Resource for anyone new to leronlimab and CytoDyn
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Posted On: 08/22/2021 2:27:04 PM
Had shared this on /cydy on reddit and thought it may be a useful summary resource for anyone new to leronlimab or anyone looking for additional information or context.
Nice and Current (to August 19, 2021) Summary of Leronlimab and COVID-19 for anyone new to CytoDyn and Leronlimab
More information can be accessed through the link below:
https://adisinsight.springer.com/drugs/800011544
The company has kindly made access free and it can be obtained through a search here: https://adisinsight.springer.com/search
Drug Profile
Leronlimab - CytoDyn
Alternative Names: Leronlimab-PRO 140; leronlimab-PRO140; PA-14; PRO-140; Vyrologix®
Latest Information Update: 19 Aug 2021
At a glance
Originator Progenics Pharmaceuticals
Developer CytoDyn; Progenics Pharmaceuticals
Class Antineoplastics; Antiretrovirals; Antivirals; Hepatoprotectants; Immunotherapies; Monoclonal antibodies; Vascular disorder therapies
Mechanism of Action CCR5 receptor antagonists; Virus internalisation inhibitors
Orphan Drug Status Yes - Graft-versus-host disease
New Molecular Entity Yes
Available For Licensing Yes
Highest Development Phases
Preregistration COVID 2019 infections
Phase III HIV infections; HIV-1 infections
Phase II Breast cancer; Graft-versus-host disease; Non-alcoholic steatohepatitis; Solid tumours
Preclinical Autoimmune disorders; Stroke; Traumatic brain injuries
Most Recent Events
11 Aug 2021 CytoDyn receives guidance from the US FDA on a dose justification report to advance its planned resubmission of BLA for leronlimab for HIV infections
04 Aug 2021 CytoDyn submits clinical trial protocol to Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) to commence phase III CD17 trial in COVID-19 infections, prior to August 2021
04 Aug 2021 The Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) approves clinical trial protocol to commence phase III CD17 trial in COVID-19 infections
Development Overview
Introduction
Leronlimab (formerly PRO 140) is a humanised IgG4 monoclonal antibody that blocks the HIV co-receptor, CCR5, being developed by CytoDyn, for the treatment and prevention of HIV-1 infections, graft-versus-host disease (GvHD), breast cancer, solid tumours, COVID-2019 infections, non-alcoholic steatohepatitis and in traumatic brain injury and stroke recovery. Leronlimab blocks the predominant HIV (R5) subtype entry into T cells by masking CCR5 without interfering with the normal function of CCR5 in mediating immune responses. CCR5 may play a role in tumour invasion, metastases, and tumor microenvironment control. CCR5 has also gained importance as a target for neural repair in stroke and traumatic brain injury. As leronlimab crosses the blood-brain barrier with 70-75% receptor occupancy of the CCR5 receptors in the brain, it is anticipated to help treat patients with traumatic brain injuries and strokes. Blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. The drug received a refusal to file letter from the US FDA for HIV infections. Candidate is under regulatory review for COVID-2019 infections in Canada. Clinical development for breast cancer, solid tumours, HIV infections, HIV-1 infections, non-alcoholic steatohepatitis (NASH), COVID-2019 infections, graft versus host is underway in USA, Philippines and the UK. Preclinical development is underway in the US for autoimmune disorders, prevention of HIV infections, stroke, and traumatic brain injuries.
CytoDyn discontinued the development of intravenous formulation of lernolimab in HIV-1 infections in the US.
Leronlimab was originally discovered and developed by Progenics Pharmaceuticals (a subsidiary of Lantheus Holding) through phase II clinical trials. Progenics was seeking to develop leronlimab as a new HIV therapy that combined infrequent dosing and a more favourable adverse effect profile than existing therapies, with the goal of developing a long-acting, self-administered therapy for HIV infection. However, the company discontinued development of leronlimab and sold it to CytoDyn in 2012[1].
CytoDyn is actively seeking partnership for the development of leronlimab in China, France, Japan and the US[2][3].
In June 2020, Progenics Pharmaceuticals was acquired by Lantheus Holdings[4].
Company Agreements
In May 2021, CytoDyn enterted into an exclusive supply and distribution agreement with Macleods Pharmaceuticals in India. The commercial agreement will enable Macleods to sell leronlimab in India, following regulatory clearance.[5]
In May 2021, CytoDyn entered into a research and development agreement with Academic Research Organization (ARO) Albert Einstein Israelite Hospital to evaluate leronlimab in two phase III COVID-19 trials including a small trial in critically ill and a large trial in severe populations in Brazil. The trials are intended to provide the Brazilian regulatory authority, ANVISA, with the requisite data to consider advancing the availability of leronlimab to Brazilians infected with COVID-2019 infections. Other details of the agreement were not disclosed.[6]
In April 2021, CytoDyn entered into a distribution and supply agreement with Biomm S.A. for the supply of leronlimab for the treatment of COVID-19 and all other leronlimab indications in Brazil.[7]
In November 2020, CytoDyn entered an agreement with amfAR to test the ability of leronlimab to mediate a functional HIV cure. CytoDyn’s partnership with amfAR will advance clinical studies to incorporate leronlimab to mimic a CCR5-deficient stem cell donor and attempt to functionally cure an HIV+ person receiving a stem cell transplant from a donor expressing CCR5.[8]
In July 2020, CytoDyn entered into a distribution and supply agreement with American Regent for the distribution of leronlimab for the treatment of COVID-19 in the US. Under the terms of the agreement, CytoDyn will supply leronlimab for the treatment of COVID-19 for distribution by American Regent and receive quarterly payments based on a profit-sharing arrangement.[9]
In June 2020, CytoDyn and the Coordinating Commission of the National Institutes of Health and High Specialty Hospitals of Mexico (NIH)entered into a Memorandum of Understanding (MOU) to conduct a phase III trial with leronlimab for COVID-2019 infections in severe and critically ill patients, with the potential to collaborate on additional COVID-19 trials. Under the terms of MOU, CytoDyn will supply leronlimab at its expense to the NIH and both parties are proceeding forward expeditiously to complete the mutually agreed protocol for trial.[10]
In February 2020, CytoDyn signed a nonbinding letter of intent (LOI) for the joint development and licensing of leronlimab in China with Longen China Group. CytoDyn and Longen will be exploring opportunities for leronlimab for the treatment of the 2019 novel coronavirus (2019-nCoV) and cancer. Financial details were not disclosed.[11]
In December 2019, CytoDyn and Vyera Pharmaceuticals entered into a commercialisation, licensing and supply agreement in the US for HIV infections. Under the terms of agreement, CytoDyn will maintain responsibility for the development and the US FDA approval of leronlimab for all HIV-related and other indications and Vyera will be responsible for exclusively market and distribute leronlimab in the US for the treatment of HIV. CytoDyn will receive upfront and regulatory and sales-based milestone payments of up to $US87.5 million, along with a royalty of 50 percent on net sales. Vyera will also make an investment in CytoDyn of $US4 million in the form of registered CytoDyn common stock.[12]
In July 2019, CytoDyn entered into an exclusive worldwide licensing agreement with IncellDX to sell non-commercial grade quantities of leronlimab for use in the development and commercialization of immunoassays for quantitative measurement of CCR5 levels on human cells. Under the terms of the agreement, IncellDX will be responsible for all aspects of assay development, regulatory clearance, including leronlimab labeling, packaging and commercialization. At the end of each month during the term of the agreement, IncellDX will provide to CytoDyn demand forecasts for leronlimab for the subsequent 3-month period.[13]
In June 2019, CytoDyn signed a Memorandum of Understanding (MOU) with Thai Red Cross AIDS Research Centre (TRCARC) for the design and conduct of a pre-exposure prophylaxis (PrEP) clinical trial of leronlimab in volunteers who are at high risk of HIV infection. Under the terms of the collaboration, CytoDyn is obliged to provide leronlimab without any other financial support whereas TRCARC will assume responsibilities for all necessary regulatory permissions and conduct of the trial under mutually agreed protocol. No additional financial terms were disclosed.[14]
In April 2019, CytoDyn signed a contract manufacturing deal with Samsung Biologics, for the manufacture of the former's bio-drugs, including leronlimab. The deal is worth $US31 million and may be increased up to $US246 million by 2027, provided that CytoDyn concludes its product development efforts and initiates commercialization.[15]
In October 2012, CytoDyn completed the acquisition of leronlimab from Progenics by paying the $US3.5 million for the transfer of ownership of the technology and related intellectual property as well as approximately 25 million mg of bulk drug substance. Progenics will be eligible for two milestone payments following initiation of a phase III trial ($US1.5 million) and the first NDA approval ($US5 million), as well as royalties on sale upon commercialisation[1]. CytoDyn had entered into an asset purchase agreement with Progenics to acquire leronlimab in July 2012. Under the terms of the agreement, an initial payment was to be made to Progenics in the amount of $US3.5 million, as well as subsequent potential milestone and royalty payments. The transaction was subject to the satisfaction of a number of closing conditions, including: (i) Progenics having received all required authorizations, consents and approvals of government authorities; (ii) Progenics having entered into and delivered intellectual property assignments; (iii) the Company and Progenics having entered into a transition services agreement; (iv) the Company having obtained the financing and raising of capital it needs in order to consummate the transactions contemplated by the Agreement; and (v) the Company having completed and been satisfied with its continuing due diligence investigation of leronlimab[16].
As part of an agreement with Progenics, Protein Design Labs humanised leronlimab. Progenics had agreed to pay a licensing and signing fee and was also liable for milestone payments and royalties on any future sales. In February 2002, Progenics announced that a humanised form of leronlimab had been selected for clinical testing. Humanised leronlimab is designed to be non-immunogenic, making it suitable for long-term therapy of patients with HIV infections[17]. In January 2006, Protein Design Labs changed its name to PDL BioPharma[18].
In July 2002, Progenics announced that it had signed an agreement to use ViroLogic's proprietary HIV resistance testing technology (PhenoSense™ HIV entry assay) in the development of leronlimab and PRO 542 [see Adis Insight drug profile 800005801(PRO 542)]. The assay will be used to assess viral susceptibility to leronlimab and PRO 542[19]. In September 2005, ViroLogic changed its name to Monogram Biosciences[20].
Manufacturing agreement
In April 2019, CytoDyn and Samsung BioLogics entered into a manufacturing agreement of 1$ billion worth of Leronlimab to meet expected demand for future revenues post approval. Effective from 29 July 2015, CytoDyn entered into a license agreement with Lonza Sales, covering Lonza’s “system know-how” technology with respect to CytoDyn’s use of proprietary cell lines to manufacture new leronlimab material. Under the terms of agreement CytoDyn is required to pay £600 000 by 15 December 2015, and a second payment of up to an additional £600 000 by 30 June 2016, in each case excluding certain value added taxes and similar amounts (CytoDyn, Form S-1, February 2016).
Key Development Milestones
In October 2020, Medicines & Healthcare product Regulatory Agency (MHRA) of the UK government has cleared CytoDyn to file its Biologics License Application (BLA) for leronlimab as a combination therapy for multi-drug resistance HIV patients in the UK. The MHRA’s clearance for the BLA filing included a treatment regimen of one injection per week of 350 mg of the Company’s product leronlimab, as contrasted to the dosage used in the phase III clinical trial conducted in the US for this indication of two consecutive injections of 175 mg per week[21].
Solid tumours
In May 2020, CytoDyn initiated a phase II basket trial of leronlimab (PRO 140) in patients with CCR5+ locally advanced or metastatic solid tumours (NCT04504942; CD09_Basket). The open-label trial intends to enrol approximately 30 participants in the US[22].
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[23]. 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[24][25][26][27].
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[28][29][30].
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[31].
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[32][33][34][35].
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[32][36].
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[37][32][3][38][39][40]. 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[41][29]. 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[42]. In February 2020, updated interim efficacy data from the trial were released by CytoDyn[25]. 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[43]. In July 2021, CytoDyn announced that the trial has successfully advanced from the phase Ib part to phase II part, and the company also confirmed that the phase II part will be assessed using 700 mg dose[44]. In July 2021, CytoDyn released preliminary interim efficacy data from a trial[45].
Leronlimab binds to CCR5 in human breast cancer, blocks cytokines induced CCR5 signaling and human breast cancer cell invasion[46].
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)[47].
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[48].
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[35].
In August 2019, CytoDyn announced that leronlimab treatment in mice models suppressed growth of colon carcinoma in both low and high CCR5 expression tumours[49]. In August 2018, CytoDyn released the preclinical data for leronlimab in human colorectal cancer. Leronlimab was in preclinical development for colorectal cancer since 2017[50].
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[51][52].
COVID-2019 infections
In April 2021, CytoDyn submitted manufacturing section (CMC) of interim order application to Health Canada for COVID-2019 infection under rolling review. CytoDyn also announced that company's manufacturing practices are in compliance with GMP requirements. The company will submit remaining sections in near future[53].
In March 2021, CytoDyn announced intention to file Accelerated Rolling Review with MHRA for COVID-2019 infections[54].
In March 2021, CytoDyn initiated the process to submit an interim order with Health Canada[54].
In March 2021, CytoDyn announced that based upon a discussion with the US FDA, MHRA, and Health Canada for the determination the best path forward for approval of leronlimab, CytoDyn intends to conduct another study of 140 patients for the treatment of COVID-2019 infections in critically ill population with the same sites as the CD12 and/or more sites added[55]. CytoDyn also announced that, it concurrently filed an additional protocol with the US FDA using the existing sites from its CD12 trial to quickly enroll patients in this population during the ongoing regulatory discussions. Also, CytoDyn is underway other regulatory authorities for the worldwide expansion of the trial[56]. In December 2020, CytoDyn announced that the US FDA provided guidance for addition of an open-label extension to the phase III CD12_COVID-19 trial [see below] and specific criteria for the continuation of eINDs for patients meeting the inclusion/exclusion criteria of this trial. The company will amend changes in the trial design and submit it to the US FDA and upon approval, all the trial sites will have option to enroll additional qualified patients with all receiving leronlimab. The US FDA also provided specific guidance to enable physicians seeking eIND for patients with COVID-2019 infections[57].
In December 2020, CytoDyn reported that the US FDA granted approval to administer leronlimab for severe-to-critical COVID-19 infection patients under emergency IND (eIND) in the US[58].
In April 2021, CytoDyn announced that the first Compassionate Special Permit (CSP) patient in the Philippines improved significantly 35 hours after receiving a 700 mg injection of leronlimab under a licensed physician’s request for CSP to treat COVID-19 patients[59]. Earlier in December 2020, CytoDyn announced the intention to file for Emergency Use Authorisation (EUA) for leronlimab as a treatment for severe-to-critical COVID-2019 patients with the Food and Drug Administration in the Philippines. Earlier in October 2020, CytoDyn had announced that it had conducted a meeting with Chiral Pharma Corporation (a subsidiary of Philippine New Marketlink Pharmaceutical Corporation), to register leronlimab (PRO 140) for potential approval from the Food and Drug Administration in the Philippines, for the treatment of patients with COVID-19 infections[60][61].
In August 2021, CytoDyn announced that Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) approved the clinical trial protocol to commence patient enrollment in its CD17 phase III trial for severe COVID-19 patients. The Academic Research Organization (ARO) Albert Einstein Israelite Hospital (AEIH) in Brazil will conduct the trial. The trial is intended to provide ANVISA with the requisite data to consider advancing the availability of leronlimab to Brazilians infected with COVID-19. The trial will be conducted in 612 patients who are hospitalized and in need of oxygenation support. Additionally, ANVISA is reviewing another protocol submitted for a second clinical trial for 316 critically ill COVID-19 patients. The company expects an interim analysis to be conducted after 40% (245) of the patients[62].
Before May 2021, CytoDyn announced that the the CD12 trial did not meet mITT endpoints. The company will soon provide an update on ongoing work with the US FDA and other regulatory agencies on using sub-population data to ensure future adequate trial design, in order to continue to further its clinical development of leronlimab in the treatment of patients with COVID-19[63] .Previously, In December 2020, CytoDyn completed the enrolment in the phase III portion of a phase IIb/III trial in patients with severe-to-critical COVID-2019, under the granted emergency IND. The randomised, double blind, placebo controlled, adaptive, multi-centre trial is evaluating the safety and efficacy of leronlimab, and was initiated in April 2020(NCT04347239; CD12_COVID-19). The primary outcome is all-cause mortality at day 28. The study enrolled 394 patients in the US and UK[64][65][66]. Earlier in April 2020, the company had filed a second clinical trial protocol for leronlimab with the US FDA for COVID-2019. Phase III portion of the trial was initiated in July 2020. In August 2020, CytoDyn received positive Data Safety Monitoring Committee (DSMC) recommendation for leronlimab for the treatment of COVID-19 infections. The DSMC did not raise any safety concerns from the data reviewed from 149 patients and recommended to continue the trial. In October 2020, CytoDyn reached the required enrolment of 195 patients in the phase III trial to perform an interim analysis and is expected to occur again after enrolment reaches 293 patients. In November 2020, CytoDyn announced that it has reached enrollment of 293 patients in the phase III trial for COVID-19 infections, thereby meeting the requested criteria for a second interim efficacy analysis by the Data Safety Monitoring Committee (DSMC). After the first interim analysis, the DSMC requested a second interim analysis of all data after enrollment had reached 293 patients or 75% of the total patients for the trial. Trial showed 82% reduction in critically ill, mechanically ventilated patients with statistically significant p value. In December 2020, CytoDyn concluded that it will be far more time efficient to forego the second interim analysis and to analyse the results of the phase III portion of the trial with the data on 390 patients, and to provide final data to the US Food and Drug Administration, Health Canada, MHRA, and Philippines FDA. In February 2021, CytoDyn unblinded the data of the trial and reported that the company has concluded its ongoing discussion with the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, Health Canada and the US FDA regarding the outcome of the trial[67][60][68][69][70][71][72][73][74][75][76][77]. In March 2021, CytoDyn released initial results from the trial and also announced the submission of results to US FDA, MHRA and Health Canada. In March 2021, updated efficacy data from the trial were released by CytoDyn. In April 2021, top line efficacy data from the trial were released by the CytoDyn [78][79][56][55].
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 severe and critically ill patients COVID-19 patients in Mexico. The small phase III trial intends to enrol approximately 25 patients in Mexico[10][80].
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[81].
In July 2021, CytoDyn completed enrolment in a phase II trial to evaluate the safety and efficacy of Vyrologix™ (leronlimab) in the treatment of patients with prolonged COVID-19 symptoms, a condition now known as Post-Acute COVID Syndrome (PACS), suffering from long-hauler symptoms (NCT04678830; CD15COVID19). The trial was initiated in March 2021 and in the same month, 20 patients were enrolled and dosed in the first 10 days of the trial for COVID-2019 long-haulers symptoms[82][83]. The randomised, double-blind, placebo controlled trial enrolled 56 patients in USA. Earlier in November 2020, CytoDyn had filed a protocol with the US FDA for the trial. The study will have an interim analysis after half of the patients are enrolled and will allow the company to report the results[84]. Patient enrolment was completed in April 2021. CytoDyn announced that, final treatment for the last enrolled patient will be in early June with results expected in July[85]. Later, in June 2021, preliminary results after unblinding the data from the trial were released by CytoDyn[86].
In August 2020, CytoDyn provided its top-line report from its recently completed phase II clinical trial [see below] for patients with mild-to-moderate COVID-19 symptoms to the Medicines and Healthcare Products Regulatory Agency (MHRA), UK. Later, in the same month, it was reported that after several months of providing requested information about manufacturing and safety of leronlimab, the MHRA of the UK Government authorised the company to enrol for its ongoing trial for severe-to-critical COVID-19 patients [see below], in the UK. The company requested the regulatory pathway for Fast Track approval noting the efficacy and safety results from the phase II trial[87][66].
In July 2020, CytoDyn completed phase II trial that evaluated the safety and efficacy of leronlimab in patients with mild-to-moderate COVID-2019 infections (CD10_COVID-19; NCT04343651)[70]. The randomized, double-blind, placebo controlled trial was initiated in April 2020 and enrolled approximately 86 patients in the US. In June 2020, enrolment in the trial was completed. In July 2020, CytoDyn announced its intention to lock and unblind the trial data later in the week[71][88][89][9][73]. Efficacy results from the trial were released by the company in July 2020[90][91]. In August 2020, adverse events and efficacy data from a phase II trial in COVID-2019 infections released by CytoDyn[92].
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[73][93][94][74][75][95][96][97][98][99][100][101][89].
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[80][102].
In May 2020, CytoDyn released the efficacy data from compassionate care treatment in critically ill patients with COVID-19 infections[103].
In March 2020, CytoDyn announced that the company will request a preliminary Breakthrough Therapy designation meeting based on the recommendations by the US FDA[43].
Nice and Current (to August 19, 2021) Summary of Leronlimab and COVID-19 for anyone new to CytoDyn and Leronlimab
More information can be accessed through the link below:
https://adisinsight.springer.com/drugs/800011544
The company has kindly made access free and it can be obtained through a search here: https://adisinsight.springer.com/search
Drug Profile
Leronlimab - CytoDyn
Alternative Names: Leronlimab-PRO 140; leronlimab-PRO140; PA-14; PRO-140; Vyrologix®
Latest Information Update: 19 Aug 2021
At a glance
Originator Progenics Pharmaceuticals
Developer CytoDyn; Progenics Pharmaceuticals
Class Antineoplastics; Antiretrovirals; Antivirals; Hepatoprotectants; Immunotherapies; Monoclonal antibodies; Vascular disorder therapies
Mechanism of Action CCR5 receptor antagonists; Virus internalisation inhibitors
Orphan Drug Status Yes - Graft-versus-host disease
New Molecular Entity Yes
Available For Licensing Yes
Highest Development Phases
Preregistration COVID 2019 infections
Phase III HIV infections; HIV-1 infections
Phase II Breast cancer; Graft-versus-host disease; Non-alcoholic steatohepatitis; Solid tumours
Preclinical Autoimmune disorders; Stroke; Traumatic brain injuries
Most Recent Events
11 Aug 2021 CytoDyn receives guidance from the US FDA on a dose justification report to advance its planned resubmission of BLA for leronlimab for HIV infections
04 Aug 2021 CytoDyn submits clinical trial protocol to Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) to commence phase III CD17 trial in COVID-19 infections, prior to August 2021
04 Aug 2021 The Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) approves clinical trial protocol to commence phase III CD17 trial in COVID-19 infections
Development Overview
Introduction
Leronlimab (formerly PRO 140) is a humanised IgG4 monoclonal antibody that blocks the HIV co-receptor, CCR5, being developed by CytoDyn, for the treatment and prevention of HIV-1 infections, graft-versus-host disease (GvHD), breast cancer, solid tumours, COVID-2019 infections, non-alcoholic steatohepatitis and in traumatic brain injury and stroke recovery. Leronlimab blocks the predominant HIV (R5) subtype entry into T cells by masking CCR5 without interfering with the normal function of CCR5 in mediating immune responses. CCR5 may play a role in tumour invasion, metastases, and tumor microenvironment control. CCR5 has also gained importance as a target for neural repair in stroke and traumatic brain injury. As leronlimab crosses the blood-brain barrier with 70-75% receptor occupancy of the CCR5 receptors in the brain, it is anticipated to help treat patients with traumatic brain injuries and strokes. Blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. The drug received a refusal to file letter from the US FDA for HIV infections. Candidate is under regulatory review for COVID-2019 infections in Canada. Clinical development for breast cancer, solid tumours, HIV infections, HIV-1 infections, non-alcoholic steatohepatitis (NASH), COVID-2019 infections, graft versus host is underway in USA, Philippines and the UK. Preclinical development is underway in the US for autoimmune disorders, prevention of HIV infections, stroke, and traumatic brain injuries.
CytoDyn discontinued the development of intravenous formulation of lernolimab in HIV-1 infections in the US.
Leronlimab was originally discovered and developed by Progenics Pharmaceuticals (a subsidiary of Lantheus Holding) through phase II clinical trials. Progenics was seeking to develop leronlimab as a new HIV therapy that combined infrequent dosing and a more favourable adverse effect profile than existing therapies, with the goal of developing a long-acting, self-administered therapy for HIV infection. However, the company discontinued development of leronlimab and sold it to CytoDyn in 2012[1].
CytoDyn is actively seeking partnership for the development of leronlimab in China, France, Japan and the US[2][3].
In June 2020, Progenics Pharmaceuticals was acquired by Lantheus Holdings[4].
Company Agreements
In May 2021, CytoDyn enterted into an exclusive supply and distribution agreement with Macleods Pharmaceuticals in India. The commercial agreement will enable Macleods to sell leronlimab in India, following regulatory clearance.[5]
In May 2021, CytoDyn entered into a research and development agreement with Academic Research Organization (ARO) Albert Einstein Israelite Hospital to evaluate leronlimab in two phase III COVID-19 trials including a small trial in critically ill and a large trial in severe populations in Brazil. The trials are intended to provide the Brazilian regulatory authority, ANVISA, with the requisite data to consider advancing the availability of leronlimab to Brazilians infected with COVID-2019 infections. Other details of the agreement were not disclosed.[6]
In April 2021, CytoDyn entered into a distribution and supply agreement with Biomm S.A. for the supply of leronlimab for the treatment of COVID-19 and all other leronlimab indications in Brazil.[7]
In November 2020, CytoDyn entered an agreement with amfAR to test the ability of leronlimab to mediate a functional HIV cure. CytoDyn’s partnership with amfAR will advance clinical studies to incorporate leronlimab to mimic a CCR5-deficient stem cell donor and attempt to functionally cure an HIV+ person receiving a stem cell transplant from a donor expressing CCR5.[8]
In July 2020, CytoDyn entered into a distribution and supply agreement with American Regent for the distribution of leronlimab for the treatment of COVID-19 in the US. Under the terms of the agreement, CytoDyn will supply leronlimab for the treatment of COVID-19 for distribution by American Regent and receive quarterly payments based on a profit-sharing arrangement.[9]
In June 2020, CytoDyn and the Coordinating Commission of the National Institutes of Health and High Specialty Hospitals of Mexico (NIH)entered into a Memorandum of Understanding (MOU) to conduct a phase III trial with leronlimab for COVID-2019 infections in severe and critically ill patients, with the potential to collaborate on additional COVID-19 trials. Under the terms of MOU, CytoDyn will supply leronlimab at its expense to the NIH and both parties are proceeding forward expeditiously to complete the mutually agreed protocol for trial.[10]
In February 2020, CytoDyn signed a nonbinding letter of intent (LOI) for the joint development and licensing of leronlimab in China with Longen China Group. CytoDyn and Longen will be exploring opportunities for leronlimab for the treatment of the 2019 novel coronavirus (2019-nCoV) and cancer. Financial details were not disclosed.[11]
In December 2019, CytoDyn and Vyera Pharmaceuticals entered into a commercialisation, licensing and supply agreement in the US for HIV infections. Under the terms of agreement, CytoDyn will maintain responsibility for the development and the US FDA approval of leronlimab for all HIV-related and other indications and Vyera will be responsible for exclusively market and distribute leronlimab in the US for the treatment of HIV. CytoDyn will receive upfront and regulatory and sales-based milestone payments of up to $US87.5 million, along with a royalty of 50 percent on net sales. Vyera will also make an investment in CytoDyn of $US4 million in the form of registered CytoDyn common stock.[12]
In July 2019, CytoDyn entered into an exclusive worldwide licensing agreement with IncellDX to sell non-commercial grade quantities of leronlimab for use in the development and commercialization of immunoassays for quantitative measurement of CCR5 levels on human cells. Under the terms of the agreement, IncellDX will be responsible for all aspects of assay development, regulatory clearance, including leronlimab labeling, packaging and commercialization. At the end of each month during the term of the agreement, IncellDX will provide to CytoDyn demand forecasts for leronlimab for the subsequent 3-month period.[13]
In June 2019, CytoDyn signed a Memorandum of Understanding (MOU) with Thai Red Cross AIDS Research Centre (TRCARC) for the design and conduct of a pre-exposure prophylaxis (PrEP) clinical trial of leronlimab in volunteers who are at high risk of HIV infection. Under the terms of the collaboration, CytoDyn is obliged to provide leronlimab without any other financial support whereas TRCARC will assume responsibilities for all necessary regulatory permissions and conduct of the trial under mutually agreed protocol. No additional financial terms were disclosed.[14]
In April 2019, CytoDyn signed a contract manufacturing deal with Samsung Biologics, for the manufacture of the former's bio-drugs, including leronlimab. The deal is worth $US31 million and may be increased up to $US246 million by 2027, provided that CytoDyn concludes its product development efforts and initiates commercialization.[15]
In October 2012, CytoDyn completed the acquisition of leronlimab from Progenics by paying the $US3.5 million for the transfer of ownership of the technology and related intellectual property as well as approximately 25 million mg of bulk drug substance. Progenics will be eligible for two milestone payments following initiation of a phase III trial ($US1.5 million) and the first NDA approval ($US5 million), as well as royalties on sale upon commercialisation[1]. CytoDyn had entered into an asset purchase agreement with Progenics to acquire leronlimab in July 2012. Under the terms of the agreement, an initial payment was to be made to Progenics in the amount of $US3.5 million, as well as subsequent potential milestone and royalty payments. The transaction was subject to the satisfaction of a number of closing conditions, including: (i) Progenics having received all required authorizations, consents and approvals of government authorities; (ii) Progenics having entered into and delivered intellectual property assignments; (iii) the Company and Progenics having entered into a transition services agreement; (iv) the Company having obtained the financing and raising of capital it needs in order to consummate the transactions contemplated by the Agreement; and (v) the Company having completed and been satisfied with its continuing due diligence investigation of leronlimab[16].
As part of an agreement with Progenics, Protein Design Labs humanised leronlimab. Progenics had agreed to pay a licensing and signing fee and was also liable for milestone payments and royalties on any future sales. In February 2002, Progenics announced that a humanised form of leronlimab had been selected for clinical testing. Humanised leronlimab is designed to be non-immunogenic, making it suitable for long-term therapy of patients with HIV infections[17]. In January 2006, Protein Design Labs changed its name to PDL BioPharma[18].
In July 2002, Progenics announced that it had signed an agreement to use ViroLogic's proprietary HIV resistance testing technology (PhenoSense™ HIV entry assay) in the development of leronlimab and PRO 542 [see Adis Insight drug profile 800005801(PRO 542)]. The assay will be used to assess viral susceptibility to leronlimab and PRO 542[19]. In September 2005, ViroLogic changed its name to Monogram Biosciences[20].
Manufacturing agreement
In April 2019, CytoDyn and Samsung BioLogics entered into a manufacturing agreement of 1$ billion worth of Leronlimab to meet expected demand for future revenues post approval. Effective from 29 July 2015, CytoDyn entered into a license agreement with Lonza Sales, covering Lonza’s “system know-how” technology with respect to CytoDyn’s use of proprietary cell lines to manufacture new leronlimab material. Under the terms of agreement CytoDyn is required to pay £600 000 by 15 December 2015, and a second payment of up to an additional £600 000 by 30 June 2016, in each case excluding certain value added taxes and similar amounts (CytoDyn, Form S-1, February 2016).
Key Development Milestones
In October 2020, Medicines & Healthcare product Regulatory Agency (MHRA) of the UK government has cleared CytoDyn to file its Biologics License Application (BLA) for leronlimab as a combination therapy for multi-drug resistance HIV patients in the UK. The MHRA’s clearance for the BLA filing included a treatment regimen of one injection per week of 350 mg of the Company’s product leronlimab, as contrasted to the dosage used in the phase III clinical trial conducted in the US for this indication of two consecutive injections of 175 mg per week[21].
Solid tumours
In May 2020, CytoDyn initiated a phase II basket trial of leronlimab (PRO 140) in patients with CCR5+ locally advanced or metastatic solid tumours (NCT04504942; CD09_Basket). The open-label trial intends to enrol approximately 30 participants in the US[22].
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[23]. 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[24][25][26][27].
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[28][29][30].
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[31].
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[32][33][34][35].
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[32][36].
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[37][32][3][38][39][40]. 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[41][29]. 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[42]. In February 2020, updated interim efficacy data from the trial were released by CytoDyn[25]. 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[43]. In July 2021, CytoDyn announced that the trial has successfully advanced from the phase Ib part to phase II part, and the company also confirmed that the phase II part will be assessed using 700 mg dose[44]. In July 2021, CytoDyn released preliminary interim efficacy data from a trial[45].
Leronlimab binds to CCR5 in human breast cancer, blocks cytokines induced CCR5 signaling and human breast cancer cell invasion[46].
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)[47].
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[48].
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[35].
In August 2019, CytoDyn announced that leronlimab treatment in mice models suppressed growth of colon carcinoma in both low and high CCR5 expression tumours[49]. In August 2018, CytoDyn released the preclinical data for leronlimab in human colorectal cancer. Leronlimab was in preclinical development for colorectal cancer since 2017[50].
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[51][52].
COVID-2019 infections
In April 2021, CytoDyn submitted manufacturing section (CMC) of interim order application to Health Canada for COVID-2019 infection under rolling review. CytoDyn also announced that company's manufacturing practices are in compliance with GMP requirements. The company will submit remaining sections in near future[53].
In March 2021, CytoDyn announced intention to file Accelerated Rolling Review with MHRA for COVID-2019 infections[54].
In March 2021, CytoDyn initiated the process to submit an interim order with Health Canada[54].
In March 2021, CytoDyn announced that based upon a discussion with the US FDA, MHRA, and Health Canada for the determination the best path forward for approval of leronlimab, CytoDyn intends to conduct another study of 140 patients for the treatment of COVID-2019 infections in critically ill population with the same sites as the CD12 and/or more sites added[55]. CytoDyn also announced that, it concurrently filed an additional protocol with the US FDA using the existing sites from its CD12 trial to quickly enroll patients in this population during the ongoing regulatory discussions. Also, CytoDyn is underway other regulatory authorities for the worldwide expansion of the trial[56]. In December 2020, CytoDyn announced that the US FDA provided guidance for addition of an open-label extension to the phase III CD12_COVID-19 trial [see below] and specific criteria for the continuation of eINDs for patients meeting the inclusion/exclusion criteria of this trial. The company will amend changes in the trial design and submit it to the US FDA and upon approval, all the trial sites will have option to enroll additional qualified patients with all receiving leronlimab. The US FDA also provided specific guidance to enable physicians seeking eIND for patients with COVID-2019 infections[57].
In December 2020, CytoDyn reported that the US FDA granted approval to administer leronlimab for severe-to-critical COVID-19 infection patients under emergency IND (eIND) in the US[58].
In April 2021, CytoDyn announced that the first Compassionate Special Permit (CSP) patient in the Philippines improved significantly 35 hours after receiving a 700 mg injection of leronlimab under a licensed physician’s request for CSP to treat COVID-19 patients[59]. Earlier in December 2020, CytoDyn announced the intention to file for Emergency Use Authorisation (EUA) for leronlimab as a treatment for severe-to-critical COVID-2019 patients with the Food and Drug Administration in the Philippines. Earlier in October 2020, CytoDyn had announced that it had conducted a meeting with Chiral Pharma Corporation (a subsidiary of Philippine New Marketlink Pharmaceutical Corporation), to register leronlimab (PRO 140) for potential approval from the Food and Drug Administration in the Philippines, for the treatment of patients with COVID-19 infections[60][61].
In August 2021, CytoDyn announced that Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) approved the clinical trial protocol to commence patient enrollment in its CD17 phase III trial for severe COVID-19 patients. The Academic Research Organization (ARO) Albert Einstein Israelite Hospital (AEIH) in Brazil will conduct the trial. The trial is intended to provide ANVISA with the requisite data to consider advancing the availability of leronlimab to Brazilians infected with COVID-19. The trial will be conducted in 612 patients who are hospitalized and in need of oxygenation support. Additionally, ANVISA is reviewing another protocol submitted for a second clinical trial for 316 critically ill COVID-19 patients. The company expects an interim analysis to be conducted after 40% (245) of the patients[62].
Before May 2021, CytoDyn announced that the the CD12 trial did not meet mITT endpoints. The company will soon provide an update on ongoing work with the US FDA and other regulatory agencies on using sub-population data to ensure future adequate trial design, in order to continue to further its clinical development of leronlimab in the treatment of patients with COVID-19[63] .Previously, In December 2020, CytoDyn completed the enrolment in the phase III portion of a phase IIb/III trial in patients with severe-to-critical COVID-2019, under the granted emergency IND. The randomised, double blind, placebo controlled, adaptive, multi-centre trial is evaluating the safety and efficacy of leronlimab, and was initiated in April 2020(NCT04347239; CD12_COVID-19). The primary outcome is all-cause mortality at day 28. The study enrolled 394 patients in the US and UK[64][65][66]. Earlier in April 2020, the company had filed a second clinical trial protocol for leronlimab with the US FDA for COVID-2019. Phase III portion of the trial was initiated in July 2020. In August 2020, CytoDyn received positive Data Safety Monitoring Committee (DSMC) recommendation for leronlimab for the treatment of COVID-19 infections. The DSMC did not raise any safety concerns from the data reviewed from 149 patients and recommended to continue the trial. In October 2020, CytoDyn reached the required enrolment of 195 patients in the phase III trial to perform an interim analysis and is expected to occur again after enrolment reaches 293 patients. In November 2020, CytoDyn announced that it has reached enrollment of 293 patients in the phase III trial for COVID-19 infections, thereby meeting the requested criteria for a second interim efficacy analysis by the Data Safety Monitoring Committee (DSMC). After the first interim analysis, the DSMC requested a second interim analysis of all data after enrollment had reached 293 patients or 75% of the total patients for the trial. Trial showed 82% reduction in critically ill, mechanically ventilated patients with statistically significant p value. In December 2020, CytoDyn concluded that it will be far more time efficient to forego the second interim analysis and to analyse the results of the phase III portion of the trial with the data on 390 patients, and to provide final data to the US Food and Drug Administration, Health Canada, MHRA, and Philippines FDA. In February 2021, CytoDyn unblinded the data of the trial and reported that the company has concluded its ongoing discussion with the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, Health Canada and the US FDA regarding the outcome of the trial[67][60][68][69][70][71][72][73][74][75][76][77]. In March 2021, CytoDyn released initial results from the trial and also announced the submission of results to US FDA, MHRA and Health Canada. In March 2021, updated efficacy data from the trial were released by CytoDyn. In April 2021, top line efficacy data from the trial were released by the CytoDyn [78][79][56][55].
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 severe and critically ill patients COVID-19 patients in Mexico. The small phase III trial intends to enrol approximately 25 patients in Mexico[10][80].
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[81].
In July 2021, CytoDyn completed enrolment in a phase II trial to evaluate the safety and efficacy of Vyrologix™ (leronlimab) in the treatment of patients with prolonged COVID-19 symptoms, a condition now known as Post-Acute COVID Syndrome (PACS), suffering from long-hauler symptoms (NCT04678830; CD15COVID19). The trial was initiated in March 2021 and in the same month, 20 patients were enrolled and dosed in the first 10 days of the trial for COVID-2019 long-haulers symptoms[82][83]. The randomised, double-blind, placebo controlled trial enrolled 56 patients in USA. Earlier in November 2020, CytoDyn had filed a protocol with the US FDA for the trial. The study will have an interim analysis after half of the patients are enrolled and will allow the company to report the results[84]. Patient enrolment was completed in April 2021. CytoDyn announced that, final treatment for the last enrolled patient will be in early June with results expected in July[85]. Later, in June 2021, preliminary results after unblinding the data from the trial were released by CytoDyn[86].
In August 2020, CytoDyn provided its top-line report from its recently completed phase II clinical trial [see below] for patients with mild-to-moderate COVID-19 symptoms to the Medicines and Healthcare Products Regulatory Agency (MHRA), UK. Later, in the same month, it was reported that after several months of providing requested information about manufacturing and safety of leronlimab, the MHRA of the UK Government authorised the company to enrol for its ongoing trial for severe-to-critical COVID-19 patients [see below], in the UK. The company requested the regulatory pathway for Fast Track approval noting the efficacy and safety results from the phase II trial[87][66].
In July 2020, CytoDyn completed phase II trial that evaluated the safety and efficacy of leronlimab in patients with mild-to-moderate COVID-2019 infections (CD10_COVID-19; NCT04343651)[70]. The randomized, double-blind, placebo controlled trial was initiated in April 2020 and enrolled approximately 86 patients in the US. In June 2020, enrolment in the trial was completed. In July 2020, CytoDyn announced its intention to lock and unblind the trial data later in the week[71][88][89][9][73]. Efficacy results from the trial were released by the company in July 2020[90][91]. In August 2020, adverse events and efficacy data from a phase II trial in COVID-2019 infections released by CytoDyn[92].
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[73][93][94][74][75][95][96][97][98][99][100][101][89].
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[80][102].
In May 2020, CytoDyn released the efficacy data from compassionate care treatment in critically ill patients with COVID-19 infections[103].
In March 2020, CytoDyn announced that the company will request a preliminary Breakthrough Therapy designation meeting based on the recommendations by the US FDA[43].
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