P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson's Disease.

Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Parkinson's disease is the fastest growing neurologic disorder across the globe. Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop Parkinson's-related disability. There are three main treatment options available for use in early Parkinson's disease: levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Of these, there is a current push toward using levodopa as the main first-line therapy. This is primarily because of the significant safety and tolerability concerns with dopamine agonists and only mild efficacy of MAO-B inhibitors. Recently, P2B001, a novel drug formulation combining once-daily, extended-release, low dosages of the dopamine agonist pramipexole and the MAO-B inhibitor rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this article, the authors review the preclinical and current clinical data on P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease.

BACKGROUND: Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD. METHODS: Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores. RESULTS: A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment. CONCLUSIONS: P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society.

A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway.

We describe a novel, potent peptide substrate mimetic inhibitor of protein kinase B (PKB/Akt). The compound selectively kills prostate cancer cells, in which PKB is highly activated, but not normal cells, or cancer cells in which PKB is not activated. The inhibitor induces apoptosis and inhibits the phosphorylation of PKB substrates in prostate cancer cell lines and significantly increases the efficacy of chemotherapy agents to induce prostate cancer cell death, when given in combination. In vivo, the inhibitor exhibits a strong antitumor effect in two prostate cancer mouse models. Moreover, treated animals develop significantly less lung metastases compared to untreated ones, and the effect is accompanied by a significant decrease in blood PSA [prostate-specific antigen] levels in treated animals. This compound and its potential analogues may be developed into novel, potent, and safe anticancer agents, both as stand-alone treatment and in combination with other chemotherapy agents.

Targeting small-cell lung cancer with novel fluorescent analogs of somatostatin.

Early, accurate detection of small-cell lung cancer (SCLC), before it becomes systemic, is essential for successful treatment. Fluorescence-based imaging provides safe, sensitive detection of malignancies. Targeted delivery of fluorophores increases sensitivity of endoscopic imaging. We synthesized novel somatostatin analogs, based on backbone cyclic peptides, and conjugated them with fluorescent agents. Nineteen conjugates differing in core peptide, length of alkyl linker and fluorescence moiety (rhodamine and fluorescein) were tested in vitro, using a receptor binding assay, and nine of the more promising conjugates were tested in vivo by fiber-optic spectrofluorimetry and quantitative spectral imaging, on an H69 human SCLC tumor mouse xenograft model. The lead compound showed exceptional tumor/normal tissue ratios, ranging from 9 to 90, and has potential for targeting SCLC overexpressing somatostatin receptors.

Backbone metal-cyclization: a novel approach for simultaneous peptide cyclization and radiolabeling. Application to the combinatorial synthesis of rhenium-cyclic somatostatin analogs.

A novel approach for the combinatorial synthesis of backbone-derived metal-cyclic peptide libraries is presented. In this approach the metalo-cyclic peptides are prepared from their linear precursors through complexation of a metal atom via two hemi-chelating arms located on the peptide backbone. Thus, cyclization and metal labeling of the peptides are achieved simultaneously. A library, composed of 48 rhenium-cyclic somatostatin analogs, was prepared. All rhenium somatostatin complexes exhibited high to moderate in vitro binding affinities toward cloned human somatostatin receptor subtype 2 (hsstr2). Five rhenium-cyclic peptides were found to be most potent with IC50 values between 1 and 3 nM making them promising leads for further development of tumor diagnostic and therapeutic radiolabeled agents. A 99mTc somatostatin cyclic analog was successfully prepared by the same method.

Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units.

Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.