Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development. METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points. RESULTS: In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months. CONCLUSIONS: The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.

Optimization of secukinumab dose regimens in patients with moderate-to-severe plaque psoriasis via exposure-response modeling.

BACKGROUND: Further dose optimization is required for patients with moderate-to-severe plaque psoriasis who do not benefit from the approved secukinumab dose regimen. This study aimed to develop an exposure-response model for secukinumab to recommend dose regimens for patients of different body weights. METHODS: We searched the PubMed and Cochrane Library databases for randomized controlled trials using PASI 75 and PASI 90 response rates as primary outcomes. A model-based meta-analysis was developed to quantitatively analyze the distribution of six secukinumab dose regimens in patients weighing 50-120 kg. RESULTS: Sixteen trials involving 6,197 subjects were included in the analysis. The established model accurately described the time-course characteristics of PASI 75 and PASI 90 response rates over 52 weeks. Simulations indicated that maintenance doses could be reduced to 150 mg every 4 weeks and to 150 mg every 3 weeks for patients weighing 50 and 60 kg, respectively. In contrast, maintenance doses of 300 mg every 3 weeks should be selected for patients weighing 120 kg. Patients weighing 70-110 kg remained on approved maintenance doses of 300 mg every 4 weeks. CONCLUSIONS: Based on patient body weights, the exposure-response model recommends efficacious and economical dose regimens for patients with moderate-to-severe plaque psoriasis.

Difference in Efficacy and Safety of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Containing 4-1BB and CD28 Co-Stimulatory Domains for B-Cell Acute Lymphoblastic Leukemia.

This study quantified the differences in the efficacy and safety of different stimulation domains of anti-CD19 chimeric antigen receptor (CAR) T therapy for B-cell acute lymphoblastic leukemia (B-ALL). Clinical trials related to anti-CD19 CAR T-cell therapy for B-ALL were searched in public databases from database inception to 13 November 2021. The differences in overall survival (OS) and progression-free survival (PFS) of B-ALL patients treated with anti-CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains were compared by establishing a parametric survival function. The overall remission rate (ORR), the proportion of people with minimal residual disease (MRD)-negative complete remission (CR), the incidence of cytokine release syndrome (CRS), and the neurotoxicity across different co-stimulatory domains was assessed using a random-effects model. The correlation between the ORR, MRD-negative CR, PFS, and OS was tested. The results showed that the median OS of anti-CAR T-cell treatment containing 4-1BB and CD28 co-stimulatory domains was 15.0 months (95% CI: 11.0-20.0) and 8.5 months (95% CI: 5.0-14.0), and the median PFS was 7.0 months (95% CI: 4.0-11.5) and 3.0 months (95% CI: 1.5-7.0), respectively. Anti-CD19 CAR T-cells in the 4-1BB co-stimulatory domain showed superior benefits in patients who achieved ORR. The incidence of neurotoxicity was significantly higher in the CD28 co-stimulatory domain of anti-CD19 CAR T-cells than in the 4-1BB co-stimulatory domain. In addition, the ORR and MRD-negative CR were strongly correlated with OS and PFS, and PFS and OS were strongly correlated. The 4-1BB co-stimulatory domain suggested a better benefit-risk ratio than the CD28 co-stimulatory domain in B-ALL.

[Long-term toxicity of Shen Yan Ling tablet and its effect on male reproductive function in rats].

OBJECTIVE: Shen Yan Ling Tablet is an innovative compound of traditional Chinese medicine, scientifically prepared with Tripterygium wilfordii, Radix Astragali, and others, with precise efficacy on renal diseases and reduced adverse effects of Tripterygium wilfordii. Based on the Guiding Principles for New Drug Toxicity Research Before Clinical Application, we investigated the long-term toxicity of Shen Yan Ling Tablet and its effect on the reproductive function in rats. METHODS: According to the clinical therapeutic dose and the results of the acute toxicity test of Shen Yan Ling Tablet, we equally divided 80 rats (males and females half-and-half) into a low-dose (1.25 g/kg body wt), a medium-dose (2.50 g/kg body wt), a high-dose (5.00 g/kg body wt) and a control group. After a 3-month medication, we conducted standardized long-term toxicity tests and observed the effects of Shen Yan Ling on the serum sexual hormones and epididymal sperm count. RESULTS: After 3 months of treatment with Shen Yan Ling, no death occurred, the general status remained unchanged, and the parameters of blood cytology and biochemistry fluctuated within the normal range, without any significant changes (P > 0.05). Some blood parameters, RBC, WBC, HGB, AST and TBIL, showed statistic changes (P < 0.05), but with no clinical significance. There were no significant differences in the mass coefficients of the main organs between the medication and control groups. The high-dose group exhibited slight hepatic and pulmonary pathological changes and significantly reduced sperm counts in the epididymis, but no significant changes in serum sexual hormones (P < 0.05). CONCLUSION: Three-month medication of Shen Yan Ling at 1.25 - 5.00 g/kg produced no significant accumulated toxicity on rats, but it had a negative effect on their reproductive function at a higher dose of > or = 5.00 g/kg.

[Effect of large-dosage of 5alpha-reductase inhibitors on the spermatogenesis of male rats].

OBJECTIVE: To identify the role of 5alpha-reductase in the spermatogenesis of male rats by studying the effect of two 5alpha-reductase inhibitors, Epristeride and Finasteride, on the spermatogenesis in male Sprague-Dawley (SD) rats. METHODS: Changes in the weight of the testis, serum testosterone and dihydrotestosterone levels, epididymal sperm count, and reproductive function were observed and analyzed after the two 5alpha-reductase inhibitors were administered to male SD rats orally. RESULTS: The experiment showed that in comparison with control animals, both the two 5alpha-reductase inhibitors: 1. suppressed the development of the prostate and reduced the weight of the testis in the experimental groups (P < 0.05); 2. decreased the serum level of dihydrotestosterone and enhanced testosterone; 3. inhibited epididymal sperm count and productive function. CONCLUSION: High dosages of the 5alpha-reductase inhibitor, Epristeride, can suppress the development of the prostate and reduce the weight of the testis, decrease dihydrotestosterone, and inhibit spermatogenesis and productive function in male rats.

[Health investigation of 3 551 middle-aged and old males in Jiangsu Province].

OBJECTIVE: To understand the state of health of the middle-aged and old males in Jiangsu Province. METHODS: A total number of 3 551 middle-aged and old males aged 46 approximately 69 years were randomly selected from 13 counties of Jiangsu Province. All of them received physical examinations, including laboratory tests of liver and kidney function, sugar and cholesterols, radioimmunoassay of testosterone and free testosterone levels in the serum, and B-ultrasonic examination of the prostate volume and remaining urine. They also underwent inquiries according to the International Index of Erectile Function (IIEF-5) and the questionnaire for PADAM (partial androgen deficiency of the aging male). RESULTS: The prostate volume differed significantly (P < 0.05), while the testosterone level showed no significant difference in different age groups (P > 0.05). The level of the free testosterone in the serum descended with the increase of age. The incidence of ED and PADAM was also correlated with the increase of age. CONCLUSION: In the old and middle-aged population of males, with the increase of age, sexual function decreases, the prostate volume enlarges, and the incidence of ED and PADAM obviously increases (P < 0.001).

[Effect of selective 5alpha-reductase inhibitor or/and testosterone undecanoate on the reproductive function of male rats].

OBJECTIVE: To investigate whether 5alpha-reductase inhibitor and dihydrotestosterone (DHT) play a role in spermatogenesis in male rats. METHODS: Thirty-two male rats were divided into 4 groups (Groups C, T, F and FT). Group C received plant oil injection and oral starch perfusion, Group T testosterone undecanoate (TU, 20 mg/kg) injection and oral starch perfusion, Group F plant oil injection and oral Finasteride perfusion, and Group FT TU (20 mg/kg) injection and oral Finasteride perfusion. Data on serum T and DHT, sperm count, sperm mobility and reproductive function were collected and analysed. RESULTS: (1) 5alpha-reductase inhibitor, Finasteride and TU reduced the weight of the testis and epididymis in the experiment groups compared with the negative control (Group C), but TU increased the weight of the prostate while Finasteride decreased it compared with the positive control (Group T). TU combined with Finasteride could counteract the effect of the weight increase of the prostate, but not that of the testis. (2) Finasteride, or Finasteride combined with TU, reduced the DHT but increased the testosterone level in comparison with the control group. (3) Both Finasteride and TU could inhibit epididymal sperm count and reproductive function compared with the control, but the effect was less significant in Group FT than in Group F. CONCLUSION: High dosages of 5alpha-reductase inhibitor, Finasteride, can suppress male reproductive function, but the inhibiting effect could be counteracted by administration of 5alpha-reductase inhibitor along with TU.

[Effect of LHRH crasis protein as vaccine on the reproductive function of male rats].

OBJECTIVE: To investigate the effect of Trx-LHRH, a new GnRH crasis protein, on antibody production and male reproductive function. METHODS: Trx-LHRH produced in vitro with a new crasis gene which crasised Trx gene and GnRH gene together, was used as vaccine, and hydroalaminum base as adjuvant, in adult SD rats. After 5 weeks of the first treatment, the same dosage was used again to enhance the effect of vaccine. Antibody level was measured by ELISA, and androgen level by RIA. RESULTS: Trx-LHRH induced successfully the polycolonal antibody at the level of 1 :1 280 approximately 2 560 after 4 weeks of the first treatment, and 1 : 2 000 after 6 weeks of the enhanced treatment. Testosterone level was reduced significantly (P < 0.01) by ELISA, but there was reasonable variation among individuals. Sperm count was also reduced by Trx-LHRH treatment. CONCLUSION: Trx-LHRH can be used as effective vaccine to induce antibody production, and at the same time, restrain the function of hypothatamas-pituitary-testis axis in vivo.

[Experimental research on spontaneous benign prostatic hyperplasia in old dogs].

OBJECTIVES: To investigate the pathoanatomize histological and biochemical characteristics of benign prostatic hyperplasia (BPH) by use of old dogs with spontaneous BPH as animal models. METHODS: Old dogs aged 6 to 13 years were recruited after anus check, B-ultrasonic examination by recta spy and measurement under surgical exploration. Ten dogs with notable prostatic hyperplasia were used as models, and 6 with non-hyperplasia prostate as control. Serum testosterone (T), estrogen (E2), ACP and prostatic specific antigen (PSA) were analyzed, and prostates were checked histologically. RESULTS: Prostate volume of the BPH group was significantly bigger than those of the control group, (14.7 +/- 2.3) and (13.8 +/- 1.9) cm3 vs (8.4 +/- 1.0) and (8.4 +/- 1.9) cm3, P < 0.01. Serum T [(14.3 +/- 2.9) vs (16.4 +/- 4.0) nmol/L] and E2 [(137.6 +/- 70.8) vs (164.4 +/- 82.0) pmol/L] were not different between the two groups (P > 0.05). ACP of the BPH group was higher than that of the control group [(6.63 +/- 2.76) vs (4.92 +/- 2.19) U/L], but the difference was not statistically significant (P > 0.05). There was significant difference between the BPH group and the control group in PSA level [(5.6 +/- 0.78) vs (3.1 +/- 0.54) microgram/L, P < 0.01]. The tissue slides of the BPH prostates showed hyperplasia with raised height of epithelium, and many long and offsetting mammillae in the gland cavity due to epithelium hyperplasia. CONCLUSION: Old dogs with spontaneous BPH are useful animal models for the etiological and pharmacological researches of human BPH.

[Effect of MPA and MPA + TU on the rat spermatogenesis and sexual hormones].

OBJECTIVES: To investigate the effect of administration of MPA with/without TU on serum sexual hormones and spermatogenesis of male rats. METHODS: Twenty rats had been classified into four groups. Each group received injection of saline(group A) or MPA(37.5 or 75 mg/kg) (group B or group C, respectively) or MPA (75 mg/kg) + TU (25 mg/kg) (group D) every month during three months. Data from serum sexual hormones (FSH, LH, T), sperm counting and motility had been collected and analysed. RESULTS: Spermatogenesis of rats undergoing administration of MPA with or without TU had been suppressed. Serum FSH and LH of group B, C, D declined, and so did serum T of group D. Testis of rats of group D atrophied and sperm counting of group D decreased remarkably compared with group B and C. But there was no statistics difference of the sexual hormone level among group B, C and D. CONCLUSIONS: Administration of MPA alone could suppress the levels of FSH and LH and block the spermatogenesis of male rats. MPA combined with TU could offer stronger suppression on spermatogenesis. Mechanism of the suppression on spermatogenesis of MPA + TU is not only limited in the feed-back of gonadotropin, but there maybe exist a direct suppression on testis.