# Presentation: 695338

## The efficacy of Artesunate rectal suppositories

- Leonard Sacks
- Medical Officer
- CDER. FDA

## FDA Review Team forNDA 21-242

- Regulatory Project Manager:
- Chemistry Reviewer:
- Microbiology Reviewer:
- Biopharmacology/BiopharmaceuticsReviewer
- Pharmacotoxicologist Reviewer:
- Statistical Reviewer:
- Medical Reviewers:

- M. Bacho, B.S.
- J. Smith, Ph.D.; D. Cummings
- K. Suvarna, Ph.D.
- J.  Meyer, Pharm. D.
- S. Kunder, Ph.D.
- R. Davi, M.S.
- L. Sacks, MB.B.Ch.
- R. Johann-Liang, M.D.

## Background

## Rationale for product development

- High mortality from malaria, especially in children, due to delays in therapy
- Malaria patients often unable to take orally
- Parenteral therapy not available in the bush

## Goal of applicant

- To develop an effective antimalarial that:
- can be administered rectally
- serves as an emergency treatment until definitive therapy can be reached
- that decreases malaria mortality and morbidity

## Indication

- For the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available
- .....must be supplemented and/or followed by effective oral or parenteral drug therapy for malaria as soon as possible

## Rectal artesunate- a suitable candidate?

- Artemisinin derivatives are potent antimalarials
- Used successfully in areas of drug-sensitive and resistant *P falciparum*

- Short half life
- Associated with recrudescence
- Potential neurotoxicity

## Clinical pharmacologyAdult healthy subjects, 400-mg single dose

- Artesunate is rapidly biometabolised to dihydroartemisinin (DHA)
- Dihydroartemisinin is also active against *P falciparum*

**Notes:**
 rapidly biometabolistDihydroaresinin

## Clinical pharmacology

- In the course of product development, the formulation used in clinical trials and the formulation to be marketed were different.

## Bioequivalence between formulation in clinical trials and formulation to be marketed

- Bioequivalence study in healthy volunteers failed to satisfy regulatory requirements
- Point estimates of AUC and Cmax were similar but 90% confidence intervals were too wide
- variablity due to difficulties in plasma measurement
- inter- and intra- subject variability in absorption, distribution, metabolism and elimination
- Study lacked adequate power to demonstrate tighter confidence intervals
- Equivalence study with clinical endpoints (014) in malaria patients showed similar parasite clearance at 24 hours

## Bioequivalence between formulation in clinical trials and formulation to be marketed(cont.)

- “totality of the data”
- technical difficulties and intra-subject variability in measurement,
- satisfactory clinical performance of to-be-marketed product in 014
- potential use for life threatening illness, where alternative treatment unavailable

## Challenge to develop appropriate clinical studies

- Prior to definitive treatment, is the emergency use of a single dose of rectal artesunate more effective than no treatment in reducing malaria morbidity and mortality?

## Challenge to develop appropriate clinical studies

- Given the high mortality from untreated malaria and the dangers of delaying effective therapy, treatment cannot be ethically withheld for the first 24 hours if effective therapy is available.
- For these reasons, the clinical trials submitted in this NDA have employed active comparators.
- In these studies, provisions are made for the “rescue” of patients showing an unsatisfactory clinical or parasitological response.
- While these studies do not directly address the advantages of rectal artesunate over no treatment, they give a relative idea of efficacy versus the “standard of care”.
- A trial (study 13) is underway to investigate the product under conditions that more closely reflect the intended use. This trial has not been submitted to FDA.

## Other problems in modeling the projected use

**Clinical studies**
- Most lived in malaria areas - some immunity
- Diagnosis was *confirmed* on smear
- Moderately severe (entry parasitemia...)
- Patients *were hospitalized*

**Projected use**
- May be used in US travelers and residents of malaria areas
- Diagnosis will *not be confirmed* before treatment
- All degrees of severity
*Not hospitalized*

## Other problems in modeling the projected use (cont’d)

**Clinical studies**
*Ancillary treatment* provided (fluids, glucose anticonvulsants, antipyretics etc)
- Suppository retention was supervised
- Patients failing on parasitological grounds *were rescued*
- Definitive therapy provided at 24 hours

**Projected use**
*No ancillary treatment* available in the field
- Retention may be supervised
*No rescue* in the field
- Access to definitive treatment depends on local infrastructure

## Selection of endpoints

- Mortality is not a realistic study endpoint
- deaths are very rare in patients with moderately severe malaria who are properly treated
- Alternative endpoints
- response in parasitemia
- clinical responses
- rates of recrudescence

## Studies of efficacy

- NDA 21-242

## Overview of clinical studies

- Pivotal studies 005, 006, 007
- Comparative, randomized, unblinded
- Employed projected dose for first 24 hours
- Bioequivalence study 014
- Compared 3 formulations of rectal artesunate, in projected dosing regimen

## Overview of clinical studies(cont’d)

- Supportive studies 003, 004
- Crossover/dose escalation studies comparing rectal and intravenous artesunate over 12 hours
- Previous published studies 010, 011, 012
- Employed twice the recommended dose- did not support efficacy of the projected dose

## Drug regimens in pivotal studies

- AS = artesunate
- SP = sulfadoxine/pyrimethamine
- MQ = mefloquine

## Comment on study drugs

- Quinine
- generally given for 7 days
- 24 hours is inadequate and on its own would result in recrudescences
- Sulfadoxine/pyrimethamine (SP)
- a long-acting agent given as a single dose
- SP resistance >60% in parts of Africa

## Comment on study drugs(cont’d)

- Mefloquine
- a long-acting agent, may be given as a single dose
- used effectively with artemisinins for treatment of drug-resistant malaria

## Inclusion and exclusion criteria

**Notes:**
Mention the other 2 arms of study 007 which are not discussed where 3 deaths occurred

## Baseline characteristics

## Criteria for providing rescue therapy

## FDA-defined study endpoints

- WHO primary endpoint was fractional remaining parasite count at 24 hours

## Study-related events with an impact on clinical results

**Notes:**
Other 3 deaths were in the arms of 007 that sere not eligible for the efficacy analysis

## 24-hour clinical success

**Notes:**
No statistically significant difference between the treatment arms in each of the studies
Remember in Malawian study no rescue in quinine qrm. If resfcue were provided the success rate would have been 14%

## 24-hour parasitological success

## 28-day recrudescences/new infections

**Notes:**

Give numbers  for PCR
Remember only 8 patients in the QN arm of SA study

## What can we conclude from pivotal studies?

- At 24 hours, the clinical success rates for rectal artesunate are *similar* to those seen with oral artesunate or quinine
- At 24 hours parasite clearance is significantly *more rapid* with rectal artesunate than with quinine.
- By 28 days, recrudescence rates are high when SP is used as definitive therapy.
- Recrudescence rates *may be higher* in artesunate-treated patients than in quinine-treated patients. This may depend on geographic location.

## What can we not conclude from the pivotal studies?

- That we have characterized the impact of rectal artesunate on malaria mortality.
- That the same result will be seen in the field where hospitalization, supportive therapy and laboratory diagnostics are unavailable.

## Equivalence study with clinical endpoints (014)

- Aimed to compare efficacy of
- 2 x 200mg (used in clinical studies)
- 4 x 100mg (to be marketed)
- 1 x 400mg (to be marketed)

## Treatment regimen (Study 014)

## Study population

- Thailand
- Hospitalized, adult patients
- Uncomplicated “moderately severe” malaria
- 23 patients per arm

## Median parasite counts/μl following treatment with 3 formulations of rectal artesunate

## Recrudescences/new infections?

## Conclusion (study 014)

*Equivalent efficacy of the three formulations*
*Also serves to demonstrate the non-comparative efficacy of rectal artesunate given alone for the first 24 hours to 69 adult patients with moderately severe, uncomplicated malaria. *
*Among these 69 patients, none were judged by the study physicians to require rescue therapy. *
*All made an uneventful clinical and parasitological recovery. *
*Outcome beyond 7 days in these patients, in terms of recrudescence or new infection is not known.*

## Studies 003 and 004

- Crossover studies- rectal and IV artesunate at 2 doses
- “Moderately severe” uncomplicated malaria
- 003- hospitalized adults (Thailand)
- 004- hospitalized children (Ghana)

## Studies 003 and 004

## “Consolidation therapy”

## Study populations in 003 and 004

## 24-hour clinical success rate

## >90% clearance of baseline parasitemia at 12 and 24 hours

## Recurrent parasitemia during 2-3 weeks after therapy

## What did we learn from 003 and 004?

- No clinical advantage in using 20mg/kg rectal AS instead of 10mg/kg rectal AS
- Rapid reductions in parasitemia were confirmed
- Despite the 12 hourly regimen, recrudescence rates were still high

## Summary

- Among 229 evaluable patients with “moderately severe” malaria treated with 10mg/kg rectal AS over first 24 hours
- 1 death- (probable fluid overload)
- 24-hour clinical success rates similar to comparator
- 24-hour parasitological success superior to comparator
- 28 day recrudescence rates from 0-45% for rectal AS, 0-25% for comparator (follow-up rates were low)

## Considerations

- Delays in therapy are one of the most important contributors to malaria mortality
- Given the potent effect on parasitemia, and the good short term clinical performance of rectal artesunate, does this imply that it will reduce malaria mortality?
- Are there potential hazards in the empirical use of rectal artesunate for emergency treatment?

## Statistical issues

- In the evaluation of these studies there are difficulties in interpreting the parasitological responses, since failing patients were “rescued” from the analysis.
- Due to significant loss to follow up at later time-points, recrudescence rates may be inaccurate.

## NDA 21-242 Rectal Artesunate

- Ruthanna Davi, M.S.
- Statistical Reviewer, FDA

## NDA 21-242 – Rectal Artesunate

- Interpretation of Parasite Count Analyses in light of Rescued Patients
- Recrudescence with Artesunate
- Other risk factors for Recrudescence

## Parasite Count Endpoint

- Numerical endpoints are statistically more sensitive than dichotomous endpoints.
- Excluding rescued subjects from the analysis is biased.
- Imputing values beyond the rescue time is biased.
- Ignoring the fact that subjects were rescued is biased.

## Slide 53

## Slide 54

## Slide 55

## Parasite Count with Rescued Subjects Excluded

## Parasite Count with Rescued Subjects Included

## Parasite Count with Rescued Subjects Included (as LOCF)

## Recrudescence with Artesunate

- Subjects malaria status assessed at 7, 14, and 28 days post-treatment.
- After positive result, subject was given additional malaria treatment.
- Obtaining complete follow-up was problematic.
- Missing values considered successes.
- Missing values considered failures.
- Missing values ignored.

## Cumulative Number of Recrudescences at Day 28

## Cumulative Recrudescence Rates Across Time in Study 6

- Missing observations considered successes.

## Cumulative Recrudescence Rates Across Time in Study 6

- Missing observations considered failures.

## Cumulative Recrudescence Rates Across Time in Study 6

- Missing observations ignored.

## Recrudescence with Artesunate

**Time-to-Recrudescence Analysis** Artesunate group experienced recrudescence earlier and more often than the Quinine group (p=0.0130).
**Exploratory Covariate Analysis** Relationships between time-to-recrudescence and variables other than treatment assignment were explored.

## Summary

- Regardless of the method used to deal with rescued patients, 12 and 24 hour median fractional remaining parasite counts
- were lower for Artesunate-treated subjects than Quinine-treated subjects in studies 6 (Malawi) and 7 (South Africa).
- were not statistically significantly different for Oral and Rectal Artesunate in study 5 (Thailand).

## Summary(cont’d)

- Recrudescence in Artesunate-treated subjects was earlier and more frequently than in Quinine-treated subjects.
- Exploratory Analysis did not reveal any other risk factors for recrudescense that might have impacted the treatment effect.