CytoDyn, in April 2020, reported conditional acceptance by the US. FDA of the proprietary name Vyrologix for leronlimab as a combination therapy for highly treatment experienced HIV patients. The final approval of proprietary name is contingent on the USFDA approval of Biologics License Application (BLA)  .
In May 2020, CytoDyn announced that it will collaborate with the of Mexican National Institutes of Health and provide leronlimab for a trial for the treatment of COVID-19 patients in Mexico  .
In May 2020, CytoDyn reported of its request submission to the US FDA for granting 'compassionate use' expanded access, for extending leronlimab availability to patients ineligible for participation in two ongoing clinical trials for coronavirus infections [see below]. At this time, the company also reported that the FDA had approved 60 emergency INDs (eINDs) for leronlimab use for treating COVID-2019 infections   .
In May 2020, CytoDyn announced intention to submit a protocol to the US FDA for a factorial design of phase III trial to compare effectiveness of leronlimab versus remdesivir and in combination with remdesivir for the treatment of COVID-19  .
In May 2020, CytoDyn released the efficacy data from compassionate care treatment in critically ill patients with COVID-19 infections  .
In April 2020, CytoDyn initiated and first patient was enrolled in a phase IIb/III trial under the same granted emergency IND for the treatment of critically ill patients with COVID-2019 infections(NCT04347239; CD12_COVID-19)  . Patients enrolled in this trial are expected to be administered leronlimab for two weeks with the primary endpoint being the mortality rate at 14 days. The study intends to enrol approximately 390 patients in the US.The company had filed a second clinical trial protocol for leronlimab with the US FDA for COVID-19, earlier in April 2020, CytoDyn intends to enrol 75 patients rapidly and report results to the FDA       .
CytoDyn in April 2020, reported that 12 severely ill COVID-2019 patients were treated in a phase II trial in the US under emergency IND approval by the US FDA. Earlier, the company released favourable data from eight patients treated in the study. A preliminary laboratory evaluation of the first four patients treated with leronlimab revealed that the immune profile in these patients approached normal levels and the levels of cytokines involved in the cytokine storm (including IL-6 and TNF alpha) were much improved. Regarding the trial, CytoDyn clarified that the treatment was not a part of the company’s proposed phase II protocol recently submitted to the US FDA. Earlier in March 2020, CytoDyn submitted an IND application to the US FDA for the conduct of the trial. Subsequently, as per US FDA suggestions, CytoDyn filed another round of modifications to its IND and protocol for the trial              .
In March 2020, CytoDyn announced that the company will request a preliminary Breakthrough Therapy designation meeting based on the recommendations by the US FDA  .
In February 2020, CytoDyn initiated the phase II basket trial of leronlimab for the treatment of approximately 22 different solid tumour cancers, including melanoma, brain-glioblastoma, throat, lung, stomach, colon carcinoma, breast, testicular, ovarian, uterine, pancreas, bladder, among other indications. The trial intends to enrol approximately 30 patients in the US, with locally advanced or metastatic solid tumours. Leronlimab will be administered subcutaneously as a weekly dose of 350 mg. In April 2020, first patient from the trial was treated  . The primary endpoint of the basket trial is progression-free survival. CytoDyn received central Institutional Review Board (IRB) approval to initiate a phase II basket trial to evaluate subcutaneous leronlimab for the multiple locally advanced or metastatic solid tumours in the US.Earlier, the company filed a protocol for the basket trial with the US FDA under its cancer IND. Based on outcome, CytoDyn intends to file for Breakthrough Therapy designation for all solid tumor cancers     .
In January 2020, CytoDyn announced the filing of Breakthrough Therapy designation (BTD) with the US Food and Drug Administration (FDA) for the use of leronlimab as an adjuvant therapy for the treatment of metastatic triple-negative breast cancer (mTNBC). In August 2019, under emergency Investigational New Drug Application of the US FDA, first patient with metastatic triple-negative breast cancer was treated with leronlimab. The CytoDyn is potential to seek Breakthrough Therapy Designation and Accelerated approval with the US FDA for the use of leronlimab, based upon the results of phase II trial    .
In November 2019, the Institutional Review Board approved the compassionate use (expanded access programme) of leronlimab for treatment of patients with triple-negative breast cancer (TNBC). This programme will allow access to TNBC patients who are not eligible to receive leronlimab under the ongoing phase II trial  .
Prior to September 2019, CytoDyn dosed the the first patient with leronlimab to treat metastatic triple-negative breast cancer through the expanded access program. Earlier in May 2019 the company announced its intention to initiate an expanded-access programme for patients with serious or life-threatening illnesses. In May 2019, the US FDA granted Fast Track Designation to leronlimab for use in combination with carboplatin for the treatment of patients with CCR5-positive metastatic triple-negative breast cancer (mTNBC). Further, in the same month, . In February 2019, CytoDyn announced that it has applied for Orphan drug status for triple-negative breast cancer. The application was based on positive results obtained in preclinical studies     .
In September 2019, the US FDA completed the safety review of the application (Protocol number CD08_mCRC) approved the conduct of a phase II trial of leronlimab in combination with regorafenib in patients with metastatic colorectal cancer. Earlier in August 2019, CytoDyn filed a phase II protocol with the US FDA   .
Earlier in January 2019, CytoDyn initiated a phase Ib/II trial of leronlimab for the treatment of patients with metastatic triple-negative breast cancer (CD07TNBC; NCT03838367). The open label trial intends to enrol 48 patients in the US. Earlier in November 2018, the US FDA approved the IND application submitted by CytoDyn for initiation of the trial. As of September 2019, the phase II portion was initiated and first patient was given injection of leronlimab. CytoDyn intends to utilise results form this trial for regulatory pathway, including potential Breakthrough Therapy Designation and accelerated approval by the US FDA for the use of leronlimab in mTNBC. As at 13 February 2020, total seven patients were treated in the trial and screening for additional patients was underway       . In December 2019, CytoDyn released the early results from the two patients of the trial demonstrating the sustained response to leronlimab. The results demonstrated shrinkage of tumour (via MRI) after three weeks of treatment with leronlimab in an emergency IND protocol. Additionally, the results from the patient enrolled at stage 4 metastatic breast cancer (MBC) demonstrated shrinkage of the tumours following the first leronlimab injection, reduction in brain edema, and remarkably, disappearance of several metastatic tumors. There were no serious adverse events reported   . In January 2020, similar positive data was released by CytoDyn from the two patients after 15 weeks of treatment with leronlimab in combination with carboplatin.No severe adverse events were reported  . In February 2020, updated interim efficacy data from the trial were released by CytoDyn  . In March 2020, the company announced the first mTNBC patient is in remission and that her oncologist suggested a termination of treatment with carboplatin and to continue leronlimab only as monotherapy  .
Leronlimab binds to CCR5 in human breast cancer, blocks cytokines induced CCR5 signaling and human breast cancer cell invasion  .
In January 2020, CytoDyn released the preclinical data from macaques which showed that the leronlimab prevented the intrarectal transmission of Simian-Human Immunodeficiency Virus (SHIV)  .
In March 2019, CytoDyn announced that its has filed application with the USFDA for Fast Track Designation for leronlimab in Metastatic-Triple Negative Breast Cancer (mTNBC) on the basis of positive preclinical data in murine xenograft models. Data showed showed significant reduction in the volume of human breast cancer tumor metastasis. The metastatic tumor volume was reduced by more than 98% after 7 weeks  .
In February 2019, preclinical data from mouse xenograft models for breast and prostate cancer showed that it reduced the incidence of human breast cancer metastasis by more than 98% during the six week treatment. Based on these results, CytoDyn is planning to expand pre-clinical animal studies into eight cancer indications  .
In August 2019, CytoDyn announced that leronlimab treatment in mice models suppressed growth of colon carcinoma in both low and high CCR5 expression tumours  . In August 2018, CytoDyn released the preclinical data for leronlimab in human colorectal cancer. Leronlimab was in preclinical development for colorectal cancer since 2017  .
In preclinical studies, leronlimab inhibited metastasis and invasion of cancer into healthy cells, following a surrogate assay for metastatic breast cancer. Treatment with CCR5 inhibitors can inhibit metastasis and invasion of prostate, breast and colon cancers, including patients with treatment-resistant colon cancer. Leronlimab detected CCR5 on metastatic human breast cancer cells and blocked their invasiveness   .
In June 2020, CytoDyn filed a request to the US FDA for a Priority Review designation for the BLA. In May 2020, CytoDyn completed the submission of rolling BLA by submitting updated clinical datasets to the US FDA. The BLA submission was initiated in March 2019 with the filing of the non-clinical portion of BLA with the US FDA. The non-clinical portion constitutes the first of three sections of the BLA submission for leronlimab as a combination therapy with HAART for HIV-infected patients. The clinical datasets were updated to tackle FDA comments for mock datasets from March 12 and March 20, 2020. Earlier, the US FDA had reviewed and accepted CytoDyn’s request to submit on a rolling basis its Biologics License Application (BLA) in March 2019. The company also plans to file for a label expansion for leronlimab as a monotherapy based on its registration-directed study [see below]        . In February 2019, the company conducted a follow-up meeting with the US FDA regarding its BLA submission for leronlimab combination therapy and positive interim data of its 700mg monotherapy trial. In the meeting, the FDA agreed to accept safety data from 100 patients in the monotherapy trial with the 700mg dose after recognising that the higher dosage of 700mg in the monotherapy trial had a much higher response rate than the 350 mg dose used in the combination therapy trial. The company has enrolled 45 patients in leronlimab monotherapy with 700mg dose; 29 additional patients who have switched from lower doses to the 700mg dose and over 40 patients currently in screening to initiate 700mg dose arm of monotherapy trial. The FDA also permitted the company to upgrade all ongoing patients who are currently on 350mg in the combination therapy to 700mg dose     .
In June 2019, CytoDyn announced that the US FDA has requested for an in-person meeting to discuss and finalise the earlier submitted protocol of a pivotal monotherapy trial of leronlimab in patients with HIV. Previously in May 2019, CytoDyn had filed with the US FDA the planned pivotal trial protocol for leronlimab as a monotherapy for HIV patients   . Earlier, in October 2018, CytoDyn reported its plan to conduct a registration-directed trial of leronlimab monotherapy for HIV-infected patients, which if successful, could support a BLA for label extension  .
In April 2019, CytoDyn initiated phase II/III trial of leronlimab to assess the efficacy, clinical safety and tolerability parameters of PRO 140 in combination with falling ART for the initial one-week treatment period, and in combination with optimized background therapy during the subsequent 24-week treatment period (PRO 140_CD02_OpenLabel; NCT03902522). Approximately, 25 patients with HIV-1 infections are to be enrolled in the USA  .
CytoDyn, in October 2016, initiated a phase IIb/III study to evaluate the safety and efficacy of leronlimab SC maintenance therapy in virologically suppressed patients with CCR5-tropic HIV-1 infection (NCT02859961; PRO140CD03). The study is expected to enrol approximately 390 clinically stable subjects in the US, who will be shifted from suppressive combination antiretroviral therapy to leronlimabsingle agent maintenance therapy for 48 weeks. As of August 2017, more than 100 patients have been enrolled in the trial. In July 2018, CytoDyn announced that it had received clearance from the independent Institutional Review Board (IRB) to increase the weekly leronlimab dose from 525mg to 700mg for newly enrolled patients. Participants in the trial who failed to maintain suppressed HIV viral load on a lower dose of the drug will be permitted to continue in the trial with a higher dose. In November 2018, efficacy data were released by the company. CytoDyn has planned to submit a pivotal monotherapy trial protocol for leronlimab as a single-agent maintenance therapy with the intention of filing for a label expansion, subject to combination therapy’s first approval     . In March 2019, CytoDyn presented the interim efficacy and safety results at the 26th Conference on Retroviruses and Opportunistic Infections (CROI-2019)   . In August 2019, CytoDyn released updated efficacy results from the trial. As of October 2019, the phase III portion of the trial was initiated   .
In July 2018, CytoDyn completed a phase III trial that evaluated the efficacy, safety, and tolerability of leronlimab in conjunction with existing ART (failing regimen) for one week and Optimized Background Therapy (OBT) for 24 weeks respectively as a component of HAART (highly active antiretroviral therapy) (PRO140CD02; NCT02483078)   . The double-blind, randomised trial was initiated in June 2015 and enrolled 52 patients in the US and Puerto Rico        . In February 2018, CytoDyn reported that leronlimab met the primary endpoint of the trial, which was the proportion of patients with ≥0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the one-week treatment period (p˂0.01). In June 2018, updated results from the trial were presented at the at the American Society for Microbiology's Microbe 2018 (ASMM-2018) and further released in July 2018          .
In February 2015, CytoDyn reported that its first phase IIb trial achieved 98% success with 4 weeks of treatment with leronlimab. This US based 14 week trial evaluated the efficacy of once-weekly leronlimab monotherapy as treatment substitution for the maintenance of viral suppression in HIV patients (n=43) who were stable on combination HAART, but needed or wished to discontinue HAART therapy temporarily (NCT02175680). The trial was completed in September 2016. Earlier, in July 2014, the company reported positive interim data from the trial, based on which, DSMB recommended the recruitment of second cohort in the trial     . The company is conducting the CD01 extension study, in which patients from the phase IIb trial were allowed to continue on the monotherapy (PRO 140_CD 01-Extension; NCT02355184). Positive interim data from this extension study were released in July 2015, followed by updated data in September 2015. In May 2018, the company reported that treatment with 350mg subcutaneously administered leronlimab weekly, as monotherapy, was generally well tolerated in HIV-1 infected patients with no treatment-related adverse events (AEs) or study discontinuations due to AEs. Out of 39 enrolled patients, 21 of them reached the trial endpoint of 14 weeks without virologic failure (two consecutive HIV-1 RNA levels of ≥400 copies/ml), and rest of the 18 patients had achieved re-suppressed viral load upon resuming their prior antiretroviral regimen. CytoDyn also reported that patients, who had successfully reached the trial endpoint, will continue to the extension study   . In August 2017, CytoDyn completed another CD02_EA extension study, that provided continued access to leronlimabto patients who had completed participation in PRO140_CD02 (NCT02759042; PRO140CD02EA) and continued to receive clinical benefit and would require leronlimab to form a viable regimen (NCT02990858; PRO 140 _CD02 Extension). The trial intends to enrol 30 patients in the US       .
In September 2014, Drexel University, in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) initiated a phase IIa trial to evaluate leronlimab monotherapy in adult patients infected with CCR5-tropic HIV-1 (PRO 140 2103; 1210001606; 5U01AI095085-03; NCT02257788). The randomised, open-label trial is intended to enrol 40 patients in the US  .
CytoDyn in June 2015 announced that the company has signed a new contract with Amarex to manage the first phase III trial of leronlimab. In January 2014, CytoDyn announced that it was preparing protocols for two phase IIb trials of leronlimab in two additional therapeutic indications. The company is collaborating with the contract research organisation Amarex Clinical Research to prepare the protocols; the first trial protocol was submitted to the FDA in February 2014, and the second was scheduled for completion in the second quarter of 2014. The study drug manufacturing and quality (CMC) of leronlimab in regard to use in other clinical trials had earlier been approved by the FDA    .
CytoDyn entered into a clinical trial agreement with the Drexel University College of Medicine, in November 2012, in relation to two phase IIb studies that the University intends to conduct with leronlimab. The trials will be funded by approximately $US10 million from the National Institutes of Health (NIH). CytoDyn will supply 5000 doses of leronlimab to the University and in return, CytoDyn is entitled to use the data from these trials to maintain its IND application for leronlimab in order to support future clinical trial applications to the US FDA  . Subsequently, the two organisations entered into a contract with Ajinomoto Althea to formulate leronlimab through a "fill and finish" process; the resulting clinical-ready vials will be used in the NIH-funded phase IIb trials that are expected to begin in 2014.
In February 2013, CytoDyn entered into a collaboration with an investigator at The Scripps Research institute to conduct a preclinical study of leronlimab in an animal pre-exposure prophylaxis model of HIV infection  .
Progenics announced, in February 2009, that it had selected the subcutaneous (SC) formulation of leronlimabfor further development, subject to funding, for which Progenics applied to government agencies. The decision followed positive results from a completed phase II trial, which were presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI-2009). The company planned to meet with the US FDA to discuss registration studies of the SC formulation  . The company has since discontinued development on programmes outside of its core focus of oncology, as reported in its Form 10-K (filed 15 March 2012).
In February 2017, Progenics withdrew a phase IIb trial prior to enrollment due to lack of enrollment, that was designed to evaluate the efficacy of leronlimab as an adjunct to a new, optimised, oral antiretroviral regimen in HIV-1-infected injection drug users with viral rebound and documented poor adherence to the previous antiretroviral regimen. The primary endpoint was percentage of patients without virologic failure at week 24 (NCT01272258)  . The trial was halted previously based on strategic business reasons. Following the acquisition, CytoDen had submitted a revised protocol to the US FDA in October 2013 and the company had received approval to commence patients screening in January 2014   .
The phase II clinical programme of Progenics for leronlimab comprised two US-based clinical trials in a total of 70 patients with HIV-1 infection. One trial was investigating intravenous (IV) administration and the other, SC administration of the drug. Both studies were in patients with early-stage HIV infection who had not received antiretroviral therapy in the previous 3 months. In the IV administration study, initiated in December 2007, approximately 30 patients with HIV-1 infection were randomised to receive one 10 mg/kg dose, or one 5 mg/kg dose of leronlimab, or placebo (NCT00613379)  . The SC administration study was initiated in April 2008 (NCT00642707)  . Patients with HIV-1 infection were randomised to one of four treatment arms: leronlimab (162mg) for three single SC doses on days 1, 8, and 15 (Arm 1); leronlimab(324mg) for three single SC doses on days 1, 8, and 15 (Arm 2); leronlimab (324mg) for two single SC doses on days 1 and 15 plus one SC dose of placebo on day 8 (Arm 3); or placebo for three single SC doses on days 1, 8 and 15. Results from the two trials showed that both IV and SC forms of leronlimab exhibited potent and prolonged activity and were generally well tolerated. These data supported the feasibility of two treatment options: monthly IV and weekly SC dosing     .
In March 2017, Drexel University and National Institute on Drug Abuse (NIDA) withdrew a phase IIb trial prior to enrolment that was designed to evaluate the efficacy of leronlimab as an adjunct to a new, optimised, oral antiretroviral regimen in HIV-infected injection drug users with viral rebound and documented poor adherence to the previous antiretroviral regimen (PRO 140 2102; NCT02438345). This randomised, double-blind, placebo-controlled trial planned to enrol approximately 76 patients in the US  .
Progenics completed enrolment and dosing of 39 patients with HIV infection in a phase Ib trial of leronlimab during December 2006. The trial evaluated the tolerability, pharmacology and antiviral activity of the antibody in this patient population. This double-blind, placebo-controlled, dose-escalation study was conducted in patients who had not taken any antiretroviral therapy within the previous 3 months and who had HIV plasma concentrations ≥5000 copies/mL. Patients received a single IV dose of leronlimab (0.5, 2 or 5 mg/kg) or placebo. Leronlimab blood concentrations and CCR5 coating were determined and compared with antiviral effects. Positive preliminary results were reported, which the company believed support the initiation of multi dose studies of the drug in combination with other agents. Detailed analysis of the phase Ib trial indicated that leronlimab was generally well tolerated and no dose-limiting toxicity was observed       .
Leronlimab (IV administration) was well tolerated and had favourable pharmacodynamic profile in a double-blind, placebo-controlled, phase Ia study in 20 healthy male subjects (NCT00110591)   . This study was conducted under the auspices of the US National Institute of Allergy and Infectious Diseases (NIAID), which provided funding for the development of leronlimab  .
Leronlimab was granted fast track status by the US FDA in February 2006, for the treatment of HIV infection as a combination therapy with HAART  .
Preclinical evaluation was conducted in collaboration with Aaron Diamond AIDS Research Center in the US. In laboratory tests, leronlimab blocked the entry and replication of multiple strains of HIV. In the mouse model, the monoclonal antibody effectively blocked replication of HIV and reduced viral levels to nearly undetectable amounts in all animals treated.
(GvHD): In October 2017, the USFDA granted orphan drug designation to leronlimab for the prevention of GvHD. The application for the orphan drug designation was filed in December 2015  (CytoDyn, Form S-1, February 2016).
CytoDyn, in November 2016, initiated a phase II trial to evaluate the safety, efficacy and feasibility of the use of leronlimab as an add-on therapy to standard GVHD prophylaxis treatment, for prevention of acute GVHD in adult patients with AML or MDS undergoing allogeneic stem-cell transplantation (NCT02737306; 140CD03GVHD). The randomised, double-blind trial is designed to enrol approximately 60 patients in the US. Previously, in October 2015, CytoDyn had reported that it had filed an IND application with the US FDA to conduct a phase II clinical trial of leronlimab in patients with GvHD, and in December 2015, received clearance from the FDA to conduct the trail. CytoDyn reported in June 2015 that leronlimab is effective in treatment of GvHD and believes that it has favourable dosing and pharmacokinetics, less toxicity and side effects and no direct stimulation (agonist activity) of the CCR5 receptor    . In March 2020, the company announced treatment of first patient in the trial under the amended trial protocol. The protocol includes reduced intensity conditioning (RIC) patients and an open-label design under which all patients receive leronlimab. The Independent Data Monitoring Committee (iDMC) had completed the interim analysis of the data from 10 patients enrolled in the trial in March 2018. Based on the analysis the company had decided to make amendments in the trial protocol and obtain concordance for it from the US FDA   . The amendments included switching the pre-treatment conditioning regimen from aggressive myeloablative conditioning to a reduced intensity conditioning, and switching from a blinded one-for-one randomised placebo-controlled design to an open-label design, under which all enrollees received leronlimab. The amendments also provided for a 50% increase in the dose of leronlimab to more closely mimic preclinical dosing. Further in June 2018, CytoDyn reported that the central Institutional Review Board (IRB) has approved the trial for GvHD and triggered the initiation of patient enrolment in five clinical sites. At that time, the company also reported that the next review of data by the iDMC will occur following enrolment of 10 patients under the amended protocol after each patient has been dosed for 30 days  .
In the near future, CytoDyn expects to file the Breakthrough Therapy designation for the treatment of GvHD in patients requiring bone marrow transplants  .
Non-alcoholic Steatohepatitis (NASH)
In October 2019, the US FDA granted approval to CytoDyn to initiate enrolment in a phase II trial for non-alcoholic steatohepatitis. Earlier in September 2019, CytoDyn submitted an Investigational New Drug (IND) application with the US FDA seeking approval to conduct a trial   .
In October 2019, CytoDyn initiated a phase II trial to evaluate leronlimab for the prevention of devastating liver fibrosis associated with non-alcoholic steatohepatitis (NASH). The protocol for this double-blind, prospective, randomised trial intended to enrol 60 participants, has been approved by US FDA   .
Results from a preclinical study of leronlimab in the treatment of NASH were released by CytoDyn, in November 2019.  .
In May 2019, CytoDyn entered into a collaboration with an investigator at The Cleveland Clinic and initiated a preclinical study of leronlimab in humanised murine NASH models  .
In March 2020, CytoDyn completed a new non-dilutive convertible debt offering with an institutional investor, which provides $US15 million of immediately available capital. The company intends to use the capital to bring leronlimab to market  .
In October 2013, CytoDyn raised $US14 million through a private offering. The proceeds are intended to be used to fund operating expenses in order to continue development of PRO 140 in HIV  .