A Phase 1, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Oral Dose, Safety, Tolerability, Pharmacodynamic, and Pharmacokinetic Study of DP13 in Healthy Male Subjects
Primary Objectives: To determine the safety and tolerability of single and multiple oral doses of DP13 in healthy male subjects To assess the pharmacodynamics of single and multiple ascending oral doses as well as dosing regimen of DP13 on suppression of serum aldosterone in healthy male subjects Secondary Objectives: To determine the single and multiple oral dose pharmacokinetics of DP13 in healthy male subjects To determine the dose-dependent pharmacodynamic selectivity of DP13 in healthy male subjects
2023-03-13·British journal of clinical pharmacology
CYP11B2 Inhibitor Dexfadrostat Phosphate Suppresses the Aldosterone-to-Renin Ratio, an Indicator of Sodium Retention, in Healthy Volunteers.
作者: Paolo Mulatero ; Michael Groessl ; Bruno Vogt ; Christoph Schumacher ; Ronald Edward Steele ; Ashley Brooks ; Stuart Hossack ; Hans-Rudolf Brunner
High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.
This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4 mg, 8 mg or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH)-stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing.
DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4 mg, 8 mg, 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-hour aldosterone suppression after 8 days of treatment, unlike the 8 mg and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge).
In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.
High-yield production of lipoglycopeptide antibiotic A40926 using a mutant strain Nonomuraea sp. DP-13 in optimized medium
4区 · 工程技术
作者: Chen, Ming ; Xu, Tao ; Zhang, Guanghao ; Zhao, Jing ; Gao, Ziqing ; Zhang, Chunzhi
The lipoglycopeptide antibiotic A40926 produced by Nonomuraea sp. is a complex of structurally related components differing in the fatty acid moiety. Besides showing an intrinsic antibacterial activity, A40926 is the precursor of the semisynthetic antibiotic Dalvance. In this work, A40926 production by a mutant strain Nonomuraea sp. DP-13 was investigated. It was found that A40926 production was markedly promoted by using poorly assimilated carbon source maltodextrin and nitrogen source soybean meal. Addition of Cu(2+) resulted in a stimulation of A40926 production, but Co(2+) had an inhibitory effect. L-Leucine addition greatly improved total A40926 production and modified the complex composition toward factor B0. An optimized production medium IM-3 was developed and a maximum A40926 production of 1096 mg/L was obtained in the 10-L fermenter. This was the highest A40926 productivity so far reported.
2003-08-01·Molecular Reproduction and Development3区 · 生物学
Degree of sex reversal as related to plasma steroid levels in genetic female chickens (Gallus domesticus) treated with fadrozole
3区 · 生物学
作者: Vaillant, S. ; Guemene, D. ; Dorizzi, M. ; Pieau, C. ; Richard-Mercier, N. ; Brillard, J.-P.
The objectives of this work were to determine whether or not plasma levels of testosterone and estradiol reflect the various grades of sex reversal in genetic female chickens treated with Fadrozole (CGS 16949 A), a nonsteroidal aromatase inhibitor, and whether gonadal aromatase activity and plasma levels of testosterone and estradiol in treated females can or not be modified by post-hatch treatments with Fadrozole or Fadrozole + testosterone. Eggs were injected with 1 mg Fadrozole on day 4 of incubation. In females having developed sex-reversed gonads, endocrine parameters (estradiol and testosterone) at and after 13 weeks of age were indicative of the degree of sex reversal, with, for example, sex-reversed females with two testes having the highest levels of testosterone and the lowest levels of estradiol. Among these females, eight (from a total of 13) produced ejaculates with scarce and abnormal spermatozoa. Some motility was observable in the ejaculates from five of them. None of the post-hatch treatments had a significant effect on plasma levels of testosterone or estradiol (measured at 3-week intervals from week 4 to week 28 post-hatch) or on gonadal aromatase activity (measured at 12 and 28 weeks). In conclusion, these results indicate that plasma levels of testosterone and estradiol at and after 13 weeks of age are valuable indicators of the degree of sex reversal in female chickens treated with Fadrozole prior to gonadal sex differentiation. In pre-cited conditions, post-natal treatments with either Fadrozole or Fadrozole + testosterone had no apparent effect on the degree of sex reversal in these birds. Finally, the occurrence of ejaculates with motile although scarce and abnormal spermatozoa, revealed that epididymes and ducti deferens can develop and become functional in sex-reversed female chickens.
A CinCor Pharma drug intended to offer a novel alternative to currently available hypertension treatments has failed a Phase 2 study. Nevertheless, CinCor points to better results in a pre-specified subgroup of patients representative of many hypertension patients. While the biotech firm contends the data will guide the design of a study that could support regulatory approval, these preliminary results could also limit the drug’s scope by tens of millions of patients.
Investors took the dimmer view of prospects for the CinCor drug, baxdrostat, and the Waltham, Massachusetts-based biotech’s shares sank Monday more than 47% from Friday’s closing price.
The preliminary results reported Monday are from a dose-finding Phase 2 study enrolling 249 patients who were randomly assigned to receive one of three doses of the experimental CinCor drug or a placebo once a day for eight weeks. Those patients have uncontrolled hypertension, defined as needing up to two blood pressure medications at the maximally tolerated doses. While reductions in blood pressure were observed at all three doses of the CinCor drug, the changes were not enough to meet the main goal of showing a statistically significant reduction in seated systolic blood pressure after eight weeks.
However, a statistically significant reduction was reported in 116 non-Hispanic patients (47% of patients in the trial), a group that includes Black patients who CinCor notes represent about 81% to 89% of people with hypertension in the U.S. In the pre-specified subgroup, CinCor reported that the highest of the three doses tested showed a placebo-adjusted reduction of 12.6 millimeters of mercury, the measure of blood pressure.
“It seems there is a sizable population that could, potentially if confirmed within a Phase 3, could benefit with double-digit reduction in this uncontrollable population,” CEO Marc de Garidel said, speaking during a conference call on Monday.
Hypertension is currently treated with drugs that lower blood levels of aldosterone, a blood pressure-regulating hormone. But extended use of these medicines–angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)–can lead to aldosterone breakthrough, in which blood levels of the hormone return and even exceed prior levels.
CinCor’s baxdrostat works differently than ACE inhibitors and ARBs. The small molecule is designed to block an enzyme that is key to aldosterone synthesis in the adrenal gland. This approach is intended to stop production of the hormone. CinCor Chief Medical Officer Mason Freeman attributed the Phase 2 failure to a high placebo response driven by lack of adherence to a drug regimen that included continuing the anti-hypertensive drugs patients had already been prescribed. Inconsistencies in taking these drugs could have affected the results, he said. Freeman pointed to five sites in particular that were notable for lack of adherence to the drug regimen. CinCor plans to measure background medication use as part of its analysis of the failed study.
Despite missing the trial’s main goal, Freeman said the study met two key company goals: identifying the patient population that had a robust response and confirming that the high dose is the most efficacious one to evaluate in a Phase 3 clinical trial.
The preliminary data reported Monday come nearly four months after a separate Phase 2 study posted data in treatment-resistant hypertension, defined as patients taking at least three blood pressure medications at the maximally tolerated doses, one of which is a diuretic. CinCor said in August that an independent committee determined that the highest dose—the same as the high dose in the uncontrolled hypertension Phase 2 study—met the main goal of showing a change in average seated systolic blood pressure after 12 weeks.
Treatment-resistant hypertension affects an estimated 13 million to 15 million U.S. patients, CinCor said in an investor presentation. Uncontrolled hypertension is the larger group, affecting between 30 million and 35 million patients in the U.S. If the CinCor drug can only address non-Hispanic or Latino patients with uncontrolled hypertension, the addressable patient population in this group will be cut nearly in half. As the company looks ahead to Phase 3 testing, Freeman said CinCor plans to test the drug in a diverse mix of ethnic and racial groups.
“We will continue to study these populations to make sure we’ve identified those who are most responsive to baxdrostat,” he said.
Deepak Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, commented on the CinCor drug’s latest results during the company’s conference call. While he commended the company for conducting a trial with a diverse patient population, he added that the modest size of the Phase 2 study and its multiple subgroups made it hard determine if biological differences based on ethnicity are driving the results. That question should be explored, he said.
“My own feeling though is it’s probably less likely biology that’s explaining this and more likely the sites, specifically, those five sites where the adherence just wasn’t as high,” Bhatt said. “So I think it’s more having to do with sites and adherence at particular sites than it is anything in terms of genetics or even in terms of race/ethnicity.”
One positive note from the failed Phase 2 test is that the drug was well-tolerated by patients. No serious adverse effects were reported in the trial, and the drug’s safety profile was consistent with what was observed in the prior mid-stage test in treatment-resistant hypertension. CinCor plans to meet with the FDA to discuss the Phase 3 path for the drug.
CinCor’s path could keep the company in the hunt along with other companies with aldosterone synthase inhibitors. Mineralys Therapeutics has reached mid-stage testing with MLS-101, a hypertension drug licensed from Mitsubishi Tanabe Pharma Corporation. Philadelphia-based Mineralys, which raised $118 million in financing last June, reported two weeks ago that its drug met main and secondary blood pressure reduction goals of its Phase 2 test in both uncontrolled and resistant hypertension. Damian Pharma is developing its drug candidate DP13 as a treatment for primary aldosteronism, a disorder in which the adrenal glands produce too much aldosterone. In October, the Switzerland-based company presented data showing statistically significant reductions in aldosterone and blood pressure.
CinCor views baxdrostat as a “pipeline in a product.” In addition to uncontrollable and resistant hypertension, the company is evaluating the molecule as a potential treatment for primary aldosteronism and chronic kidney disease. The company expects to report preliminary Phase 2 data in both indications in the second half of 2023.
Public domain photo by Flickr user agilemtkg1