Moleculin reports additional positive interim results from ph 1 trial glioblastoma

Walter Klemp, Chairman and CEO of Moleculin, stated, “The trial in adults has been important in leading the way to establishing a safe and tolerable human dose level for what we believe is a first-in-class compound that crosses the blood-brain barrier and is being developed for the treatment of central nervous system malignancies.  In animal models, WP1066 has been shown to stimulate immune responses that successfully modulate oncogenic transcriptional activity in tumor cells and repress their ability to drive tumor growth.”

According to Mr. Klemp: “In addition to providing valuable pharmacokinetic data, this trial also creates the foundation for future studies in WP1066, including another investigator-initiated study, which is currently being proposed to examine the combination of WP1066 with radiation for the treatment of GBM.  This next clinical trial is being proposed as a result of recent discoveries presented in a peer-reviewed article published in Clinical Cancer Research (Clin Cancer Res June 30 2020 DOI:10.1158/1078-0432.CCR-19-4092), which reported findings that Moleculin’s STAT3 inhibitor, WP1066, used in combination with traditional whole brain radiation therapy, resulted in long-term survivors and enhanced median survival time relative to monotherapy in mice with implanted human brain tumors.”

Encouraging interim data from ph 1/2 study of Pfizer/BioNTech *redacted* vaccine candidate

The ongoing U.S. Phase 1/2 randomized, placebo-controlled, observer-blinded study is evaluating the safety, tolerability, and immunogenicity of escalating dose levels of BNT162b1. The initial part of the study included 45 healthy adults 18 to 55 years of age. Preliminary data for BNT162b1 was evaluated for 24 subjects who received two injections of 10 µg and 30 µg, 12 subjects who received a single injection of 100 µg, and 9 subjects who received 2 doses of placebo control.

The participants received two doses, 21 days apart, of placebo, 10 µg or 30 µg of BNT162b1, or received a single dose of 100 µg of the vaccine candidate. Because of a strong vaccine booster effect, the highest neutralizing titers were observed seven days after the second dose of 10 µg or 30 µg on day 28 after vaccination. The neutralizing GMTs were 168 and 267 for the 10 µg and 30 µg dose levels, respectively, corresponding to 1.8- and 2.8-times the neutralizing GMT of 94 observed in a panel of 38 sera from subjects who had contracted *redacted*.

At the 10 µg or 30 µg dose levels, adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following dose 2, 8.3% of participants who received 10 µg and 75.0% of participants who received 30 µg BNT162b1 reported fever ≥ 38.0 °C. Local reactions and systemic events after injection with 10 µg and 30 µg of BNT162b1 were dose-dependent, generally mild to moderate, and transient. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 100 µg dose, which was severe. No serious adverse events were reported. Given higher numbers of subjects experiencing local reactions and systemic events after a single 100 µg dose with no significant increases in immunogenicity compared to the 30 µg dose level, the 12 participants in the 100 µg group were not administered a second dose.

In all 24 subjects who received 2 vaccinations at 10 µg and 30 µg dose levels of BNT162b1, elevation of RBD-binding IgG concentrations was observed after the second injection with respective GMCs of 4,813 units/ml and 27,872 units/ml at day 28, seven days after immunization. These concentrations are 8- and 46.3-times the GMC of 602 units/ml in a panel of 38 sera from subjects who had contracted *redacted*.

*redacted*

The BNT162b1 candidate remains under clinical study and is not currently approved for distribution anywhere in the world. If the ongoing studies are successful and the vaccine candidate receives regulatory approval, the companies expect to manufacture up to 100 million doses by the end of 2020 and potentially more than 1.2 billion doses by the end of 2021.

Intra-Cellular announces positive results from ITI-214 ph 1/2 study in heart failure

Reported adverse events were all mild to moderate and consisted of three occurrences of orthostatic hypotension and three episodes of non-postural hypotension. Patients were monitored by continuous telemetry, and no changes in heart rhythms were noted. No serious adverse events were reported.

In this study, compared to placebo, single doses of ITI-214 increased mean left ventricular (LV) power index and cardiac output while systemic vascular resistance and mean arterial blood pressure decreased.

ITI-214 is a potent and selective phosphodiesterase type 1 (PDE1) inhibitor. ITI-214 is the lead compound in the Company’s PDE1 portfolio and is in development for the treatment of symptoms associated with Parkinson’s disease and for the treatment of heart failure. ITI-214 has been generally well tolerated with a favorable safety profile in six Phase 1 clinical trials. ITI-214 works by slowing the breakdown of cyclic nucleotides (cAMP, cGMP), thus allowing these molecules to build up in the cells and to exert important functions. The PDE1 enzyme is highly active in pathological or disease states, and our PDE1 molecules are designed to reestablish normal function in these disease states through the inhibition of the PDE1 enzyme.

In heart disease, excessive PDE1 activity may limit the beneficial effects of cAMP or cGMP, so inhibitors like ITI-214 have the potential to act as a therapy. ITI-214 is an inodilator that can improve cardiac function by both increasing the force of heart contractions and reducing the resistance to pushing blood through the vascular system. Preclinical research has shown that ITI-214 increases cardiac contractility and decreases vascular resistance without increasing abnormal heart rhythms, and the clinical results announced herein indicate that similar, potentially therapeutic physiologic effects can be attained in heart failure patients. ITI-214 is being developed for the potential treatment of heart failure with reduced ejection fraction (HFrEF).

Previous studies have described the mechanism of action of ITI-214 in the brain. The mechanism of action of ITI-214 and our other PDE1 inhibitors suggests therapeutic potential across a variety of diseases including neurological and cardiovascular diseases.


PDE1 inhibition also modifies cyclic AMP, but it does so in a different manner linked with a novel intracellular pathway that involves adenosine A2B receptor signaling but not ß-adrenergic signaling to stimulate heart contractility. ITI-214 did not cause calcium levels to rise in cardiomyocyte cells. In all of the studies to date, activation of the PDE1-regulated pathway has not triggered arrhythmia.

First patient dosed in ph 1 study of Alpine’s ALPN-202

NEON-1 includes two parts: dose escalation and expansion cohort(s). It will enroll adults with advanced solid tumors or lymphoma refractory or resistant to standard therapy, including checkpoint inhibitors when indicated. Measurable disease is required for most participants, as are an ECOG status of 0 to 2 and adequate hematological, renal, and hepatic function. Dose escalation begins with single-participant cohorts to minimize the number of participants anticipated to receive subtherapeutic doses, followed by standard 3 + 3 cohorts where two dose regimens, weekly versus every three weeks, will be studied in parallel. Expansion cohorts will explore specific tumor types and/or biomarker-selected tumors, based upon the experience during dose escalation. Safety endpoints include dose-limiting toxicities, adverse events, and circulating cytokines. Objective responses will be assessed by RECIST v1.1 for solid tumors and Lugano criteria for lymphoma. Pharmacokinetics and pharmacodynamics will also be evaluated.

NEON-1 is currently enrolling. Estimated primary completion is December 2024.

CUE-101 ph 1 update in Recurrent/Metastatic HNSCC

-101 has been overall well-tolerated with treatment-related adverse events (AEs) primarily being mild-to-moderate (Grade 1 or 2) with no discontinuations due to AEs. One patient from dose cohort 4 at 1.0 mg/kg experienced a Grade 3 adverse event (anemia and fatigue) that was reported on day 19 of the 21-day safety evaluation period. Of note, this patient had an underlying condition, and following a blood transfusion the anemia resolved, allowing for the patient to receive the second planned dose of -101 at the same 1.0 mg/kg dose on June 8 which to date, appears to have been well tolerated. This patient remains on study. On June 5, the Safety Review Committee designated this event as a possible drug-related dose limiting toxicity (DLT), and thus an additional three patients will be enrolled at the 1.0 mg/kg dose level within cohort 4 per protocol. This will allow for a more thorough evaluation of -101 pharmacodynamics and clinical activity in order to better define the therapeutic window. The fourth patient in cohort 4 has received their cycle 1 dose and the other two patients have been identified and are scheduled to receive their first dose of -101 before the end of this month. If no additional DLTs emerge within these three additional patients, the company will proceed to the cohort 5 dose.

Preliminary observations:

  • Pharmacokinetic data indicating drug exposure that is in line with preclinical projections and is dose-proportional; furthermore, comparable exposures have been observed upon repeated administration;
  • Pharmacodynamic data indicating selective expansion of the targeted T cells in the peripheral blood of several patients across cohorts 2 and 3; evaluation of activity in patients from cohort 4 is ongoing;
  • Preliminary radiographic evidence indicating -101 is clinically active, with a patient from cohort 2 experiencing reduction of target lesion following two cycles of -101 that was sustained through day 84 of treatment, at which point the patient was confirmed as having stable disease; this patient continues to be on study.

Cue will also be launching combination trial with Merck’s Keytruda (pembrolizumab) as well as a neo-adjuvant trial later this year to generate clinical data sets pertaining to tumor-infiltrating lymphocytes, or TILs, from the targeted T cell population.

The -100 series consists of Fc-fusion biologics that incorporate peptide-MHC (pMHC) molecules along with rationally engineered IL-2 molecules. This singular biologic is anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells directly in the patient. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.