Internalizing Nanoparticle Therapeutic Development

By Matthew Pillar, Editor, Bioprocess Online

COUR Pharmaceuticals has been, as its newly-appointed President & CEO Dannielle Appelhans puts it, flying under the radar for a long time. COUR made a splash back in 2015, when it formed up around a biodegradable nanoparticle encapsulating gliadin proteins that proved to reverse the effects of gluten in animal models. That initial celiac disease candidate became TAK-101, developed in partnership with Takeda, and it’s now approaching phase 3 clinical trials. TAK-101 served as a proof-of-concept for the company’s nanoparticle platform, which induces tolerance to specific problematic antigens without impacting systemic immune functionality. Its pipeline has expanded to include Phase 2 programs in Myasthenia Gravis (MG) and Primary Biliary Cholangitis (PBC), as well as a soon-to-be-filed IND program in Type 1 Diabetes (T1D).

Appelhans joined COUR as Chief Operating Officer in the summer of 2023 on the heels of a career that reads like a who’s-who of big pharma (Abbott Labs, Eli Lilly, Novartis, and Sandoz, among others). She had already transitioned to biotech – in fact, it was a competitive intelligence exercise during her time at Rubius Therapeutics that exposed her to COUR. “Though COUR was a relatively quiet company, their clinical data on immune tolerance made them the one to beat,” she says. We caught up with Appelhans, who became CEO of the company in September of this year, to learn about the company’s platform and its approach to developing and manufacturing immune-modifying nanoparticles.

NANOPARTICLE + ANTIGEN = TARGETED TOLERANCE

COUR’s proprietary nanoparticle technology, a polymer PLGA (polylactic-co-glycolic acid), was licensed from Northwestern in 2013. “What's important about the nanoparticles are their 500 nanometer size and negative surface charge,” explains Appelhans. “Their size and charge ensure that, upon intravenous administration, the nanoparticles send a tolerogenic signal after binding to monocytes in the spleen and liver where immune responses start.”

The platform nanoparticles encapsulate a disease-specific antigen. When taken up in the spleen and liver, the antigens are released by apoptosis, and the resulting debris is consumed by antigen presenting cells. Those cells present the disease-specific antigens, along with negative co-stimulating factors, to the adaptive immune system. Adaptive immune T-cells interact with the antigen-presenting cells, and in the absence of inflammatory signals they “perceive” the antigen as self. These T-cells then respond by undergoing deletion or anergy, or by inducing a T regulatory response. The T-regulatory cells then migrate to sites of disease, where they continually down regulate the immune response in the presence of the disease specific antigen.

“Effectively, we’re hiding the antigen, which would otherwise be reactive, in the nanoparticle so it can slip in undetected and retrain the immune system,” says Appelhans.

The platform’s pipeline potential was a major element of its appeal to Appelhans. “There’s a very long list of autoimmune diseases that are antigen specific, and the knowledge of the antigens driving disease is exceptional in most cases. That means that our platform can potentially be applied to any T-cell-mediated disease where the antigens are known,” she says. The antigen itself represents just 1% to 2% of the therapeutic. The rest, that polymer PLGA nanoparticle, is a copolymer used in a number of FDA-approved therapies and devices, which gives COUR a regulatory leg up.

Because the FDA recognizes our drug master file, we can jump right into a 2A study for these future indications. “We know what the safety profile is, we've done the toxicology studies, and because it's mediated by the nanoparticle, that stays the same every time,” says Appelhans.

FINANCING CLINICAL PROGRESS

Appelhans says COUR was the only company she’d seen that demonstrated immune tolerance through clinical data (in its Celiac study), and she’s particularly bullish on the platform and its expansion potential. But she admits that when she joined, very little had been done on the CMC development front.

With the ultimate goal of taking its diabetes drug to the clinic and scaling its MG trial, the company needed two things in short order: expertise and money. A $105 million Series A, led by Lumira Ventures and Alpha Wave Ventures and closed early in Q1 of this year, ensued. The effort was supported by Roche Venture Fund, Pfizer, Bristol Myers Squibb, Angelini Ventures, and JDRF T1D, and it funded a strategic hiring initiative that has yielded the technical development team COUR needed to push that candidate forward. “We had already done the work to open the IND in MG, so getting that series A behind us was a critical step toward that and preparing our T1D program for the clinic,” she says. In MG, COUR dosed its first patient in October ‘24. It’s planning an IND for the T1D program in the first half of 2025. Meanwhile, it’s mapping out its development strategy for PBC.

SCALING CMC FOR PIPELINE EXPANSION

Appelhans says her sole focus since joining the company has been exploiting the opportunity this technology presents, which hasn’t always been easy. “We wanted to take on T1D, and to do so, we needed to make drug substance from four recombinant proteins to put inside our nanoparticle.” Four is the magic number, because one therapy with all four antigens covers more than 95% of the relevant epitopes in that indication. With this approach, patients can be treated safely without extensive screening to determine what kind of antigen is driving their disease. “We can cover more than 100 epitopes with these four proteins, so we don’t have to pick one horse,” she says.

COUR knows its nanoparticle inside and out, but it had never before manufactured any drug substance. In this case, it had to. COUR had done its due diligence on sourcing a CDMO that was up to the task, but the prospect of long development timelines and millions of dollars spent was untenable at the time.

Two of the four proteins COUR needed had in fact never been expressed before. To make that happen, COUR built out internal drug substance production capabilities. It devoted considerable resources to the development of an E. Coli-based system to express these difficult proteins, but ultimately developed a cell-free production system and processes, from scratch. “Cell-free isn’t common, but it worked well for us because a couple of these are transmembrane proteins that can't be easily expressed in mammalian or insect systems,” she says. “It’s one thing to do it in a small R&D lab at a very small milliliter scale, but it's a completely different thing to be able to make that into a GMP process at the scale that's necessary to support clinical trials and, ultimately, commercialization.”

Today, COUR produces its own final drug product in-house, encapsulating the antigen in its sourced polymers, and it’s internalized the bulk of analytical development and QC release testing as well. “We really are controlling our own future from a capabilities perspective,” says Appelhans. The ‘make versus buy’ question that late- clinical-stage companies must inevitably address, she says, will be less weighty for COUR thanks to its in-house mastery of development processes and analytical methods. “The internal expertise we’ve developed gives me confidence for a smooth transfer in any event,” says Appelhans.

Now that COUR Pharmaceuticals is on your radar, learn more at www.courpharma.com.