NEW YORK (GenomeWeb) – Twelve years after its founding, Germany-based rare hereditary disease diagnostics firm Centogene is preparing to expand into the US as it awaits clearance from the US Food and Drug Administration for its diagnostic tool for generating reports on clinical variants.
For the entirety of its history, Centogene has focused on the emerging markets — the Middle East, Asia, and Latin America. In December, to facilitate its growing operation, the firm moved to a bigger 15,000-square-foot facility in Rostock, Germany, following a Series A financing round in June that raised €25 million ($31 million).
But Centogene realized that further growth required a push into the US, which its CEO Arndt Rolfs called "the most important market worldwide … for genetic testing." With that in mind, Centogene opened an office in Boston in December, and in April it plans to open a CLIA-certified lab there.
The push into the US market "is one of the expansion plans for both our diagnostics and industry segment in order to accelerate the growth of the company," Rolfs said recently from the sidelines of the 36th annual JP Morgan Healthcare Conference in San Francisco.
In particular, it would potentially broaden its footprint in the crucial pharmaceutical market, which currently accounts for roughly half of Centogene's revenues, according to Rolfs. In 2017, it posted $35 million in revenues, and in 2018 revenues are anticipated to grow 40 percent year over year, he said.
Among its current pharma partners are Shire, Alexion Pharmaceuticals, and Alnylam, as well as "all the bigger mid-sized" firms and smaller ones developing orphan drugs, Rolfs said, adding Centogene is in negotiations with additional drug partners, though he did not want to disclose details yet.
In pursuing drug development partnerships, Centogene aims to improve the epidemiology of a disease.Additionally, it is facilitating the early diagnosis of disease, primarily by providing biomarkers to pharma that they can use to test the efficacy of their drugs.
The earlier that a diagnosis can be made, "the better we understand the clinical phenotype, the better we can support our partners with quantifiable parameters like biomarkers, [so that they can decide] whether this is an indication to jump in and initiate the treatment," Rolfs said.
With a growing emphasis on companion and complementary diagnostics, biomarkers have become important tools in the drug development process, but, Rolfs said, many pharma firms still don't see themselves having a role in disease diagnosis. Centogene aims to convince them that partnering with the company in the early diagnosis of disease can translate to getting patients started on a drug regimen earlier, resulting in better patient management and additional revenues. This is especially true for rare diseases, he said.
At the core of Centogene's business is its CentoMD genotype and phenotype mutation database containing more than 5.2 million variants culled from about 200,000 anonymized patients who gave their consent for use of their data. Each quarter, data from 15,000 to 18,000 new patients are added to CentoMD, Rolfs said.
The firm last week announced it had surpassed 1 billion identified alleles within CentoMD. In 2016, Centogene submitted an application to the FDA for 510(k) review of CentoMD, but following the implementation of the 21st Century Cures Act, it was determined that the agency no longer had oversight for CentoMD, and it is no longer under FDA review, according to Rolfs.
After discussions with the agency, Centogene submitted a redesigned product called CentoMDx, which he said is a "diagnostic tool in which a clinician may upload a variant call format file, and CentoMDx would provide a diagnostic report for positive variants."
The device is currently under FDA de novo review, and a decision on its marketing clearance could be made as early as this month, Rolfs said.
Additionally, the company has submitted its Centocard DBS Kit, as well as three undisclosed biomarkers, to the FDA for possible clearance.
Centocard is a filter paper-based technology for the collection of 10 drops of blood, which is then used by Centogene to run its tests, including deletion/duplication tests, exome and/or single-gene tests, and biomarker detection tests.
In the fall, Centogene and Qiagen reached a deal for use of CentoMD to integrate sample-to-insight research with clinical testing for rare diseases. Qiagen already had a database called the Human Gene Mutation Database, which contains information about inherited disease mutations, but though HGMD contains data on disease-causing inherited variants published in the literature and is included in medical guidelines as a reference to assess variants, it does not include a clinical pathogenicity assessment, Rupert Yip, director of global product management for genetic disease at Qiagen Bioinformatics, said in an email. CentoMD data, by comparison, is based on patient cases and provides a pathogenicity assessment for variants observed in these patients. As such, CentoMD data "is very compelling for labs wanting to know how these variants have been assessed by another clinical lab."
Also, the majority of CentoMD's data is unpublished, a major difference between it and HGMD, as well as ClinVar, a public database of genotype-phenotype relationships that Qiagen also uses."Manual expert curation of reported cases in literature remains important," said Sean Scott, vice president of market development, genomics and bioinformatics at Qiagen. "And capturing clinically annotated variants from diagnostic labs where cases and observed variants may not be reported in literature or submitted to ClinVar (which is the large majority of observed variants) is also important — thus why Qiagen partnered with Centogene."
Another defining feature of CentoMD is that it contains data from different ethnicities, not just from Caucasian populations, Rolfs noted, adding that Centogene is active in more than 110 countries with a network of more than 35,000 doctors who send patient samples to the company.
Ethnic diversity is important because while a variant may suggest a risk for a certain disease among some ethnic groups, the same variant may be benign in other ethnicities. For example, he said a BRCA mutation has been well-established as being associated with breast cancer in the Franco-Canadian population, and those patients often are counseled to get mastectomies. The same mutation, however, is not associated with breast cancer in the Japanese population, and, thus, mastectomies may not be recommended for those patients.
"So, this is a simple example that genetic interpretation has to be done within the ethnicity context. If you don't have access to the different ethnicities, you might lose the proper focus, to the [hindrance] of the patient," Rolfs said.
For its drug development work, Centogene's worldwide cohorts allows its partners to understand in which regions specific mutations result in specific phenotypes. "Centogene can show pharma companies where patients for a given disease are located geographically, how many of them there actually are," as pharma firms often miss large portions of patients, "and what symptoms [they] should look for," since some patients may not present all symptoms, leading to misdiagnosis, he said.
Rolfs acknowledged, though, that there are ethnic gaps in CentoMD. For any ethnicity, statistically speaking, samples from 100,000 to 150,000 patients are needed before the data should be considered clinically relevant, according to Rolfs. Centogene has tested some 130,000 Caucasians, and "for that, we have reached [a] critical point," he said.
By comparison, the number of Arab patients tested by Centogene is between 80,000 and 90,000, and for the Mongolian, Russian, and Japanese populations, "we are just at the beginning," Rolfs said.
Centogene also uses a multiomics approach to data collection, which, he said, provides a fuller and more complete clinical picture of a person. In late 2016, it began offering whole-genome sequencing as a service and through its CentoGenome test, in addition to clinical exome sequencing that had been on its menu since 2014. In total, the company offers genetic testing for more than 3,500 genes.
It also offers transcriptomic tests, using RNA as "the informative tool for diagnosis," as well as proteomic and metabolomic tests. For a comprehensive diagnosis, "typically you have to have access to all of these different, more general platforms," Rolfs said.
Centogene is not alone in its multiomics approach to disease diagnosis and biomarker detection. Other companies taking a similar approach include biotech firm Berg, whose Interrogative Biology platform also uses multiple omics methods to accelerate biomarker discovery. Also, Paradigm Diagnostics launched a registry study in April, using its multiomics test to collect patient health and outcomes information. The test combines DNA sequencing, mRNA expression analysis, and immunohistochemical assays covering a broad panel of proteins.
On the research side, University of Pennsylvania researchers announced during the summer a project involving multiomics profiling of urine samples to search for biomarkers related to kidney transplant outcomes in adults and children.
However, Centogene is unique because its exclusive focus is rare inherited diseases, Rolfs said. The firm offers tests for approximately 7,000 hereditary rare diseases, of which it can diagnose 4,000. For the remaining 3,000, "we are able to see the phenotype," but Centogene is unable to identify the disease-causing gene, he said.
In total, including enzyme-based tests, clinical chemistry tests, and biomarker tests, the firm offers 8,000 tests. Biochemistry tests cost between $115 and $410, while biomarker tests are priced from $210 to $290. Genetic tests are priced at $150 to $4,800.
Between 30 and 40 percent of the tests Centogene performs are done free of charge to the patient, Rolfs said, because they cannot afford to pay for it. In return, with the consent of the patient, Centogene receives clinical data from the patient samples that it then uses to improve and update its CentoMD database.
Once its Boston lab is operational, the company will pursue CAP accreditation and CAP ISO 15189 certification, he said.
In the US, the company most likely will not seek payor reimbursements, and if a patient cannot pay for the test, Centogene will absorb the cost, he added.
In the longer view, this model makes more economic sense as the clinical information it can glean from a patient's test sample could prove valuable, according to Rolfs. "If I'm burning some €10 for the genetic testing, but based on the collaboration with the pharmaceutical companies, I will get it back with €100, €500, then it's not a bad deal," he said.