Targeted protein degradation (TPD)

Clinical Degrader Drugs 
Targeted protein degradation (TPD) is an emerging field in drug discovery that aims to selectively remove disease-causing proteins from cells. By directly targeting and eliminating proteins, TPD has the potential to address a wider range of disease targets, including those that have been traditionally considered “undruggable.”
Many highly selective PROTAC molecules with improved drug-like properties are entering clinical trials.
Some of the most exciting compounds being profiled are highlighted below

💊Vepdegrestrant (ARV-471), an orally bioavailable estrogen receptor (ER) protein degrader for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer.

💊Bavdegalutamide (ARV-110), an orally bioavailable androgen receptor (AR) protein degrader for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

💊ARV-766, an orally bioavailable AR degrader for the treatment of mCRPC.

💊NX-2127, an orally bioavailable Bruton’s tyrosine kinase (BTK), Ikaros (IKZF1) and Aiolos (IKZF3) degrader for the treatment of R/R B cell malignancies.

💊NX-5948, an orally bioavailable BTK degrader for the treatment of R/R B cell malignancies.

💉DT-2216, an IV administered selective B-cell lymphoma-extra large (Bcl-XL) protein degrader for the treatment of T-cell lymphomas.

💉FHD-609, an IV administered BRD9 protein degrader for the treatment of synovial sarcoma.

💊CFT1946, an orally bioavailable mutant BRAF kinase protein degrader for the treatment of various BRAF V600E-driven cancers.

💊CFT8634, an orally bioavailable BRD9 protein degrader for the treatment of synovial sarcoma.

💊KT-474, an orally bioavailable IRAK4 protein degrader for the treatment hidradenitis suppurativa (HS) and atopic dermatitis (AD).

💉KT-413, an IV administered IRAK4, IKZF1 and IKZF3 protein degrader for the treatment of  MYD88-mutant B cell lymphomas.

💉KT-333, an IV administered STAT3 protein degrader for the treatment of Peripheral T-cell Lymphoma (PTCL).

💉KT-253, an IV administered MDM2 protein degrader for the treatment of r/r high grade myeloid malignancies and solid tumors.


💉SD-36, an IV administered STAT3 tool protein degrader.

💉MD-224, an IV administered MDM2 tool protein degrader.

Another amazing summary from Chris De Savi

Oculis announces positive top-line results from diamond Stage 1 Phase 3 trial in diabetic macular edema with OCS-01 eye drops

today’s #cyclodextrin:
Oculis, a global biopharmaceutical company purposefully driven to save sight and improve eye care, announced positive top line results from Stage 1 of its Phase 3 trial of OCS-01 (dexamethasone formulated in gamma-cyclodextrin #nanoparticles) eye drops in Diabetic Macular Edema (DME). DME is the leading cause of visual loss and legal blindness in patients with diabetes, affecting around 37 million people worldwide, with a significant number of patients left untreated due to a lack of convenient treatment options.
OCS-01, in this 3-month trial, has met both clinical efficacy endpoints (main BCVA change, proportion of patients with 3 lines gain) that are required for regulatory approval if met at 12 months treatment duration.

See the official annoucement here

Alveron Pharma starts the first clinical trial of a new drug for the treatment of intracranial hemorrhage

today’s #cyclodextrin:
this may be a historic moment. Since sugammadex, no new cyclodextrin has been dosed in humans as an active ingredient for a novel indication. Yesterday, Alveron Pharma finally announced that it starts the first clinical trial of a new drug for the treatment of intracranial hemorrhage.
OKL-1111, is an undisclosed new cyclodextrin drug for the treatment of Intracranial Haemorrhage (ICH) and other life-threatening bleeds associated with the use of anticoagulants or platelet inhibitors. The clinical trial is taking place in the UK and will investigate safety, pharmacokinetics, and pharmacodynamics in man.
ICH is a devastating condition with a 30-50% mortality rate and is also responsible for approximately 50% of disabilities associated with stroke as a whole. The use of anticoagulants or platelet inhibitors greatly increases the probability and severity of ICH, and with an aging population, this is a growing problem. One of the major reasons for poor outcomes in ICH is that patients are treated too late with reversal agents. Current mainstream therapies require the identity of the anticoagulant, consultation with an expert, dose calculations with some requiring patient weight, and reconstitution of multiple vials of powder into solution. This process can take over one hour.
Alveron’s drug OKL-1111 is positioned as a rapid, first-line therapy as it has a truly universal mode of action, not requiring anticoagulant identification. OKL-1111 is being developed as a ready-to-use solution for injection also eliminating a very time-consuming preparation step. The pre-clinical safety data indicates a very low risk of thrombotic overshoot, reducing the need for expert risk/benefit evaluation prior to use. OKL-1111 has the potential for rapid administration with greatly improved outcomes.
OKL-1111’s product profile is also potentially suitable for use in ambulances which may become feasible with the introduction of mobile diagnostic technologies. This would further reduce the time to treatment, radically improving outcomes.
The drug OKL-1111 originates from a joint research project between Okklo Life Sciences and Sanquin Blood Supply Foundation.

Congratulations to Ben NicholsHarshad (Hash) PatelStephan PetersAlex Zwiers and all involved, worked and persisted in making this happen. I admire your work and cross fingers for your success in this important therapeutic target.

See the official post here: Alveron Pharma starts the first clinical trial of new drug for treatment of intracranial hemorrhage

Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia

Positive Phase 1/2 clinical data published on uproleselan (GMI-1271), a novel E-selectin antagonist that disrupts cell survival pathways, enhance chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo.
The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies.
Brian Jonas, Jane Jane Liesveld, Dale Bixby, Paula Marlton, John Magnani, Helen Thackray, Eric Feldman, Pamela Becker et al. – GlycoMimetics

See the full clinical trials report here.

Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia

Cyclo Therapeutics Announces First Patient Dosed in Phase 2b Study of Trappsol® Cyclo™ for the Treatment of Early Alzheimer’s Disease

Cyclo Therapeutics, Inc. announces first patient dosed in Phase 2b study of Trappsol® Cyclo™ for treating early Alzheimer’s disease.

Trappsol® Cyclo™ is the Company’s proprietary formulation of hydroxypropyl beta-cyclodextrin. In multiple clinical studies, it has shown encouraging results in effectively managing the transportation of cholesterol, a known defect in neurodegenerative diseases. Many known risk factors for Alzheimer’s disease are associated with cholesterol metabolism.

Cyclo Therapeutics is currently testing the same investigational Trappsol® Cyclo™ drug in Phase 3 clinical trial (TransportNPC™) and a long-term extension study for the treatment of Niemann-Pick disease Type C1, a rare, fatal, and progressive genetic disorder. Taking the place of the defective NPC1 protein, Trappsol® Cyclo™, with its cyclic structure, facilitates the transport of accumulated cholesterol out of cellular lysosomes so it can be further processed and excreted out of cells. With the biological similarities demonstrated between Niemann-Pick disease Type C1 and Alzheimer’s disease, including cholesterol accumulation in regions of the brain, elevated levels of Tau in cerebrospinal fluid (“CSF”), and amyloid plaques in the brain, the Company believes Trappsol® Cyclo™ has significant potential to be an effective treatment option for Alzheimer’s disease.

Read the full announcement here

Comparison of the Efficacy and Safety of Adamgammadex with Sugammadex for Reversal of Rocuronium-Induced Neuromuscular Block: Results of a Phase II Clinical Trial

The success of Sugammadex inspired several further cyclodextrin research, including the development of other antidotes and discovering “follow-up” compounds for the same indication. The most advanced candidate in this field is Adamgammadex (developed by Adamerck) with its efficacy recently compared to SGM in a Phase II trial lead by Sichuan University. Although it was used in 2-3 times higher concentrations, the previously reported adverse effects were not observed in this study, including anaphylaxis, haemorrhage, recurarization, abnormal basic vital signs, or lengthened QRS intervals and QT intervals. Adamgammadex was found to be effective for reversing rocuronium-induced neuromuscular block as sugammadex.

See the full article here

Beren Awarded Expedited Roadmap for Treatment of Homozygous Familial Hypercholesterolemia

Fascinating news from Beren Therapeutics:
Beren Awarded Expedited Roadmap for Treatment of Homozygous Familial Hypercholesterolemia
Beren’s novel lead asset, BRN-002, was awarded an Innovation Passport under the United Kingdom’s Innovative Licensing and Access Pathway (ILAP), for the reversal of atherosclerosis in patients with Homozygous Familial Hypercholesterolemia. The ILAP aims to accelerate the time to market for innovative medicines that address the needs of patients with life-threatening or seriously debilitating diseases.
“We are excited to begin work under ILAP and look forward to collaborating with other regulators, payors, and governments to expedite the development and identify and remove access barriers.” – commented Jason Camm, CEO. Jules Payne from HEART UK – The Cholesterol Charity added that “Significant unmet needs remain, and with this advancement, we are hopeful for a new treatment option that can truly alter the course of the disease for the children and patients living with HoFH.”
Beren Therapeutics, P.B.C. is currently in stealth.

See the full article here

New clinical trial upcoming using cyclodextrin as active

Cyclo Therapeutics, Inc. sponsors Phase II trial for early Alzheimer’s disease. The study will enroll approximately 90 male and female patients aged 50 to 80 years who will be given a minimum active dose of 500 mg/kg of Trappsol Cyclo (equivalent to 18,500 mg/m2) as an intravenous (IV) infusion once every 28 days for 6 months.
We wish the best of success to our colleagues at Cyclo Therapeutics and hope this therapy will prove useful for the benefit of these patients.
Having programs ourselves in developing NCEs for neurodegenerative diseases, we find this study particularly essential.

Read more about the clinical trial here

ZyVersa Therapeutics and Larkspur health acquisition corp. announce business combination, interim financing, and pipe investment update

A little business for today:
ZyVersa Therapeutics Inc., a clinical-stage specialty biopharmaceutical company developing, among others, a cyclodextrin drug candidate (VAR 200), announced an aggregate committed financing in support of the business combination at $10.0 million.
This investment will enable Zyversa to advance clinical evaluation of the cholesterol efflux mediator candidate (VAR 200) in patients with orphan renal disease, FSGS, and to progress into Phase 1 trials – said Steve Glover and Daniel J. O’Connor
Read more on the ZyVersa website