Recent advances within the medical field have prompted the development of RNA therapeutics for many different applications. These therapeutics have the potential to greatly change the treatment landscape and create more personalized options for patients.

Recently, I sat down with Geoff Nosrati, PhD, the Chief Business Officer of Nutcracker Therapeutics. Nutcracker Therapeutics is an early-stage RNA medicines company looking to create breakthrough RNA therapies for – currently – a range of oncological indications. During our discussion, we discussed why RNA therapeutics are so unique; NTX-0565, a patient-specific therapeutic for cutaneous T-cell lymphoma (CTCL); and how the company hopes to grow in the future.

Nutcracker Therapeutics: An Overview

PW: So tell me a little bit more about Nutcracker Therapeutics and what your company aims to do.

Geoff: Nutcracker Therapeutics is an RNA therapeutics company. Right now, Nutcracker Therapeutics is about four years old. Our CEO, Igor Khandros, made a bet on RNA as the future of medicine back in 2018. Four years later, we’re seeing those beliefs validated.

So far, we have raised around $240M in financing to accelerate the development of our revolutionary RNA manufacturing platform. We combine RNA biochemistry with proprietary biochip-based microfluidic systems to manufacture GMP-grade RNA drug substances and drug products. RNA manufacturing is extraordinarily difficult to outsource, but our platform is scalable from the research to development and commercialization. Our goal is to use this platform to more quickly and effectively discover and develop therapies – and bring medicines to patients faster.

Nutcracker Therapeutics sits at the intersection of science, engineering, and medicine. In the world of biotech, we’re unusual because of all the different things that we do. We have around 145 people working with us and it means a lot to work with a team that is so passionate about making changes in the lives of patients.

PW: Very interesting! Can you tell me more about your proprietary platform?

Geoff: We are using our own software platform to enable the rapid development of novel RNA medicines. Our proprietary CodonCracker™ software optimizes constructs along multiple dimensions, such as expression levels and manufacturability. Our platform includes a proprietary, special delivery method – “Nutshell” nanoparticles – as delivering naked RNA is not a valid treatment approach. We have also developed our own manufacturing technology and through this, we are able to develop batches of RNA which are suitable for clinical-scale development. Finally, our platform is unique because we can make the medicine in-house for patient-specific therapies, allowing us to fulfill patient needs at a more efficient rate.

PW: So the goal of Nutcracker Therapeutics is to advance RNA-based treatments for different diseases as quickly as possible. What are the therapies in your pipeline for?

Geoff: Currently, we have a pipeline of three internally-developed RNA medicines in oncology. NTX-0250 is a multimodal RNA therapy designed for patients with HPV-driven tumors. We are currently in IND-enabling studies for NTX-0250 and should be in clinical testing by the second half of next year. Next, we have NTX-0565 for patients with cutaneous T-cell lymphoma. Then, finally, we are developing NTX-0470 for genitourinary tumors. We’re still in the discovery stage for NTX-0470.

NTX-0565: A Personalized Therapy for Cutaneous T-Cell Lymphoma

What is Cutaneous T-Cell Lymphoma (CTCL)?

Cutaneous T-cell lymphoma (CTCL), which exists under the umbrella of non-Hodgkin’s lymphoma, refers to a group of disorders characterized by abnormal malignant T-cell accumulation on the skin. Subtypes of CTCL include granulomatous slack skin, mycosis fungoides, Sézary syndrome, and subcutaneous panniculitic T-cell lymphoma. Mycosis fungoides is considered to be the most common CTCL subtype, followed closely by Sézary syndrome. Doctors are unsure what causes CTCL. However, there are risk factors, which include being African-American or being aged 50+. Symptoms vary based on subtype, but may include:

• A red, scaly rash which may appear on the breasts, back, stomach, groin, chest, or thighs
• Intensely itchy skin plaques
• Swollen lymph nodes
• Peeling or swollen skin
• White spots on skin
• Tumors which may ulcerate
• Thickened fingernails or toenails
• Alopecia
• Drooping eyelids
• Enlarged liver or spleen

PW: What is NTX-0565? How does it work?

Geoff: NTX-0565 is a patient-specific multimodal RNA therapeutic. It contains four components – three immune modulators and patient-specific antigens encoded in mRNA. The therapy is neoantigen-based. This means that we can sequence a patient’s tumor, look for and source neoantigens, and then create a personalized treatment for patients based on their specific tumor-induced mutations.

Our goal is to get NTX-0565 in patient hands as quickly as possible. This isn’t something that we want to see take six months. If a patient’s tumor has already been sequenced, our aim is to take only a few weeks to create a personalized treatment. If we need to do a biopsy and sequencing, it’ll take a few more weeks. We hope to always improve on our timeline but we also need to show that our product is safe, and make sure that we’re going to benefit our patients.

But so far, our testing has shown very promising preclinical results. In our mouse model, 1/10 mice became tumor-free with no treatment. 3/10 became tumor-free with the antigens and one immunomodulator. But with the combination of multiple immunomodulators and the specific antigens, 9/10 mice were tumor-free. We have also tested personalized Nutcracker mRNA constructs against CTCL patient PBMCs to determine the level of T-cell recall response in five individuals. There was a huge tumor specific T-cell response. Combining immunomodulators with T-cell eliciting approaches in NTX-0565 has shown very impressive efficacy in our models.

PW: What made you want to develop a treatment option for CTCL in particular?

Geoff: One reason is that there are just not a ton of effective therapies for patients with CTCL. It’s a smaller cancer and, just looking at research, drug development, and patient feedback, you can see that there is a real unmet need in this space.

We also know that there are certain areas of the genome where cancer mutates, which gives us a good target and jumping off point. For CTCL, we know that there are specific mutated T-cell receptors, which helps us make more targeted treatments. We are able to screen many different immune modulators – we have a library of over 100 – and test different combinations in relation to patient-specific antigens to see what works best. That’s what makes this very exciting.

PW: Do you see Nutcracker Therapeutics expanding to any other disease states in the future?

Geoff: RNA can be used in a lot of different disease areas – and all of them are of interest to us. We see a lot of promise for using RNA therapies in rare diseases. Some potential expansions could include glycogen storage disorders, cystic fibrosis, Pompe disease, Gaucher disease, or other inherited errors of metabolism that could be fixed via RNA.

A lot of patients in these disease states currently become intolerant to treatments like enzyme replacement therapy (ERT). ERT has been great for patients who have no treatment options. However, when the ERT is given systemically over a long period of time, it can cause anti-drug antibodies to develop. Over time, it becomes more difficult for the treatment to reach the cells due to these neutralizing antibodies.

Alternately, RNA therapeutics can be more effective and can contribute to long-term, beneficial change for these patients. We think that by delivering these enzymes in RNA form, we can minimize the risk of neutralizing antibody formation and ensure that patients can benefit from treatment over extended periods of time.

You can iterate and do things so quickly in RNA; it’s much faster than conventional protein work. People talk about vaccines all of the time, but that’s really only tapping the surface of what RNA can do. The real magic is the speed in which proteins can be tested, evaluated, and moved forward. That’s why we’re so excited about our platform – not just because of what we’re doing now, but because of where we can see the benefits for patients in the future.

To learn more about Nutcracker Therapeutics, head here.