Amphotericin B, current marvel of pharmaceutical science that persists for over 70 years

Dr. Ali Khamesipour and his team work extensively in the development of vaccines and topical treatment against cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a serious threat to public health in some endemic areas, reaching from 600 thousand to 1 million cases worldwide annually. The treatment is a challenging subject, although several versions have been introduced as a candidate treatment, but only antimonial agents are commonly used to treat the disease. Topical treatment is an attractive alternative that avoids the toxicity of parenteral therapy since it is administered in a simple and painless way. Currently different topical formulations, especially paromomicin, have showed promising results in pre-clinical and clinical studies and are commercialized. Recently, liposomal formulations of amphotericin B have been increasingly more used in the treatment of several types of leishmaniasis. In

September, an article entitled Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran, whose main author is  renowned Dr. Ali Khamesipour, leader of the topical use of amphotericin B. According to the research, Lip-AmB 0.4% alone or in combination with the standard treatment has shown acceptable efficacy and safety for the treatment of lesions caused by L. major and deserves additional investigation in phase 3 clinical trials. To learn more about the subject, the Press Advisory of the Brazilian Society of Tropical Medicine (BSTM) interviewed Dr. Khamesipour, who lectures immunology at the Medical Sciences University at Tehran, the capital and main city in the Islamic Republic of Iran.

Check the interview in full:

SBMT: Professor Ali, you are one of the leaders in the use of topical treatment with amphotericin B. Could you tell us a little about your work in this area?

Dr. Ali Khamesipour: Our team is extensively working on the development of vaccine and topical treatment for cutaneous leishmaniasis (CL). For the topical treatment of CL, liposomal formulations of approved drugs like Glucantime, paromomycin and Amphotericin B (AmB) were used to deliver more effectively the drugs to the different layers of skin. Liposomal formulations of Glucantime, paromomycin and AmB were developed and studied from the bench to Phase3 trials in human, so far, the overall assessment of different formulations showed that topical liposomal AmB is very well effective for the treatment of CL. We have carried out pre-clinical studies for the topical liposomal AmB with the generous support of DNDi, and completed phase 1-2 clinical trials and then phase 3 clinical trial was completed with WHO/EMRO support. It took almost 15 years to complete the development of topical liposomal AmB and at last to get approval of FDO of Health Ministry of Iran in 2018. Topical liposomal AmB with the trade name of SinaAmpholeish® is now available in Iran and is used for the treatment of CL.

SBMT: A pilot study was recently published, in which you sign as the lead author, on the safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in the Islamic Republic of Iran. What were the main findings and what is the importance of this research?

Dr. Ali Khamesipour: This study was completed during the time that due to various factors mainly political sanctions, antimonial derivative drugs were not easily available in the country and as such the CL patients were mostly treated with intralesional (IL) injections of Glucantime. The aim of the pilot study was to evaluate safety and efficacy of topical liposomal AmB in the treatment of CL patients compared to the national standard treatment. In this study 66 patients with CL lesions due to L. major were recruited. Among 14 patients with 84 lesions who received national standard treatment (IL or systemic Glucantime) combined with topical liposomal AmB twice a day for 28 days, 11 of 12 patients with 70 lesions showed a complete cure (92% efficacy). Among 22 patients with 46 lesions who received only topical liposomal AmB twice a day for 28 days, 19 patients completed the study and 18 showed complete cure (95% efficacy). In the safety evaluation, in general patients showed no adverse events; such as, itching, burning, inflammation, or pain. However, 2 of the 36 patients reported a burning sensation that was tolerable and the patients preferred to continue the treatment with topical liposomal AmB. In the 30 patients who received national standard treatment alone (weekly intralesional Glucantime, 7 session of IL injections plus biweekly cryotherapy, 3 to 4 sessions), 33 lesions in 15 patients showed complete cure (48.5% efficacy) on day 42 follow-up.

In conclusion this study showed that topical liposomal AmB alone or in combination with national standard treatment is safe with a high efficacy rate and warranted further investigation in phase 3 clinical trials.

SBMT: In your opinion, how could topical treatment for cutaneous leishmaniasis with amphotericin B save lives?

Dr. Ali Khamesipour: Available treatment for CL is awful any treatment with less pain is needed, We think topical liposomal AmB would be very effective to treat CL. Since, we have already conducted phase 3 clinical trials using topical liposomal AmB under trade name of SinaAmpholeish® for the treatment of CL caused by Leishmania major and Leishmania tropica and the results were promising (Data has not published yet).

In regards to the phase 3 clinical trial study of CL caused by Leishmania major, we had two groups; in one group, 63 patients received SinaAmpholeish® alone topically twice a day for 8 weeks. The other group of 63 patients received combination therapy of intralesional Glucantime (once a week) plus cryotherapy (once every two week) for 8 weeks. The percent of cure rate for SinaAmpholeish® alone was 100% and for intralesional Glucantime plus cryotherapy was 96.5%.

In regards to the phase 3 study of CL caused by Leishmania tropica. The patients were recruited and received IL Glucantime (once a week) and double blind randomly received either topical SinaAmpholeish or topical placebo twice a day for 28 days. At day 90 of the study (visit 10), 42 out of 49 patients who were treated with SinaAmpholeish plus Glucantime treatment were cured (efficacy 85/7%), only 7 patients were not cured (14.3%), 33 patients who received the placebo plus Glucantime treatment were cured (efficacy 60%) and 22 patients were not cured (40%). At day 180 of the study (visit 11), in SinaAmpholeish plus Glucantime treatment group, no patient showed relapse amongst the 42 cured patients (efficacy 85/7%), but in placebo group whom received Glucantime treatment alone, 4 patients experienced relapse (efficacy 52/7%).

These two phase 3 clinical trials clearly showed that SinaAmpholeish® is effective in the treatment of CL.

Meanwhile, one of the key advantages of this topical formulation is easy to apply the gel by the patient, even in rural areas, comparing to the standard treatment (IL or systemic Glucantime injections, plus cryotherapy) which are injectable and needs experienced medical staffs for injections.

SBMT: Could the same formulation developed by you and your team be used in Brazil to carry out clinical studies? If so, what would be needed for this?

Dr. Ali Khamesipour: Yes, absolutely, we can provide the SinaAmpholeish® for the clinical trials. If you develop a proposal, then according to the proposal we can provide the SinaAmpholeish®. Any other suggestion is welcome.

SBMT: Could you tell us about the efficacy of topical liposomal amphotericin B versus intralesional meglumine antimoniate (glucantime) in the treatment of cutaneous leishmaniasis?

Dr. Ali Khamesipour: Please check the answers to question 2: In the 30 patients who received national standard treatment alone (weekly intralesional Glucantime, 7 IL injections plus biweekly cryotherapy, 3 or 4 sessions), 33 lesions in 15 patients showed complete cure (48.5% efficacy) on day 42 follow-up.

SBMT: What are the next steps and what do you expect to find?

Dr. Ali Khamesipour: SinaAmpholeish® is now used routinely for the treatment of CL in Iran. However, we would like to have the approval of this drug in other countries like Brazil and also we would like to get the approval of the drug by WHO.

SBMT: What is the burden of cutaneous leishmaniasis in the world and why is it still so neglected?

Dr. Ali Khamesipour: According to WHO, the annual incidence rate of skin form of leishmaniasis is about 1,000,000, which is underestimated, the real number is 4-5 times more than the recorded.

SBMT: Would you like to add something?

Dr. Ali Khamesipour: The current available treatment for CL is similar to ancient torture and not tolerable by the patients, not acceptable by the physicians/authorities, in my opinion it is very important to work on development of new treatments for CL, especially if it is topical which was a dream for years.