The recurrent fixation of newly arising, beneficial mutations in a species reduces levels of linked neutral variability. Models positing frequent weakly beneficial substitutions or, alternatively, rare, strongly selected substitutions predict similar average effects on linked neutral variability, if the product of the rate and strength of selection is held constant. We propose an approximate Bayesian (ABC) polymorphism-based estimator that can be used to distinguish between these models, and apply it to multi-locus data from Drosophila melanogaster. We investigate the extent to which inference about the strength of selection is sensitive to assumptions about the underlying distributions of the rates of substitution and recombination, the strength of selection, heterogeneity in mutation rate, as well as the population's demographic history. We show that assuming fixed values of selection parameters in estimation leads to overestimates of the strength of selection and underestimates of the rate. We estimate parameters for an African population of D. melanogaster ((s) over cap similar to 2E-03, 2N (lambda) over cap similar to 2E-04) and compare these to previous estimates. Finally, we show that surveying larger genomic regions is expected to lend much more discriminatory power to the approach. It will thus be of great interest to apply this method to emerging whole-genome polymorphism data sets in many taxa.

Brutons tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.

Objective

To assess the relationship of adherence and pregnancy in participants using an estetrol and drospirenone combined oral contraceptive.

Methods

We performed a secondary analysis for which we pooled data from two parallel, multicenter, phase 3 trials (United States and Canada, Europe and Russia) that enrolled participants 16-50 years of age to receive estetrol 15 mg and drospirenone 3 mg in a 24 hormone and four placebo pills regimen for up to 13 cycles. Participants reported pill intake, sexual intercourse, and other contraceptive use on paper diaries. We limited this efficacy analysis to at-risk cycles (one or more reported acts of intercourse and no other contraceptive use) in participants 16-35 years of age at screening. We excluded cycles with other contraceptive use unless pregnancy occurred in that cycle. We assessed primarily the relationship between number of pills not taken per cycle and pregnancies and, secondarily, when pregnancies occurred during product use with a test for trend and χ 2 analyses as appropriate.

Results

Among 2,837 participants in this analysis, 31 on-treatment pregnancies occurred during 26,455 at-risk cycles. Pregnancies occurred in 0.09%, 0.25%, 0.83%, and 1.6% of cycles in which participants reported they took all hormone pills (n=25,613 cycles) or did not take one (n=405 cycles), two (n=121 cycles), and more than two (n=314 cycles) hormone-containing pills, respectively ( P <.001). No pregnancies occurred in 2,216 cycles when one or more pills were missed and missed-pill instructions were followed. All pregnancies related to not taking pills occurred in the first three cycles. Pregnancy rates ranged from 0% to 0.21% per cycle with no significant trend by cycle ( P =.45).

Conclusion

Pregnancy occurs more frequently when combined oral contraceptive users report not taking all hormone-containing pills per 28-day cycle and exceeds 1% only when more than two pills are not taken. Pregnancies in participants who reported missed pills occurred only when missed-pill instructions were not followed. A 0.09% pregnancy risk per cycle among users of a 24 hormone and four placebo pills formulation who report taking all pills likely approximates a true method-failure rate.

Funding source

Estetra SRL, an affiliate company of Mithra Pharmaceuticals.

Clinical trial registration

ClinicalTrials.gov , NCT02817828 and NCT02817841.

INTRODUCTION:: A new contraceptive vaginal system (CVS) for 13 cycles of use has been developed that releases a daily mean of segesterone acetate (SA) 0.15 mg and ethinyl estradiol (EE) 0.013 mg. We evaluated endometrial safety during use of the SA/EE CVS for up to 13 cycles. METHODS:: In this multicenter, open-label, phase 3 study, 2308 women used the SA/EE CVS on a 21-day in/7-day out regimen for up to 13 cycles. Women could choose to participate in an endometrial safety sub-study at 5 study sites. Three blinded pathologists histologically examined endometrial biopsies at screening, at cycle 6 in the first 25 women reaching 6 cycles, and at the end of study (cycle 12/13) or early study termination in the remainder. Women with endometrial hyperplasia or cancer at baseline were excluded. We evaluated histologic changes in women with both screening and follow-up biopsies. RESULTS:: Of the 156 women who participated, 83 had follow-up biopsies. Pathologists identified no cases of endometrial hyperplasia or carcinoma at cycle 6 (n=24), cycles 12/13 (n=30) or other end of therapy times (n=29). The most frequent histologic diagnoses were atrophic/inactive or secretory: atrophic/inactive (29%, 27% and 28%, respectively), secretory (29%, 37%, and 45%, respectively), proliferative (17%, 7%, and 21%, respectively), mixed (17%, 10% and 3%, respectively), menstrual (4%, 7%, and 0%, respectively), or insufficient/no tissue (0%, 10%, and 3%, respectively). CONCLUSION:: Use of the SA/EE CVS for up to 13 cycles did not result in any unexpected endometrial safety effects based on endometrial histology.