Feliza Mirasol is the science editor for 

Feliza Mirasol

On May 22, 2024, Biogen announced that it is acquiring Human Immunology Biosciences (HI-Bio), a privately-held US-based clinical-stage biotechnology company specializing in targeted therapies for severe immune-mediated diseases (IMDs). The transaction is worth potentially up to $1.8 billion, which includes a $1.15 billion upfront payment and up to $650 million in potential milestone payments. The deal is expected to close in the third quarter of 2024, subject to necessary regulatory approvals and customary closing conditions.

With the acquisition, Biogen gains felzartamab, HI-Bio’s lead asset. Felzartamab is a fully human anti-CD38 monoclonal antibody (mAb) that has been shown to selectively deplete CD38+ cells in clinical studies. This selective depletion includes plasma cells and natural killer (NK) cells. This action may allow for additional applications that improve clinical outcomes in a broad range of immune-mediated diseases, Biogen stated in a company press release.

“We believe this late-stage asset, which has demonstrated impact on key biomarkers and clinical endpoints in three renal diseases with serious unmet needs, is a strategic addition to the Biogen portfolio as we continue to augment our pipeline and build on our expertise in immunology,” said Priya Singhal, MD, head of Development at Biogen, in the press release. “We look forward to welcoming HI-Bio employees into Biogen and, together, working to advance potential therapies for patients with rare immune diseases with high unmet need.”

FDA has granted felzartamab breakthrough therapy designation and orphan drug designation for development in treating primary membranous nephropathy (PMN). The mAb has also received orphan drug designation for treating antibody-mediated rejection (AMR) in kidney transplant recipients. Felzartamab has completed Phase II studies in PMN and AMR and remains in ongoing Phase II studies in immunoglobulin A nephropathy (IgAN). HI-Bio plans to advance the mAb to Phase III studies in each indication; the company is presenting two abstracts at the 

 in Stockholm, which is occurring May 23–26, 2024. HI-Bio’s presentation includes complete Phase II data from the AMR study in kidney transplant patients and interim data from the Phase II IgAN study, according to the press release. Studies have also generated clinical data for felzartamab in the AMR, PMN, and IgAN indications.

“With its deep development and commercialization capabilities, Biogen is in a position to accelerate the development of new medicines, including felzartamab, for patients with severe immune-mediated diseases,” said Travis Murdoch, MD, chief executive officer of HI-Bio, in the release. “We are excited to combine the HI-Bio team’s expertise with Biogen’s global footprint.”

In addition to the felzartamab lead program, HI-Bio’s pipeline consists of izastobart/HIB210, an anti-C5aR1 antibody currently in a Phase I trial. This candidate has the potential for continued development in a range of complement-mediated diseases. HI-Bio also has discovery-stage mast cell programs with potential application in a range of immune-mediated diseases.

The treatment of IMDs has largely benefitted from the evolution of targeted biologic therapies. Targeted biologics have demonstrated efficacy, speed of onset, and tolerability. What’s more, research efforts have shown that clinically unrelated immune-mediated inflammatory conditions can share similar immune dysregulation. This discovery has since led to a shift in way IMDs and other inflammatory disorders are managed (1).

1. Kuek, A.; Hazleman, B. L.; Ostör A. J. Immune-Mediated Inflammatory Diseases (IMIDs) and Biologic Therapy: A Medical Revolution. 

 (978), 251–260. DOI: 10.1136/pgmj.2006.052688

Articles

With the acquisition, Biogen gains felzartamab, HI-Bio's lead investigational mAb candidate being developed for the treatment of a range of immune-mediated diseases. 

Biogen to Acquire HI-Bio in Deal Worth Potentially Up to $1.8 Billion

Regeneron’s Bari Kowal gave insight into how the biopharma industry views the application of AI in R&D.

Exploring the use of AI in R&D at the US Pharma and Biotech Summit

® at the US Pharma and Biotech Summit, Regeneron's Bari Kowal, senior vice-president, head Development Operations & Portfolio Management, talked about the implementation of artificial intelligence (AI) in the R&D space. For example. Regeneron, Kowal explained, has been using AI for quite some time. Though not a new technology, she observed, AI has allowed the company to leverage many large language models and advanced searches for the past few years. Because of this, the company has built up collections of data in different areas, such as in genomics, protein databases, or for operational uses, including patient populations, study-level data, information about investigators, and quality of documents, among others.

“[Much] of our work is crossing over multiple facets of the drug development lifecycle early on in the discovery space, looking at how we manufacture and improving those processes, but also really looking at how we execute trials and reach out to the patients create diversity in the populations,” Kowal said. “We utilize some of the genomic data for finding the targets and more personalized medicine. [There are many] ways that we're leveraging AI.”

However, she emphasizes that the real value of AI is the ability to use it for existing data, especially in the search for optimizing operational efficiency. “Looking in the future, how do we use this to help our decision making and really better predict molecules that will have a tremendous effect? The biggest benefit that I can see, at least today, is that operational efficiency. If we can streamline drug development, from start to finish, our mission is to bring important medicines to patients at the end of the day, and so the time it takes today for drugs to be developed is too long. It's not measured in years, it's measured in decades,” she remarked. “If we can go from the research space to the development space in [a] few years, that is so much better and more beneficial to the patients that are waiting for those treatments.”

While speaking on a panel at the summit about diverging schools of thought on how AI should be used in R&D, Kowal observed that there were not necessarily divergent views by the panelists on how to use AI, but rather that the panelists had like-minded views on the topic. “I think we all believe that AI can be transformative. I think we believe that, ultimately, we're scratching the surface of what AI can do, but we also understand the human component and the context of human intelligence that you have to apply,” she stated.

 occurred on May 16, 2024 in New York, NY.

Videos

Bari Kowal, senior vice-president, head Development Operations & Portfolio Management, Regeneron, discussed the utility of AI and how it can benefit R&D work.

A Discussion on Using AI in R&D at the US Pharma and Biotech Summit

Interview with Ken Keller, president and CEO, Daiichi Sankyo, at US Pharma and Biotech Summit

Ken Keller, CEO of Daiichi Sankyo sat with 

® at the US Pharma and Biotech Summit to discuss how to effectively create productive partnerships in the bio/pharmaceutical industry. He noted that a key component is for prospective partners to have a shared commitment to the therapeutic area that is the focus of a drug development program. “If it's strategically important to your partner, then it usually works out very, very well,” Keller said.

Relevant experience in the therapeutic area is also important. “Specifically, we work in oncology. So, if we're looking at a drug that has potential in breast cancer, we'll be looking for someone that's showing success in oncology in breast cancer very recently.”

Challenges involved in creating partnerships for developing therapies include creating a clinical data plan and committing to developing a stable supply chain going forward, Keller points out. “[A clinical data plan] is really the roadmap for whatever asset you have, that looks out five or 10 years, because sometimes it takes that long to complete the trials and the challenges, you've got to design them to deliver the evidence that not only prescribers will find attractive, but also payers.”

“I think it starts with the CEO and the C suite, doing something that only they can do. So as a leader, you've got to set the expectations for how bold you want that team to be,” says Keller. “The most important thing when two companies decide that they're going to do something together, is to really find a cohesive relationship, where you both believe that you can do more together than separately.”

Ken Keller, president and CEO, Daiichi Sankyo, discusses the foundation of partnership and takes a look at the future of biotech partnerships at the US Pharma and Biotech Summit.

A Look at the Future of Bio/Pharma Partnerships at the US Pharma and Biotech Summit

Regeneron’s work in CAR-T cell therapy development includes engineering receptor architecture to improve CAR-T cell sensitivity and improve immune response.

Improving the Sensitivity and Action of CAR-T Cell Therapies (ASGCT 2024)

®, Phillip Gregory, PhD, senior vice-president and head of Regeneron Cell Medicines, Regeneron, discussed current challenges with chimeric antigen receptor T cell (CAR-T) therapies at the 

American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting

, occurring on May 7–11, 2024 in Baltimore, Md.

“The most arduous challenges in CAR-T cell therapies come from the complexity of fusing three different fields,” Gregory said. “There's the field of generating binders that can redirect a cell to a tumor antigen. There's the field of making that T cell do the right thing when it connects with that antigen, and then there's the problem of making those CAR-T cells at the scale and in a GMP [good manufacturing practice] fashion that produces a drug product. Thus, creating a successful CAR-T cell requires advancements across all three of those disciplines,” he explained.

Juggling these three fields is what takes time when creating the CAR-T therapies seen today, he noted. Meanwhile, the most successful aspects of CAR-T cell therapy to date have been in the hematologic malignancies, such as B-cell lymphomas and myeloma, where, Gregory points out, a number of approved therapeutics already exist that are having transformative impacts on patients.

“But this platform has the potential to do much more than just hematologic malignancies,” Gregory enthuses. “[There are] now explorations into autoimmune diseases as well solid tumors, and for solid tumors, that's where we need additional technologies to unlock the potential of cell therapy,” he stated.

In a talk Gregory gave at ASGCT, he highlighted CAR-T cell receptors and “receptor architecture”. He explained that these are engineered proteins that allow a cell to recognize a tumor antigen. “The current CAR-T cells do a great job of that, but there are also limitations to how those function. For example, they're not regulated, so they work whenever they see an antigen. That means that we can't control when those cells act to kill the tumor cell or not,” Gregory explained.

One area that Regeneron is working on is creating regulatable CAR-T cells that only function when the investigator provides an exogenous small molecule. The company is also working on the sensitivity of CAR-T cells. “Unlike the natural way in which T cells recognize an antigen, which is through the T-cell receptor (TCR), CAR-T cells use a chimeric approach, which turns out to be a little bit less sensitive or requires more antigen on the cell surface. That means there's the potential for the tumors to escape by down-regulating the expression of that antigen,” Gregory said. “We've been working on architectures that increase the sensitivity of the CAR-T cell by exploiting the natural regulation and signaling of the TCR itself,” he stated.

“I think that CAR-T cells offer a tremendous platform for the combination [of] a plethora of technologies that exist in oncology; that includes bispecific antibody technologies as well as antibody-based technologies,” Gregory added.

Phillip Gregory, PhD, senior vice-president and head of Regeneron Cell Medicines, Regeneron, discussed how engineering receptor architecture can be a tool to improve CAR-T cell sensitivity to tumor antigens.

Using Receptor Architecture to Improve CAR-T Cell Sensitivity in Oncology (ASGCT 2024)

Sven Moller-Tank with Regeneron spoke about the use of bispecific antibodies to retarget AAV specificity.

Advancing Delivery of AAV Vector-Based Gene Therapies Using Bispecific Antibodies (ASGCT 2024

Sven Moller-Tank, PhD, director of Viral Delivery Technologies, Regeneron Genetic Medicines, Regeneron, spoke with 

 about the challenges of working with viral vectors. The ASGCT annual meeting is occurring on May 7–11, 2024 in Baltimore, Md.

There have been several challenges facing the viral vector field over the past few decades. The first challenge is pre-existing immunity because people have naturally been exposed to adeno-associated virus (AAV) and have developed immune responses. This makes it a challenge to run clinical trials, when patients have pre-existing immunity, Moller-Tank stated. The second challenge has been delivery; as a whole, it has been extremely difficult to get enough virus to the peripheral tissues, as opposed to the liver, where it can cause issues with your immune response, and thirdly, there has always been an issue with cargo capacity, he explained. “AAVs can only package about 4.7 kb, and [many] therapeutic genes really don't fit into that capacity,” he said.

A fourth challenge dealing with viral vectors would be sustained expression, Moller-Tank added. “The idea with AAV gene therapies generally is that it's a one-and-done therapeutic. However, there [are many] unknowns about how long it's going to express. We're now seeing [in] clinical trials [that] it can indeed last a long time, but it's really unknown for maybe more junior populations, children, where they're going to grow over time, and, after receiving a therapeutic, they may lose expression,” he observed.

Moller-Tank emphasized that the field has seen much success in terms of viral delivery, at least in mice, “Often, however, that has unfortunately not translated very well to non-human primates and to humans. Over the past decade, the industry has really focused on doing screenings and developing relevant animal models. That's gone a long way to improving the translate-ability,” he said. However, this work has not really addressed the issue of off-target delivery, which has an impact on the immune response and the safety of AAVs.

Regeneron has been working on using bispecific antibodies to retarget AAV specificity. “The concept is you have one arm against your target receptor—and we identify specific receptors that are expressed in the tissues of interest, so we can control the specificity of the delivery—and then you have another arm against the AAV. The idea, essentially, is that [the] antibody is bridging the AAV capsid to the target cell of interest,” Moller-Tank explained.

“We show, maybe for the first time and most convincingly, that bispecifics are a viable approach to deliver AAVs 

. I think, historically, the field has been using bispecifics 

 delivery has been a challenge,” Moller-Tank remarked.

Regeneron's Sven Moller-Tank, PhD, director of Viral Delivery Technologies, Regeneron Genetic Medicines, discusses the company's work in using bispecific antibodies for redirecting AAV target specificity.

The Role of Bispecific Antibodies in Redirecting AAV Vectors (ASGCT 2024)

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Certain additives or a combination of additives in downstream bioprocessing have demonstrated an improvement in the separation and clearance of empty and partially full capsids during the manufacturing of viral vectors, noted Ohnmar Khanal, PhD, Downstream Technology Lead, Spark Therapeutics, at the 

, which is being held from May 7–11, 2024 in Baltimore, Md.

 on the work her team has been doing to test the removal of empty and partially filled adeno-associated virus (AAV) capsids in the downstream processing stage of AAV vector production. Khanal stated that she and her team have been looking at additives and the role they play in AAV purification. In particular, her team focused on copper ions and conducted oversaturated loading experiments using multicolumn anion exchange (AEC) chromatography.

“A current challenge in the downstream purification of recombinant [AAV] is the separation of transgene-containing capsids from empty [capsids] and undesired capsid variants,” Khanal stated. “AEX resin is often used below its saturated binding capacity to separate empty and full AAV particles on a single column. However, the outcome of the traditional single-column operation can be impacted by variability in load composition, sensitivity to buffer composition, and fractionation strategies,” she explained.

Khanal noted that, in reviewing past studies, her team found that the removal of empty and partial capsids with a high yield was rarely demonstrated in the literature. In her talk, Khanal presented three-stage separation strategies for two recombinant AAV constructs (rAAV) and demonstrated a way to overcome the trade-off between yield and purity.

In the first strategy, a resin chemistry (Poros XQ, Poros HS, Poros I) is selected and used with a concoction of kosmotropic agents (e.g., ammonium sulfate or sodium sulfate). These agents (i.e., additives) were used to promote capsid stability at low ionic strength. Meanwhile, metal ions (e.g., copper, magnesium, calcium) were used to promote selectivity of the desired capsid. “Using copper ions improved the resolution between empty and full capsid separation and helped remove other product-related impurities,” Khanal pointed out in her presentation.

In the second strategy, the team used an appropriate resin/media structure and geometry to exclude AAV from smaller resin pores (e.g., Poros XQ). Doing so minimized particle dispersion and improved resolution. “Monolith and membrane chromatography showed better peak resolution than traditional resin-based on favorable transport behavior,” Khanal said.

Finally, in the third strategy, the transition from single column to multiple columns in series was tested. This was done by loading 1.5x the resin saturation capacity. Khanal noted that this allowed for over 40% reduction of partial capsids and over 95% removal of empty capsids. “Using these strategies, we provide the best modality to achieve maximum empty and partial capsid removal with a yield of over 80%,” she concluded.

Experiments conducted by the downstream technology team at Spark Therapeutics involving metal ion-containing additives showed improved capsid clearance in AAV production.