#445 - What Can Japan Teach Us About Treating Human Milk Fortifier as a Drug?

Hello friends 👋

What does it take to turn a single struggling baby into a national standard of care? In this episode, Ben sits down with Professor Katsumi Mizuno (Showa Medical University) and Dr. Melinda Elliott (Chief Medical Officer, Prolacta Bioscience) to discuss the landmark Jasmine Trial, the first randomized controlled trial of an exclusive human milk diet (EHMD) in Japan. The results: significantly better weight and length gain, fewer antibiotic days, and improved feeding tolerance in very preterm infants. After an eight-year regulatory journey, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) granted Prolacta's human milk-based fortifier PreemieFort drug-level designation, a global first, ensuring equitable, nationally reimbursed access for every preterm infant in the country. The conversation also looks ahead to the Fuji Trial and what Japan's precedent-setting decision could mean for Europe and the US.

Link to episode on youtube: https://youtu.be/IsOAZm0rOwE

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Short Bios:

Dr. Katsumi Mizuno: Dr. Katsumi Mizuno is a distinguished pediatrician and neonatologist who currently serves as a Professor in the Department of Pediatrics at Showa University. With an extensive academic background that includes research fellowships at the University of Miami and Harbor-UCLA Medical Center, he has become a leading authority on neonatal nutrition and the clinical applications of human milk. In addition to his medical practice, he holds prominent leadership roles as the President of the Japanese Society for Breastfeeding Research and a key official for the Japan Human Milk Bank Association, where he advocates for the advancement of donor milk safety and accessibility.

Dr. Melinda Elliott: Dr. Melinda Elliott is the Chief Medical Officer of Prolacta Bioscience and a board-certified neonatologist with over 30 years of clinical experience. She has held prominent leadership and clinical positions at prestigious institutions, including The Johns Hopkins Hospital and Sinai Hospital of Baltimore, where she dedicated her career to the care of vulnerable premature infants. An accomplished researcher and educator, Dr. Elliott earned her medical degree from West Virginia University and completed her training at the University of Florida, focusing much of her work on the benefits of an Exclusive Human Milk Diet (EHMD) in the NICU.

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The transcript of today's episode can be found below 👇

Ben Courchia (00:00) Hello, everybody. Welcome back to The Incubator Podcast. We're back after the review of the Jasmine Trial, and we have the pleasure of being joined in the studio by two distinguished guests — Dr. Melinda Elliott and Professor Katsumi Mizuno. Professor Mizuno, Dr. Elliott, thank you so much for making the time to come and talk to us about this study and about the work that is being done in Japan.

Pr. Mizuno & Dr. Elliott (00:29) Thank you for having us. Yeah, thank you.

Ben Courchia (00:32) Professor Mizuno is coming to us from Japan. He's a distinguished pediatrician and neonatologist who currently serves as professor in the Department of Pediatrics at Showa Medical University. He has an extensive academic background that includes research fellowships at the University of Miami and Harbor-UCLA Medical Center. He has become a leading authority on neonatal nutrition and the clinical applications of human milk. In addition to his medical practice, he holds prominent leadership roles as the president of the Japanese Society for Breastfeeding Research and a key official for the Japan Human Milk Bank Association, where he advocates for the advancement of donor milk safety and accessibility.

Dr. Melinda Elliott is with us and she's the Chief Medical Officer of Prolacta Bioscience. She's a board-certified neonatologist with over 30 years of clinical experience. She's held prominent leadership and clinical positions at prestigious institutions, including the Johns Hopkins Hospital and Sinai Hospital of Baltimore, where she dedicated her career to the care of very vulnerable preterm infants. She's an accomplished researcher and educator. Dr. Elliott earned her medical degree from West Virginia University and completed her training at the University of Florida, focusing much of her work on the benefits of an exclusive human milk diet (EHMD) in the NICU.

I would like to begin this conversation by asking Professor Mizuno about the Jasmine Trial — and maybe starting with why it was important for you to be a part of this trial and lead this group through this particular effort.

Pr. Mizuno & Dr. Elliott (02:10) The reason I wanted to start the Jasmine Trial — let me talk about that. There was a baby girl who struggled with weight gain and growth. She was born at 20 weeks and 740 grams. She had hyperinsulinemic hypoglycemia and she needed a central venous (CV) line for a long time.

We fortified mother's own milk with a cow's milk-based fortifier, and we couldn't see any growth. Then I decided to ask if Prolacta could send me the +6 and +8 products. The baby showed excellent growth and excellent improvement. The direct bilirubin level went down, and we could keep the glucose level above 60 mg/dL.

I thought there were many more very preterm infants struggling with weight and growth, and babies recovering from gastrointestinal surgeries. There were other doctors and hospitals I worked with in Japan, and I asked Prolacta to send products for those babies too. But there were other doctors at other hospitals who didn't know there was such a human milk-based fortifier. We couldn't do anything for those babies, and that wasn't fair. So that's why we started the Jasmine Trial. I wanted all neonatologists in Japan to know how effective an EHMD is for very preterm infants.

I'm happy to report that the results of the Jasmine Trial were significant. Shall I stop here?

Ben Courchia (04:08) No, that's perfectly fine. I think you're going to give people a lot of ideas — now everybody is going to think they can call Prolacta and get some product sent over. We discussed a little bit the background section of the article, which talks about how things currently work in Japan. Can you tell us how the outcomes of the Jasmine Trial compare to existing real-world data supporting exclusive human milk diets?

Pr. Mizuno & Dr. Elliott (04:44) I'm happy to report that the results of the Jasmine Trial were significant. Weight gain and length gain were significantly better, and head circumference approached significance.

We know this growth is important for brain development. Babies in the human milk group also spent significantly fewer days on antibiotics. That matters because sepsis is the leading cause of death in premature infants in Japan.

Interestingly, and by chance, there were twice as many infants born at 22 to 23 weeks in the Prolacta arm. This makes the findings even more significant, as these infants are the hardest to grow. This evidence confirmed for the Pharmaceuticals and Medical Devices Agency (PMDA) — which is Japan's equivalent of the FDA — that our high safety standard was not compromised by re-fortification with PrimiFort.

Ben Courchia (06:40) Professor Mizuno, I wanted to know if you had any thoughts on what could explain the better growth seen in this population on an EHMD compared to the standard arm.

Pr. Mizuno & Dr. Elliott (06:58) Babies with EHMD didn't show any feeding intolerance. In other words, babies on the standard diet showed abdominal distension and increased gastric residuals, so doctors couldn't increase the volume of enteral nutrition. That's one of the reasons why EHMD produced better growth compared to the standard diet.

And Ben, there may be something else Professor Mizuno would like to elaborate on — something I learned when I went to Japan. In many institutions, they're still waiting for mother's milk to come in. They don't start as early. So it was a big change.

Ben Courchia (07:42) Yes, that's something I brought up during my review of the article, and I was very impressed by it. Because of the dedication to an EHMD and sometimes the inability to access either mother's own milk or donor breast milk, many clinicians — a significant portion of them — will wait, especially for very small babies, until mother's own milk arrives or donor breast milk becomes available, rather than using a bovine formula to bridge that gap. I found that very interesting.

You mentioned that for babies less than 750 grams, or even less than 500 grams, about 15 to 20% of clinicians will wait — which is quite notable. There are several papers published in Japan documenting those attitudes.

Pr. Mizuno & Dr. Elliott (08:47) Yes. But now we have the human milk bank, and all NICUs can start enteral nutrition within 24 hours of age, as long as NICUs want to use donor human milk.

Ben Courchia (09:03) That's right, and it's also something that is developing in Japan. As we mentioned in the background section of the paper, as of a couple of years ago, 60% of NICUs now have access to donor breast milk through the milk bank. Hopefully that 60% can grow even further in the years to come.

Pr. Mizuno & Dr. Elliott (09:20) Yes. I hope so.

Ben Courchia (09:29) How important were the findings of this trial in discussions with Japanese regulators — especially considering how fresh the data is? How significant were these findings in conversations with the PMDA about how to address the classification of human milk fortifiers?

Pr. Mizuno & Dr. Elliott (09:56) We started this journey quite a while ago — it's been a total of an eight-year journey from Professor Mizuno's first phone call asking for product for that one baby. Since then, we actually developed the trial in cooperation with the PMDA. We had to go back and forth on the trial protocol, with Professor Mizuno going to the PMDA and revising it per their recommendations.

We did the trial they wanted us to do because, when they looked at the evidence, they felt the existing global evidence was sufficient — but not quite enough to warrant drug designation in Japan. So we had to conduct a Phase 3 randomized controlled trial (RCT) to simply demonstrate efficacy — growth, in this case — and safety. The PMDA told us that's what was required because they considered these products to be drugs.

Ben Courchia (10:56) That's very interesting. I think it speaks to the value of collaborating with a national regulatory body to actually answer the questions they have. There's a lot we could do similarly in the US. But I think what's also important in the paper — for those who read it in detail — is the significant emphasis on the effect of an EHMD specifically in Japanese patients. The point being to demonstrate the benefits within the national population. Is that correct?

Pr. Mizuno & Dr. Elliott (11:37) That's absolutely correct. The PMDA in fact insisted that among infants enrolled consecutively at the 10 participating institutions, they asked us to delineate which infants were of Japanese descent. The vast majority were, of course, but there were a few who were not. So we had to conduct a Japan-infant analysis in addition to the all-infants analysis.

Ben Courchia (12:00) Yes, that's something you read in a paper and might not immediately understand — that's why these conversations are so helpful. So with this data, Japan's equivalent of the FDA approved Prolacta as a medication, rather than how it is currently viewed in the US and Europe, which is as a nutritional product.

I'm curious why this designation is important — both for you, Professor Mizuno, as a clinician, and for you, Dr. Elliott, as a representative of the company.

Pr. Mizuno & Dr. Elliott (12:45) I can speak from both sides here. It's a global first. There has never been a human milk-based nutritional product subsequently granted drug-level designation. That reflects, at least for the PMDA, the strength of the clinical evidence and the quality of Prolacta's products.

These human milk fortifiers are not just nutritional supplements — they are a therapeutic intervention. And drug status in Japan is what enables national reimbursement under the universal healthcare system. As a clinician — and I'd love Professor Mizuno to speak to this — that means access is equitable, consistent, and not hospital-dependent.

As I mentioned before, many doctors were not aware of EHMD and how important it is for very preterm infants. They were probably not using human milk-based fortifiers, not using donor milk, and just waiting for mother's own milk — and eventually resorting to formula. That's the worst-case scenario for very preterm infants.

But now, because PrimiFort is classified as a pharmaceutical drug, every neonatologist in Japan is aware that a human milk-based fortifier exists. That changes mindsets — they start using donor milk. Essentially all babies in Japan can now benefit from the EHMD. Because it is considered medicine, all neonatologists start thinking: every baby should receive EHMD for their best future.

Ben Courchia (15:01) What this signals to me is quite unprecedented — the way a country can stand behind what the data shows. As neonatologists, we all recognize the importance of a human milk-based diet, but to have a regulatory body say, "we're going to stand behind that data and put the mechanisms in place" — that's remarkable.

That was going to be my next question, Dr. Elliott. Japan operates under a universal healthcare system, which means this level of evidence-based medicine is accessible to everyone. What does that change in terms of significance for families — beyond the fact that through health insurance they can now access human milk fortifiers? Can families also access it as outpatients? Because that's a concern in the US.

Pr. Mizuno & Dr. Elliott (16:06) PrimiFort is approved for inpatient use only. The prescription drug designation means it is considered a very important medicine for very preterm infants. It also means families of very preterm infants are fortunate — because in Japan, all babies can use PrimiFort. Their baby won't just survive; they will have the best chance to thrive, thanks to better early growth.

Some of the principal investigators (PIs) in the trial also reported that babies tolerated PrimiFort much better compared to bovine milk-based fortifier. There was no concern about early fortification, and families will notice their babies are not struggling to digest their feeds.

Although financial limitations may influence how we feed the most vulnerable infants, a baby's future should never be determined by economics — because babies are our hope and our future. We now know that EHMD improves long-term outcomes in very preterm infants. Knowing this, why should we deny them the best possible start in life?

Ben Courchia (17:22) Very true. That answers a lot of questions for those of us not living in Japan.

Going back to the regulatory journey — were there significant regulatory hurdles beyond providing the PMDA with the data they needed?

Pr. Mizuno & Dr. Elliott (18:02) Neither I nor Prolacta had ever done a new drug application before, so we all learned a lot. The journey, as I said, took eight full years.

The first critical requirement was that Phase 3 RCT, which we developed in cooperation with the PMDA and our partners in Japan, Clinogen. We had to show improved growth without compromising Japan's already exceptional outcomes — their low NEC rates and low mortality rates. That was non-negotiable. Japan is probably one of the best in the world, and the regulators would not accept anything less.

Once we completed the trial, we filed a new drug application in July 2024 — more paperwork than I've ever seen in my life. We then had to pass a clinical trial inspection and a manufacturing inspection. The PMDA sent representatives to California to inspect the manufacturing facilities in March 2025. Finally, in December of last year, we received approval.

Pr. Mizuno & Dr. Elliott (19:43) There were still a few more steps after that — going through a separate ministry to have the product listed, priced, and covered under the insurance system. But finally, literally last week, PrimiFort became available to Japanese clinicians.

Ben Courchia (20:00) That's incredible. Do you feel this decision from the PMDA is a one-off regulatory exception — unique to Japan — or could it become a template for other countries to follow?

Pr. Mizuno & Dr. Elliott (20:18) I think it's probably both. Europe is already changing. Japan classifies human milk products as drugs under the name PrimiFort — these are the exact same products marketed in Europe as Humavant and in the US as Prolacta Plus.

In Europe, regulators have already said human milk is no longer a food. In 2027, that will change officially. The regulation classifies it as a Substance of Human Origin (SOHO). These SOHO regulations include human milk alongside blood and other tissues — excluding them from food regulation because food law is not considered fit to manage clinical intent, donor protection, ethical constraints, and biologic risks. These are exactly the things we discuss as neonatologists when we talk about human milk.

We don't yet know exactly how it will be regulated in Europe — whether as a biologic or a drug. But it's coming, and it's clearly not going to be food. As for the US, I have no idea. But there is definitely an ongoing conversation. Once Japan has changed and Europe changes, I suspect the FDA will make some changes as well.

Ben Courchia (21:37) So the wind is blowing west, not east — it looks like it will need to go through Europe before coming to the US. Do you believe the Jasmine Trial will represent sufficient evidence to keep the ball rolling in other countries, or will each country — the EU, the US — require a similar study conducted in their own population?

Because the trial itself ran from October 2021 to March 2023 — it's not something you can put together and publish in a few months. That could significantly add to the timeline. Do you believe the current body of evidence is sufficient, or will more trials be needed?

Pr. Mizuno & Dr. Elliott (22:50) What we're hearing from Europe is that through the SOHO regulations, the EU has said human milk is not a food. But then they've also said each individual country will determine how to implement that — which will be interesting to watch.

We're already operating in a number of European countries. Notably, Croatia has recently adopted EHMD with national reimbursement, and Poland has adopted the same products and is close to receiving national reimbursement. So some European countries have already moved in that direction. Germany has not yet — there's still a Diagnosis-Related Group (DRG) system and uncertainty about how SOHO regulations will affect it. Every country is different, just as every hospital is different in the US.

Ben Courchia (23:41) Along those lines, does that mean the reimbursement model will differ by country? So for example, we could look at Japan's model for some idea of what reimbursement might look like — but that may not translate to what's needed in Europe or the US. Is that correct?

Pr. Mizuno & Dr. Elliott (24:19) I don't know how each country will handle that — it's not my area of expertise. But what I do know is this: if we continue to evaluate whether EHMD is appropriate for these babies solely based on necrotizing enterocolitis (NEC), we're missing the bigger picture. Japan has a NEC rate of approximately 1.58%.

So they're adopting EHMD for the big picture. Professor Mizuno called us and wanted to talk about the future for these babies — not just about NEC. In the US, I think we've been somewhat stuck on NEC. We need to look more broadly — it's about NEC, yes, but also survival, sepsis, and long-term outcomes.

Ben Courchia (25:11) Absolutely. And in the US, the shift in probiotic use is something that has set us back. Anything we can use to move forward again will be valuable.

Professor Mizuno, as this change takes place — as something previously considered nutrition becomes a medication — how does that affect things in the NICU? Does it change your protocols, how you prescribe it, or the standard of care guidelines? Is there any practical change in day-to-day practice?

Pr. Mizuno & Dr. Elliott (25:58) We have already published guidelines for very preterm infants in NICUs, recommending that all neonatologists in Japan use PrimiFort for fortification. When fortification starts and how it is advanced has already been published in the journal. That's probably going to make a significant difference going forward in terms of enteral nutrition management.

Ben Courchia (26:36) And that means when you're rounding and seeing patients, you order Prolacta the same way you'd order acetaminophen — it now becomes part of the ordering set.

Pr. Mizuno & Dr. Elliott (26:52) Yes. Most NICUs have already adopted that procedure. The main variability between hospitals remains in enteral nutrition — specifically when to start and how to advance. Those details differ between NICUs.

Ben Courchia (27:16) There's always variability in how people advance feeds.

Pr. Mizuno & Dr. Elliott (27:20) Yes. But many published papers have already shown that standardization of enteral nutrition is very important for very preterm infants — not only for reducing NEC, but also for bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). Earlier enteral nutrition is important for decreasing BPD and ROP, as well as for brain protection.

Ben Courchia (27:46) In the paper, you described the protocol for initiating and advancing feeds. Was it difficult to get all sites to follow the same protocol?

Pr. Mizuno & Dr. Elliott (27:59) At the beginning, yes, it was difficult. But once people became accustomed to it, it got easier.

I can tell you, as someone who saw the data — I would love to do studies in Japan all the time. Because when they receive a protocol, they follow the protocol. Unlike some institutions in the US, they are exceptional partners for research.

Ben Courchia (28:31) Is there a word for equipoise in Japanese? That's what we'll have to find out.

Time is flying and I had more questions, but I want to make sure I get to this one: is this now an endpoint, or is this the starting line? Now that the PMDA has approved PrimiFort as a medication, what comes next for the collaboration in Japan and for human milk diet research in the smallest infants?

Pr. Mizuno & Dr. Elliott (29:13) I think the first thing is the Fuji Trial.

We are going to follow the outcomes of the patients enrolled in the Jasmine Trial. The babies are already over three years old, and we have developmental quotient (DQ) data at 18 months and three years for nearly all enrolled infants. We can compare DQ between the EHMD group and the standard diet group.

Because Japan already has strong clinical outcomes overall, we'll also need population-level data to see real-world changes. PrimiFort has already been added to the Neonatal Research Network Japan (NRNJ), so researchers will be able to use this national database to compare outcomes at a much larger scale.

I'm very optimistic we will see real change in the neurodevelopmental outcomes of Japanese children.

I agree. The Jasmine Trial enrolled approximately 70–77 infants per arm, so hopefully we'll see some developmental differences. The NRNJ is an amazing national database — most NICUs in Japan participate, and they follow children to age six. The fact that this data exists is very encouraging. Even if we don't see a statistically significant difference in the Fuji Trial itself, over the next few years we may see shifts in overall outcomes — consistent with the recent neurodevelopmental studies associating EHMD with improved cognitive outcomes, such as the work from Dr. Hare, or the study published last year by Dr. Chow out of Kaiser showing better motor outcomes at age three compared to infants who did not receive EHMD.

Ben Courchia (31:25) The NRNJ needs no introduction — people have seen their data published and it's one of the few networks worldwide that peers truly look to for outcomes data. When do you expect to see results from the Fuji Trial?

Pr. Mizuno & Dr. Elliott (32:17) Fuji goes to age six — so Fuji is still ongoing.

Ben Courchia (32:19) So you're safe on that front! Professor Mizuno, Dr. Elliott, thank you so much for joining us and sharing the backstory and development behind these findings. It's phenomenal work. Congratulations, and we'll be looking out for the results of the Fuji Trial. Thank you very much for your time.

Pr. Mizuno & Dr. Elliott (32:40) Thank you.