,000 GeneXpert systems worldwide, with a placement of more than 10,000 systems in LMICs supported by donor funding. These systems tend to be lab-based because they require electricity, some training to operate, and are a bit hefty for true point-of-care use. They are mainly used in HBDCs for the diagnosis of active tuberculosis, although they also run Cepheid's menu of 30 or so CE-marked tests.
Into this HBDC footprint, there were 12 million public sector sales of Xpert MTB/RIF cartridges in 2018, each sold at the subsidized rate of $9.98, according to the Time for $5 Coalition technical briefing.
The coalition hired an engineering consultancy to dissect Cepheid's test cartridges and estimated a cost of goods as low as $3 per cartridge, given annual volumes of 10 million. The $5 price the coalition proposed would also be more in line with FIND's global access policy that notes its goal in collaborating with manufacturers it to arrive at "the lowest sustainable product price based on the manufactured cost of goods plus an agreed reasonable profit margin."
TAG's Branigan said the pricing isn't just about ethics and morality, it is about making sure innovation systems serve the needs of public health, "especially where there is public investment in the development of these products."
In the end, Deborggraeve and Branigan are of the belief that Cepheid's decision to cancel Omni was "purely commercial."
"There is nothing wrong with the machine," Deborggraeve said, citing FIND's published evaluation and the South African field trials.
A new TB urgency
Cepheid debuted the Omni at the 2015 AACC conference. While most other vendors set up booths and demonstration areas with sales staff demonstrating their products, Cepheid additionally commissioned actors to portray various use cases in videos. There were displayed on screens behind lifelike statues of the same actors, posed to show the Omni in use.
One of the vignettes showed the Omni being used at the point of care on a young girl, brought to a healthcare clinic by her worried-looking mother. Another appeared to demonstrate an HBDC use case, with Omni operated by a healthcare worker in an outdoor setting with red dust on the ground, a white pickup truck in the background.
Whether one found the mannequins inspired or absurd, they certainly left an impression.
And if the need for this type of point-of-care testing was already pressing in 2015, it is even more urgent in 2022.
Tuberculosis is a curable disease that infects more than 10 million people each year. Around 40 percent of these cases remain undiagnosed, untreated, and at risk of spreading the disease. Overall, TB kills approximately 1.5 million people each year.
Infection rates had declined over the past decade — in part due to faster diagnosis with Cepheid's legacy GeneXpert systems — but they have rebounded during the COVID-19 pandemic, which set back efforts to reduce the global burden of TB by five years, according to a WHO report.
This has led to an additional 300,000 TB deaths in 2020 compared to 2019. The agency estimated that the number of undiagnosed cases have increased to levels not seen since 2012 and forecasts even worse impacts in 2021 and 2022.
A conglomerate of global health stakeholders — including WHO, the United States President's Emergency Plan for AIDS Relief (PEPFAR), the United States Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and Tous Unis pour Aider (Unitaid) — paid Cepheid $11M in 2012 to buy down the price of Cepheid's TB cartridges from $16.86 to $9.98. The buy-down agreement expires this year, according to a report from USAID.
While Unitaid did not fund the development of Omni specifically, spokesperson Hervé Verhoosel said in an email the global health agency's support of legacy GeneXpert systems "enabled more patients to be more easily tested" and started on effective treatments, helping to slow burgeoning transmission of TB.
"There is a pressing need to further support innovation in the field of diagnostics to improve access and close the testing gap," Verhoosel said, noting that technologies like true point-of-care diagnostics or targeted next-generation sequencing for rapid TB drug-susceptibility testing are "very promising."
An eerie silence
Overall, though, many other stakeholders appear to be reluctant to discuss Omni or TB diagnostics for HBDCs.
FIND has been a leader in advocating for the development of new diagnostic tests for a range of diseases, including TB and HIV, but it declined to comment on Omni specifically, except to say that its past support of the system's development was public knowledge.
Just as Cepheid and FIND no longer want to discuss the Omni, other companies developing point-of-care TB assays for low-resource settings — including FujiFilm, Abbott, and LumiraDx — also declined to provide substantive updates on their TB tests or Rome Action Plan commitments for this story.
And, other than the public letter from the Time fo $5 coallition in October, there do not appear to have been any letters or commentaries made publicly available from the usually vocal global health stakeholders about Omni's cancellation.
"Because of the massive impact the pandemic has had on TB — and life in general — the cancellation of Omni has not generated any significant response from the TB community," confirmed Madhukar Pai, a researcher at McGill International TB Centre in Montreal.
Pai and his colleagues highlighted the impact of COVID-19 on TB in a New England Journal of Medicine article earlier this year, calling for COVID-19-inspired molecular testing to now be used for TB detection.
Despite the most promising technology falling through, aid groups are now requesting eye-popping support for TB diagnostics.
Unitaid, for example, adopted a new five-year, $1.5 billion plan in June to fight deadly infectious diseases, including the support of late-stage diagnostics development and establishing market availability.
And earlier this month, the STOP TB Partnership and its global collaborators unveiled a plan to end TB as a global health threat by 2030. The plan calls for $250 billion in investments over the next eight years, most of which would be earmarked for test development and distribution.
This may sound like a tall order, but, by comparison, R&D investments for COVID-19 diagnostics were approximately $804 billion in 2020, according to TAG estimates.
When Cepheid won its initial buy-down agreements, it was a relatively small company, with annual revenues in 2011 of $277.6 million. It overcame manufacturing woes for Xpert cartridges and quickly saw revenue growth driven by the HBDC business. By 2015 its full-year revenues had nearly doubled, to $538.6 million.
In 2016 the firm was acquired by Danaher in 2016 for $4 billion.
If the cancelation of Omni has damaged the reputation of either Cepheid or Danaher, it hasn't shown up in their earnings results. Last week, Danaher reported its revenues rose 7 percent year over year in the second quarter, while the Cepheid business was up almost 30 percent.
Environmental, social, and governance (ESG) metrics have taken on increasing prominence with investors, as unethical behavior, and subsequent bad press, can sink stock prices.
Cowen analyst Dan Brennan said in an interview that investors with whom he regularly interacts have high regard for Danaher, as does he, and neither reputational risk nor the Omni have come up in his recent conversations with them.
This might be because Omni is a tiny part of the business for Danaher, Brennan said. Diagnostics makes up approximately 33 percent of the firm's revenues, and within that, the Cepheid business represents 13 percent. Stripping out COVID testing, that proportion shrinks to 5 percent, he said.
"Within that, you have HBDC, which is going to be a much smaller portion," he added, estimating that HBDC might be less than 1 percent of Danaher's total revenues. As such, it unlikely to be considered a key driver of the business.
In Danaher's most recent sustainability report, the firm wrote that access to healthcare, including access to innovative medical devices and other technologies, "is a critically important focus for the global health community and our company." Published in October 2021, the report also noted that Cepheid continues to enhance the HBDC program for TB testing, "with lifesaving innovations such as remote calibration and an expanded low-cost testing menu." The text is paired with an image of Omni being used outdoors in a grassy, remote setting.
From a business perspective, it is possible that making tests for people who can't readily pay for them is unlikely to increase returns for shareholders, particularly after public-private support expires.
Brennan noted that at least one firm in the diagnostics space has a substantial and ongoing HBDC business that is sustainable, albeit for HIV rather than TB – OraSure Technologies.
In an interview its CFO Scott Gleason acknowledged that the donor-driven HBDC market can be less predictable, but said the firm does a lot of the business for its HIV self-tests on a volume basis.
"It is work we are very proud of as a company," he said, but noted as well, "It is not an area where we've really made significant profit, or any profit."
OraSure posted $4.4 million in HIV self-tests and $1.2 million hepatitis C tests last quarter outside of the US, but Gleason said these markets tend to be very price competitive, and donors want to make sure dollars are going as far as possible to help the greatest number of people.
Cost structures have also changed significantly in the last 18 months, he said, affecting the entire industry, and OraSure's donor subsidies expired in June of last year. "It has impacted our profitability and our market structure," he said. Nevertheless, the firm believes providing these tests "is the right thing to do," he said, citing as well OraSure's recent ESG report. And, the HBDC business also has a side benefit that the resulting higher manufacturing volume "helps in terms of overhead and fixed cost absorption," Gleason noted.
OraSure has also committed to the Rome Action Plan for HIV testing, specifically to get the company's self-test qualified for use in children as young as 2 years of age. It has so far accomplished this for tests administered by a healthcare worker.
"The company has done a lot in terms of increasing HIV testing, and has been pretty successful in driving awareness on the African subcontinent with millions of tests every year," Gleason said, adding that the company "takes a lot of pride" in helping to address a major health concern.
A review of POC technologies for TB diagnosis published in Science Translational Medicine noted that a legacy GeneXpert system "requires constant electricity, calibration, regular maintenance, and storage of temperature-sensitive reagents." As many as 10 percent of the firm's Xpert MTB/RIF tests fail in Cambodia, Botswana, and India, "primarily because of inadequate sample processing and frequent power failures, highlighting the barriers of POC diagnostics in resource-limited settings," the authors wrote.
In 2018, Cepheid launched the GeneXpert Edge, a system that was meant to be a stopgap for point-of-care testing for some parts of the world until Omni's launch. The Vatican Rome Action Plan update noted that Cepheid now intends to use its GeneXpert Edge platform to "respond to the need for further decentralization."
But, the STM study noted that while Edge "can resolve both geographical and financial constraints and thus may be suitable for [point of care tests] in peripheral healthcare facilities ... [it] does not completely solve the disruption of electricity access because a fully charged battery can only support four tests daily, and further evaluation on its feasibility in resource-limited settings is pending." The access price for the Edge system is $8,945.
MSF's Deborggraeve said it is important to foster healthy competition for POC molecular platforms for use in low-resource settings, including regional diversification and local production of diagnostics, because Cepheid has had "a monopoly for a decade."
The good news is that the outlook on the TB diagnostics pipeline is "optimistic," Branigan wrote in a TAG pipeline report.
Although the COVID pandemic drove an upsurge in TB cases — in part through missed diagnoses during lockdowns — it also led to an influx of funding for extant technologies as well as a burgeoning of new approaches.
These may now fill the unmet point-of-care TB diagnostics need after Omni's exit.
Paul Drain, an expert in diagnostic point-of-care testing in resource-limited settings at the University of Washington, said that, "Rapid diagnostic tests that can be used to diagnose active TB disease in community or home-based settings, as we've succeeded in developing for SARS-CoV-2, will be a critical element to eliminate TB worldwide," particularly if they also incorporate stakeholder needs.
A parallel approach might be to support other molecular diagnostics systems already commercially available that have validated TB assays.
The STOP TB Partnership is supporting the rollout of a system from India's Molbio called TrueNat, providing 301 instruments to nine high-burden countries at "global access prices" of between $10,000 and $18,000 for instrumentation and $9 per TB assay.
The STM study also noted that TrueNat assays, "involve more hands-on steps for sputum sample preparation and PCR, and may face similar inadequate sample processing problems as the Xpert" tests. The system, however, has comparable performance to the legacy Cepheid GeneXpert systems, according to a recent study. It also has the support of FIND and endorsement from WHO.
Four other companies — SD Biosensor, Bioneer, Biomeme, and Qlife — are being supported with $21 million from FIND to enable price reductions and production scale-up of HIV and tuberculosis testing. The Biomeme PCR platform, in particular, is portable and can identify up to 27 targets in a single test.
Disposable molecular systems — such as the DASH system from Minute Molecular Diagnostics, the DnaCartridge from DnaNudge, and the Veros from Sense Biodetection — could potentially fit the bill, particularly for non-sputum testing. Other small molecular instruments slated to be low cost and portable, or even handheld, include systems from Visby Medical, QuantuMDx, Co-Diagnostics, MatMaCorp, and Domus Diagnostics, while the Hemex Gazelle is rugged, and could theoretically be adapted to non-molecular tuberculosis testing.
New TB tests that can process non-sputum samples are urgently needed to increase testing, especially for children. Alternative sample types include urine, blood, and stool. TAG's Branigan noted that swabs of the back of the tongue are a very promising alternative sample as well, particularly when paired with highly sensitive molecular testing. Cepheid has also updated the Rome Action Plan to note that it is actively developing a blood-based test for TB and is validating a stool test.
Sequencing-based TB testing and resistance determination is also gaining momentum, particularly through a FIND project called Seq&Treat. And a team at Tulane University has even developed a CRISPR-based test for bits of TB bacteria in blood.
"If there was a better diagnostic test than Xpert, then the World Health Organization and national TB Programs would certainly review those data with interest," said Drain.
Nevertheless, from his perspective, the cancellation of Omni should be balanced with the success of the legacy GeneXpert systems.
"Cepheid has entered the diagnostic testing market to address diseases in low-income countries, and the same cannot be said for many other prominent diagnostic companies," Drain said.
Still, after a decade of GeneXpert access, the global inequities remain huge, TAG's Branigan said.
"If we are going to develop the diagnostics that are needed, at prices that are affordable, and allow low- and middle-income countries to actually scale up the testing in accordance with WHO recommendations, there needs to be a shift in how things are done," he said. This may come now that COVID has put diagnostics higher on the political agenda, but transparency will be key, he said.
Whether diagnostic companies have a moral responsibility to provide access to lifesaving diagnostics is open for debate, but for MSF's Deborggraeve, Omni's cancellation offers a lesson to public funders and the global community that pours limited resources into diagnostics meant to save lives from infectious diseases.
While funders do not want stringent contracts to scare away small startups, he said, or even larger companies with promising technologies, it is also important to be good stewards of public resources. Branigan recommended access conditions on public funding, such as transparency in the cost of production and pricing structure.
That said, "We really need more teeth in any public funding agreements with companies," Deborggraeve emphasized, as trust in good intentions is clearly not enough.
"Companies like Cepheid just don't care about ethics," Deborggraeve said.