Candidate: Vyrologix™ (leronlimab; PRO 140)
Type: Humanized IgG4 monoclonal antibody. Vyrologix is CytoDyn’s lead candidate, and is a CCR5 antagonist for patients who experience respiratory illness as a result of COVID-19 with potential for multiple therapeutic indications. Acquired by CytoDyn from Progenics Pharmaceuticals in 2012.
2021 Status: First Patient Dosed in Phase III Briazil Trial—CytoDyn said September 9 that it dosed the first patient in its pivotal Phase III trial in Brazil fassessing Vyrologix (leronlimab) in patients with severe COVID-19 symptoms. The company plans to conduct an interim analysis 28 days following the enrollment of 245 patients, which is 40% of the total number of patients to be enrolled in the trial.
The trial is being conducted by Academic Research Organization (ARO) Albert Einstein Israelite Hospital. This trial is intended to provide Brazil’s regulatory authority ANVISA (Agência Nacional de Vigilância Sanitária) with the requisite data to consider advancing the availability of leronlimab to Brazilians infected with COVID-19. The trial will be conducted in up to 35 clinical sites with 612 patients who are hospitalized and in need of oxygenation support, CytoDyn said.
SEC, DoJ Issue Subpoenas—CytoDyn disclosed in its Form 10-K annual report for the year ended May 31, filed July 31 with the U.S. Securities and Exchange Commission (SEC), that it received subpoenas from the SEC and U.S. Department of Justice “requesting documents and information concerning, among other matters, leronlimab, the Company’s public statements regarding the use of leronlimab as a potential treatment for COVID-19 and related communications with the FDA, investors, and others, and trading in the securities of CytoDyn.”
“The SEC has informed the Company that this inquiry should not be construed as an indication that any violations of law have occurred or that the SEC has any negative opinion of any person, entity or securities trading activity,” CytoDyn reported.
The company added that it, and an unspecified number of unnamed executives, received subpoenas in connection with an investigation being conducted by the Justice Department: “The subpoenas seek testimony and/or records concerning, among other matters, leronlimab, the Company’s public statements regarding the use of leronlimab as a potential treatment for COVID-19 and related communications with the FDA, investors, and others, and trading in the securities of CytoDyn.”
FDA REBUKE—The FDA on May 17 issued a summary rebuking some claims made by CytoDyn about its Vyrologix program after the company said results of two trials showed clinical benefits for the COVID-19 treatment. At issue are results from the 86-patient Phase II CD10 study (NCT04343651), which studied Vyrologix’s effect on mild-to-moderate COVID-19; and the 394-patient, Phase IIb/III CD12 trial (NCT04347239), which studied the drug’s effect on severe symptoms of respiratory illness associated with COVID-19.
In CD10, the FDA reported, Vyrologix showed no clinically meaningful differences in average change in “total clinical symptom score” from baseline to Day 14 between study arms (-3.5 in the leronlimab group versus -3.4 in the placebo group). Also, CD10 met none of its secondary endpoints—including mortality, time to symptom resolution, and time to return to normal activity.
In CD12, the FDA continued, no difference was seen in mortality (20.5% in the leronlimab treatment group and 21.6% in the placebo treatment group); or on any of the secondary endpoints, for example, with no difference on the average length of hospitalization (21.4 days in both the leronlimab and the placebo treatment groups). CytoDyn, however, cited a sub-group analysis showing that Vyrologix decreased mortality at 14 days by 82% in 62 critically ill patients (hospitalized patients receiving invasive mechanical ventilation (IMV) or ECMO (See March 30, below).
“With the conclusion of both the CD10 and CD12 clinical trials, it has become clear that the data currently available do not support the clinical benefit of leronlimab for the treatment of COVID-19,” the FDA declared in a statement that was unusual because the agency typically does not comment on unapproved drug candidates.
CytoDyn said it will respond to the FDA during a May 18 webcast. “The company will provide further clarification on the secondary endpoints met in the critically ill pre-specified sub-population. As we continue to work with the FDA and other regulatory agencies, we ask investors to limit their outreach and respect the regulatory approval processes.
Investors responded to the FDA rebuke with a selloff that sent shares of CytoDyn falling 27% on May 17, to $2.04 from $2.80.
India Supply Agreement: CytoDyn said May 13 that it signed an exclusive supply and distribution agreement with Mumbai-based Macleods Pharmaceuticals that will enable Macleods to sell Vyrologix in India following regulatory clearance. “Currently India has zero product approved for critically ill COVID-19 patients and we are delighted to be working toward being the first approved drug for this population,” stated CytoDyn President and CEO Nader Pourhassan, PhD.
On April 19, CytoDyn submitted the chemistry, manufacturing, and controls (CMC) section of the application for an Interim Order to Health Canada under a rolling review. That section is intended to document that the company’s CMC practices are in full compliance with GMP requirements. The Company added that it anticipated the remaining sections will be submitted “in the very near future.”
Nader Pourhassan, PhD, CytoDyn’s President and CEO, stated that two clinical trial protocols for Vyrologix in COVID-19 will be submitted to Brazil’s regulatory agency ANVISA, while in the U.S., the company will “soon” finalize a COVID-19 trial protocol to potentially include a dosage regimen utilizing a first IV dose followed by three subcutaneous doses: “We are moving quickly to advance leronlimab along multiple regulatory paths, including securing additional manufacturing from Samsung BioLogics in 2021 and 2022.”
CytoDyn said April 8 that its Phase II COVID-19 long-haulers study (CD15; NCT04678830) was fully enrolled at 56 patients, in less time than expected. The multi-center, two-arm, randomized, double blind, placebo-controlled study aims to assess the safety and efficacy of Vyrologix (leronlimab) in patients with prolonged COVID-19 symptoms, or Post-Acute COVID Syndrome (PACS). Patients will be given eight weekly doses of Vyrologix or placebo. The final treatment for the last enrolled patient in CD15 will be in early June, with results expected in July, CytoDyn said.
A day earlier, CytoDyn said it delivered leronlimab to a Philippine hospital for administration to 28 additional critically ill COVID-19 patients under a new Compassionate Special Permit (CSP). Chiral Pharma Corporation, CytoDyn’s commercial partner in the Philippines, is working closely with the Philippine FDA and the hospital.
On April 5, the first CSP patient treated with Vyrologix in the Philippines was removed from high-flow oxygen and breathing on his own 35 hours after receiving a 700 mg injection of the treatment under a licensed physician’s request for CSP to treat COVID-19 patients.
The patient was discharged from the hospital on April 3. Before treatment with Vyroloigix, CytoDyn said, he spent 10 days on high flow oxygen, was treated with multiple doses of dexamethasone and then tocilizumab, without showing improvement.
Four days earlier on April 1, CytoDyn filed a new protocol with the FDA seeking to extend treatment to four weeks in the Phase IIb/III CD12 registrational trial assessing Vyrologix in patients with severe-to-critical COVID-19. The company said its decision followed several weeks of talks with the FDA and analysis of CD12 trial data, specifically the 82% drop in mortality compared with placebo after two weeks of leronlimab treatment.
CytoDyn plans to begin patient enrollment in multiple countries, including Brazil, which as of March 31 had more than 20,000 COVID-19 patients in ICU. The company reasons that four weeks of leronlimab treatment would be sufficient to calm cytokine storm and increase the survival rate at four, and potentially eight, weeks.
On March 30, CytoDyn reported results from the CD12 trial showing that when Vyrologix was added to standard of care (SoC), leronlimab decreased mortality at 14 days by 82%, the company said, based on statistical analysis of the 62-patient critically ill population (hospitalized patients receiving invasive mechanical ventilation (IMV) or ECMO. Patients who received Vyrologix were over five times more likely to be alive at day 14 than those who received SoC only.
Vyrologix administration was associated, according to CytoDyn, with a 400% improvement in the ranking on the 7-point ordinal scale at 14 days when given in conjunction with SoC in the critically ill population. That result “provides direct evidence of tangible patient improvement,” CytoDyn added.
In a March 8 regulatory filing, CytoDyn reported modified intention to treat (mITT) results from the CD12 trial showing that that when used in addition to “commonly used COVID-19 treatments” in the 309 patients receiving them, Vyrologix showed a clear benefit in the primary endpoint of all-cause mortality at day 28 with an absolute risk reduction of death of 6.5% and a relative risk reduction of death of 28.1%. That benefit was also seen in 233 patients treated with Vyrologix plus dexamethasone, in the primary endpoint of all-cause mortality at day 28 with an absolute risk reduction of death of 5.7% and a relative risk reduction of 26.0%. Length in hospital stay decreased by 5.5 days in the 62-patient critically ill population.
The regulatory filing also showed mortality benefit at day 28 with an absolute risk reduction of death of 20.9% and a relative risk reduction of death of 73% when Vyrologix was used in addition to “commonly used COVID-19 treatments” in the critically ill population aged ≤ 65 years old. The absolute risk reduction of death was 16.3%, and a relative risk reduction of death 73.5%, when Vyrologix was used in addition to dexamethasone in the critically ill population ≤ 65 years old, CytoDyn added.
2020 Status: CytoDyn said December 30 that the FDA accepted CytoDyn’s protocol submitted two days earlier for adding an open-label extension to the Phase III portion of its Phase IIb/III CD12 registrational trial assessing its renamed candidate Vyrologix in patients with severe-to-critical COVID-19 (NCT04347239). Hospitals that previously participated in the CD12 trial now have the option of enrolling additional eligible patients, with all patients receiving leronlimab. Treatment for eligible patients will continue until further notified by the FDA and/or CytoDyn, the company said.
The FDA also provided specific guidance for physicians seeking access to leronlimab under an emergency IND (eIND) for COVID-19 patients, which must first meet the inclusion/exclusion criteria of the CD12 study. The agency specified certain subgroups of patients will be excluded from eIND authorization: Mild/moderate COVID-19, mechanically ventilated with PEEP <15 cmH20 with Pa02/FiO2 >150 mmHg and on vasopressors >48 hours.
On December 15, CytoDyn said it reached full enrollment in the Phase III portion of its Phase IIb/III CD12 registrational trial assessing its renamed candidate Vyrologix in patients with severe-to-critical COVID-19 (NCT04347239). Data from all 390 patients will be analyzed in approximately 28 days, with expected results to be announced shortly thereafter, the company said.
On November 23, CytoDyn reached enrollment of 293 patients in the trial, thus meeting the requested criteria for a second interim efficacy analysis by the study’s Data Safety Monitoring Committee (DSMC).
Approximately five weeks earlier, the DSMC completed the first interim analysis on 195 patients (or 50% of the 390 planned patients) and recommended the trial continue without modification to achieve the primary endpoint and requested another interim analysis when enrollment reached 75% level (or 293 patients) to review patient mortality and other clinical outcome data.
“If the pace of enrollment we have experienced in the last two weeks continues, we will have the CD12 enrollment completed before the end of the year,” CytoDyn President and CEO Nader Pourhassan, PhD, stated. “The Company is in full swing to obtain full enrollment in the Phase III COVID-19 trial before year end and initiate our Phase II trial for COVID-19 patients with multiple long-hauler symptoms and perhaps complete enrollment in 4-6 weeks.”
On October 20, CytoDyn said the DSMC of its Phase IIb/III CD12 trial recommended that the company continue the study as planned, with the protocol defined sample size and power to achieve the primary endpoint. The DSMC recommendation followed an interim analysis of data from the trial’s first 195 (50%) of 390 planned patients. However, the DSMC requested another interim analysis once enrollment reaches 75% level (293 patients) in order to review patient mortality and other clinical outcome data between the two study arms (leronlimab vs. placebo).
CytoDyn acknowledged September 16 during a conference call with analysts that the FDA and the U.K. government’s Medicines & Healthcare product Regulatory Agency (MHRA) are awaiting interim data from the Phase IIb/III CD12 trial (NCT04347239) assessing leronlimab in patients with severe/critical COVID-19 before acting on the company’s applications for emergency use authorization and fast track designations for leronlimab. Investors responded with a stock selloff that sent CytoDyn shares down 15%, to $3.42 from $4.03.
CytoDyn said it was collaborating with the FDA to develop a protocol for a Phase III trial evaluating four weekly injections of leronlimab in moderately ill patients with COVID-19, reasoning that such patients, including “long haulers” who have had the virus and have never fully recovered, represented the fastest path to an approval.
During the conference call, Nicholas Agresti, MD, whose patients received leronlimab under an FDA emergency IND (eIND) program, said: “The four patients that have had remarkable recoveries in our intensive care unit may have been due to leronlimab,” with clincal improvement seen “in as little as 24 hours.” Agresti is a board-certified gastroenterologist at Southeast Georgia Physician Associates-Gastroenterology in Brunswick and St. Marys, GA. “I’m very optimistic based on what we’ve seen in our patients.”
The Wall Street Journal reported August 26 a denial attributed to an unnamed “senior [Trump] administration official” of comments by a former advisor to the company, IncellDx CEO and founder Bruce Patterson, MD, who six days earlier told TV and radio host Drew Pinsky, MD (“Dr. Drew”) that CytoDyn was under consideration for federal funding through Operation Warp Speed–the program through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021. Shares fell 7.5% to $3.52 as of 2:30 p.m., still above the $3.43 closing price of August 21, after shares jumped 13% following Patterson’s remarks.
On August 25, CytoDyn said it reached the requisite number of 195 patients needed an interim analysis after reaching 28 days in its Phase IIb/III trial (NCT04347239) assessing leronlimab in patients with severe/critical COVID-19.
Patients are randomized to receive weekly doses of 700 mg leronlimab or placebo, administered via weekly subcutaneous injection for two weeks. The study has three phases lasting 28 days: Screening Period, Treatment Period, and Follow-Up Period.
According to CytoDyn, at Day 28. Secondary outcomes measured are: (1) all-cause mortality at Day 14, (2) change in clinical status of subject at Day 14, (3) change in clinical status of subject at Day 28, and (4) change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 14.
CytoDyn said August 20 that the Clinical Trials Unit of the U.K. government’s Medicines & Healthcare product Regulatory Agency (MHRA) authorized the company to enroll for its ongoing Phase III COVID-19 trial for severe-to-critical patients in the U.K. CytoDyn said the decision followed several months of review by the agency of the company’s manufacturing processes and leronlimab’s safety profile.
A day earlier, CytoDyn requested from the MHRA emergency use approval and a regulatory pathway for Fast Track approval of leronlimab based on topline safety and efficacy data from its completed Phase II CD10 clinical trial (NCT04343651) assessing leronlimab in patients with mild-to-moderate COVID-19 in the U.S. CytoDyn has submitted its report of topline data and has also requested emergency use approval from the FDA, as well as from the European Medicines Agency and regulators in Mexico and the Philippines.
The CD10 trial was designed to assess the efficacy and safety of leronlimab, with the 75 enrolled patients randomized to receive either weekly doses of 700 mg leronlimab or placebo, both administered via subcutaneous injection. In July, CytoDyn said 11 serious adverse events were reported in six of 28 patients (21.4%) receiving placebo, compared to eight serious adverse events in five of 56 patients (8.9%) receiving leronlimab. None of the serious averse events in the leronlimab arm were deemed related to study drug administration by the investigators, CytoDyn said.
Safety data from the Phase II trial showed patients treated with placebo were more than twice as likely to experience severe adverse events or adverse events compared to patients treated with leronlimab, CytoDyn said.
As for efficacy data, in all treated patients at End of Treatment (Day 14), 50% of leronlimab patients experienced a beneficial improvement in their National Early Warning Score 2 (NEWS2) scores compared to 20% of placebo patients, the company announced. However, the study’s reported primary endpoint was clinical improvement as assessed by change in Total Clinical Symptom Score or TCSS (for fever, myalgia, dyspnea and cough) at Day 14 following treatment—for which no data was included in the company’s announcement of Phase II results.
CytoDyn said NEWS2 offered the advantage of objective parameters compared with the patient-reported TCSS and thus could better identify patients most at risk for ICU admission, cardiac arrest, or death within 24 hours.
In patients with TCSS of ≥ 4 at baseline, more subjects treated with leronlimab at Day 3 reported improvement in TCSS compared to placebo patients (90% vs. 71%). Among patients with more symptoms at baseline, those who received leronlimab had a greater treatment effect than patients who received the placebo, CytoDyn added, citing a subgroup analysis.
CytoDyn is also studying leronlimab in a Phase IIb/III trial (NCT04347239) in patients with severe/critical COVID-19. The trial continues to enroll patients at several U.S. hospitals, the company said.
CytoDyn finished the year ending May 31 with a net loss of $124.4 million, more than double the $56.2 million reported for the year ending May 31, 2019. The company attributed its increased net loss in part to a non-cash legal settlement charge of $22.5 million related to the issuance of shares of common stock as a settlement for a claim filed by a noteholder alleging that it was owed additional shares upon conversion of its note.
Other reasons cited by CytoDyn for the higher net loss include increased R&D expenses of approximately $10.1 million, an increase in G&A expenses of approximately $7.9 million, an increase in interest expense of approximately $14.9 million, and an increase of approximately $11.2 million in the change in fair value of derivative liability.
CytoDyn said August 6 its ongoing Phase III CD12 trial of leronlimab in patients with severe to critical COVID-19 had been reviewed by an independent Data Safety Monitoring Committee (DSMC), which reported finding no cause to modify the study. The Phase III study had 173 enrolled patients as of August 6. CytoDyn said it will conduct a full interim analysis once 195 patients are enrolled, as provided in the trial’s protocol.
In July, CytoDyn signed an exclusive Distribution and Supply Agreement with American Regent, a Daiichi Sankyo Group company and manufacturer of injectables, to distribute leronlimab for the treatment of COVID-19 in the U.S. Under the agreement, whose value was not disclosed, 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.
In June, CytoDyn said it entered into a Memorandum of Understanding with the Coordinating Commission of the National Institutes of Health and High Specialty Hospitals of Mexico (NIH) to conduct a COVID-19 clinical trial with leronlimab for severe and critically ill patients, with the potential to collaborate on additional COVID-19 trials.
CytoDyn agreed to supply leronlimab at its expense to the Mexico NIH, adding that both parties “are proceeding forward expeditiously to complete the mutually agreed protocol for this clinical trial.” The company said the Mexico NIH was impressed with anecdotal data from the more than 70 critical COVID-19 patients treated with leronlimab under emergency IND authorizations by the FDA.
On May 5, a research team that included CytoDyn CEO Nader Z. Pourhassan, PhD, and five other investigators with ties to CytoDyn published a preprint study on Research Square and MedRxiv describing the immunological mechanism by which leronlimab restoredimmune function and impacts disease in 10 terminally-ill, critical COVID-19 patients. Leronlimab was shown to restore immunologic deficiencies, and reduce SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis.
A day earlier, CytoDyn disclosed in a regulatory filing that Pourhassan sold more than 4.8 million (4,821,174) shares of CytoDyn stock between April 30 and May 4, reaping $11.96 million, after acquiring the shares by exercising stock options, then selling the resulting stock. The selloff reduced Pourhassan’s stake in the company by about half after the company had appeared on financial news shows in recent weeks to promote leronlimab, according to STAT.
Pourhassan explained the selloff as a transaction in which he borrowed $3.8 million to buy shares from CytoDyn, sold them for about $15.8 million, paid back the loan and kept the difference. He said the transaction would help the company pay for manufacturing and other expenses, without potentially denting the price of his company’s stock by raising the cash on the market.
Four days earlier, CytoDyn reported mostly positive results for 49 patients that had been treated with leronlimab. They include four of 11 severe COVID-19 patients in one New York hospital whose lives CytoDyn said were saved due to treatment with the drug; three of six severe disease patients at a Southern California hospital who were extubated; two of three Georgia patients who were also extubated; a patient at a second New York hospital who was taken off oxygen and discharged after treatment; and a Northern California patient who was weaning from a ventilator and transferred to a rehabilitation hospital.
CytoDyn said in April it would dedicate all resources to ensure availability of leronlimab for COVID-19 patients while the FDA reviewed the company’s BLA for the drug in combination with highly active antiretroviral therapy (HAART) in treatment-experienced HIV patients. In July, the FDA sent CytoDyn a “Refuse to file” letter regarding its BLA, and later agreed to answer by September 4 CytoDyn’s questions on what additional information the FDA requires to resubmit the BLA.
The company has won FDA conditional acceptance of Vyrologix as the proprietary name for leronlimab.
Also, CytoDyn appointed its Chairman, Scott A. Kelly, MD, to the additional position of Chief Medical Officer and Head of Busines Development, a move it said would accelerate evaluation of leronlimab for COVID-19 and other indications.
CytoDyn has highlighted positive results from seven patients with severe COVID-19 after seven days of treatment with leronlimab: All seven showed “dramatic” immune restoration, especially in the CD8 T-lymphocyte population, and a “further dramatic” reduction in the critical cytokine storm cytokines IL-6 and TNF-alpha. At a “leading medical center in Southern California,” CytoDyn said, one severe COVID-19 patient was removed from external ventilation three days after treatment with leronlimab, and two moderate COVID-19 patients were removed from external oxygen support one day following leronlimab treatment, and discharged from the hospital. Based on these results, another four patients with moderate COVID-19 have been administered leronlimab and results are pending, CytoDyn said.
In the U.K., CytoDyn is collaborating with the U.K.’s Department of Health to provide emergency access to leronlimab for severe and critically ill COVID-19 patients, with a formal request to be submitted soon to the MHRA.
CytoDyn said April 2 eight severely ill COVID-19 patients treated with leronlimab showed “significant improvement” in immunologic biomarkers: “We continue to see increases in the profoundly decreased CD8 T-lymphocyte percentages by Day 3, normalization of CD4/CD8 ratios, and resolving cytokine production including reduced IL-6 correlating with patient improvement,” stated Bruce Patterson, MD, CEO and founder of IncellDx, a diagnostic partner and advisor to CytoDyn.
CytoDyn and Longen China Group has said they will begin exploring leronlimab as a potential treatment for coronavirus as well as cancer.
Leronlimab has completed nine clinical trials in over 800 people, according to CytoDyn, including meeting its primary endpoints in a pivotal Phase III trial in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. Leronlimab has the FDA’s Fast Track designation as a combination therapy with HAART for HIV-infected patients, and for metastatic triple-negative breast cancer.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: