Gene Expression

Advancing Pharmacogenomics from the Benchto the Clinic with qPCR — Insights from Astrid
Irwanto, Cofounder and COO of NalaGenetics
An in-depth conversation with this research scientist turned entrepreneur reveals how her
education and research led her to generate innovative solutions and help pave a future where
pharmacogenomics drives healthcare decisions.
Introduction
Astrid Irwanto is the cofounder and chief operating officer of NalaGenetics, a company taking a novel,
personalized approach to understanding genetic susceptibility to drug reactions in Southeast Asian
populations. Irwanto obtained a PhD in human genetics and then explored aspects of many complex humangenetic diseases in her postdoctoral research, specifically how genetic variations relate to disease risks;
her PhD and postdoctoral work, along with personal experiences, now fuel her pursuits at NalaGenetics.
Bio-Rad’s Candice Cox recently met with Astrid to ask about the history of NalaGenetics within the areaof pharmacogenomics and why she decided to apply her academic research to a molecular diagnostics
company using techniques such as qPCR on the CFX Opus 96 Dx Real-Time PCR System, among others.
Candice: Astrid, this company has been a great fit for yourresearch interests. Could you speak about how NalaGenetics
came to be and how it proposes to impact human health inSoutheast Asia?
Astrid: During my PhD and postdoctoral work, we published aNew England Journal of Medicine paper on the biomarkers usedto detect an adverse drug reaction called dapsone hypersensitivity
syndrome. It occurs in some individuals treated for leprosy,
which is prevalent in Indonesia, ranking at number three globally.
However, in countries like Singapore and the U.S., leprosy is almost
nonexistent. As it turns out, dapsone hypersensitivity syndrome iscaused by an HLA variant primarily present in Asian populations,most abundant in East Indonesians or Aboriginal groups with
Melanesian ancestry. So, when we discovered this association,
we decided not just to publish it but also to take action.
We first created a simple qPCR assay, and all our subsequent
qPCR assays began from that one biomarker. We aimed tomake this as affordable as possible and managed to have theassay done for less than $5, USD, with shipment to Indonesia.
To date, this assay kit has been used to screen much of the East
Indonesian population, especially in the Papua region, using theMinistry of Health budget.
For leprosy patients, before administering a drug, they are given astrip pack from Novartis and the WHO to test if they are positive
for the HLA variant, HLA-B*13:01. If positive, they are excluded
from dapsone but can take the other two antibiotics. Nala is still
committed to providing that test at cost.

But then we had other projects we wanted to pursue, owing to
my own personal story. My father is tetraplegic, paralyzed fromthe chest down, due to the administration of two anticoagulants
20 years ago for a chest pain that was thought to be a
cardiovascular issue.
Candice: What side effect did the anticoagulant cause?
Astrid: It caused bleeding in his gums and apparently in the C3
region of his spine that was not identified, and he lost sensation
the next day, about 12 hours later. This problem occurred dueto the adverse reaction to the anticoagulant. So, the question
became what can be done to prevent this because at least 30% of
these adverse reactions to these common drugs are linked to ourgenetics. We feel there are many actions we can take, especiallyin this part of the world, [as the adverse reaction is more common
in countries] with large Asian populations. In fact, when we started
looking at the CYP2D6 gene, we realized that commercial kits
don’t detect or screen for a key mutation or variant for this gene,
called *36, occurring in 20–30% of people in Asia, especially [thoseof] Chinese descent. So, the vision for our Nala PGx Core® Assay
Kit, is to be as inclusive as possible and put in all the prevalentbiomarkers in Asian countries, making pharmacogenomic tests
relevant and affordable for these populations. Our vision is to makethis technology as accessible as possible.
Candice: With that introduction, I don’t think I need to ask
about the mission of your company; clearly, it came from a very
personal perspective.
Astrid: Yes, we always write on our internal web page that we wantto make DNA tests as ubiquitous as blood tests.

Advancing Pharmacogenomics from the Bench to the Clinic with qPCR — Insights from Astrid Irwanto, Cofounder and COO of NalaGenetics

Candice: How do you accomplish the goal of understanding
population variation in Southeast Asia?

to make sure that the outputs are compatible with other real-time
PCR systems [not from Bio-Rad].

Astrid: We still do a lot of research to make sure we always refer tothe local population reference data if available. And we’re trying tokickstart our government to do more of this work. For example, last
week we signed an agreement with the government of Indonesia tobegin their first human genome project. Finally!

Candice: In terms of your assay development, were there any
specific features of the hardware or software that made the CFX
Opus Real-Time PCR System more useful to you?

Candice: That’s a significant achievement right there.
Astrid: And we really do need that, especially in Indonesia,
where we already see population diversity between people in
Papua versus those in Java and Sumatra. These differences inethnicity can impact whether we have the right biomarker for thedapsone hypersensitivity syndrome. For example, in the Javanese
population, it’s almost zero.
These groups are not that far from each other in terms ofgeographical distance, so we need to get to know this information
better to target or predict disease risk. We’re now focused on
preventative medicine, which is challenging and not as attractive abusiness as treatment since people don’t always have the mindsetof the importance of prevention.
Candice: How does that affect the delivery of healthcare?
Astrid: The community is still very reactive because they havefinancial resources available for treatment of disease but not for
preventative care. Also, the ability to obtain health insurance varies.
It could be established in one area, but elsewhere, it can be justbeginning to be offered. In our case, the genetic testing that we’reoffering is linked to the insurance format available in some settings,
as it is preemptive testing.
Candice: Your recent application note with us discusses how
you validated your Nala PGx Core® Assay on Bio-Rad’s new
CFX Opus Real-Time PCR System. Why did you choose tovalidate the compatibility of your pharmacogenomics assay withthis thermal cycler?
Astrid: Initially for the CFX96 [Touch Real-Time PCR Detection
System], we already had experience with your reagents; weobviously want to make sure that an assay we make is compatible
with your instrument. We chose it because we know your real-timethermal cycler is ubiquitous in this part of the world and affordable
too. We also found that most of our clients actually have your realtime PCR systems, which further confirmed our decision.
Then, when we saw that the CFX Opus System was replacing theCFX Touch System, we decided to validate it on the new platform.
We also found that a few of our clients planned to switch from theBio-Rad CFX96 System to CFX Opus 96 System, so we needed tosupport them in that transition. The CFX Opus fits our premise of
making an offering that is accessible and affordable. In diagnostics,
it’s a question of cost per test, right?
If customers don’t have the CFX platform, we provide suggestions
for other instruments as well. We have optimized the thresholds

Astrid: We liked the fact that it is a standard qPCR machinewith five-channel detection, which was important because ourNala PGx Core® Kit requires three detection channels. For aparticular variant in the CYP2D6 gene, it has three different typesof nucleotides in the population. It makes a difference whether you
carry a T or an A in this position because it actually determines
whether you’re going to have a decreased or a loss-of-function
enzyme that will impact your recommendation to take the drug.
Candice: So, your assay requirements and the widespread
availability of the CFX platform drove your decision to use this
instrument. Is Nala promoting preemptive testing in hospitals sothat clinicians know patients’ genetic risk of an ADR [adverse drugreaction] before their hospital visit? And why is preemptive testingsafer for patients compared to testing just at the time ofa new prescription?
Astrid: Pharmacogenomics is most beneficial when used at theright time. You want physicians to make the right recommendations
for products and doses. Testing someone’s genetics three days
after a heart attack isn’t practical. The issue today is that thisinformation isn’t readily available, which can lead to trial and error
if a patient needs immediate medication. Having this information
available in advance, during a patient’s healthy state, can savetime and enhance medical checkups. It also offers incentives forpatients and payers. Some insurance companies now reimburse
for these tests in the U.S. In our region, we have three insurancecompanies covering it for their clients. For example, if a client hasa critical-illness policy, they’re asked to take our test. Our test cansave costs for insurers by reducing hospitalization for adverse
reactions and the trial and error of different drugs.
Candice: How do you ensure data privacy and security forpatients’ genetic information with preemptive genetic testing?
Astrid: We’re very cautious about how we store data. While HIPAA
isn’t enforced in Southeast Asia, we follow its principles. HIPAA
keeps genetic and personal information separate so that even if
hacked, it can’t be linked directly to personal data. We don’t have
HIPAA certification here, but we do have an ISO 27001 certification
related to information security. We also comply with government
regulations, such as Singapore’s PDPA [Personal Data Protection
Act] and Indonesia’s policy prohibiting health data from leaving thecountry. We keep data on local servers and use a secure API torelay it to healthcare providers. Yearly audits ensure compliance.
Candice: What is the advantage of a clinical customer using
the Nala PGx Core® Kit to determine the genetic risk of ADRs
compared to running a large NGS screen?
Astrid: Nala PGx Core® focuses on the most impactful genes
related to pharmacogenomics, making it cost-effective andAdvancing Pharmacogenomics from the Bench to the Clinic with qPCR — Insights from Astrid Irwanto, Cofounder and COO of NalaGenetics

efficient for clinical customers. You don’t need all the world’s
genes for a pharmacogenomics test. You can target a smaller
subset with the most significant impact on your population; itfits well into qPCR settings. It allows for quick results with fewer
samples and is cost-effective compared to large NGS screens. As
pharmacogenomics gains acceptance and becomes a national
screening program, NalaGenetics is ready to scale up with morehigh-throughput platforms.
Candice: Do you use other molecular techniques besides qPCR inyour product development?
Astrid: Yes, we offer a user interface for clinical decision support
that enables laboratory technicians, physicians, and clinics
to access a knowledge base with curated information, drug
recommendations, and bioinformatics pipelines. Besides qPCR,
we can analyze pharmacogenomics results from microarray andshort-read NGS, and are moving towards long-read NGS
technology to support a wider range of platforms.
Candice: How do you integrate these different technologies
with qPCR?

Astrid: Each technology has its strengths and limitations. qPCR
excels in cost-effectiveness and fast turnaround, making it suitablefor preemptive testing. While NGS offers more comprehensive
data, it’s not as cost-effective. To promote pharmacogenomics,
we need to change the mindset of the medical community.
Education and outreach efforts are essential to drive the adoptionof these technologies.
Candice: Thank you for sharing this great example of a
successful collaboration using the Nala PGx Core® on
Bio-Rad’s CFX Opus 96 Dx System for in vitro diagnostics andCFX Opus 96 System for research use applications. It truly
showcases the positive impact of the pilot study approachand highlighting the significance of preemptive testing forthese individuals.
Your journey from academic researcher to creator of NalaGenetics
shows your commitment to revolutionizing healthcare in SoutheastAsia. We hope that NalaGenetics, under your leadership as thecofounder and COO, can achieve its mission to provide affordable
and accessible genetic testing solutions and shift the medical
community’s mindset about the ability to enhancepatient outcomes.
BIO-RAD is a trademark of Bio-Rad Laboratories, Inc. All trademarks used herein are theproperty of their respective owner. © 2024 Bio-Rad Laboratories, Inc.
NALAGENETICS and Nala PGX Core® are trademarks and products developed byNalagenetics Pte. Ltd. The content presented, including any statements, opinions, andinformation, reflects the views of Nalagenetics Pte. Ltd. and its representatives.

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