Visceral Leishmaniasis

One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral IMPAVIDO at a target dose of 2.5 mg/kg/day for 28 days (50 mg capsule once daily if weight was less than 25 kg and 50 mg capsule twice daily if weight was 25 kg or greater). Patients ranged between 12 and 64 years of age. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). Ninety-nine (99) patients received 1 mg/kg/day amphotericin B deoxycholate intravenously every other day for 15 doses. A statistically significant higher percentage of men received IMPAVIDO compared to amphotericin B. 

Less than 1% of patients who received IMPAVIDO died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of IMPAVIDO recipients (6/299) and 1% of amphotericin B recipients (1/99). Approximately 3% of patients discontinued treatment in each treatment arm due to an adverse reaction. Serious adverse reactions and adverse reactions leading to drug discontinuation that were thought to be related or possibly related to IMPAVIDO included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN). 

In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of IMPAVIDO recipients and in 40% of amphotericin B recipients at the end of therapy. Ten percent of subjects in each arm had Cr elevations ≥1.5 times above baseline at 6 months follow up. No IMPAVIDO recipient discontinued therapy due to Cr elevation.

Elevations of transaminases during therapy occurred in up to half of IMPAVIDO recipients and up to a third of amphotericin B recipients. The elevations were mild (< 3x ULN) or moderate (3-5x ULN) in 94% and 6% respectively of IMPAVIDO-treated patients who experienced an elevation. No patient discontinued therapy due to elevations in transaminases. 

At the end of therapy, 62% and 2.4% of IMPAVIDO recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively. 

Cutaneous Leishmaniasis

The efficacy of IMPAVIDO in the treatment of cutaneous leishmaniasis was evaluated in one placebo-controlled trial conducted in Colombia and Guatemala and in two comparative trials conducted in Bolivia and Brazil respectively. In the placebo-controlled trial, eighty-nine (89) patients 12 years of age and older received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and forty-four (44) received placebo. In the comparative trials, one hundred and twenty (120) patients 12 years of age and older received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and fifty-eight (58) patients received 20 mg/kg/day pentavalent antimony (meglumine) parenterally for 20 days.

In the placebo controlled trial, 12/89 (13.4%) IMPAVIDO subjects had Cr increases of 1.5-3 times above baseline, compared to 2/44 (4.5%) placebo subjects at end of therapy. In the comparative trial, a similar percentage of subjects who received IMPAVIDO or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of IMPAVIDO subjects and 11% of pentavalent antimony subjects had Cr elevations 1.5-3 times above baseline at the end of therapy in the two active controlled trials. The frequency of AST and ALT increase above upper limit of normal at end of therapy was similar in IMPAVIDO and placebo recipients (approximately 5%). 

Other adverse events seen at <2% incidence in the IMPAVIDO group included anemia, lymphadenopathy, abdominal distension, constipation, dysphagia, flatulence, fatigue, malaise, abscess, cellulitis, ecthyma, paresthesia, testicular pain, testicular swelling, Stevens-Johnson syndrome, urticaria, rash, pyoderma.

Adverse Effects on Semen Quality and Spermatogenesis

In an open-label, uncontrolled, single-center study that assessed the effects of IMPAVIDO on sperm parameters, a total of 58 Bolivian adult males with cutaneous or mucosal leishmaniasis were administered IMPAVIDO for 28 days at a target dose of 2.5 mg/kg/day. Patients underwent repeat semen analysis testing at baseline (prior to treatment), at the end of treatment (Day 25 to 28 of treatment), and at 3 months after completing treatment. If sperm concentrations were markedly reduced at 3 months, per protocol, one additional semen sample was collected at 6 months after completing treatment.

The primary safety endpoint was determined at the end of treatment and included the number and percentage of patients with abnormal sperm parameters and clinically relevant changes from baseline in semen volume, total sperm count, sperm concentration, sperm motility and sperm morphology as shown in Table 5. The secondary safety endpoints included: mean changes from baseline in semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. Mean changes from baseline in serum testosterone and FSH concentrations were also evaluated.

A total of 53 patients completed the study. The median patient age was 34 years (range 18 to 51 years). The majority of patients (70.7%) had cutaneous leishmaniasis, while 24.1% had mucosal leishmaniasis, and 5.2% had both forms. 

Treatment with IMPAVIDO was associated with reductions in all sperm parameters at the end of treatment (see Table 5). All sperm parameter reductions, except for sperm concentration, recovered on follow-up assessments at 3 and 6 months after treatment completion. For sperm concentration, small mean decreases persisted on follow-up assessments at 3 and 6 months after treatment completion, with approximately 26% of subjects showing post-treatment sperm concentrations reductions of ≥ 50%, and 8% showing reductions to the lower limit of normal (< 20 million/ mL), on their last observed assessment.

Table 5 shows the results for the primary safety endpoint, the number and percentage of patients with abnormal sperm parameters at the end of treatment and in the post-treatment follow-up period, including assessments at 3 months or 6 months after treatment completion.

Semen analyses were not conducted beyond 6 months in any patient; therefore, the duration of effect of IMPAVIDO on sperm concentration after treatment is unknown.

Table 6 shows the results for the secondary safety endpoints, mean sperm parameters at baseline, end of treatment, and 3 and 6 months after treatment completion.

No clinically meaningful changes were observed in serum testosterone or FSH concentrations at the end of treatment or 3 months after treatment.