Virpax in Pact With U.S. Army Institute of Surgical Research

 Virpax® Pharmaceuticals, Inc. ("Virpax" or the "Company") (NASDAQ: VRPX), a company specializing in developing non-addictive products for pain management, post-traumatic stress disorder, central nervous system (CNS) disorders and anti-viral indications, today announced that it has entered into a cooperative research and development agreement (CRADA) with the U.S. Army Institute of Surgical Research (USAISR) to evaluate Virpax’s Probudur™, an injectable long-acting liposomal bupivacaine in a hydrogel formulation that is injected at the wound site. Probudur is being developed to significantly reduce or eliminate the need for opioids after surgery in approved indications. Probudur is a local anesthetic that binds to the sodium channel, preventing pain signals from reaching the brain. In pre-clinical trials, Probudur has shown long duration pain control for at least 96 hours. The USAISR is the U.S. Department of Defense’s (DOD) primary laboratory for developing solutions for trauma and critical care challenges in combat casualties.

https://finance.yahoo.com/news/virpax-pharmaceuticals-enters-crada-u-130000028.html

Cassava Updates on Phase 3 Clinical Program

 Overview of On-going Phase 3 Clinical Program

Our Phase 3 program consists of two double-blind, randomized, placebo-controlled studies of simufilam in patients with mild-to-moderate Alzheimer’s disease. Both Phase 3 studies have Special Protocol Assessments (SPA) from the U.S. Food and Drug Administration.

A total of over 120 subjects have now been enrolled in our Phase 3 studies. Studies are being conducted in over 115 clinical trial sites across the U.S., Canada and Puerto Rico.

Overview of Each On-going Phase 3 Study - RETHINK-ALZ and REFOCUS-ALZ
Our Phase 3 study called “RETHINK-ALZ” is designed to evaluate the safety and efficacy of oral simufilam 100 mg in enhancing cognition and slowing functional decline over 52 weeks. This randomized, double-blind, placebo-controlled study plans to enroll approximately 750 patients with mild-to-moderate Alzheimer’s disease.

Details of the RETHINK-ALZ Phase 3 study include:

• Subjects are randomized (1:1) to simufilam 100 mg or placebo twice daily.

• The co-primary efficacy endpoints are ADAS-Cog12 (a cognitive scale) and ADCS-ADL (a functional scale). A secondary efficacy endpoint is iADRS, a clinical tool that combines cognitive and functional scores from ADAS-Cog & ADCS-ADL.

Our Phase 3 study called “REFOCUS-ALZ” is designed to evaluate the safety and efficacy of oral simufilam 100 mg and 50 mg over 76 weeks. This randomized, double-blind, placebo-controlled study plans to enroll approximately 1,000 patients with mild-to-moderate Alzheimer’s disease.

Details of the REFOCUS-ALZ Phase 3 study, include:

• Subjects are randomized (1:1:1) to simufilam 100 mg, 50 mg, or placebo twice daily.

• The co-primary efficacy endpoints are ADAS-Cog12 (a cognitive scale) and ADCS-ADL (a functional scale). A secondary efficacy endpoint is iADRS, a clinical tool that combines cognitive and functional scores from ADAS-Cog & ADCS-ADL.

https://finance.yahoo.com/news/cassava-sciences-reports-first-quarter-130000375.html

Enlivex Gets 2 U.S. Patents Covering Methods of Treating Sepsis with Allocetra

  Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the “Company”), a clinical-stage macrophage reprogramming immunotherapy company, today announced the issuance of U.S. Patent Nos. 11,304,976 and 11,318,163. Each patent provides Enlivex with added intellectual property (IP) protection in the United States until at least 2036 with respect to claims covering methods of treating sepsis with Allocetra^TM.   

Oren Hershkovitz, PhD, CEO of Enlivex, stated, “These latest patents add important depth to the IP portfolio protecting our sepsis program, with one specifically covering the treatment of sepsis derived from pneumonia, urinary, or biliary tract infections. These are three important sepsis subtypes that we intend to evaluate in our Phase II trial of Allocetra™. As we continue to advance this trial and our other programs, we plan to pursue additional patents in key geographies around the world to help maximize the value of our pipeline.”

Enlivex is developing Allocetra^TM as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra^TM has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as “unmet medical needs”, as a stand-alone therapy or in combination with other therapeutic agents.

https://www.biospace.com/article/releases/enlivex-announces-issuance-of-two-u-s-patents-covering-methods-of-treating-sepsis-with-allocetra/

Using CRISPR to Reset Anxiety, Alcohol Use Disorder

 Researchers at the University of Illinois at Chicago have uncovered the possibility of utilizing gene editing to reverse a cause of anxiety and alcohol use disorder (AUD). The study, published by Science Advances, provides a new approach to a disorder that affects 15 million U.S. adults.

The gene-editing treatment would be effective in patients who began abusing alcohol at an early age, which impairs normal epigenetic and transcription changes associated with brain maturity. This disruption in development is linked to AUD, anxiety and various other psychiatric disorders that can persist through adulthood.

One of the changes that are decreased with early alcohol consumption is the activity-regulated cytoskeleton-associated (Arc) gene expression, in the brain’s amygdala. The arc protein is critical for coordinating synaptic plasticity, such as long-term memory. Arc activity also regulates non-selective histone deacetylase (HDAC), which is important for cognitive function.

Using CRISPR-dCas9, the arc gene activity was able to be evaluated and upregulated to increase histone acetylation. The Cas9 technology was chosen for the ability to easily change specific epigenetic marks, without cutting genetic material or introducing opportunities for error.

With increased histone acetylation of the arc gene, AUD and anxiety decreased in rat experiments.

Subhash Pandey, a senior author of the study, Joseph A. Flaherty Endowed Professor of Psychiatry and director of the Center for Alcohol Research in Epigenetics at UIC, commented on the findings.

"Early binge drinking can have long-lasting and significant effects on the brain, and the results of this study offer evidence that gene editing is a potential antidote to these effects, offering a kind of factory reset for the brain, if you will." 

Historically, treating addictions that began early in life is very difficult. This difficulty was echoed by Anthony Tennyson, co-founder of Awakn Life Sciences, in a previous interview for BioSpace. 

“There are few effective treatments for addiction that address its root causes," Tennyson said. 

Tennyson has a different approach to treating addictions. Awakn combines psychotherapy and psychedelics to treat addiction at its core, instead of just treating the symptoms. For alcohol use disorder, the company uses MDMA (methylenedioxymethamphetamine).

For the scientists at UIL, the method was different, but the end goal was the same. The study included the use of anesthetized adult rats and dCas9 modified lentiviruses. The viruses were modified using dCas9 to increase arc gene activity. The virus was infused directly into the rat brains, and behavior was observed after one week of recovery.

Behavioral tests included an ethanol two-bottle choice drinking paradigm, a sucrose 2BC drinking paradigm, an EPM exploration test and a light-dark box exploration test. These tests show how the rats respond to anxiety-inducing stimuli and drinking preferences when given options. After humane sacrifice, the rats’ amygdala were examined using a ChIP assay to examine genome proteome linkages, real-time PCR, a 3C real-time PCR, and immunofluorescent staining.

The research is funded through grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Department of Veterans Affairs Senior Research Career Scientist Award. The funds were given to support the exploration of additional treatment options for those with AUD or anxiety, as current options are limited to therapy and Alcoholics Anonymous support groups, along with medications that modulate alcoholic dependence or anxiety symptoms. The research conducted by the University of Illinois Chicago is a treatment that would reverse the effects stemming from early alcohol abuse.

https://www.biospace.com/article/researchers-use-crispr-to-get-to-the-root-of-alcohol-use-disorder/

BioCryst's Orladeyo Launch Overshadowed by FDA Hold on PNH Asset

 Although BioCryst probably wanted to tout the success of its Orladeyo launch in its first-quarter financial report, it was overshadowed by the news that the U.S. Food and Drug Administration had placed a partial clinical hold on three of its clinical trials evaluating a development-stage asset, BCX9930.

On April 8, BioCryst, which is based in Research Triangle Park, N.C., announced it had paused enrollment in the REDEEM-1, REDEEM-2 and RENEW clinical trials of BCX9930 while it evaluated increased serum creatinine levels observed in some patients. Patients already enrolled were continuing. The drug is an oral Factor D inhibitor to treat complement-mediated diseases. 

REDEEM-1 is evaluating the drug alone in PNH patients with inadequate response to a C5 inhibitor. REDEEM-2 is studying it alone in PNH patients not currently receiving complement inhibitor therapy. RENEW is evaluating the drug in patients with either C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or primary membranous nephropathy (PMN).

The company reported the FDA had placed a partial clinical hold, which means BioCryst cannot enroll new patients, although patients already enrolled who appear to be receiving clinical benefit from the treatment and who have no other options can continue to be dosed.

BioCryst has found that three patients with PNH (paroxysmal nocturnal hemoglobinuria) in the REDEEM trials who received BCX9930 had early-onset, and moderate or severe, elevations in serum creatinine after receiving 500 mg twice a day for several weeks. Two of the patients were taken off therapy, while one, who had the lowest serum creatinine increase, is continuing treatment. About one-third of patients receiving the drug in the REDEEM studies had early increases in serum creatinine. And about 40% of patients in the long-term extension of the proof-of-concept trial, after switching to a 500 mg twice-daily dose, had a slowly evolving, late-onset, mild to moderate serum creatinine increase. It wasn't observed at lower doses.

"As we complete our investigation, we will continue to be comprehensive and deliberate, with a primary focus on patient safety," said Dr. William Sheridan, M.D., BioCryst's chief medical officer.

Otherwise, the focus was on Orladeyo (berotralstat), a once-daily therapy for the prevention of hereditary angioedema (HAE) attacks. The drug's net revenue for the first quarter was $49.7 million. About half of patients currently on the drug have switched from another prophylactic treatment, half of which were on lanadelumab, Takeda's Takhzyro.

"We are very pleased that strong patient demand continued to drive growth in the first quarter and overcome the traditional Q1 reimbursement headwinds," said Charlie Gayer, BioCryst's chief commercial officer. "With outstanding reimbursement in place, patients continuing to enjoy an excellent experience on Orladeyo and the expansion of both our new and existing prescriber bases, we expect steady growth throughout the remainder of 2022 as we achieve no less than $250 million in Orladeyo net revenues for the year."

The drug has also been launched in Denmark, France, Germany, Japan, Norway, Sweden, the United Arab Emirates and the United Kingdom.

Total revenues for the quarter were $49.9 million, up from $19.1 million in the previous year. The quarter's research and development expenses rose to $65.4 million from $42.4 million in the same period in 2021, primarily due to investment in its Factor D program, including BCX9930. Net loss for the quarter was $74.2 million, or $0.40 per share. The company reported as of March 31 that it has $446.8 million in cash, cash equivalents, restricted cash and investments. Cash spent on operations for the quarter was $71.0 million.

Investors, likely concerned about the clinical hold, weren't enthused, with shares down 9% in premarket trading.

Jon Stonehouse, president and chief executive officer of BioCryst, stated, "We are now over a year into the Orladeyo launch and are excited to see strong and continuing patient demand and steady expansion in our prescriber base among both new and existing prescribers. These trends continued in the first quarter of 2022 and reinforce our confidence that we will achieve no less than $250 million in new Orladeyo revenue in 2022 and peak Orladeyo sales of $1 billion."

https://www.biospace.com/article/as-part-of-q1-conference-call-biocryst-announces-fda-partial-clinical-hold-/

Context Therapeutics Targets Progesterone to Outsmart Tumors in Women’s Cancers

 A lot of companies are developing therapies targeting women’s cancers – breast, ovarian and endometrial – but none of them are curative beyond, perhaps, early-stage diagnoses. Even if the tumor is removed, it recurs in 5-10% of patients. One of the reasons is that tumors become non-responsive to estrogen-based approaches over time.

Context Therapeutics is addressing that gap by targeting progesterone receptors. Its pipeline, therefore, targets those receptors specifically for hormone-driven female cancers.

“Estrogen and progesterone are the drivers for about 70% of breast, ovarian and endometrial cancer patients. The industry has had great estrogen blockers for 30 or 40 years, but hasn’t yet developed a progesterone blocker,” Martin Lehr, co-founder and CEO, told BioSpace. That’s a problem, he explained, because “Cancer cells are very smart. If you block estrogen, they will make progesterone and will activate other signaling pathways to promote their survival.

“Progesterone is strongly immunosuppressive, which makes the tumors inherently cold and unresponsive to immunotherapies. Our collaborators at the University of Kansas Cancer Center showed at the American Association of Cancer Research (AACR) 2022 annual meeting that when you block the progesterone receptor, you potentially can turn the tumors from cold to hot,” Lehr said.

Courtesy of Context Therapeutics

Context Therapeutics’ lead compound, onapristone extended release (ONA-XR), is an oral progesterone receptor antagonist that is taken twice daily. ONA-XR prevents interaction between progesterone and its receptor, downregulates cancer stem cell mobilization and blocks immune evasion. Basically, it primes the cancer cells to be more responsive to combination therapy and to anti-hormonal therapy.

Phase Ib/II and Phase II trials are underway involving ONA-XR for:

• first-line metastatic breast cancer
• second-line metastatic breast cancer
• granulosa cell tumor in ovarian cancer (which has FDA Fast Track designation)
• recurrent endometrial cancer

Updates for each program are expected this year. Biomarkers are used for patient selection. “If a patient has the progesterone receptor, there is a better chance she will respond to this drug,” Lehr said.

ONA-XR data presented at AACR by Lauryn Werner, M.D./Ph.D. candidate showed nearly complete inhibition of progesterone-positive mammary gland tumors. At day 25 post-administration, tumor volume was near zero compared to a volume exceeding 150 cubic millimeters for placebo-treated subjects. Werner noted that depletion of T cells decreased the efficacy of ONA-XR, underscoring the role of the progesterone receptor in immune regulation.

Other data at AACR highlighted an immuno-oncology approach involving the CDK4/6 inhibitor and the progesterone receptor, which suggest another way to use ONA-XR.

That study, presented by Elisabetta Marangoni, Ph.D. from Institut Curie, indicated that the combination of fulvestrant, ONA-XR and palbociclib decreased tumor volume. When ONA-XR was administered alone, or when fulvestrant and palbociclib were administered in combination, however, tumor volume grew. Therefore, she concluded, “The triple combination decreased the interaction between progesterone receptors and estrogen receptors, down-regulated estrogen response and proliferation genes, and upregulated genes involved in cell death, interferon responses, Kirsten rat sarcoma virus (KRAS), tumor necrosis factor alpha (TNFα) and signal transducer and activator of transcription 3 or 5 (STAT3/5) signaling.”

ONA-XR also has the potential to be combined with selective estrogen receptor degraders or PI3Kα inhibitors.

“We’re also interested in bi-specific antibodies,” Lehr said. The company is developing an anti-claudin 6 x anti-CD3 bispecific monoclonal antibody known as CLDN6xCD3 bsAb. Currently in the preclinical stage, the goal of the program is to redirect T-cell mediated lysis toward malignant cells that express claudin 6.

“CD3 is a well-known T-cell engager that has wonderful efficacy, and clinicians are doing a much better job of managing its toxicity,” Lehr said, but, “Claudin 6 is a totally new target.” As an oncofetal protein, it is required for fetal development but is transcriptionally repressed at birth. “It is highly enriched in gynecologic cancers and, to a lesser extent, in testicular, lung and gastric cancers. It is a unique, cancer-only target.”

The challenge, however, is that claudin 6 is part of a family of about two dozen claudin proteins that Lehr said “are reasonably widely expressed” throughout our bodies. Inhibiting them causes significant toxicities, such as lipase activation “which is a hallmark of pancreatic stress and a precursor to pancreatitis. Our task, therefore, is to thread the needle.

“Selectivity is extremely important,” he said. Therefore, the claudin 6 binding arm Context Therapeutics designed is more than 100 times more selective for that antibody than for claudin 9 (which is expressed in the gut and ears), and possibly 10 times more selective than competing anti-claudin 6 therapeutics.

Other companies are also developing therapeutics targeting claudin 6. BioNTech, for example, is combining CAR T therapy with mRNA. The company reported an overall 43% response rate and a disease control rate of 86% in initial trials reported at the recent AACR annual meeting. That work further validated the claudin 6 target for Context Therapeutics.

Lehr’s goal, he said, is to build Context Therapeutics into “a strong, independent biotech company that is focused preclinical through Phase II projects, and that has a scalable team and infrastructure.”

“We don’t need a huge research team, because there’s more than enough good science to bring in, and we don’t need a huge commercial sales force because we can (hopefully) partner with large pharma.” It’s even comfortably funded. After going public last October, the company raised approximately $60 million in Q4 2021. “That gives us cash into 2024,” Lehr said.

To execute, he said, “We just need a well-oiled machine to focus on the middle area of drug development.”

https://www.biospace.com/article/context-therapeutics-is-targeting-progesterone-to-outsmart-tumors-in-women-s-cancers-/

Report: Porcine Virus May Have Killed Heart Transplant Patient

 New light may have been shed on the death of a man who died two months after his heart was replaced with that of a pig. New research indicates the heart that David Bennet received was infected with porcine cytomegalovirus, a virus that can cause respiratory and pregnancy complications in pigs.

First reported by MIT Technology Review, the porcine virus has been linked to previous transplant issues. Physicians who have been examining the case of why the transplant failed suggest that Bennet’s death could have been prevented if the virus had been detected. Although porcine cytomegalovirus is not thought to infect humans, previous research on transplanted porcine organs has shown that some organs that were transplanted into baboons and later discovered to have the virus failed.

The pig heart that Bennet received had been genetically altered by Revivicor, a company owned by Maryland-based United Therapeutics. The pig heart had undergone genetic modifications before its birth. It had 10 genes modified to make it a candidate for a potential heart transplant. As BioSpace previously reported, three genes that were likely to trigger a human immune response that would reject the heart were “turned off.” Also, six human genes were added to the pig in order to prevent blood from coagulating in the heart, improve compatibility and further reduce rejection.

Additionally, the pig was also modified to prevent typical growth. At one year old, a pig can weigh about 450 pounds. The gene-edited pig only weighed about 240 pounds when its heart was removed. This modification was made to prevent the animal’s heart from growing too large to be used in a human.

Following his transplant, Bennett was doing well for weeks and there was no sign of rejection. He spent time with his family and participated in physical therapy to help regain strength. However, about two months after the procedure, he took a turn for the worse and ultimately succumbed.

According to the new report, previous xenotransplantation research has shown that pig organs that were discovered to have the porcine cytomegalovirus that was implanted in baboons did not last long. It has been speculated that the immune suppression that occurs in the patient that receives the transplanted organ is unable to keep the virus in check. Also, it is thought that once the organ has been removed from the pig, the virus that may have been under control from a pig’s own natural antibodies is also free to continue infecting cells, Jay Fishman, a specialist in transplant infections at Massachusetts General Hospital, explained to MIT Technology Review.

Joachim Denner of the Institute of Virology at the Free University of Berlin, who conducted some of the early research into how the virus caused the failures in baboon patients, noted that the porcine cytomegalovirus is difficult to detect. However, he speculated that if more thorough testing is done to ensure the latent virus is not found in a pig being genetically altered to provide organs for humans, there is no reason to think that a patient like Bennett could not see sustained life in the future.

While the virus appears to be a likely culprit, Denner added that Bennett himself had been quite ill for a long time and there could be other contributing factors to his death. With Bennett's own heart failing, the transplant was the only thing that could prolong his life.

https://www.biospace.com/article/report-porcine-virus-may-have-killed-heart-transplant-patient/