Exclusive: $NRIX | Nurix Therapeutics
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Nurix ($NRIX): Less of a degrader, more of a discoverer
Commentary
Nurix is a clinical biotech focused on both developing TPD drugs and E3 ligase inhibitors. The focus on developing E3 ligase inhibitors as a drugs class differentiates Nurix from its competitors. Their primary assets are focused on degrading Bruton’s Tyrosine Kinase (BTK) and inhibiting CBL-B.
NX-5948 is BTK degrader that is being developed for B cell malignancies and autoimmune disease. BTK is a tyrosine kinase has long been known as a key player in the development and function of B cells. Ibrutinib, a BTK inhibitor is the standard of care for the treatment of B-cell malignancies, including CLL, and has tremendously improved the lives of patients. Ibrutinib, sold by Johnson & Johnson and Abbvie under the name imbruvica, racked up ~$8.4 billion in sales in 2020. Ibrutinib’s mechanism of action involves the formation of a covalent bond with residue Cys481. Resistance to ibrutinib has been seen to develop in patients and the most commonly mutated residue of BTK in the case of acquired resistance is Cys481. Additionally, ibrutinib has off target effects including the inhibition of homologous tyrosine kinases in the Tec family. Due to its role in disease progression, the acquisition of resistance to BTK inhibitors in patients and off target effects of BTK inhibitors, BTK is a reasonable target for TPD.
While NX-5948 makes sense as a treatment for B-cell malignancies, the link of BTK to autoimmune diseases is tenuous. Nurix has published preclinical data for NX-5948 using mouse models for Rheumatoid Arthritis (RA). Nurix seems to be targeting the RA and Systemic Lupus Erythematosus (SLE) indications. While preclinical data demonstrating the efficacy of BTK inhibitors in murine models of these diseases have been published, several clinical trials using BTK inhibitors for these indications have been conducted and failed to demonstrate the efficacy of the treatment. However, there is a subset of RA patients, anti-citrullinated protein antibody positive, who may benefit from this treatment.
NX-2127 is a BTK and IKZF1/3 degrader being developed for B cell malignancies, including chronic lymphocytic leukemia (CLL). IKZF1/3 is the target of IMiD drugs and clinical trials have demonstrated the efficacy of lenalidomide as a treatment for CLL. NX-2127 uses a similar strategy to KT-413, where a monofunctional degrader is linked to the ligand of a different protein of interest for the degradation of several targets. However, NX-2127 targets the B-cell receptor pathway instead of IL-1R. Currently, Phase I clinical trials have begun.
NX-1607 is an inhibitor of E3 ligase CBL-B. CBL-B is a E3 ligase involved in the regulation of the T-cell receptor (TCR) signaling pathway. CBL-B deficiency in murine models results in T-cells that are hyper-responsive to TCR stimulation and are resistant to inhibition by regulatory T cells and PD-L1. Preclinical data demonstrating the anti-tumor effects of NX-1607 has been published. The data shows that following CBL-B inhibition with NX-1607: survival in murine models, activity of T-cells in biochemical assays, and production of IL-2 all increased.
Building off NX-1607, Nurix decided to develop cell therapy programs. These programs are focused on using an ex vivo CBL-B inhibitor, NX-0255, to enhance the anti-tumor activity for two autologous T-cell therapies, chimeric antigen receptor T-cell (CART) and tumor-infiltrating lymphocyte therapy (TIL). The CAR-T technology has been spun into a wholly owned subsidiary called DeCART. IL-2 is the most common cytokine used to culture cells for adoptive cell therapies, such as TIL and CART. Instead of adding IL-2 to the cultures, Nurix is using a CBL-B inhibitor to slow the degradation of IL-2, increasing its effective concentration. Enhancing cell therapy by the inhibition of CBL-B is also being pursued by Apeiron Biologics, but they are using a different approach where small interfering RNA (siRNA) is used to silence CBL-B at the mRNA level. Overall, the idea of using a CBL-B inhibitor to enhance cell therapy makes sense.
Nurix’s platform, DELigase, uses DNA-encoded libraries to identifying binders of E3 ligases. The discovery of binders of the POI seems like a secondary concern. Their platform is sold as they have massive DELs that allows them to screen a broader section of the chemical very quickly and detect weaker binders than other players in the space. Unlike other companies they do not mention using software to model the ternary complex or design of the linker. Their description of their lead optimization process can be summed up as rational design. Their discovery process sounds like a brute force algorithm. Perhaps brute force is good enough and developing a bunch of fancy computational tools is a misallocation of resources that could wind up biasing search in a different way. Given that they claim they have >30 ligases in discovery and their deals with Sanofi and Gilead are based around their DELigase platform, we are inclined to think it is progressing well relative to other TPD players’ partnered DELs.
We view Nurix as a company that is focused on selectively perturbing the function of ubiquitination machinery to control protein concentration. We find it especially attractive that their pipeline feeds off itself. The work with NX-2127 probably makes the development of NX-5948 relatively straightforward, and the work with NX-1607 enables Nurix to pursue drug enhanced cell therapies. We do not think that they are all that interested in TPD and are more focused on using their discovery platform to explore the ligandability and druggability of E3 ligases. As such, the TPD portion of their pipeline is underwhelming. Their BTK degrader, NX-5948, is low hanging fruit and the need isn’t that great. Their BTK and IKZF1/3 combo degrader, NX-2127, is going after the same indications as KYM-413, but KYM-413 has an edge. This company is solid and their focus on developing E3 ligases as a therapeutic target gives them an edge, but they are not a ‘true’ TPD company and more of a discovery platform (with 30+ E3 ligases currently in discovery).
Nurix’s emphasis on its DELigase platform from its investor presentation.
Overview
Nurix has a hybrid approach: it uses E3 ligases together with proprietary DNA-encoded libraries to create DELigase. This is an integrated discovery platform that identifies novel drug candidates that modulate proteins.
They own DeCART Therapeutics, which enhances CAR-T cells with small molecule targeted protein modulation.
Four Phase 1 trials to be initiated by YE 2021, so Nurix is still deeply in its infancy and more behind on trials
Pipeline
Nurix’s pipeline is wholly owned by themselves, with most drug candidates still pre-clinical or earlier
There are two leading targets in BTK, which is a validated target ($7B market in 2020) but is still in a deeply crowded space with 10+ drugs by other competitors.
Slide from their presentation on BTK inhibitors:
Save the Date
NX-2127 (B-cell malignancies): Phase 1 initial pharmacokinetic (PK) and pharmacodynamic (PD) data from the dose escalation portion is due by YE 2021.
NX-5948 (BTK degrader), NX-1607 (CBl-B inhibitor), and eTIL-0255 (drug-enhanced TIL) all to be in phase 1 trials by year-end 2021
Things to note
Nurix invested, built from scratch, and scaled up their DNA-enabled library called DELigase. It took 8 years and is also completely proprietary. Lots of open job roles dedicated to the DNA platform that tracks billions of molecules.
The CEO/Chairman of Seagen was recently appointed to BoD. While the rest of the BoD may not be as strong as the other TPD players, we find that directors still sit on lots of well-known and loved biotechs boards.
We expect more big pharma partnerships with Nurix that leverage Nurix’s DELigase platform for drug discovery (in addition to Sanofi & Gilead below)
Partnerships
Nurix & Sanofi
In 2020, Sanofi signed a deal that gave Nurix $55 million upfront and up to $2.3 billion in milestone payments to develop 3 targets with an option to develop 2 more targets. They exercised the option in January 2021 to develop 2 more targets and gave Nurix another $22 million in upfront payments.
Nurix & Gilead
In 2019, Gilead signed a deal that gave Nurix $45 million upfront and up to $2.3 billion in milestone payments. They have 5 undisclosed targets that are being developed. At the time of the deal Gilead’s CSO John McHutchison commented, “There are many molecular targets involved in disease pathways that have been traditionally been challenging to manipulate using conventional approaches. Nurix’s innovative protein degradation discovery technology provides Gilead with a new strategy to interrogate these drug targets, as we continue to build a pipeline of small molecule therapeutics.” The finer details of these deals are unknown.
Financial Health
Around $386M cash with a cash burn rate of $26M per quarter
ARVN is 87% held by institutions, <3% by insiders, and has a float of 63% (out of 44.4M shares outstanding)
Who’s with us?
Ownership by Percentage: Column Group 15%, Third Rock Ventures 12%, Redmile 7.5%, Baker Brothers 5.5%, EcoR1 Capital 4.6%, Bain 2.9%, Boxer 2.8%, Eventide 2.7%
Price Targets
$42 - RBC
$60 - Piper
$56 - JPM
$48 - Needham
Note: as $NRIX and the rest of TPDs are still in early innings, we will likely update and revisit this company next year after more mature readouts.