CRL Requirements and their interpretation

What do the CRL requirements for Lorcaserin mean in practice?

1.    Non-clinical issues

Issue 1.1  “Detailed accounting of all microscopic pathology slides prepared from FEMALE rats that contributed to the mammary tumor incidence data in each update to the FDA and the final study report”

                      a.      Requirement: account for all slides done on those tissues – exactly what it says – an accounting issue.

                      b.      In total, 65+65+75 = 205 FEMALE rats were given lorcaserin along with 65 untreated control FEMALE rats  - see Table 6 in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin” (Mammary Tumors).

                      c.      This task should not take more than 4 months, leading to a revised report (if needed).

Issue 1.2  “Independent pathologists/group of pathologists to re-adjudicate all mammary and lung tissues from all FEMALE rats (205)”

                      a.      Requirement:  It is unclear why lung tissue is included here and this is a specific question for the FDA.  For the mammary tissue, it appears this refers to a discrepancy between the week-96 tumor incidences at all doses and this should also be confirmed with the FDA.  If this is indeed the reason for the accounting check – these independent pathologists would re-read the histological slides and give a final decision on what the true incidences are, so as to settle any misinterpretation or discrepancies.

This re-adjudication procedure should not take more than 4 months.  The response does not require a new study based on advice from a non-clinical safety assessment toxicologist.

                      b.      During the Arena conference call on October 25, 2010, the reason for the discrepancy was provided: The preliminary slides were reviewed on a set frequency by one pathologist and initial findings were sent to the FDA prior to the final submission – this was not required but was a courtesy preview for the FDA to observe the interim results. However, at the end of the study, three independent pathologists’ performed a peer review of the data and submitted their results and these were included in the final NDA. 

                      c.      The perceived discrepancy between assessments made by the different pathologists was mentioned in the section: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (5^th paragraph; Mammary Tumors), where Dr. Alavi (FDA nonclinical pharmacology / toxicity presenter) makes the following statement: 

“In subsequent updates and in the final study report, the incidence of adenocarcinoma in the MD and HD females was lower than that reported at week 96 (Table 7a). The incidence of adenocarcinoma increased in the controls and stayed consistent in the low dose group over the same period. The incidence of fibroadenoma increased in all dose groups from week 96 to the final study report, though the numbers notably varied in the mid- and high dose groups (Table 7b). It appears that some of the decrease in the number of adenocarcinoma after week 96 was accompanied by an increase in fibroadenoma, potentially a consequence of the sponsor/CRO reclassifying the observed tumor types.”

This raises an important question.  Why did Dr. Alavi not know that the slides had been reviewed by a single pathologist during the study and then by three independent pathologists at the end of the study?  It is well known that inter-observer variation can occur in assessments of this nature. This should have been taken into account, rather than implying that the sponsor/CRO had acted improperly in respect of the discrepancy in the final numbers.     

Issue 1.3  “Demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is REASONABLY irrelevant to human risk assessment.”

a.       Requirement: With regard to the re-adjudicated results, a statistical analysis must be conducted to assess the significance of rat incidence of fibroadenomas and adenocarcinomas with respect to human risk.  This is not a new study, but a re-assessment of the previous analysis.  Unless the re-adjudication accounting yields different results, then a new study will not be necessary; however, this approach should be confirmed with the FDA.

b.       The results are expected to be the same.  If they are the same, then Arena needs to demonstrate that the adenocarcinomas seen at the very high and toxic Lorcaserin doses, and the statistically significant increases in fibroadenomas, do not portend a risk to humans.

c.       The following information is relevant to this analysis:

The incidence of malignant adenocarcinoma tumors identified in the 10 mg/kg/day female group was no different to the normally-occurring incidence of these tumors identified in the untreated control group.  Furthermore, in the 30 mg/kg/day female group, a dose 24-fold greater than the anticipated human therapeutic dose, the incidence of malignant mammary tumors was no greater than the normally-occurring malignant mammary tumor incidence reported in the untreated control female rats. Only at 100 mg/kg/day was there a statistically significant increase in adenocarcinoma incidence, but this lorcaserin dose is 82-fold that intended for human use. (Note that if Arena decides to fall into the FDA ‘mechanism of action (MOA) involves prolactin’ “trap”, they will fail and spend an eternity attempting to find the answer. They should not attempt to open Pandora’s box. There are numerous drugs on the market today for which the MOA for pathology is not understood).

Although the fibroadenoma incidence in the rats was found to be statistically significant at all doses, and the practice of combining benign tumors with malignant tumors is commonly done when the cell types are the same, this does not pose a human risk for the following reasons:

·        Fibroadenoma and adenocarcinoma arise from cell types with different histogenesis. Adenocarcinomas are classified under the epithelial histotype, fibroadenomas under the epithelial-stromal histotype (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989).

·        Benign mammary fibroadenomas can only be transformed to malignant mammary carcinosarcoma and never to mammary adenocarcinoma (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989). These are distinctly different tumors.

·        The rat model of tumorigensis closely mimics human breast tumor development.

·        Fibroadenomas rarely progress to adenocarcinoma in the rat.

·        Fatalities from benign fibroadenomas do not translate as a risk to humans.

·        Fibroadenomas rarely progress to adenocarcinoma in the human female and are relatively common (London, et al. 1992).

Issue 1.4  “Provide ADDITIONAL DATA/INFORMATION regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.”

                      a.      Requirement:  Since brain partitioning—brain to plasma (BPD) ratio—was not determined in humans, the FDA is concerned that estimates of safety margins based on extrapolation from monkey brain-to-plasma ratios are not reliable.  Additional documented information and data are required to address this issue.  Proven case studies may also help to demonstrate validity, although this approach should be confirmed with the FDA.

                      b.      An assumption made by Dr. Alavi regarding the reliability of extrapolating monkey BPD ratios to human subjects is paraphrased as follows: 

Brain partitioning in human subjects was not determined. Thus, estimating safety margins based on assumptions of partitioning in human subjects is not entirely reliable. Assuming that the monkey best models human partitioning, the estimated safety margin to a non-tumorigenic dose in rats may range from 11x to 17x, with tumors associated with brain exposures that are 40x to 59x higher than clinical exposure. More conservatively, safety margins based on plasma drug levels, which is known for rats and humans, yields a safety margin to the non-tumorigenic dose in rats of 5x, with brain tumors occurring at doses of lorcaserin 17-fold higher than the clinical dose” from the section in the FDA briefing document: from the section “Genotoxicity and Carcinogenicity Assessment For Lorcaserin. (Note this abstract is paraphrased, not a verbatim quote).

                      c.      The actual measured BPD ratio for lorcaserin is not known in humans since it is a novel new drug that has not yet been studied in this way.  However, we do know:

·        The BPD ratio for lorcaserin for mice is 25 times higher in the brain vs. plasma (of note, there were no brain tumors in mice including the high dose group).

·        The BPD ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma.

·        The BPD ratio for lorcaserin for monkeys is 10 times higher in the brain vs. plasma.

                      d.      The solution:  An extensive review on this very issue (Shen, Artru and Adkison, 2004) clearly indicates that extrapolated partitioning in human subjects can be a reliable means of estimating risk safety margins.  Referring to the monkey model, the authors state:   

“In the second part of our analysis, we examined the issue of whether CSF penetration studies in animals are predictive of human data. We obtained animal and human CSF data on 27 drugs, including 13 antiepileptics, 1 psychotropic drug, 5 anesthetics or analgesics, 5 antibiotics, 1 antiretroviral, and 2 anticancer drugs, and across six animal species, including rats, dogs, rabbits, cats, guinea pigs and monkeys. As can be seen in Fig. 9, there is a reasonably good correlation for the majority of drugs in this survey."

In the same article the authors conclude that:

"Despite the complexity of CSF physiology and pharmacokinetics, CSF penetration studies in animals remain a practical option for the assessment of CNS drug delivery in early preclinical drug development"

                      e.      The interpretation:  Monkey brain partition studies can, therefore, be used with reasonable assurance for estimating a drug's margin of safety in the human brain.  The brain-to-plasma ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma and the for monkeys it is 10 times higher in the brain vs. plasma

                       f.      Lorcaserin application:  There is 29x more lorcaserin in the rat brain, so the dose given to rats at the LD, MD, and HD will be much higher in the CSF and therefore more toxic.  In practice, this means that at any given dose, the higher the brain exposure in rats, the higher will be the estimated brain exposure in humans.  Tables 13 and 14 in the FDA document in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin (Brain Astrocytoma)”:

·        Brain exposure in the rat at 30mg/kg (brain tumors present in the rat) = 405-591 mcgm/ml.

·        Using the brain-to-plasma ration of 10x in the monkeys (multiple the brain exposure in rats by 10).

·        Brain exposure in humans at the 30 mg/kg (brain tumors present in the rat) = 40x-59x multiple of the clinical dose (10mg bid (twice a day).

·        Therefore, from the Table, we can see that the margin of safety is at 11x-17x multiple of the clinical dose, which would satisfy the concern brought up in the CRL.

·        The 17x dose is when the tumors first appeared (the 30 mg/kg dose).  Hence the tumorigenic dose for humans, when discussing brain/plasma ratios, would then be 40-59x multiple of the clinic dose - far above the 25-fold limit dose in the FDA guidelines. 

·        So from the data on the male rats the risk of developing statistically nonsignificant astrocytomas in the human, assuming that this can be transferred to human risk, would only arise at 40-59 x multiple of the clinical dose. The margin of safety dose would be 17x multiple and perhaps anywhere up to 39x multiple, although the precise value would have to be determined at incremental increases in the dose of lorcaserin (which is not necessary).

·        However because Dr. Alavi used plasma levels, he concluded that the nontumorigenic dose (level where there are no tumors) gave a margin of safety at only a 5x multiple of the clinical dose. Our analysis suggests that he erred in doing this.

                      g.      Astrocytoma was only statistically significant in male rats in the high dose group, but none of these tumors was found in the female rats.

                      h.      The solution:  To address the Astrocytoma issue Arena must supply all MBTD and brain-to-plasma ratio data to FDA in a simple, easy-to-read format.  Given adequate resources, this administrative task should not take long.

2.    Clinical issues

Issue 2.1  Provide BLOOM-DM trial results and analysis with respect to efficacy and diabetic health factors.

                      a.      Results on the BLOOM-DM trial results.  There is nothing more to say on this point.

3.    Labeling requirements

Issue 3.1  Labeling requirements will include the following. 

                      a.      Schedule IV: This is not a significant issue.  Schedule IV does not necessarily preclude long-term use, although FDA may add restrictions to that effect.  They did leave the door open for removal of this label later after certain post approval studies are completed. 

                      b.      Arena must discuss with FDA any nonclinical studies conducted to address abuse concerns regarding the long-term use of lorcaserin.

4.    Conclusions

In conclusion, no new studies need to be done except perhaps brain partitioning studies on humans. However, this may not be necessary if the information provided above is correct. If such studies were performed, they would not be long-term experiments and could be completed in a relatively short period, and they may not even need to be carried out under GLP conditions.  However, I sense Arena already has all the data required to address this particular concern.  Every other aspect of the CRL involves a REVIEW of existing information, nothing else.  If everything is submitted in a timely manner, the estimated timeframe for the completion of these reviews should be less than 6 months. 

REFERENCES CITED

London, S.J., Connolly J.L., S.J. Schnitt, and G.A. Colditz. "A Prospective Study of Benign Breast Disease and the Risk of Breast Cancer." JAMA 267 (1992): 941-4.

Russo, Jose, Barry A. Gusterson, Adrianne E. Rogers, Irma H. Russo, Seft R. Wellings, and Matthew J. Van Zwietien. "Biology of Disease: Comparative Study of Human and Rat Mammary Tumorigenesis." Laboratory Investigation, 1990: 267.

Russo, Jose, Irma H. Russo, Matthew J. van Zwieten, Adrianne E. Rogers, and Barry A. Gusterson. "Integument and Mammary Glands of Laboratory Animals." In Classification of Neoplastic and Non-neoplastic Lesions of the Rat Mammary Gland, edited by T.C. Uones, U. Mohr and R.D. Hunt, 275-304. Berlin:Springer-Verlag, 1989.

Shen, Danny D., Alan A. Artru, and Kimberly A. Adkison. "Principles and Applicability of CSF Sampling for the Assessment of CNS Drug Delivery and Pharmacodynamics." Advanced Drug Delivery Reviews, 2004: 1825-1857.

Daniel P. Lopez, M.D., F.A.C.O.G.

Diplomate American Board of Obstetrics and Gynecology

BORG Member