Protein Degraders – Degraded..
Updated: May 8
BULL BEAR BRES|NAHAN
UPDATED Monday, May 8, 2023
As of -> 12:47 EET
This is going to be a living post, I'll update it as I go (same for formatting).. Time constraints and all that jazz!
I'll start w/ some mere pasting from recent releases, CapIQ data (don't shoot me - some is surely off) and go from there..
br. -john
p.s. note the links (IR, deck, release), latest news (e.g., conferences) coming *soon*, etc.
p.p.s. just the public entities, though it is likely worth looking into the entirety at some point
Protein Degraders – Degraded..
The entirety of this sub-sector (protein degraders and related ilk) have seen quite the rollercoaster over the past few years..
All six are now well off their highs with only Kymera managing a respectable enterprise value.. Their combined enterprise value is a mere $1.27 billion, set that against their aggregate all time high of ~$14.5 billion!! Yes, they're collectively down more than 90% from their peak..
Surely, a peak (for each) combined valuation of ~$14.5 billion must have come with a grand promise..
"Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules."
Békés, M., Langley, D.R. & Crews, C.M. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov21, 181–200 (2022). https://doi.org/10.1038/s41573-021-00371-6
Being over 90% off that peak, one might wonder if the potential has fizzled along with sentiment.. yet we're only just set to find out; intriguingly, these are likely the early innings - even if they were a long time coming..
"In the last 20 years, the field of TPD has progressed from proof of concept to a stage where the first rationally designed degraders are in clinical development .. With success, investment can expand from validated targets to first-in-class opportunities. Through this target expansion, TPD can truly deliver on the promise of ‘drugging the undruggable’ and bring hope to patients without effective treatment options.."
O’Brien Laramy, M.N., Luthra, S., Brown, M.F. et al. Delivering on the promise of protein degraders. Nat Rev Drug Discov (2023). https://doi.org/10.1038/s41573-023-00652-2
Let's get more subjective, shall we..
Now biotech is fairly long duration on a good day, if you peruse the expected milestones/ catalysts below you'll see that 2023 is on the light side - adding even more duration to these entities..
Which brings up a point that needs mulling, sources of incremental return:
idiosyncratic - what happens at the company level X
one step up, TPD in general - what's happening in this sub-sector X
yet another, small/ mid cap biotech - peers across industry X
general participant 'animal spirits' - risk appetites X
and so on, until you're really at that systemic risk - overall level (interest rates and so on) X
If you work your way through that list, just about everything is going to come up with a big fat X.. Here, let's annotate that in.
Not a green spot anywhere, not even a yellow.. Perhaps therein we find an inherent sentiment indicator - at no level is this working sans perhaps Kymera which seems to have some Sanofi speculation tagged on (Arvinas has lost their Pfizer spec it seems)..
Take a look at some of the history leading up to this moment and then start looking forward; as it sure feels as if we're at one of those pivotal moments..
"But molecular glues allow us to imagine a future where cellular circuitry can be rewired at the level of proteins.."
Stuart L. Schreiber, The Rise of Molecular Glues, Cell, Volume 184, Issue 1, 2021, Pages 3-9, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2020.12.020
Publication frequency is markedly higher and with that increased familiarity you can expect people to venture outside current comfort zones.. First, however, we need someone to hit something - even if it is crowded (IMHO)..
Rarely one to go too deep into the weeds, the TPD landscape does jump out.. It's like that scene from Forest Gump, where they're listing out ways to prepare shrimp..
"orthodox PROTACS.. BacPROTACs.. Antibody-based PROTACs (AbTACs).. Ribonuclease-targeting chimeras (RIBOTACs).. Phosphatase-recruitment chimeras (PHORCs).. Oligonucleotide-based PROTACs.. Phospho-dependent PROTACs (phosphoPROTACs).. Light-controllable PROTACs.. Dual/trivalent PROTACs.. Chaperone-mediated protein degradation (CHAMP).. Homo-PROTACs.. BioPROTACs.. Macroautophagy degradation-targeting chimeras (MADTACs) AUTACs/ATTECs/AUTOTACs.. Lysosome-targeting chimeras.. Hydrophobic tagging.. Molecular glues..
Jin Li, Xinxin Chen, Aiping Lu, Chao Liang, Targeted protein degradation in cancers: Orthodox PROTACs and beyond, Cell, Volume 4, Issue 3, May 2023, https://doi.org/10.1016/j.xinn.2023.10041
Founded 2013
Market Cap $1.4B
Net Cash $1.2B
TEV $228mm
> phase 3
Upcoming Milestones & Expectations
ARV-471
With Pfizer, the companies plan to:
Initiate a Phase 3 trial with ARV-471 + palbociclib as a first-line treatment in patients with ER+/HER2- locally advanced or metastatic breast cancer (2H 2023)
Initiate additional arms of the Phase 1b combination umbrella trial (TACTIVE-U) with other targeted therapies (2023)
Provide an update with preliminary data from the Phase 1b combination trial with palbociclib (1H 2023)
Submit and present data from the Phase 1b combination trial with palbociclib at a medical congress (2H 2023)
AR Franchise (Bavdegalutamide/ARV-110, ARV-766)
Initiate a global Phase 3 trial with confirmed bavdegalutamide dose in metastatic castration-resistant prostate cancer (mCRPC) for patients with AR T878/H875 tumor mutations (2H 2023)
Complete enrollment in the Phase 1b combination study with bavdegalutamide plus abiraterone (2H 2023)
Share Phase 1 dose escalation trial data with ARV-766 in mCRPC (2Q 2023)
Initiate a Phase 1b or Phase 2 trial in patients who have not previously received novel hormonal agents (2H 2023)
Pipeline:
Submit two investigational new drug (IND)/clinical trial authorization (CTA) applications for the Company’s BCL6 (oncology) and LRRK2 (neuroscience) PROTAC protein degraders by year-end 2023
Progress at least two additional PROTAC protein degrader programs into IND- or CTA-enabling studies by year-end 2023
Founded 2015
Market Cap $1.6B
Net Cash $542mm
TEV $1.0B
> post phase 1
Upcoming Milestones & Expectations
Collaborate with Sanofi to initiate KT-474 Phase 2 clinical trial
Publish results of KT-474 Phase 1 trial including patient cohorts
Demonstrate clinical anti-tumor activity in target patient populations for KT-333 and KT-413
Initiate KT-253 Phase 1 trial in solid and hematological tumors and demonstrate clinical proof-of-mechanism in patients
Deliver at least 2 new development candidates (DC)/Investigational New Drugs (IND) from the preclinical pipeline in areas of large clinical and commercial opportunity and pathways where TPD has potential to provide either the only or the best-in-class solution
Further expand the capabilities of Kymera’s Pegasus™ platform and continue to leverage Kymera’s E3 Ligase Whole-Body Atlas of over 600 unique E3 ligases, with a focus on tissue restricted E3 ligases
Expand novel molecular glue franchise in areas of unmet medical need, exploiting a newly identified degron motif
Advance existing collaborations, or execute additional strategic partnerships, that support the company’s evolution into a fully integrated, global biopharmaceutical company
Founded 2015
Market Cap $152mm
Net Cash $250mm
TEV -$98mm
> phase 1
Upcoming Milestones & Expectations
CFT7455: Present Phase 1 dose escalation data from the Phase 1/2 clinical trial of Arm B1, evaluating CFT7455 as a monotherapy in MM, in the second half of 2023.
CFT8634: Present Phase 1 dose escalation data from the Phase 1/2 clinical trial in the second half of 2023 in synovial sarcoma and SMARCB1-null solid tumors.
CFT1946: Continue site activation and patient enrollment of the dose escalation portion of the CFT1946 Phase 1/2 clinical trial in BRAF V600 mutant solid tumors. Present new preclinical data on the discovery and characterization of CFT1946 at 2023 AACR Annual Meeting in April.
CFT8919: Submit an Investigational New Drug (IND) application for CFT8919 for the treatment of NSCLC in the first half of 2023.
Founded 2009
Market Cap $410mm
Net Cash $361mm
TEV $48mm
> phase 1
Title: NX-2127: A first-in-class clinical-stage degrader of BTK and IKZF1/3 for the treatment of patients with B cell malignancies
Title: NX-5948 promotes selective, sub-nanomolar degradation of inhibitor-resistant BTK mutants
Upcoming Milestones & Expectations
NX-2127: Nurix’s lead drug candidate from its protein degradation portfolio, NX-2127, is an orally bioavailable degrader of BTK with immunomodulatory activity for the treatment of patients with relapsed or refractory B-cell malignancies. Nurix anticipates presenting additional clinical results in the second half of 2023. Nurix also anticipates defining a regulatory strategy for NX-2127 in the second half of 2023 based on emerging clinical data and feedback from the FDA. Additional information on the clinical trial can be accessed at www.clinicaltrials.gov (NCT04830137).
NX-5948: Nurix’s second drug candidate from its protein degradation portfolio, NX-5948, is an orally bioavailable BTK degrader designed without immunomodulatory activity for certain B-cell malignancies and autoimmune diseases. Nurix is evaluating NX-5948 in a Phase 1 clinical trial in adults with relapsed or refractory B-cell malignancies and expects to present initial clinical data from the Phase 1a portion of the study in the second half of 2023. In addition, Nurix expects to define a dose for Phase 1b cohort expansion. Additional information on the clinical trial can be accessed at www.clinicaltrials.gov (NCT05131022).
NX-1607: Nurix’s lead drug candidate from its targeted protein elevation portfolio, NX-1607, is an orally bioavailable inhibitor of the E3 ligase CBL-B for immuno-oncology indications including a range of solid tumor types and lymphoma. Nurix is evaluating NX-1607 in an ongoing, Phase 1 trial in adults with a variety of oncology indications and expects to present clinical data from the Phase 1a portion of the study and to define a dose for Phase 1b cohort expansion in the second half of 2023. Additional information on the clinical trial can be accessed at www.clinicaltrials.gov (NCT05107674).
Selection of new drug candidate: Nurix expects to select a new targeted protein degrader development candidate in 2023.
Continued advancement of strategic collaborations with Gilead Sciences and Sanofi: Nurix expects to continue to achieve substantial research collaboration milestones throughout 2023 from its collaborations with Gilead Sciences and Sanofi.
Founded 2019
Market Cap $362mm
Net Cash $215mm
TEV $147mm
> phase 1
Appoints Dr. Jan Skvarka to Board of Directors
Upcoming Milestones & Expectations
Disclosure of initial clinical data including PK, PD, safety and available initial efficacy data from the Phase 1 arm of the ongoing Phase 1/2 clinical trial evaluating MRT-2359 is expected in the second half of 2023
Nomination of multiple development candidates from Lead Optimization programs in immunology, inflammation and/or oncology and initiation of IND-enabling studies in 2023
Disclosure of multiple new discovery programs
Expand molecular glue degrader platform beyond CRBN
Additional preclinical data from the MRT-2359 program will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting, April 14-19, 2023, in Orlando, FL
Founded 2015
Market Cap $251mm
Net Cash $294mm
TEV -$43mm
> phase 1
Upcoming Milestones & Expectations
FHD-286. FHD-286 is a potent, selective inhibitor of the BRG1 and BRM subunits of the BAF chromatin remodeling complex, where dependency on BRG1/BRM is well-established pre-clinically with multiple tumor types, including uveal melanoma, acute myelogenous leukemia (AML) / myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC) and prostate cancer.
mUM Update. Phase 1 dose escalation of FHD-286 in metastatic uveal melanoma (mUM) continues to enroll patients per protocol. Initial Phase 1 safety and efficacy data are expected in the first half of 2023.
AML/MDS Update. In August 2022, the U.S. Food and Drug Administration (FDA) placed a full clinical hold on the Phase 1 dose escalation study of FHD-286 in relapsed and/or refractory AML and MDS. The Company anticipates providing clarity on the development path for FHD-286 in AML/MDS in the first half of 2023.
FHD-609 Update. FHD-609 is a potent and selective heterobifunctional protein degrader of BRD9, which is a component of the BAF chromatin remodeling complex and a protein synovial sarcoma cells rely on for survival. Patient enrollment is continuing in the Phase 1 dose escalation clinical study of FHD-609 in synovial sarcoma and SMARCB1-loss tumors, with initial safety and efficacy data expected in mid-2023.
Newly Disclosed Selective EP300 Degrader. Foghorn disclosed a selective EP300 degrader targeting CBP mutant cancers and subsets of EP300 dependent malignancies. The Selective EP300 program has potential in various cancers which include bladder, NSCLC and various lymphomas and leukemias, and could provide a new therapeutic option for more than 100,000 people a year.
Differentiated Pipeline Advancement. Foghorn continues to expand its platform and pipeline. The Company has the potential for six new molecular investigational new drug (IND) applications in the next four years. The Company continues to progress programs for multiple targets which include chromatin remodeling complexes, transcription factors, helicases and other chromatin related factors. These targets include Selective BRM, CBP, EP300 and ARID1B as well as other undisclosed targets, which combined could address more than 20 tumor types impacting more than 500,000 new people annually.
Strategic Collaborations. Foghorn expects continued progress across its strategic collaborations with two leading pharmaceutical companies.