Nurix Therapeutics (NASDAQ:NRIX) has been able to post initial positive results from both of its early-stage studies using its protein degraders known as NX-2127 and NX-5948 for the treatment of patients with B-cell malignancies. Both candidates were able to achieve their intended mechanism of actions that were evaluated. With respect to NX-2127 in the phase 1a/1b study, it was noted that it was able to achieve sustained protein degradation of BTK along with Ikaros degradation as well [targeting of neosubstrates]. On the other hand, with respect to NX-5948 it was shown in a phase 1a/1b study that there was also sustained protein degradation observed. While these trial data are early in nature, I believe that there is a huge opportunity here based on the company’s protein degradation platform. Why is that? That’s because you have the many available and development-stage Bruton Tyrosine Kinase [BTK] inhibitors that are tackling the large multibillion dollar market.
However, they are currently split into covalent and non-covalent BTK inhibitors. Where Nurix Therapeutics comes in play is to be entirely different compared to all these other BKT inhibitors. To accomplish this, it is advancing the BTK protein degraders NX-2127 and NX-5948 noted above. The thing is that these BTK protein degraders have two advantages over their BTK inhibitor counterparts, which I’m going to note below. While early data is a bit impressive thus far, there were several pharma companies that wanted to get their hands on this protein degradation technology, which are: Gilead Sciences (GILD), Seagen now part of Pfizer (PFE) and Sanofi (SNY). The significance of these early partnerships is that it brings non-dilutive capital into the mix so that Nurix can further advance its pipeline.
Next Generation BTK Targeting With Protein Degraders
As I noted above, Nurix Therapeutics is advancing two protein degraders in its pipeline known as NX-2127 and NX-5948 for the treatment of B-cell malignancies. It has been able to not only test out both of these clinical candidates in early-stage studies, but has also been able to post early pharmacokinetic [PK], pharmacodynamic [PD] and safety data. With respect to the first candidate NX-2127, this is a protein degrader that has two functions. This drug is supposed to degrade BTK and Ikaros [IKZF1] and Aiolos [IKZF3], which are neosubstrates that are responsible for cell transcription. With this drug having a dual mechanism of action there is a chance that it could end up being a better protein degrader molecule. This was a bit proven with the released clinical data from the phase 1a/1b study at the 2022 ASH Medical Conference. There is an example of several patients that benefited with such a treatment. For example, there was durable complete responses [CRs] reported in 2 patients with Mantle-cell lymphoma [MCL] and diffuse large B-cell lymphoma [DLBCL]. Such responses were not only achieved, but were also ongoing for more than 1 year. Then, with respect to one chronic lymphocytic leukemia [CLL] patient, it was noted that treatment with NX-2127 resulted in an overall response rate [ORR] of 41% and best overall response rate of 33%. One thing to note is that is that the longer the patient was treated [duration] the better the ORR ended up being in the 12 evaluable CLL patients. It went from 16.7% at 2 months to 50% at 6 months. The other protein degrader NX-5948, which only degrades BTK [no neosubstrate degradation like the other one] also achieved some initial positive efficacy. It was noted in a phase 1a/1b study treating patients with relapsed/refractory B-cell malignancies had also seen positive preliminary efficacy data. That is, there was clinical benefit seen in 6 out of 7 patients with CLL at doses ranging from 50 mg to 200 mg of NX-5948. Things are going particularly well for this program, which is using this particular candidate to treat patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma [r/r CLL/SLL] after at least two prior lines of therapy [including treatment with a prior BTK inhibitor [BTKi]. How so? Well, the FDA apparently liked the clinical data released for NX-5948 for these patient populations, because it granted it Fast Track Designation by the agency. Such a designation was given several days ago and this will allow Nurix to have the potential for expedited development and review of this drug.
The main thing to note is that Nurix Therapeutic is not going to be a “me too” BTK inhibitor biotech company. It hopes to overtake the large BTK inhibitor market with its protein degraders NX-2127 and NX-5948. The global Bruton Tyrosine Kinase [BTK] inhibitors market is expected to reach $27.33 billion by 2031. This is a very large market opportunity, but where would Nurix fit in? Well, it provides an entirely new approach to targeting BTK. It hopes to eventually establish several advantages over these other drugs. They are as follows:
- Ability to counter BTK resistance that occurs [all covalent and non-covalent BTK inhibitors share common resistance mutations – more potent cell killing in resistant mutations
- Able to target a larger chunk of the B-cell malignancies market due to the unique approach
- Destruction of the BTK scaffolding, which means no BTK in place allows full pathway inhibition and full antiproliferative functioning
Another advantage is that once the function of NX-2127 happens, it doesn’t have to actively be bound to the targeted protein to inhibit its function. This means, less drug is needed to achieve a similar function.
Financials
According to the 10-Q SEC Filing, Nurix Therapeutics had cash, cash equivalents and marketable securities of $268.7 million as of August 31, 2023. The thing is that this biotech is in good shape in terms of cash. How so? Well, that’s because after August, it has since been able to obtain additional financing through non-dilutive means. For starters, it was able to generate a deal with Seagen, now part of Pfizer. This deal was made so that both companies could develop a portfolio full f degrader-antibody conjugates [DACs]. Nurix received an upfront payment of $60 million for this deal and could also be eligible to earn up to $3.4 billion in milestone payments as well.
Along with the ability to earn from mid-single to low double-digit tiered royalties on net product sales. Other deals were made with Gilead Sciences and Sanofi as I highlighted above as well. To date, Nurix received a $45 million upfront payment and $67 million in licensing fee and milestone payments to date from Gilead. Then, from Sanofi, it was able to obtain an upfront payment of $77 million and approximately $7 million in milestone payments. It believes that it has enough cash on hand to fund its operations into the 2nd half of 2025, which gives plenty of cash runway. Based on this projection, I don’t believe that it will need to raise additional cash in the near-term.
Risks To Business
There are several risks that investors have to be aware of before investing in Nurix Therapeutics. The first risks to consider would be with respect to the advancement of NX-5948, which is being developed for the treatment of patients with relapsed/refractory B-cell malignancies. Even though positive data was achieved in the ongoing phase 1a/1b study thus far, there is no assurance that it will continue to do so in upcoming data releases. On the flip side, NX-5948 is only a BTK degrader. This means that while only degrading BTK might not be enough, there is a second shot on goal with another clinical candidate which may be better. How so? Well, that would be with respect to the other candidate degrading BTK, which is NX-2127. The reason why is because not only does it degrade BTK, but it also acts to use cereblon, which is an E3 ligase active in hematopoietic cells of a person. Why is this cereblon important? That’s because it is responsible for immunodulation [making the immune system to work better] and for cell metabolism. Thus, with NX-217 having the addition of using this, it can degrade neosubstrates Ikaros [IKZF1] and Aiolos [IKZF3]. The logic is that by degrading these neosubstrates, along with BTK, then better efficacy could be achieved.
This brings up a second risk, which is that there is no assurance that NX-2127 will be able to achieve its intended function upon the next data release from the ongoing phase 1a dose escalation and phase 1b dose expansion cohorts. These cohorts targeted patients such as chronic lymphocytic leukemia, mantle cell lymphoma [MCL] and diffuse large B-cell lymphoma [DLBCL]. That’s because at the ASH data release is was noted that these patients given NX-2127 had dose-dependent PK activity, leading to robust degradation of BTK and Ikaros [neosubstrate].
A third risk to consider would be with respect to competition, which could ultimately be in the way. That’s because as I stated above, there are many other BTK inhibitors on the market. It is a large market for sure, but the key thing to note is that all the current BTK inhibitors share resistance mutation vulnerabilities. The most popular BTK inhibitor ibrutinib [IMBRUVICA] is a 1st-generation type. Covalent inhibitors are acalabrutinib [CALQUENCE] from AstraZeneca (AZN) and zanubrutinib [BRUKINSA] from BeiGene (BGNE). A non-covalent inhibitor would be pirtobrutinib [JAYPIRCA] from Eli Lilly (LLY). While all these are okay, they share the problem of resistance described directly above. Where Nurix Therapeutics can succeed is overcoming this resistance, plus the fact that not having the BTK scaffolding in the way, may allow for full pathway inhibition compared to all these other BTK drugs.
The fourth and final risk to consider would be with respect to the ongoing partnerships I described above. Even though many of them have already resulted in some upfront milestone payments, there is no guarantee that it will be able to obtain all the intended milestone payments. Even if positive data is achieved in ongoing clinical testing, there is no assurance that all partners will want to continue funding trials to completion. Thus, there is a chance that one or any of the partnerships could come to an end without any warning.
Conclusion
Nurix Therapeutics has been able to advance two solid protein degraders, which are NX-2127 and NX-5948. I believe there is potential here with this biotech, because it hopes to stand out from all other BTK inhibitors. That is, some patients being treated with such inhibitors either don’t respond or are resistant to them. If it can show that its BTK protein degrades remove the BTK protein effectively, then it believes that not only can it overcome such mutation resistance, but that it could also improve efficacy across the board. Even though these are early-stage studies, there is huge promise here based on preliminary data alone. However, the partnerships it has been able to achieve, is another factor to consider. Nurix retains the option for U.S. profit share and co-promotion for 6 drug clinical candidates across 3 partnerships noted above. If it continues to deliver in the clinic, then it has the ability to continue to obtain non-dilutive cash to advance its pipeline forward.
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