Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

carbohydrates, drug development,

There are multiple challenges in developing carbohydrate/cyclodextrin-based drugs that we also face at CarboHyde every day. One is to develop proper analytical techniques, which are especially difficult for biological samples and if the drug is not a single compound but a mixture of components (just like HP-b-CD used in Niemann-Pick C). While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking.
That being said, we particularly welcome the study disclosing method for a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. Investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. The following changes in the proteome suggest that HP-b-CD promotes exocytosis in this neuron-like model. Utilizing state-of-the-art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP-b-CD as a potential therapeutic.
Antony Cougnoux, (Karolinska Institutet), Melissa Pergande, Fidel Serna-Perez, and Stephanie Cologna (University of Illinois Chicago)

See the full article here: Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

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

drug development, ,

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 Nichols, Harshad (Hash) Patel, Stephan Peters, Alex 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

carbohydrates, drug development, ,

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

Targeting bacterial virulence as a novel treatment against AMR infections

drug development, ,

Have you known that Arivin Therapeutics uses cyclodextrin for targeting bacterial virulence as a novel treatment against AMR infections? Among their MoA claims, the following are listed:
– Targeting virulence factors is effective, also against extensively resistant isolates
– Targeting virulence avoids rapid resistance
– Direct reduction in inflammatory responses
– Potentiates the function of antibiotics
Also, there is a spectacular video about how CDs develop their effect as antibacterials.

https://arivintx.com/our-science

Hydroxypropyl-β-cyclodextrin inhibits the development of triple-negative breast cancer by enhancing antitumor immunity

drug development, ,

After sharing news on treating lymphedema, we came across another potential therapeutic use of cyclodextrin. In this preprint from Hefei University of Technology and Emory University authors demonstrate that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inhibited the growth and metastasis of triple-negative breast cancer (TNBC) both in vitro and in vivo, although the underlying mechanisms are unclear.
Cholesterol supplementation can attenuate HP-b-CD-inhibited TNBC growth and metastasis both in vitro and in vivo. In vivo, HP-β-CD promoted the infiltration of T cells into the tumor microenvironment (TME) and improved the exhaustion of CD8+ T cells via reducing endoplasmic reticulum (ER) stress and immune checkpoint molecules. Additionally, HP-β-CD inhibited the recruitment of tumor-associated macrophages to the TME by reducing the CCL2-p38MAPK-NF-kB axis. HP-β-CD also inhibited the epithelial-mesenchymal transition (EMT) of TNBC cells mediated by transforming the growth factor-b (TGF-b) signaling pathway.
In summary, the data in the current study suggest that HP-β-CD effectively inhibited the proliferation and metastasis of TNBC and melanoma, highlighting HP-β-CD may be a potential general antitumor clinical drug.

See the full article here

The authors found that HP-b-CD inhibits the proliferation and metastasis of TNBC by reducing cholesterol levels. HP-b-CD promotes T cell recruitment to the TME and improves CD8+ T cell exhaustion. Additionally, HP-b-CD inhibits TAMs accumulation.

Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl

drug development,

Lyle Isaacs and his team from University of Maryland has something fascinating to show. Not only have they published a potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl (similar to the Sugammadex concept) but they also shared this cool video on the mechanism of action:

This is how you should present science! Amazing!
Adam Brockett, Canjia Zhai, Shivangi Rastogi, Volker Briken

See the full article 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

drug development, drug discovery, , ,

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