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There is no shortage of bottlenecks in the drug development process, particularly for genetic medicines; to learn more about addressing these challenges and ensuring success from the business perspective, 

sat down with Shawn Davis, CEO of Liberate Bio.

The company leverages artificial intelligence (AI) and machine learning (ML) to accelerate drug development, as well as enhance the efficacy of these medicines through novel delivery vehicles.

Can you provide some background on Liberate Bio?

 From the outset, Liberate was created to take on the biggest challenge in the genetic medicines space: delivery beyond the liver. When we thought about what we wanted to accomplish, we knew we had to take a new approach to the discovery process. We had all experienced the slow pace and high cost of traditional development.

For example, most molecules are tested on cells and, if they look okay and you get good engagement with the target, then you move to rodents. Then, if things look good in rodents, you move to non-human primates, which makes sense from a cost and life-saving point of view. While this approach has worked for most classes of therapeutic molecules, for nucleic acids and especially for bioaccumulation of these materials, the only way to know what works is through testing on primates.

Everything leading up to those experiments can give you confidence that your materials are not toxic and give you an early readout of expression, but to a large degree, those are well-understood issues for which experienced chemists and biologics can design from the outset. Then you get into testing on rodents, which always gets your hopes up, because everything looks like it works. You get excited, and then when it almost inevitably doesn’t translate in primates with functioning immune systems, you rinse and repeat hoping to eventually bridge the translational gap between species.

We were thinking through how to get the most relevant data as soon as possible in a cost-efficient way. That's where the RNA-barcoding platform from Michael J. Mitchell, PhD, at the University of Pennsylvania comes in; it allows us to apply the same concept of parallel processing in computing to biology.

Instead of testing one new nanoparticle design in a single animal, we can test tens or even a hundred nanoparticle designs in a single experiment in one animal because we’ve added unique barcodes inside each particle. Not only does it minimize the number of animal experiments we conduct, but we can also speed up the discovery process by testing concepts in parallel.

We no longer optimize the chemistry of the lipid, then modify the formulation to get that right, and finally add a targeting moiety if it’s necessary. We are testing all of these conditions at the same time, in the same experiment, and in a single animal, or multiple animals for the sake of proving everything works. It's very efficient, cuts the cost almost 100-fold, and dramatically speeds up the discovery process.

What role does augmented intelligence and automation play in this process?

Once you resolve that testing bottleneck, then you look at the rest of the design-make-test-analyze cycle. You still have to generate hypotheses (design) and synthesize materials (make) at a rate that takes advantage of your improved testing if you want to speed up the full cycle. When it comes to making materials, you need automation to be able to make hundreds of formulations in a time-efficient manner.

The 'analyze' and 'design' phases are both augmented by AI and ML. Initially, they help you synthesize the information from those experiments into actionable insights. What is it about this particular chemistry that make it work better? How do we double down on that element?

Finally, generative AI is a great tool for creating new ideas. I don't know if you've played around with ChatGPT at all, but you can input a command like 'give me 100 ideas for company slogans.' It would take me an hour or two, but ChatGPT completes the task in 30 seconds. We do the same thing, but instead of asking for slogans, we ask for new chemical structures that are similar to something we think is a good starting place.

The best description I've heard is that ChatGPT is like having an intern with infinite patience to track things down. However, this intern will occasionally lie to you. So, you still have to apply quality checking (QC). If you have infinite time, you can put anything in there. In this case, it's a bit like having a bachelor's-level chemist that would spit out thousands of ideas.

Then a PhD chemist with experience in the field looks at those thousands of ideas. They may note that a lot of it is garbage, but some of it may be interesting. AI doesn’t hand down the perfect molecule from day one; however, a chemist may go from considering it an 'atom blender' to another great chemist to bounce ideas off of. This is the 'augmented intelligence' I’m referring to. A brilliant human working with an algorithm that is still learning.

I was at Amgen setting up the first centralized innovation group for the organization with a focus on digital health, diagnostics, and drug delivery. Most people understood the latter two, but digital health was much more unknown around 2014 or 2015. A lot of people didn't understand where it was going.

Then you'd run into somebody like Philip Tagari, who was the head of translational science at the time for Amgen. His team had already figured out the five key questions they were trying to answer and were determining the questions they had enough data to work with. He was probably miles ahead of everyone else in the industry at that time.

In terms of how AI and ML are revolutionizing drug development, what are Liberate Bio’s next steps in terms of leveraging these tools, and are you looking to do that internally or through partnerships?

 Everything I’ve described is like having tools in a toolbox that you can use to build something useful for patients. For us, we’re building delivery vehicles for genetic medicines that are extrahepatic. When you look at the golden standard of delivery vehicles today, you've got the lipid nanoparticle—billions of doses have been delivered with the COVID-19 vaccine.

Unfortunately, it's almost entirely trapped to delivery to the liver. Within the first two or three minutes of administration via IV, almost 80–90% of it is taken up by the liver. Let's say you have a magic targeting widget attached to the surface; would it even have time to do anything? I think it wouldn’t. Liberate Bio is trying to create these vehicles by first getting the chemistry right and giving it a long enough circulating half-life, so it's not taken up by the liver immediately. This allows it to redistribute to other organs of the body so that we can carry genetic medicines there.

From a business-model standpoint, we want to be a therapeutics company. The key here is recognizing the evolution of the relative contribution of delivery and the therapeutic cargo. I've been in drug delivery for 20 years, and I'm self-aware and humble enough to recognize that we're almost always second fiddle when it comes to the efficacy and safety of a therapeutic. We can make the dosing less frequent or easier for patients to administer the medication, which can offer commercial differentiation, but it’s not making or breaking the product.

That's true until you get to nucleic acids. Without an effective delivery vehicle, you don't have a therapeutic. Post COVID-19, the commoditization of these nucleic acid modalities has been stunning. I was at AstraZeneca (AZ) during COVID-19; we were working on Defense Advanced Research Projects Agency’s (DARPA) pandemic prevention programs even before that. It cost a fortune to make tiny amounts of research-grade mRNA. Post COVID-19, there can be five vendors competing for the business to figure out who can make it the cheapest, fastest, and best for you.

That really shifts the balance. If there are these commoditized mRNA—let's say you're going after Fanconi anemia in the hematopoietic stem cell—I can make an mRNA for that tomorrow with no problem. Optimization exists that could make it better, but the delivery vehicle is going to be what separates that product in terms of its efficacy. That's our basis for becoming a therapeutic company and requires us to have access to these cargos, so it limits what fields we can go into. However, it also means that we have the opportunity with those vehicles to have a second path to that business model, which is through licensing.

When you think about building a business, especially in therapeutics, you usually start with determining which target to go after and what indication it aligns with. That tells me about the patients, population, and projected value. When it comes to delivery vehicles, they're not target or indication-specific. They're cell-specific. If I solve delivery to a cardiomyocyte, I don't have one target to go after; I have half a dozen well-validated genetic mutations that I could address. Those underpin four of the largest cardiovascular indications in the world.

One of those might be for Liberate, the other three might be for others that already have therapeutic cargo waiting for a delivery vehicle. Let's say you give away mRNA for target C, and you then do a second deal for CRISPR-Cas9 for target A, and then I hold onto something else. That gives me a faster path to clinical validation, revenue, and, frankly, to curative potential for patients. So many companies have identified targets and have good cargos to go after them, but don't have the delivery. That's an important stream for us, but it is secondary to us building our own pipeline.

It can be difficult to place Liberate Bio on the financing spectrum. Are you a seed company? Where do you fall in that financing structure?

 We are a seed company and a venture creation activity by Khosla Ventures. Nessan Bermingham, PhD, who was the founder of Intellia, is also an operating partner at Khosla Ventures. He got together with Mike Mitchell to form Liberate Bio and brought on the rest of the team. They've put in seed and convertible note funding up through now. We're doing some fundraising to do a proper seed round.

For the first 12 months, the company was establishing that platform we talked about. Then at the start of this year, we felt confident; we had done the first non-human primate study. We proved mathematically that you could test 100 nanoparticles and so we hit the ground running. We basically had a freezer full of chemistry that we had already design and manufactured, so we screened 150 novel nanoparticles in those three months. We did that not just in the non-human primates for bioaccumulation, but also in parallel with rodents for expression.

What's great about those complementary and orthogonal screening approaches is that there are many reasons they won't match up. AI suggested certain things would accumulate like crazy in a non-human primate, and they did, but then they didn't express at all in the rodent. I don't know what stopped it from working, but it didn't work. Similarly, we had some rodent data that, when I saw it, I couldn't believe. Can you get 5% only to the liver and 95% to the other organs?

When the two screens do overlap, we start getting excited. Even in the first batch of materials, that's exactly what we saw in the bone marrow, spleen, heart, and skeletal muscle. We're focused on screening broadly and unbiasedly, but you need to direct it in some way. We’re excited about cardiomyocytes, hemopoietic stem cells, and podocytes in the kidney.

This is because each of those cell types has multiple, well-validated targets unpinning indications with unmet need. They're also reasonably scientifically tractable. There is so little in the field for delivery to anything other than hepatocytes in the liver, there is value virtually everywhere else. It comes down to what you think you can do. Because of the distribution we achieve with delivery via IV, we felt confident about hemopoietic stem cells in the bone marrow. It’s a similar story for the heart, I’m personally excited about the potential for these indications.

It is interesting hearing about startup cell and gene therapy companies dipping their toes into the cardiomyocyte realm, but there hasn’t been much notable progress yet. Can you weigh in?

 If 20 years in drug delivery has taught me anything, it’s that if you really want something somewhere, you poke a hole in it, and you put it right there. The heart is nice because, with some work, you can put it directly in the heart. AZ has demonstrated direct intracardiac administration that requires you to crack a chest open, which is not most people's preferred route of administration. But you can do intracoronary administration, go into the femoral artery, and deliver it directly to the heart, and that will avoid a lot of this first-pass uptake in the liver and allow it to concentrate in the heart.

Going back to the toolbox analogy, you have to be open-minded about what tools you have at your disposal to make sure it gets where you want it to go. Unlike bone marrow, the heart provides that opportunity. Even the kidney provides that opportunity. I didn't realize there were nine direct administration routes in the kidney.

So far, unfortunately, we haven't had much success in the kidney, so that’s a future opportunity. However, we're seeing 20–30x greater accumulation in the bone marrow than we are with the lipids published in the literature. In the heart, we see 5–6x, the spleen, maybe 5–10x. These are all really exciting, both for immune cells in the spleen as well as potential in both cardiomyocytes and hemopoietic stem cells.

Articles

Shawn Davis, CEO of Liberate Bio, shares some insights into the world of drug discovery, development, and delivery, as well as process optimization 

Improving the Efficacy of Genetic Medicines

Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio interview

The Benefit of Long-Read Sequencing in Gene Therapies

At the American Society of Gene and Cell Therapy (ASGCT) conference in Baltimore, Md. in May 2024, 

® sat down with Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio, about the benefits of long-read sequencing in cell and gene editing.

According to Sellami, long-read sequencing detects information that short-read sequencing cannot capture. “And in contrast to other long-read sequencing methods, it has higher accuracy while maintaining the same read length,” she says in this video interview. “So, for example, you can see long indels that you might get from gene editing. You can sequence the entire AAV [adeno-associated virus] molecule, ITR [inverted terminal repeat sequence] to ITR. You can sequence plasmids. You can sequence full length mRNA [messenger RNA] and so many more sequencing applications.”

DNA sequencing is important for the design, production, and quality of gene therapies, says Sellami. Click the video box above to view the full interview.

For more coverage from the 2024 ASGCT conference, visit PharmTech.com’s 

Highlighting Personalized mRNA-Based Vaccines for Pancreatic Cancer

Research Shows that HIC Can Effectively Separate Deaminated Capsids from Non-Deaminated Capsids

Using Receptor Architecture to Improve CAR-T Cell Sensitivity in Oncology

The Role of Bispecific Antibodies in Redirecting AAV Vectors

Videos

Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio, talks about long-read sequencing for cell and gene editing in a video interview. 

Gabi Hanna, MD, CEO and co-founder of Lamassu Pharma. 

In the realm of drug development, the industry puts a great deal of emphasis on centering the patient experience. As a result, it is imperative that drug developers consider how they translate scientific and medical knowledge into actionable insights that support the patient journey. To delve deeper into this topic, 

 sat down with Gabi Hanna, co-founder and CEO of Lamassu Pharma, to talk about the company’s beginnings, as well as its novel small molecule MDM2 inhibitor that activates P53 to control cancer growth.

Starting with the inception of Lamassu Pharma and the corporate focus, can you tell us about initial clinical indications?

 The company was founded in 2018 by three founders who are physicians and scientists. We focused on addressing unmet needs and translating scientific knowledge to patient care. When we started, there was a lot of knowledge but few options for conveying it to patients. That was the big gap we tried to bridge. I'm the director of the drug development center at Duke University. The second co-founder, Rabi Hanna, MD, is the director of pediatric oncology at the Cleveland Clinic. The third co-founder, Greg Palmer, PhD, is the associate director for the Duke Cancer Institute. With our experience, we had the basic knowledge to achieve our goal and maintain a focus on science while also remaining patient centric.

Our first project involved partnering with Mayo Clinic in 2019 to develop a treatment for acute pancreatitis. In just a few years, we advanced it to Phase I, partnered with another group, Arrivo BioVentures, completed Phase I successfully, and are now in Phase II. Two years ago, we partnered with the European company Adamed. We developed a very novel oncology platform focused on wild-type P53, which potentially can target 50% of all cancers. P53 is perhaps the most important gene regulating cancer; in fact, it's called the "guardian of the genome." Our therapy, a small molecule MDM2 inhibitor, activates P53 to control cancer growth.

What's the trajectory in sarcoma? Where are you in terms of development, and when will you initiate the clinical trial?

 The MDM2 inhibitor can potentially target up to 50% of cancers. We are focusing on sarcoma, a field in which treatment has not changed in ~30 years. We received investigational new drug (IND) approval from the United States Food and Drug Administration (FDA), and we have a novel therapeutic protocol agreed upon by the FDA. Our leading site is the Cleveland Clinic, so it will be a multi-site study that first starts with the Cleveland Clinic and lead to expansion. There is a consortium we will expand to, but we will begin with the acceleration phase, treating the first few patients at the Cleveland Clinic with our strategic partners leading the trial. We expect to have the first patient treated within the next two months.

Will this be a traditional dose-escalation study to find the optimal dose in Phase I?

 Yes. The approach will be traditional but also innovative. The FDA has allowed us, given the significant unmet need, to use a smaller group of patients to escalate the dose more quickly. Typically, dose escalation starts at a low, safe dose and gradually increases to find the best dose. However, this can be ethically challenging for cancer patients who might receive sub-optimal doses initially. The FDA is helping us by allowing a smaller patient group to escalate quickly. We will start with one patient to find the optimal dose faster, benefiting sarcoma patients who have limited treatment options.

Are you envisioning running the study entirely within the company, or will you potentially partner with pharmaceutical companies?

 We do not use contract research organizations (CROs). We run the trials directly due to our expertise, experience, and network. As mentioned, we come from academia, with scientific and practical backgrounds. We already have partnerships with the National Cancer Institute (NCI) and the National Institutes of Health (NIH). We have direct knowledge and collaboration with principal investigators and scientists. We've run CROs before, so we have the team to manage the trial directly. This approach serves patients best, accelerates development, and allows us to react in real time to any issues, which is crucial given that we are treating very sick patients.

We manage direct patient care with the principal investigator (PI) and the hospital. Our goal is to advance the drug to NDA approval. If we find a good partner along the way, we will partner, but we are not planning to conduct a study and then wait for a partner. However, like with our acute pancreatitis program, if we find a good partner, such as Arrivo BioVentures, we will collaborate. We are open to partnering in oncology at any stage if we find a suitable partner.

Other companies have studied the MDM2 pathway. What makes your approach different? Is it the P53 wild-type aspect?

That's correct. We consider our approach as more of a third-generation solution, addressing some of the safety issues seen before. There's no approved MDM2 inhibitor drug currently. One advantage of coming into this area later is learning from previous lessons, identifying potential pitfalls early, and testing whether we can overcome them. The disadvantage is that we are a bit behind, but we believe our asset could potentially be best in class. Our in-house testing shows it to be more potent and to have a better safety profile.

Additionally, P53 MDM2 represents a significant market. Targeting 50% of all cancer patients is a huge opportunity, with room for multiple routes if proven efficacious and safe. Sarcoma is one of the biggest unmet needs, with over 90% of sarcoma patients having P53 wild-type. Because it's a smaller market, with around 13,000 patients in the US, development can be faster. It falls under the rare oncology category. As a smaller company, we focus on early proof of concept before tackling larger cancer types. Scientifically and ethically, it is good to address the biggest unmet needs first. Starting strategically with the biggest unmet needs and smaller, more controllable studies allows us to expand to larger cancer treatments later.

In terms of clinical development priority, given that you're already in Phase II, would pancreatitis be your lead indication with cancer following that?

These are two different categories. We partnered with Arrivo BioVentures for pancreatitis, but they are not involved in the cancer aspect. Pancreatitis is inflammation, while cancer is a separate focus.

Tell us about the leadership team at Lamassu Bio and the growth trajectory in terms of expanding the team. How many full-time employees do you have right now?

We intentionally keep the team small to maintain direct oversight and efficiency. We aim to have three to four assets maximum, keeping the group small and focused. We work closely with universities and rely on outsourcing. We do have more than 10 but aim to keep it under 20. This smaller size allows for direct interaction and fewer hierarchical levels, enabling faster decision-making and problem-solving, especially when treating very sick cancer patients. We prioritize patient care over company interests, adhering to our ethical code.

Do you have any additional thoughts on the future directions of the company?

We are in discussions to bring in more partners and assets, particularly in oncology. We are expanding our team to manage trials directly and are also expanding to Canada, specifically Montreal, where we have established a partnership with McGill University. Our focus will be on oncology and direct management.

Gabi Hanna, MD, CEO and co-founder of Lamassu Pharma talks about a novel oncology platform and the link between science and patient care. 

Lamassu Pharma Bridges Scientific Knowledge and Patient Care

Dave Bearss, PhD, CEO, Halia Therapeutics. 

During BIO International Convention 2024, CEO Dave Bearss, PhD, of Halia Therapeutics, discussed the biopharmaceutical company’s progress in inflammation drug discovery. Founded in 2017, Halia Therapeutics supports the discovery and development of novel therapies to improve the lives of patients with inflammatory disorders and neurological diseases. 

Bearss discussed the clinical pipeline, upcoming announcements, and study readouts that others in the industry should look forward to, and personal thoughts regarding the industry’s focus on caring for patients with, or at risk for, chronic inflammatory diseases and neurodegeneration.

What is the current state of myelodysplastic syndromes (MDS) and inflammatory pain? What are your expectations, looking into the future clinical pipeline?

 It's been a busy year and an even busier summer. We’ve got a ton of good things going on. We have fully enrolled our post-procedural information study, meaning the evaluation of inflammatory pain after surgery. We are going to report the results of that study very soon. This is a randomized, placebo-controlled, blinded study. It will be the very first NLRP3 targeted drug to have randomized Phase II data reported out, so we are excited about this. We're excited to see what that data looks like. We are optimistic that there’s a positive signal there.

We started with a focus on MDS because we know the NLRP3-related inflammatory pathway is the driver of that disease and here we can sample the affected tissue. It's hard to do that in the brain, lung, liver, or heart. You can't. However, we can take bone marrow pretty easily and watch what happens from baseline. The reason why we started here is because we can read out results quickly and show that the drug is affecting biology in the way we expect.

We provided an update at EHA, the European Hematology Congress (2024). We've treated 16 people so far in that study, and we have 26 people in screening right now. And so, the study has really picked up. There are 40 patients total, planned to be in the study. We hope to have them all enrolled this year (2024). 

After four months of therapy, we want to look at hematologic improvement, marrow improvement, and quality of life. One of the challenges associated with MDS is that patients feel terrible all the time. In addition to being terribly anemic, they have active inflammation throughout their body, in their marrow. Because of this, they have cytokines constantly being pumped out. 

Having the capabilities to lower these, we should be able to make people feel better. So, we're very encouraged. I’d like to add that this is an open label study, so we can watch what's happening. So far, the longest patient on the study has been on it for six months. We started the Phase 2 study in December, so we're just analyzing the marrow from the first few individuals right now. This summer, we’ll have several more. We are hoping to get good objective responses.

For this specific indication a few drugs have been approved more recently, but they haven't really made an impact on the disease. We hope that we will be able to share something with the potential to modify the history of the disease and put people in a different place. We continue to generate data in the lab ourselves, and with collaborators that suggest that this pathway is the driver for these bone marrow failure disorders and anemia, more broadly. 

People don't realize how common anemia is. A lot of people walk around anemic and don’t realize that they are. In fact, most of anemia is not because they're iron deficient. Our body is efficient at absorbing and recycling iron. Most anemia is the result of inflammation.

Anemia of chronic disease, or anemia of chronic inflammation is a very common condition that is difficult to treat. Patients just learn to cope and live with the condition. The condition is associated with patient age, because we all have more chronic inflammation as we get older. In fact, the condition is very common. Almost one-quarter of the world's population has anemia. Some of that is transient, but a lot of it is chronic and impacts patients for a long time.

In addition, there’s a phenomenon called clonal hematopoiesis that no one ever speaks about and is not well understood. When we're young, our blood is produced by lots of different stem cells and clones in our body. As we age, a single clone actually starts to produce most of our blood. There are sensitive techniques available to help analyze this.

As we get older, our hematopoiesis shifts and that shift is driven by inflammation. Inflammation in the bone marrow can prevent the differentiation of normal hematopoietic stem cells. Those precursor cells there give rise to myeloid and erythroid cells, and platelets that come from a progenitor cell in the bone marrow. When you have inflammatory signaling in the marrow, it can block that differentiation.

I tell people the marrow is the hardest working tissue in our body. We have billions of blood cells. Our tissue is working like crazy. We have to have blood. Your body will find a way to fix whatever needs to be fixed. This is done by selecting mutations to overcome suppression. 

Obviously, having mutant blood cells doesn't sound like a positive thing, and it's not. And as patients age, mutations can accumulate in your marrow. They don’t necessarily lead to cancer, although they can. But they can increase the risk for the development of other diseases. If there are mutations found in a person’s white blood cells that were derived or were selected to overcome inflammation, those white blood cells are not normal anymore.

Halia Therapeutics headquarters in Lehi, Utah. 

What clinical data readouts can we expect over the course of the next 12 to 18 months?

 We’ll have the formal readout on the post-surgical information study by the end of this summer (2024). We’ll publish and present that data. That will be the first placebo-controlled randomized study for our program.

The MDS trial is actually a two-stage design. The initial stage will be analyzed this summer. The trigger to initiate an expansion study will be dependent upon seeing a certain level of responses in the first stage. We'll have that readout this summer as well.

We also have some other exciting data in other areas that we'll be releasing this summer. We have already publicly stated, but we'll announce the first patient treated on a new program that targets Alzheimer disease (AD). We're approaching AD very differently, and we are looking at high-risk populations—people who are APOE4 positive. APOE4 has been well established. It’s not a rare marker. In fact, 20-30% of the population has at least one APOE4 mutation or allele, and 2-3% of the population has two. Patients who are double positive have more than a 90% risk of developing AD. 

And our entire company, Halia Therapeutics, was founded on a genetic observation. We discovered a way to protect people who have APOE4 from developing AD. Through a human genetics study, we found another mutation that protects against this risk. And so, we have a clinical program, following up on that observation, that we’ll announce results on next month.

We've got a rapid development strategy for that in APOE4-positive patients who are pre symptomatic, so we're going to try to prevent AD, which is cool. Waiting and then trying to treat late-stage AD is a bad idea, right? You can't unscramble scrambled eggs. Once you have too much neurodegeneration, it’s hard to come back from that. A lot of great work has been done getting imaging endpoints and biomarker strategies validated and even FDA approved, and we believe we can leverage those tools to look at high risk populations and show they have changes pre-symptomatically, before they have cognitive effects. We already know their brain chemistry is starting to change. 

So, we're looking at people over age 50 who are double positive APOE4 and already shows signs of being on the on the path to AD, and are exploring the potential to take them off this path to AD. The human genetic experience says that we should be able to do this. There is another mutation that we found in a protein, RAB10. If we can inhibit RAB10 function, we can block the progression of AD down that pathway, specifically in people who are APOE4 positive. We’re very excited about this.

We are always looking for new, non-invasive ways to monitor symptoms of disease and to objectively track things. One of the big challenges in studying CNS disorders is a lot of the data is subjective. We’ve been looking to see if there are more objective ways to do this. In fact, we have a partner, Canary Speech, in Utah who has been developing specific vocal biomarkers, or speech biomarkers. It turns out that how we talk is indicative of a lot of things that are happening physiologically, especially things in our brain. We can measure things such as how much pain somebody's in. You can talk to physicians who, based on clinical experience, can pinpoint whether a patient is faking their symptoms based on certain cues. 

With help from Canary Speech, we’ve been training algorithms using speech biomarkers. In a 30 second recording, we can pick up over 2500 biomarkers that are reproducible and can distinguish between different disorders. We can assess for cognitive decline, depression, anxiety, etcetera. Maybe we can apply these to pre symptomatic patients and identify issues earlier than normal cognitive tests would detect symptoms.

When we consider the future and shifts toward digital capabilities like telemedicine, it’s been challenging. Physicians haven’t had the tools to help manage patients appropriately via a virtual call. But if you could put patients into a virtual waiting room and have them speak to an algorithm and then look at the data to assess pain levels, anxiety levels, etcetera, now physicians have something they can work with. So, we think there’s a future there. We are trying to get better at giving people tools to be able to monitor this stuff. And especially for things related to the brain, I think this all makes perfect sense.

 Even though the field has had a couple of approvals in the AD space, I don’t believe anyone thinks those are game changers, in terms of altering cognitive decline. I think everybody accepts the notion that we must get out in front of these diseases and determine how to prevent them. I’ve been reading statistics and we’re an aging population. Our birth rate has been declining for decades but the population is living longer. 

We have made some advances to help prolong life, but the problem with life prolongation is corresponding chronic conditions. I just read a statistic that if you add just one year of general health to the entire world's population, it is worth trillions of dollars to the economy. This is something we should all be thinking more about.

We all joke that nutrition and regular exercise is the answer to everything. In reality, there is a role, especially for patients with genetic predispositions or those who are predisposed to metabolic disorders or neurological disorders, to supplement healthy habits with interventions, and early. This has already been demonstrated. Statin therapy is probably one of the most successful examples. 

In regards to statin therapy, we had a biomarker that we could measure early, we had a drug that we could tie to that, and we've made an impact. It’s one of the reasons why we're living longer, right? The drug can be taken at a pretty low dose and has very few adverse effects. Right now, GLP-1 inhibitors are a perfect example. Everyone is excited about the potential for weight loss, but the long-term effects are exciting. It's not just weight loss. You're restoring a metabolic defect. We spoke earlier about the immune system. 

The immune system is actually very sensitive to the environment that those immune cells find themselves in and the nutrients they have available to them. The oncology world has been excited about taking the break off the immune system, but the gas of the immune system is the nutrients. If there are too many or too few, the way the immune system responds to certain signals is altered. 

Metabolic syndrome certainly affects what our immune system does. We're starting to see, already, some of the long-term benefits of these GLP-1 drugs aren't necessarily tied directly to weight loss but, instead, are tied to the restoration of metabolic function and can normalize the immune system. Even for Parkinson disease, a recent readout highlighted that GLP-1 drugs have demonstrated alleviation of symptoms. That's a game changer. We’re looking forward to releasing some data on targeting inflammation and using GLP-1.

What does the future hold for Halia Therapeutics?

 It’s very interesting. Right now, pharma is changing. We, as a field, are considering swinging the pendulum back, the other direction, to focus on some of the big problems we are facing, instead of only focusing on niche issues. At the start of my career, when statin therapy first began making an impact, stakeholders in the industry were very excited about the “big problems.” 

And then, the focus shifted to personalized medicine and isolation of small, more specific patient populations. Obviously, we've made progress and great advances, but I really like where we're headed. Let’s look at big stuff again and go after the big problems.

Novel approaches against chronic inflammation could potentially prevent certain inflammatory diseases and neurological conditions.

Pushing Boundaries to Revolutionize Chronic Inflammation Therapy

Considerations in Pharmaceutical Facility Design

The Pharmaceutical Technology Group spoke with John Bertagnolli, vice-president of Commercial Operations, at the 2024 CPHI North America event, about what it takes to create a new pharmaceutical facility. According to Bertagnolli, the building of greenfield facilities by contract manufacturing organizations (CMOs) is a new trend in the outsourcing industry. “It's usually an aging … pharma-owned, Big Pharma-owned facility [that is] repurposed as a contract manufacturing organization, or an existing company has … other parts of it built on so that they can do different parts of contract manufacturing,” Bertagnolli says.

He points to three milestones that CMOs should meet when building a new facility: completion of the facility, completion of the first aseptic process simulation (APS), and regulatory approval and manufacture of the first product. “[W]hen we're talking about the APS, it's what used to be referred to as the media fill, but [FDA] has put some much … tighter bounds around what they call aseptic process simulation. And because of that, it truly is the final exam for a facility to say, yes, we know we can manufacture sterile product to the correct level that would meet [FDA] requirements. [I]n the case of building a brand-new greenfield site, that also means that you've done all of the characterization of the site from a microbiological perspective, so that you know how all the monitoring is done, that all of the utilities have been established and validated, and you have data to make sure that they're doing exactly what they should be doing.”

Click the video above to watch the full interview. CPHI North America occurred May 7–9 in Philadelphia.

John Bertagnolli, vice-president of Commercial Operations at Selkirk Pharma, discusses considerations when building and scaling up pharmaceutical facilities, including contamination control and aseptic processing challenges.

Considerations in Pharmaceutical Facility Design (CPHI North America 2024)

John Dunlop, PhD, chief scientific officer at Aliada Therapeutics.

[Editor’s note: This interview has been lightly edited for brevity and clarity.]

At BIO 2024 in San Diego, John Dunlop, PhD, chief scientific officer at Aliada Therapeutics, sat down for an interview with 

 platform and its potential impact on therapeutic delivery for brain-related conditions. The platform leverages highly optimized protein domains that target the transferrin receptor (TfR) and CD98 receptor, which are key for transporting agents across the blood-brain barrier.

Can you tell us about Aliada’s MODEL platform and discuss the science driving this novel approach?

 Starting with the name, the term MODEL stands for Modular Delivery, which I think speaks to the breadth and flexibility of our platform. We have several design tools with the key components of the MODEL platform being highly optimized protein domains that bind to either the transferrin receptor or the CD98 receptor. These are both highly expressed on brain endothelial cells and are responsible for transporting physiological agents across the blood-brain barrier: transferrin via TfR and CD98 as part of a heterodimer of the large amino acid transporter. We take advantage of those by engineering highly optimized TfR or CD98 binders that we can then use to attach to different types of cargo. The cargo can be therapeutic antibodies, or enzymes for enzyme replacement therapy, for example (See 

. MODEL leverages the transferrin and CD98 receptors (TfR and CD98) with engineered protein domains attached to cargoes that can cross the blood-brain barrier via transcytosis. Image courtesy of Aliada Therapeutics.

. Because TfR and CD98 are expressed on resident cells inside the brain as well as the epithelial cells of the BBB, MODEL can also mediate cargo uptake by neurons, microglia and macrophages through a process known as receptor-mediated endocytosis. Image courtesy of Aliada Therapeutics.

We are also placing a major strategic focus on oligonucleotide therapeutics. The current standard of care is to deliver these through an intrathecal route of administration. Our premise is that we can generate antibody-oligonucleotide conjugate scaffolds using the TfR or CD98 delivery modules, which allows for the potential of a peripheral route of administration via IV—maybe even subcutaneous in the future—and achieve target knockdown of a particular gene of interest in the brain. We are solving one of the big challenges with this direct intrathecal delivery, which is very invasive and associated with numerous toxicities.

The MODEL platform contains a number of different components. The workhorse delivery module is a single chain Fv, a component of the antibody that typically binds to the antigen. We have stabilized that through proprietary stapling technology. Those protein domains are typically inherently very unstable, so that is one of our true differentiators. The fact that it is just a single chain Fv gives us the ability to attach it to different types of cargo in a very flexible way. Finally, there are several different antibodies we utilize like scaffolds, one of which we call the mono IgG. It has a single Fab arm that is addressing either TfR or CD98. The importance is that with the Fc retained there, you can use it as “real estate” where you can conjugate things like oligonucleotides. We are starting to do a lot more work in that area to really build that up.

 What are the main areas of focus as Aliada develops its MODEL platform?

: The first is reducing the platform to practice, particularly around RNA therapeutics, and that'll be both in the field of siRNA as well as antisense oligonucleotides.

And then the other primary focus is our lead program [ALIA-1758], which is an antibody-based therapeutic that is enabled with our transferrin single-chain Fv delivery module, developed for early Alzheimer's disease. It is an amyloid beta (Aβ) targeted antibody that targets the pyroglutamate forms of Aβ. These are highly aggregate-prone forms of Aβ and are very much expressed in the plaques in the human brain. It is the same epitope that is targeted by a molecule called donanemab which is in development by Eli Lilly.

We have engineered some important attributes that I believe will differentiate us from donanemab. In terms of the pyroglutamate binders, we have a significantly increased affinity for pyroglutamate compared to donanemab. Additionally, we have configured the molecule with our single-chain Fv transferrin brain shuttle, so we get much more of the antibody delivered into the brain. With these two factors, we believe we could have a once-monthly, subcutaneous administration at a very low dosage level. Other agents in the field are IV administration, so you need to go into an infusion center and spend time there. We think we can really bring what could be a best-in-class asset to Alzheimer's patients.

The exciting part there is that we are imminently about to start our clinical trial. It will be a single ascending dose study in healthy volunteers to understand safety, tolerability, and initial pharmacokinetics. That will set us up ultimately to then do a multiple ascending dose study in Alzheimer's patients. It will be very exciting for us to be able to say we are a clinical-stage company, and that's going to happen very soon.

Are you excited about the seemingly accelerating progress in the Alzheimer’s disease field in recent years?

 I think there has been just tremendous progress in the Alzheimer’s disease space. Biomarkers now really make us very confident that subjects coming into trials already have evidence of amyloid pathology in the brain, because we can look at it through PET imaging and we can measure different beta-amyloid and tau species in the blood that are also correlated with those PET images. When you think back to the initial trials of some of the initial Aβ antibodies almost 30 years ago, about a third of the subjects who were enrolled in those trials didn’t actually have amyloid pathology in their brain, which we learned when they passed away. They had some other type of dementia, instead. This factor was diluting the potential to see a signal in a clinical trial. Now we can very definitively recruit subjects with Alzheimer’s disease, and we are very biomarker-enabled to track the progress of our therapeutics. So, we’re very excited to be starting our clinical program very soon.

At BIO 2024 in San Diego, John Dunlop, PhD, chief scientific officer at Aliada Therapeutics, sat down for an interview with Pharmaceutical Technology to discuss the firm’s MODEL platform and its potential impact on therapeutic delivery for brain-related conditions. 

Therapeutic Delivery for Brain-Related Conditions

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan

Flexibility in Outsourcing Models

Outsourcing pharmaceutical manufacturing and development processes can provide pharmaceutical companies with financial flexibility, according to Jessica Madigan, director of Business Development, Nucleic Acid Modalities, at BIOVECTRA. The PharmTech Group spoke with Madigan after the BIO International 2024 Convention to learn more about the flexibility outsourcing models can provide.

“At BIOVECTRA, we offer flexible pricing models that can help companies manage cash flow and financial risks,” said Madigan. “[Pharmaceutical companies can reduce] capital investments by leveraging the infrastructure and specialized equipment that is already onboarded at CDMOs [contract development and manufacturing organizations]. This can be especially important for startups and small biotechs. … it allows them to direct the resources to their other business areas, rather than building up infrastructure and investing in specialized equipment.”

Madigan details the five different models her company provides, including a dedicated facility model what includes an entire building or facility reserved for the customer. Fractional ownership of a facilities with other customers is also available. “That way, we can [leverage] essentially a platform manufacturing process or a similar platform manufacturing process across several clients, that offers flexibility of capacity between those different partners, and allows a lower entry into a larger capacity.”

Click on the video above to watch the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan, about the concept of flexibility in outsourcing and the 2024 BIO Convention.

 Flexibility in Outsourcing Models (BIO 2024)

Lonza’s Joe Garrity and Jerry Jiang discuss the importance of not only automating CGT manufacturing, but also standardizing across processes.

The Need for Automated and Standardized CGT Manufacturing (BIO 2024)

While cell and gene therapy (CGT) manufacturing must remain flexible out of necessity, it is also important to standardize processes at an industry level while establishing aseptic-friendly automated operations. Standardization, in particular, is important from a scaling perspective, says Joe Garrity, senior director and head of Autologous Cell Therapy, Lonza.

During BIO 2024, Garrity pointed out the many challenges incurred on the cell therapy side. “It stems from supply chain to operations to clinical sites. There's just so much that needs to go into, specifically, autologous cell therapies, with the batch quantities going into the hundreds and thousands that we're seeing from some of [the] large drug developers.” Thus, he says, standardizing the manufacturing process allows for robustness and process control across the board.

Garrity also notes, however, that even with standardization, “it's not a one size fits all”. Instead, he says, “[much of the time,] it's a little bit of a one size fits most, and you're going to have to be relatively variable, but in the end, the overall standardization of the manufacturing process and the intent of that remains the same because it's better control at scale. Once you find something that really funnels that process robustness and that scalability, you … stick with it so it's reproducible time and time again.”

In discussing whether it’s possible to have manufacturing processes that are both standardized and flexible, Jerry Jiang, clinical application specialist, Personalized Medicine, Cell and Gene Therapy, Lonza, says, “Definitely. One of the things that we really have to start standardizing is the release criteria and the quality of the cells that are being put into the patients. [The] material that comes in is going to be different, but standardizing what we expect the cells to do and behave and what they look like is going to be a huge part of what the standardization process needs to overcome right now.” However, flexibility remains in the details. “[T]he standardization is the same, but the flexibility of the process allows these different companies to optimize the process with their ‘secret sauce’ that will really differentiate their treatment from all the other treatments out there,” says Jiang.

“We definitely need to standardize the way we are inspecting and checking the cells before it goes into a patient, but the flexibility allows each company to … show off their technology and allow for them to shine with the advancements that they've made,” Jiang adds.

Click above to view the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

Lonza’s Joe Garrity and Jerry Jiang discuss the latest trends and challenges in commercializing new CGTs. 

Trends and Obstacles in the CGT Field (BIO 2024)

Cell and gene therapies (CGTs) remain an important focus in the biopharma industry. During BIO 2024, Joe Garrity, senior director and head of Autologous Cell Therapy, and Jerry Jiang, clinical application specialist, Personalized Medicine, Cell and Gene Therapy, both at Lonza, discuss the latest trends and hurdles in the CGT space.

“Moving from the 2017 timeframe into 2020, we saw a heavy focus on a [significant amount of] money floating around focusing on autologous cell therapies and how we can better provide these life changing therapies to patients,” Garrity says. From the autologous cell therapy perspective, efficacy has been achieved, but the challenge remains that an autologous cell therapy is one manufacturing batch, or one dose, per patient. “The scaling is a little bit of a challenge,” Garrity says, noting, “This is where the allogeneic approach has taken over, and in the cell therapy space, we've really seen that shift … seen [focus] go from two-thirds autologous to one-third allogeneic to almost a 50/50 split.”

Garrity expects this trend to continue to where the industry may see a rise in allogeneic cell therapies, from a molecule number standpoint. “We're seeing a [bigger] influx of allogeneic cell therapies trying to provide a secondary option to commercially viable CAR-T [chimeric antigen receptor T cell]/CAR-NK [chimeric antigen receptor natural killer cell] drug products,” he states.

“At the end of the day it’s really about providing access and availability of cell therapies to those who really need it,” Jiang adds. “The cell therapy production process can be complex, and current solutions are not sufficient to be able to scale to the patient demand. So, as a result, new technologies are being developed to help reduce timelines and cost and improve scalability.”

Another issue Jiang points out is the difficulty in finding technicians who are able to work with and produce these therapies. “We've seen [many] different manufacturers try to figure out different ways of scaling down … either making the process faster or taking out other aspects of their manufacturing process to really streamline this process, as well as just reducing the costs [of these] therapies.”

Click the video above for the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

Lars Petersen, CEO, FUJIFILM Diosynth Biotechnologies discusses the company’s strategic goals and meeting market demand for mammalian cell culture capacity.

Demand Remains Strong for Mammalian Cell Culture Capacity (BIO 2024)

Demand for mammalian cell culture capacity remains strong and is growing, notes Lars Petersen, CEO of FUJIFILM Diosynth Biotechnologies, during BIO 2024. The company’s main strategic goals for this year centers around meeting this demand. “We are starting up a facility right now in Denmark (1), which is maybe the highest priority,” Petersen says, who also emphasizes that the company has “multiple CAPEX [capital expenditures] projects that we need to finish up.”

“In general, we are we shifting the business after COVID, after some of the financial challenges, to [focus on] what demand is most important … and we see a lot of new interest coming in. Being ready for that [demand] … is the most significant goal of the year,” Petersen says.

As for the company’s expansion of its Holly Springs, N.C., mammalian cell culture facility (2), Petersen explains that this expansion “has really been driven by demand … Demand is high.”

The market for mammalian cell culture needs more capacity, according to Petersen. “There's so much volatility shift and demand from new products coming in, shifting the market from innovators to CDMOs [contract development and manufacturing organizations] [for] new modalities [in treating diseases] like Alzheimer's. The pressure is on [for] other modalities that all end up with higher demand,” he says.

In terms of the future of therapeutic modalities, Petersen sees antibody drug conjugates making a comeback after about a decade and, conversely, a bit of slowdown in messenger RNA. “All these modalities, they really are difficult to foresee,” he observes. However, he expects that monoclonal antibodies will remain a major therapeutic modality for potentially the next 10–15 years, at least.

Click the video above for the full interview. BIO 2024 is being held in San Diego, Calif., on June 3–6.

1. FUJIFILM Diosynth Biotechnologies. FUJIFILM Diosynth Biotechnologies Breaks Ground For Major Expansion of Its Large Scale Biologics Production Facility in Denmark. Press Release, March 3, 2021.
2. FUJIFILM. FUJIFILM to Invest Additional $1.2 Billion to Expand its Large-Scale Cell Culture CDMO Business in North Carolina. Press Release, April 11, 2024.