Advances in NIPT Technology at Sequenom

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Phillips Khul:

Hello, this is Phillips Khul. I've been the conference producer for CHI's annual conferences on advances in prenatal molecular diagnostics. An area in which there's been tremendous activity and tremendous advances over the last few years. We've held 3 annual conferences in Boston. From a US prospective, the next of our meetings will be the upcoming European meeting in Lisbon, in early April.

Today, I'll be taking with Daniel Grosu, who's Chief Medical Officer from Sequenom. Hello, Daniel.

Daniel Grosu:

Hello, Phillips.

Phillips Khul:

I'm interested in information as to how Sequenom looks at applying new technology to address the next sets of clinical questions for noninvasive prenatal testing.

Daniel Grosu:

Well, Phillips, Sequenom launched the field of noninvasive prenatal cell-free DNA screening in October 2011, with the tests for trisomy 21, also known as Down Syndrome. That does have far greater sensitivity and specificity than previous blood based prenatal screening approaches. Now, we have continued to be an innovation leader in this space, which is also known as noninvasive prenatal testing or NIPT. Over the years, we broadened the content of fetal conditions that can be screened noninvasively to include other trisomies, such as trisomy 18 and 13, and sex chromosome aneuploidies, such as Turner Syndrome and Klinefelter Syndrome.

The study published in 2015, in the American Journal of Obstetrics & Gynecology, used data from over 450,000 pregnancies that were screened through the California Prenatal Screening Program and determined that about 0.6% of those pregnancies had a fetal chromosomal abnormality. Further, the study estimated that, so called, traditional NIPT, which only interrogates the major trisomies and the sex chromosome aneuploidies, would detect less than 80% of those abnormalities.

To us, this highlighted a major unmet need in NIPT, which we set out to address through MaterniT GENOME, our latest innovation in the field. This test, which is available now for clinical ordering through our [inaudible 02:05] lab in San Diego, was designed using the latest biochemistry and bioinformatic advances to detect duplications and deletions across the entire genome, had karyotype resolution. That is about 7Mb and above. It also reports on many specific micro-deletions smaller than 7Mb in size. For example, those associated with the DiGeorge, Cri Du Shot, and Wolf-Hirschhorn syndromes among others. Actually, more details can be found in our report on the clinical validation of the test, which was recently published in the American Journal of Obstetrics & Gynecology.

Phillips Khul:

Could you discuss some of the ways in which this approach differs from prior approaches for cell-free DNA based prenatal testing.

Daniel Grosu:

Sure. MaterniT GENOME reads over 30 million DNA fragments for every sample, higher than any other NIPT currently available. This high fragment count combined with biochemistry and bioinformatics innovations accumulated over 5 plus years of experience in cell-free DNA testing, allows for unprecedented resolution in detecting deletions and duplications across the entire genome. The 7Mb karyotype level resolution is important because abnormalities of this size typically encompass dozens of genes and are, generally, regarded as clinically significant. The test is also designed to report on several deletions that are even smaller than 7Mb but, are linked to well defined clinical syndromes.

One thing that's important to note is that, MaterniT GENOME does not employ a targeted approach. Rather, it performs a hypothesis free interrogation of 10s of millions of DNA fragments across the entire genome. This allows for detection of very rare conditions, such as unbalanced translocations and rearrangements, that may not have been suspected clinically. It can also detect rare whole chromosome aneuploidies that may be reflective of [inaudible 04:08] and could impact the course of the pregnancy, even if fetal genome is not implicated. MaterniT GENOME is able to detect, noninvasively, most of those conditions that make up the 20%, or so, gap, previously thought to be undetectable by NIPT. This is a real leap forward and is arguably the biggest news in NIPT since the introduction of the first NIPT test back in 2011.

Another key benefit of this hypothesis free genome approach is, the exquisite specificity of the asset. The test algorithm assigns 100s of DNA fragments to each of 10s of 1000s of small bins that are about 50kb per bin. Now, for a deletion or duplications that is many megabases in size to be reported, the individual fragment counts in over 100 of these 50kb bins would have to be elevated or depressed simultaneously and contiguously. The probability of that happening by chance is obviously very small.

Last year, we published our experience with microdeletion testing with the MaterniT PLUS test in over 170,000 clinical samples which shows only 3 confirmed false positives out 55 reported positives, resulting in very high relative DPE for these difficult to detect abnormalities. MaterniT GENOME uses a similar genome wide approach as MateriT21 PLUS, but with double the number of DNA fragment counts. We expected specificity to be no less impressive.

Phillips Khul:

In what clinical experience can you report, thus far, with the newer test?

Daniel Grosu:

We have tested nearly 5000 clinical samples since the asset was launched. Results to date have revealed several very interesting observations. First, the positivity rate has been around 6%, which is more than twice as high as from 21 PLUS. This, to us, suggests that right now the asset is used primarily by maternal fetal medicine specialists for cases that are particularly complex and are likely to have a positive finding. This is appropriate for the early phase of adoption of a highly innovative and complex test. Second, we find that approximately 25% of the positive findings are unique to MaterniT GENOME. That is, they would not be detectable by other NIPT currently available.

These unique findings consist primarily of abnormalities scattered across the genome that are individually very rare but cumulatively are quite prevalent, such as unbalanced translocations, intrachromosomal rearrangements, and rare whole chromosome aneuploidies. This observation and practice aligns fairly closely with the theoretical expectation that MaterniT GENOME would detect, by design, a large fraction of those abnormalities that would not have been previously detectable by NIPT. Further testament to the genome wide power of the test is that, within the first 4000 reported cases the test identified at least 1 abnormality for each of the chromosomes in the human genome.

We aim to follow up diligently on all positive results through our genetic counselors and lab directors and any reported discrepancies, in order to continue learning about the performance of the test in a clinical setting. As the clinical experience builds over time we intend to share it with the community through abstract and peer view publications as we have done for our previous tests over the years. Bottom line is MaterniT GENOME enaugerated a new era in NIPT and we are just getting started on a very interesting journey.

Phillips Khul:

Thank you, Daniel. I look forward to your participation in that of Sequenom, at the upcoming conference in Lisbon in early April.

Daniel Grosu:

Thank you, Phillips. I look forward to the same.