第三代单分子测序报道-Direct Genomics revives Helicos sequencing system for China’s hospitals

122 VOLUME 34 NUMBER 2 FEBRUARY 2016 NATURE BIOTECHNOLOGY

N E W S

Proteasome play C4 debuts

Start-up C4 Therapeutics of Cambridge, Massachusetts, in January raised $73 million in series A funding to develop therapeutics that target disease-causing proteins and facilitate their degradation through the ubiquitin/proteasome system. C4 was founded by a group from Boston’s Dana-Farber Cancer Institute, including Jay Bradner, whose laboratory invented C4’s

targeted protein degradation (TPD) platform, which links drug-like small molecules to the cellular ubiquitin/proteasome system to eliminate designated proteins by tagging them with ubiquitin for destruction by the proteasome. Announcement of the funding coincided with news that C4 has entered into a strategic collaboration with the Basel-based pharma Roche to identify TPD drugs against a set of prespecified protein targets. Celgene, in Summit, New Jersey, has also inked proteasome-oriented collaborations with startups, including San Francisco’s

Nurix and Forma Therapeutics in Watertown, Massachusetts. Cleave Biosciences in Burlingame, California is currently in a

phase 1 trial for myeloma with CB-5083, an inhibitor of p97, a AAA ATPase that regulates the ubiquitin/proteasome system. Proteasome inhibition is a core strategy in treating multiple myeloma: sales of the leading

myeloma drug, Celgene’s proteasome inhibitor Revlimid (lenalidomide), are projected to rise above $6 billion in 2016. In November, the US Food and Drug Administration approved Ninlaro, a proteasome inhibitor directed at the subunit beta type-5, from Takeda Pharma in Osaka, Japan (p. 126).

and Technology of China, returned to China and set up his company to build a sequencer geared towards diagnostics. Quake now leads the scientific advisory board for this new company.

Direct Genomics’ instrument is meant only for the clinical market. The GenoCare analyzer enables ‘direct’ reading of raw, unmodified DNA in single molecules. Whereas conven-tional sequencers require amplification of DNA with PCR and several other steps, the GenoCare analyzer is an amplification-free technology. It intensely focuses light on DNA molecules and prevents illumination of con-taminants to allow detection of the tiny signal from a single strand of DNA. Though it can-not match Illumina or Thermo Fisher sequenc-ing platforms on volume in whole-genome sequencing, the technology promises fast and cheap sequencing of critical areas of patient genomes so that doctors can tune in on partic-ular mutations and tailor treatment to patients. “I really like it. It takes advantage of sort of ‘traditional’ sequence by synthesis methods like 454 and Ion and Illumina, but gets to single-molecule detection,” says Michael Weiner, a sequencing expert and biotech entrepreneur at the life sciences tools provider AxioMx, in Branford, Connecticut.

As whole human genome sequenc-ing descends into the $1,000 range, Direct Genomics intends to offer $100 clinical

Direct Genomics, a Shenzhen, China-based sequencing company, is mounting a chal-lenge to San Diego-based Illumina and other sequencing giants with a low-cost sequencer for clinical use. Last October, the company launched its GenoCare analyzer, a single-molecule genome sequencer specifically for clinical applications. Since then, competition in the genomic sequencing spaces has contin-ued to heat up. In January, at the JP Morgan H ealthcare conference in San Francisco, Illumina launched the MiniSeq System, an integrated benchtop analyser designed for clinical diagnosis, which will begin shipping the this quarter. And Human Longevity, the San Diego-based company co-founded by J. Craig Venter unveiled its oncology program, a set of products still in development for whole germline, tumor genome and whole cancer exome analysis.

For now, Direct Genomics has set its sights on China. The company is taking advan-tage of patents licensed from Caltech, using a sequencing method first brought to mar-ket by H elicos Biosciences of Cambridge, Massachusetts. Helicos was founded in 2004 by Stephen Quake, who came up with the idea of single-molecule sequencing, though Helicos eventually went bankrupt in 2012. A postdoc in Quake’s laboratory, He Jiankui, now Direct Genomics CEO and a biophysicist and genom-ics researcher at South University of Science

Direct Genomics revives Helicos

sequencing system for China’s hospitals

Jiankui He, president and CEO, Direct Genomics, pictured with GenoCare sequencer. The green, red and yellow spots represent a single fluorescence dye labeling a nucleotide. Each spot is a single molecule.

X i n j i e T i a n .

“I don’t know of anyone who has

thought this through as a realistic policy innovation because it has never been even close to happening” John McDonough, a former aide to Senator Edward M. Kennedy and professor at the Harvard T.H. Chan

School of Public Health. McDonough feels the prospects of the US government negotiating drug prices are slim, despite lip service given to it by some politicians. (STAT, 6 January 2016)

“Your genetics don’t determine your destiny, rather just your potential.” #ISB100K http://ow.ly/WBTi7 Leroy Hood comments on genetic reductionism. @ISBLeeHood

“Doctors get the data and often don’t know what to do with it. [But in the future,] we’ll be able to find utility in that data.” Teresa Wang, senior research manager at the digital health investment firm Rock Health, in San Francisco, commenting on the new health apps rolled out at this year’s Consumer Electronics Show in Las Vegas. Among them are an app that confirms that you

snore (EmfitQS), one that responds to mood swings by playing music or talking you down (Sensaura), and one that maps out dry facial skin (MAPO mask). (STAT , 6 January 2016)

X i n j i e T i a n

n p g

? 2016 N a t u r e A m e r i c a , I n c . A l l r i g h t s r e s e r v e d .

NATURE BIOTECHNOLOGY VOLUME 34 NUMBER 2 FEBRUARY 2016 123

N E W S

“Individuals will be told, ‘We found these variations in your genes that might be important, but we really don’t know if they are going to make you sick or what to do about them’. That will be quite confusing and could generate unnecessary fear.” Ellen Wright Clayton, of Vanderbilt’s Center for Biomedical Ethics and Society, commenting on the recent JAMA paper showing that in people carrying two gene variants associated to potentially lethal heart rhythm problems—long-QT syndrome and Brugada syndrome—only a small

proportion have evidence of the condition, calling into question the wisdom of telling patients about incidental findings from genetic analysis. (STAT, 5 January 2016) “As money and excitement enter a field, there is a risk the patient population will incorrectly believe that clinical treatments are—or at least ought to be—available”. R. Alta Charo, legal scholar and

bioethicist at the University of Wisconsin Law School. Charo was commenting on genome editing biotech and Editas’ announcement of its plan to go public, which is adding to the (already over-) hyped status of CRISPR-Cas9

technology. (STAT, 5 January 2016)

New partner for Galapagos

JAK drug

Three months after losing a large pharma company collaborator for filgotinib, a phase 3–ready inhibitor of Janus associated kinase-1 (JAK1) for treating inflammatory diseases,

Galapagos, in Mechelen, Belgium, is partnering with Gilead Sciences to complete development of the drug. The new deal calls for Gilead, in Foster City, California, to make and market filgotinib, with Galapagos retaining a right to co-promote in certain European territories. Gilead is paying $725 million upfront, which includes an approximately 15% equity stake in Galapagos. Phase 2 trial data show that filgotinib may be used to treat rheumatoid arthritis (RA) and Crohn’s disease, and the companies expect to start phase 3 trials in

these two conditions in 2016. Despite favorable phase 2b results in April 2015, North Chicago’s Abbvie declined its option on filgotinib and is focusing on developing its home-grown JAK inhibitor for treating RA, ABT-494. New York-based Pfizer’s Xeljanz (tofacitinib) is the only JAK inhibitor approved as an RA therapy (Nat. Biotechnol. 31, 3–4, 2013); Incyte, in Wilmington, Delaware, and Indianapolis, Indiana-based Eli Lilly are developing the JAK3 inhibitor baricitinib, which is now in phase 3 for RA and phase 2 for psoriasis. The Gilead deal sets up filgotinib as a leading asset for the top-tier biotech to treat inflammatory diseases, alongside its matrix metalloproteinase 9 inhibitor GS-5745 for autoimmune diseases, now in a late-stage study in ulcerative colitis and a phase 2 in Crohn’s. Gilead is also

developing the JAK1/2 inhibitor momelitinib, in myelofibrosis and pancreatic and non–small cell cancer.

sequencing—something that He says will bring it under China’s national insurance coverage. “Once we drive down the cost, and make it $100, the 1.3 billion Chinese will be able to take clinical sequencing as routine test,” says He. “And the entire process from taking blood

to report will be less than 20 hours.”

The company has already started an ‘early-access program’ in collaboration with three hospitals, all in Guangdong in southern China. The first targets of its pilot projects are a non-invasive prenatal test for Down’s syndrome and other trisomies (chromosome 21, 13 and

18 trisomies); cancer panel, including 50 can-cer genes; and genetic disease panel, including 100 genetic diseases. Such tests can now cost $500 or more. In January, Direct Genomics signed up its first noninvasive prenatal test-ing customer, Harmonicare Medical of Hong Kong, a holding company for 30 mother and child hospitals.

Sequence providers, potential customers, are

in wait-and-watch mode. Ruiqiang Li, CEO of the Beijing-based

genomics services provider Novogene, which has one of the

few Illumina H iSeq

X Ten whole genome

sequencing plat-forms in China, says that by avoiding PCR

amplification, single-molecule sequencing avoids bias, but a high

error rate has proved a challenge. “It’s a very important step forward. But we see that Helicos failed, and PacBio and Oxford Nanopore have very high sequencing error rate,” says Li. “However, we are interested, and hope to see the commercial launch of the instrument.”

Direct Genomics’ He says they are working to correct such problems. “We compensate the errors by sequencing the DNA over 1,000 times,” says He. Their error rate is then close to Illumina and Thermo Fisher sequencers,

says He, referring to results (https://www.wendangku.net/doc/b17703773.html, 2015, doi:10.1101/029686) from sequencing cancer genes and hepatitis B virus, in which fivefold sequencing produced accuracy of 100%.

China’s sequencing providers are gearing up to launch a precision medicine program that is rumored to have a budget of RMB60 billion ($9.1 billion) over the next 15 years (Nature 528, 9–10, 2016). It is expected to be announced officially this spring, and major hospitals around the country are quickly assembling precision medicine centers.

He estimates that Chinese patients will be getting 20 million noninvasive prenatal diag-nosis, 3 million cancer panels, 20 million genetic disease tests, 30 million cancer early diagnosis tests and 10 million hepatitis B virus tests annually. He hopes to sequence just under half with GenoCare.

Since its establishment in 2013, Direct Genomics has raised RMB120 million ($18.3 million) through three rounds of investment and government funding. Then, in a series C fundraising closed in December, a medical device company invested another RMB200 million ($30.4 million). He hopes to gain China Food and Drug Administration approval,

through China’s green-light channel, in 2017. Will narrowing the market to clinical use work? “It still isn’t a way to routinely or prac-tically sequence the whole genome, so

it’s only going to be for a limited mar-ket,” says Weiner. “For resequencing, I’m not sure they are much cheaper than Illumina and the cost of their instrument and the way it’s per-formed means it isn’t quite as multiplexable.” But, Weiner says, “It could work where labor costs are reduced. It would be able to fill a niche in a rather large resequencing market.” He sees his company as a third-generation sequencing provider and

hence not in direct competition with already established outfits. “Our threat comes from nanopore sequencing technology, such as [those from] Genia (a Roche company) and Oxford Nanopore.”

Sequence providers are happy to have more options. “In all, it’s a hot area,” says Li. “Thermo/Life Tech, Illumina, PacBio, Qiagen all launched new sequencing instruments. We

hope to see more technologies, so that users can choose the right one for specific clinical applications.” David Cyranoski Beijing

China’s sequencing providers are gearing up to launch a

precision medicine program that is rumored to have a budget of RMB60 billion

($9.1 billion) over the next

15 years (Nature 528, 9–10, 2016)

n p g

? 2016 N a t u r e A m e r i c a , I n c . A l l r i g h t s r e s e r v e d .