Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.

Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population.

Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.

Contribution of hierarchical clustering techniques to the modeling of the geographic distribution of genetic polymorphisms associated with chronic inflammatory diseases in the Québec population.

OBJECTIVES: The purpose of this project was to evaluate the potential of the downward hierarchical clustering analysis (DHCA) for studying genetic heterogeneity, i.e. differences in allele frequency in subpopulations, such as the 15 public health regions of the province of Québec (Canada). METHODS: The study relied on an anonymized sample of 1,680 individuals who had participated in the Québec Heart Health Survey in 1990-1991. The genotyping of 11 variants in 8 candidate genes known to be involved in chronic inflammatory diseases, namely asthma and cardiovascular diseases, was performed using the amplification refractory mutation system and restriction fragment length polymorphism techniques. Only variants showing an allelic frequency >2% in the Québec Heart Health Survey (n = 8) were selected. DHCA techniques were then applied to model the geographical distribution of these 8 genetic variants in 15 Québec public health regions and to study genetic heterogeneity. RESULTS: The DHCA allowed to group public health regions and gene variants on the basis of genetic variability. For both asthma and cardiovascular diseases, 3 significant clusters of public health regions and 1 cluster of gene variants were identified. DISCUSSION: This study suggests that DHCA might be useful in studying genetic heterogeneity at the population level and for public health activities.

New estimates of intergenerational time intervals for the calculation of age and origins of mutations.

Intergenerational time intervals are frequently used in human population-genetics studies concerned with the ages and origins of mutations. In most cases, mean intervals of 20 or 25 years are used, regardless of the demographic characteristics of the population under study. Although these characteristics may vary from prehistoric to historical times, we suggest that this value is probably too low, and that the ages of some mutations may have been underestimated. Analyses were performed by using the BALSAC Population Register (Quebec, Canada), from which several intergenerational comparisons can be made. Family reconstitutions were used to measure interval lengths and variations in descending lineages. Various parameters were considered, such as spouse age at marriage, parental age, and reproduction levels. Mother-child and father-child intervals were compared. Intergenerational male and female intervals were also analyzed in 100 extended ascending genealogies. Results showed that a mean value of 30 years is a better estimate of intergenerational intervals than 20 or 25 years. As marked differences between male and female interval length were observed, specific values are proposed for mtDNA, autosomal, X-chromosomal, and Y-chromosomal loci. The applicability of these results for age estimates of mutations is discussed.

A genealogical study of Alzheimer disease in the Saguenay region of Quebec.

We performed an analysis of inbreeding and kinship among the ascending genealogies of 205 autopsy-confirmed Alzheimer disease (AD) subjects recruited in the Saguenay area of Québec. We hypothesized that if some traits pertaining to the disease were determined by inherited factors, and if the corresponding genes were not too frequent in the population, it might be possible to detect some clusters of patients related to common ancestors and presenting a level of kinship and/or inbreeding higher than is observed in the unaffected population of the same age. In view of the heterogeneity of the disease, we also verified if some of the factors investigated could be associated more specifically with subsets of cases based on age of onset and on apolipoprotein E (APOE) genotype. Results were compared with those obtained on 205 controls matched for gender, place and year of birth. We found that late-onset AD cases with an APOE-epsilon 4 were significantly more inbred than controls and that this increase was explained by the high level of inbreeding of a few cases whose parents were related at the first-cousin level. This could possibly indicate the implication of a recessive element in a small subset of AD cases in the Saguenay population. We also found that late-onset epsilon 4+ cases were significantly more closely related among themselves than with controls. This increase in kinship may be attributable to the presence of the epsilon 4 allele or to some other unidentified genetic factor possibly acting in conjunction with APOE-epsilon 4.

Season of birth and Alzheimer's disease: a population-based study in Saguenay-Lac-St-Jean/Québec (IMAGE Project).

The birth distribution of 399 cases of Alzheimer's disease (AD) identified in the region of Saguenay-Lac-St-Jean (Québec) was compared with that of: (a) the population currently living in the area; and (b) the population born during the same period in the same area. AD cases have been recruited since 1986 by the IMAGE Project. Cases and controls were grouped according to the month of birth and according to the day of birth using density estimation. Analyses showed a significant deficit of births in the month of May. We believe these preliminary results deserve further attention and we suggest two possible explanations that could lead to a deficit of AD births at specific periods during the year.