Discussing Oligonucleotides, Sustainability, and Yams with Rafael Antunes (DCAT Week)

Rafael Antunes is vice-president of Business Development, Europe, at Aurisco, a chinese pharmaceutical company specializing in API products. Antunes spoke with Grant Playter, associate editor, during DCAT week to discuss the company’s oligonucleotides pipeline partnership, their recent partnership with Cytiva, how the company works to promote sustainability, and much more.

Aurisco has developed what you’re calling a “clinical toolbox.” Can you talk about the potential and clinical benefit to the toolbox?

Rafael Antunes: The company started manufacturing APIs doing the chemical steps with certain steroids in our kind of chemistry. And then we felt the need to back integrate fermentation — that gave us a lot of learning into biocatalysis, into synthetic biology.

Soon, we also developed technologies like photochemistry to selectively produce enantiomers of interest, for example. So, with this specialized knowledge we felt that we could tackle more and more complex products. And customers in Europe and US was asking us to build these complex APIs, peptides, oligonucleotides. Now, for example, we're using asymmetric hydrogenation to selectively reproduce chiral molecules and solid phase synthesis to make oligonucleotides.

Talk a little bit about your partnership working with the oligonucleotides pipeline. What clinical benefits and the potential market did you see there?

Antunes: Well, the company has developed on its own a list of generic oligonucleotides, like Inclisiran and Nusinersen, and we're working as a CRDMO with innovators that are developing new modalities in the RNA space. And we produce samples for them in terms of research development and later on for the GMP clinical, and hopefully commercial, production.

So, the expertise the company has today allows us to work in both generic and innovative spaces. And you see a lot of promising in these products. Like tackling things like weight control, which is massive today in addressing cholesterol, hypertension, and a number of life-threatening diseases.

Let’s take a minute to talk about the broader state of the biopharma market. Particularly in a European context, we've seen a lot of supply chain disruptions in the wake of COVID and the political climate in Europe is a little unstable at the moment. Can you just talk about the difficulties with navigating that and how you characterize that?

Antunes: So, in terms of the biopharma space, we see a lot of growth and potential. I think COVID helped boost the belief on RNA treatments. The industry is now working with regulators to establish new guidance for these products because they believe oligonucleotides are currently classified as small molecules but they actually fall between small molecules and biologics, so they resemble much more to biologics than the small molecule. And the industry is now calling for a specific guidance for these that really address the points for bioequivalence of generic oligonucleotides, for example. Aurisco is attending all these conferences on oligonucleotides and proteins to understand and work together with its partners to really address these questions on getting oligonucleotides approvals, or getting bioequivalence demonstrated.

Now, regarding supply chain disruptions, Aurisco is a pioneer and we were the first company in China to be a part of Rx-360 industry consortium on supply chain security. So, ten years ago, we were already passing inspections by Rx-360 before people were even concerned about their supply chains. So, when COVID came, we were already prepared and we faced very limited impact and we were able to supply our customers with the products because first, we were working with them on forecasting on building inventories and we were able to ship them before lockdowns. We managed pretty well based on those practices we had already implemented.

Just building off that a little bit, would you say the long-term ramifications of COVID are going to be felt, say, 10 years down the line in this regard?

Antunes: Companies are recovering from that impact. And I guess this is nothing new. There were drug shortages before COVID. There are drug shortages after COVID. I think we need to understand exactly why these were happening.

I think FDA had pointed out the issue of drug shortages well before COVID. There was a report from FDA from October of 2019 that addressed the three pillars of drug shortages. Because currently generics have such a low price that they become unsustainable, and it's pushed manufacturing out of Europe or US into China and India. And now it's pushing even those suppliers out, because either they go bankrupt or stop producing. And that is a key cause for this disruption. So, either generics pricing policy changes, or we will keep facing this problem.

We need to really recognize reputable companies that have mature quality systems in place. And we need a more agile system to deal when a disruption happens. So, we seen authorities expedite the approval of the vaccines, showing that it is possible to do it faster. So, I think we need to learn how to do this for tackling disruptions that happen and will keep happening.

Do you have any thoughts on how we can promote manufacturing agility in companies? Is it something we should be leaving to regulatory authorities? Or is it just a matter of good business and the market will sort it out?

Antunes: Well, I think economy is like sustainability. Either you address it on a global way or it will not work. And businesses tend to find their way just like rivers find their way to the ocean. So, I'm sure that the economy will adjust in a way that good companies will find that they need to have dual sourcing, probably they need to qualify companies in Asia and in US or Europe or in India, and have these multiple geographies to cope with unexpected situations. I think that is key for addressing these on a longer term.

I want to talk about new platform investment that you're working with. Can you explain what it was and the strategy behind it?

Antunes: In 2020, we started Aurisco's biotechnology subsidiary focusing on peptides and oligonucleotides. We invested upfront in large scale capacity and pilot scale capacity. So today, we can produce from milligrams up to kilo scale, both non-GMP and GMP. But we felt the need of adding commercial capacity.

So, we recently announced the signing of an agreement with Cytiva, which is a key manufacturer of solid-phase synthesizers for oligonucleotides and we're installing this oligo process unit that will allow us to enter into the tens of kilos production scale that can go up to 200 kilos of oligonucleotides GMP. And this is only the first of three units that we are installing.

So today, companies working in this space struggle because CDMOs have no capacity and their projects go into line and you have to wait for 12, 18 months, if not more. So, what we're really offering here is available capacity to start their programs now and expedite their programs and get the clinical materials out and this has received a significant welcome from companies in the space.

What factors played a role in making this decision?

Antunes: So, our vision stands in two legs. Basically, we have our own generic pipeline and the CRDMO support with innovators. On the generic sides, we are now doing process validation of the first generic which we'll file a DMF before the end of the year that's Nusinersen. The CRDMO space, we are now working with companies that have programs in late phase II and phase III. And of course, we need to prepare now to have capacity. So, if they move forward, and they need commercial quantities, we have to be able to supply.

Of course, we're taking the risk on our own to invest in these capabilities, but we feel that the market needs this and patients need this. And this is very much aligned with the strategy of the company. We've always taken the risk on behalf of our customers so that when they need it, we were ready, and it has worked fine.

Aurisco is celebrating its 25th anniversary. How has the company progressed from then to now?

Antunes: Back in 1998, when the company established, this was a group of people with technical backgrounds, and they wanted to do something useful with their chemistry. They decided to enter the business of corticosteroids and doing the chemistry of betamethasone, dexamethasone type of products. It was quickly understood that we had to do vertical integration with the fermentation steps, and to create an independent supply because everybody else was using yam which is kind of a sweet potato, but this was really not sustainable and there was a lot of market fluctuations around these products. We were the first company in China to develop the fermentation based on phytosterols, which allows us to have a steady supply with a better quality.

And this really supported our customers, which then went into life-saving drugs like fluticasone or beclomethasone for asthma and COPD. Because we succeeded in doing these challenging things, they kept asking us to go into more complex products. So, we went into the biocatalysis and assymetric hydrogenation to make more complex multi-carbon molecules, and then after into peptides and oligonucleotides.

So, we went from a small plant in Tiantai into having currently three GMP inspected facilities, and we are now building our fourth facility. We've opened offices here in the US in New York, in Europe in Portugal, and in South America in Brazil, and we are now planning to expand our industrial footprint and get our own R&D and manufacturing facilities in the US and in Europe. And this should happen in the coming one or two years.

Interesting, I was not expecting yams to be the base for anything.

Antunes: But that is a key for the sustainability of the company. Now, when you're using a food resource that is the basis of food in certain countries, in Africa especially and Asia, and if you're having an industrial consumption of that, that will put pressure of the prices really restricting access to food to a lot of people. If you use phytosterols, you're using agricultural byproducts, so you really having a more sustainable approach.

Can you talk about Aurisco’s approach to sustainability?

Antunes: We have always had a science-based approach to sustainability. Of course, it's important when you can do improvements on the logistics on new packaging. It's much more powerful if you can change the process to make it more sustainable. And I'll give you a good example. We are working on a chiral molecule where the standard processing in the industry requires a final step of chromatography where you waste 50% of what you've produced and you cannot recycle it because the chiral center is in the ring.

So, what we did was develop a catalyst that allows us to do asymmetric hydrogenation process to produce only the enantiomer of interest. And with this, we've eliminated the chromatography step. We reduced the solvent per kilo of the API from close to 500 kilos of solvent per kilo of API to just 60 kilos of solvent per kilo of API produced. And that's a really dramatic impact in terms of sustainability because you're saving solvent consumption, reducing solvent waste, and eliminating energy waste in a process that is just a purification step. So, I think that is our science-based approach to sustainability.

Do you have any bold takes about what the biopharma market will look like five years from now?

Antunes: Well, there's around 7,000 diseases looking for treatments where current standard of care is to alleviate the symptoms and not really to treat the cause. The new modalities bring an opportunity to really cure the disease. And I think this will explode in terms of how pharma approaches the treatment, and we want to be part of that effort. So, we're jumping in early. We're preparing for that because I think this will completely go off the roof in terms of the solutions to the patients.

And we need to be prepared to do smaller quantities, personalized medicines, but do it in an efficient way. And I think that is the key. The key to biopharma is how can we make it in a sustainable way? How can we make it affordable to more patients? Because today, the cost of biopharma drugs is very expensive. But Aurisco offers the possibility to really get into a broader range of patients by doing it in a more competitive way.

For more of our coverage on DCAT in 2023, viewers can visit this page.