FDA Approves Klisyri (tirbanibulin) for the Treatment of Actinic Keratosis on the Face or Scalp

Athenex, Inc., (NASDAQ: ATNX), a global biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies for the treatment of cancer and related conditions,   announced  the U.S. Food and Drug Administration (FDA)   approval of Klisyri (tirbanibulin) for the topical treatment of actinic keratosis (AK) on the face or scalp. Klisyri is the first FDA approved branded proprietary product for Athenex and will be launched in partnership with Almirall in the U.S. during the first quarter of 2021. Klisyri will be manufactured by Athenex, highlighting the vertically integrated capabilities of the company ranging from a preclinical lead to a developed product for market launch.

“The FDA approval of Klisyri is a significant milestone for Athenex. Klisyri is a home-grown product discovered and characterized by Athenex scientists and developed from pre-IND to NDA by the Athenex team. We are extremely proud of our team’s excellent execution,” said Dr. Johnson Lau, Chairman and Chief Executive Officer of Athenex. “Approval demonstrates our ability to execute upon the entirety of the drug development and registration process. We are excited to partner with Almirall to bring this first-in-class microtubule inhibitor to patients with actinic keratosis in the US.”

Dr. Rudolf Kwan, Chief Medical Officer of Athenex added, “The FDA approval of tirbanibulin ointment represents a first-in-class microtubule inhibitor for the treatment of actinic keratosis. We believe this small molecule platform has the potential beyond actinic keratosis and are leveraging the platform to develop therapies for other oncology indications.”

Mr. Peter Guenter, CEO of Almirall, stated, “We are delighted to partner with Athenex to market Klisyri in the U.S. and in Europe. This approval from the FDA represents a new option for Dermatologists and marks an important further step for Actinic Keratosis patients. What makes this new therapy particularly exciting is the 5-day course of treatment and its good tolerability. We look forward to the launch of Klisyri in the US in the first quarter of 2021.”

The FDA approved Klisyri based on the data from two pivotal, randomized, double-blind, vehicle-controlled Phase III studies (KX01-AK-003 and KX01-AK-004) that evaluated the efficacy and safety of Klisyri (tirbanibulin) ointment 1% in 702 adults with actinic keratosis of the face or scalp. Tirbanibulin demonstrated complete clearance of actinic keratosis lesions at day 57 in treated face or scalp areas in a significantly higher number of patients compared to vehicle. The most common adverse events were application site pruritus and pain reported by 9% and 10% of treated patients, respectively.

Actinic keratosis is a pre-cancerous skin lesion and is the second most common diagnosis made by dermatologists in the United States. If left untreated, 10-15% of AK lesions will develop into skin cancers.

Athenex has partnered with Almirall (Almirall, S.A., BME: ALM) to market Klisyri for the treatment of actinic keratosis on the face or scalp in the US and EU (including Russia) markets. In addition to the partnership with Almirall, Athenex has partnered with PharmaEssentia (6446.TWO) for actinic keratosis in Taiwan and has partnered with Xiangxue Pharmaceuticals (SHE:300147) for actinic keratosis in China, Hong Kong, and Macau.

https://en.wikipedia.org/wiki/Tirbanibulin

FDA Approves Klisyri (tirbanibulin) for the Treatment of Actinic Keratosis on the Face or Scalp

FDA Approves Orgovyx (relugolix) as the First Oral Gonadotropin-Releasing Hormone (GnRH) Receptor Antagonist for Advanced Prostate Cancer

Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, today announced that the U.S. Food and Drug Administration (FDA) has approved Orgovyx (relugolix) for the treatment of adult patients with advanced prostate cancer. Orgovyx, which was granted Priority Review by the FDA, is the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist for men with advanced prostate cancer. The approval is based on efficacy and safety data from the Phase 3 HERO study of Orgovyx in men with advanced prostate cancer. Orgovyx is expected to be available in January 2021.

“I am enormously pleased by the approval of Orgovyx and believe it has the potential to usher in a new standard of care for men with prostate cancer requiring androgen deprivation therapy,” said Neal Shore, M.D., medical director of the Carolina Urologic Research Center and HERO program steering committee member. “For the first time, we now have a once-daily oral treatment that effectively and rapidly suppresses testosterone, with a safety analysis showing a lower incidence of major adverse cardiovascular events compared to leuprolide injections, the current standard of care, as evaluated in the Phase 3 HERO study. The COVID-19 pandemic has heightened the importance of oral treatments as men with prostate cancer continue to experience difficulties and risks traveling to receive injections.”

“Prostate cancer is a very personal journey, but a universal truth is that those of us living with this disease want better treatments and options. That is why the approval of Orgovyx is such an exciting milestone that brings a long-awaited oral treatment option to men with advanced prostate cancer,” said Thomas Farrington, president and founder of the Prostate Health Education Network. “It is so important for men to speak with their doctor and explore what treatment is right for them as they focus on their overall health.”

“With the approval of Orgovyx, men with advanced prostate cancer now have a new oral treatment option that has demonstrated robust efficacy and safety, all with one pill taken once-a-day,” said Lynn Seely, M.D., chief executive officer of Myovant Sciences, Inc. “We have successfully built our commercial capabilities to bring this newly approved treatment to the urologists and oncologists who care for men with advanced prostate cancer, with the goal of establishing Orgovyx as the new standard of care. We are incredibly grateful to the men and investigators who participated in the HERO study and to the FDA for expediting the review and approval of Orgovyx through its Priority Review pathway.”

In the Phase 3 HERO study, Orgovyx met the primary endpoint and achieved sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks in 96.7% (95% confidence interval [CI]: 94.9-97.9) of men, compared with 88.8% (95% CI: 84.6-91.8) of men receiving leuprolide acetate injections, the current standard of care. Orgovyx also achieved several key secondary endpoints compared to leuprolide acetate, including suppression of testosterone to castrate levels at Day 4 and Day 15 (56% versus 0% and 99% versus 12%, respectively) and profound suppression of testosterone (< 20 ng/dL) at Day 15 (78% versus 1%). Orgovyx lowered prostate-specific antigen (PSA), on average, by 65% at Day 15 and by 83% at Day 29. In a substudy, 55% of men treated with Orgovyx achieved normal testosterone levels (> 280 ng/dL) or returned to baseline within 90 days of treatment discontinuation. The most frequent adverse events reported in at least 10% of men in the Orgovyx group were hot flush, musculoskeletal pain, fatigue, constipation, and mild to moderate diarrhea. The HERO data were previously presented in an oral presentation at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, with simultaneous publication in the New England Journal of Medicine.

https://en.wikipedia.org/wiki/Relugolix

FDA Approves Orgovyx (relugolix) as the First Oral Gonadotropin-Releasing Hormone (GnRH) Receptor Antagonist for Advanced Prostate Cancer

FDA Approves Gemtesa (vibegron) Tablets for the Treatment of Patients with Overactive Bladder (OAB)

Urovant Sciences (Nasdaq: UROV) announced    the U.S. Food and Drug Administration (FDA)  approval of  the New Drug Application (NDA) for once-daily 75 mg Gemtesa (vibegron), a beta-3 adrenergic receptor (β3) agonist, for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence (UUI), urgency, and urinary frequency in adults. This approval marks the first new oral branded OAB medication approved by the FDA since 2012, and it is the first product approval for Urovant Sciences.

“The FDA’s approval of Gemtesa is an important milestone for the tens of millions of patients living with overactive bladder and for Urovant, as it is our first drug approval. We look forward to launching Gemtesa in the coming months and believe that it will provide a compelling alternative for the many patients suffering from the burden of an overactive bladder. We also remain committed to bringing more new therapies to market that address unmet medical needs of patients suffering from urologic diseases,” said Jim Robinson, president and chief executive officer of Urovant Sciences.

“The clinical data for once-daily 75 mg Gemtesa demonstrated clear efficacy on the key symptoms of OAB by reducing urinary frequency, urge urinary incontinence, and urgency. In addition, data specifically showing reduction in urgency episodes are included in the Prescribing Information of Gemtesa, which is unique among currently-available OAB treatments. Urgency episode reduction data are particularly relevant for OAB patients and their health care providers, as they show Gemtesa’s direct impact on a hallmark symptom of the condition,” said Cornelia Haag-Molkenteller, M.D., Ph.D., chief medical officer of Urovant Sciences. “By successfully treating clinical symptoms, Gemtesa may allow patients to overcome the devastating impact that OAB can have on their daily lives.”

Gemtesa is an oral, once-daily tablet containing 75 mg of vibegron, a small-molecule β3 agonist which helps relax the detrusor bladder muscle so that the bladder can hold more urine, thereby reducing symptoms of OAB.

“Gemtesa is the first beta 3-agonist available as a once-daily pill which does not require dose titration,” said David Staskin, MD, clinical trial investigator and a leading urologist with St. Elizabeth’s Medical Center in Boston. “Notably, Gemtesa did not have any increase in the adverse event of hypertension compared to placebo in the key EMPOWUR study and has no interactions with medications metabolized by CYP2D6, which is important since many common medications are metabolized by CYP2D6.”

The FDA’s approval is based on results from an extensive development program involving more than 4,000 OAB patients, including the 12-week double blind, placebo-controlled Phase 3 EMPOWUR study with a dose of 75 mg and the double blind EMPOWUR long term extension study.1 These data show that treatment with Gemtesa resulted in statistically significant reductions in daily UUI, micturitions, and urgency episodes and an increase in the volume voided when compared to placebo in EMPOWUR.

The most common adverse reactions of Gemtesa from the double blind, placebo-controlled EMPOWUR study in ≥2% of patients were headache, nasopharyngitis, diarrhea, nausea, and upper respiratory tract infection. Gemtesa demonstrated the same rates for the adverse events of hypertension and increased blood pressure as placebo.

https://en.wikipedia.org/wiki/Vibegron

FDA Approves Gemtesa (vibegron) Tablets for the Treatment of Patients with Overactive Bladder (OAB)

FDA Approves Orladeyo (berotralstat) as the First Oral, Once-Daily Therapy to Prevent Attacks in Hereditary Angioedema Patients

BioCryst Pharmaceuticals, Inc. (Nasdaq: BCRX)  announced the U.S. Food and Drug Administration (FDA) approval of  oral, once-daily Orladeyo (berotralstat) for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older.

“Orladeyo offers people with HAE and their physicians the first orally administered non-steroidal option for preventing HAE attacks and represents an important and welcome step in making more treatment options available to physicians and patients,” said Anthony J. Castaldo, president and chief executive officer of the US Hereditary Angioedema Association (HAEA). 

In the pivotal Phase 3 APeX-2 trial, Orladeyo significantly reduced attacks at 24 weeks, and this reduction was sustained through 48 weeks. HAE patients who completed 48 weeks of treatment (150 mg) saw reductions in their HAE attack rates, from a mean of 2.9 attacks per month at baseline to a mean of 1.0 attacks per month after 48 weeks of therapy. In the long-term open label APeX-S trial, patients completing 48 weeks of therapy (150 mg) had a mean attack rate of 0.8 attacks per month.

Orladeyo was safe and well tolerated in both trials. The most frequently reported adverse reactions in patients receiving Orladeyo compared with placebo were gastrointestinal reactions. These reactions generally occurred early after initiation of treatment with Orladeyo, became less frequent with time and typically self-resolved.

“Patients and physicians acknowledge that HAE treatments can add a burden to patients’ lives.  As an oral, once-daily option, Orladeyo can provide significant attack reduction and lessen the burden associated with injections and infusions,” said Marc Riedl, M.D., professor of medicine and clinical director, U.S. Hereditary Angioedema Association Center at the University of California, San Diego, and an investigator in the APeX-2 trial.

“With this new treatment option, physicians and patients can continue to have collaborative discussions to choose the treatment that meets each patient’s needs, life circumstances and preferences,” Riedl added.

HAE patients note a significant treatment burden associated with existing prophylactic therapy. In addition to reducing HAE attack rate, data from APeX-2 show that patients reported meaningful improvements in both quality of life and overall patient-reported satisfaction, and significant reductions in their monthly use of standard of care on-demand medicine, while taking oral, once-daily Orladeyo (150 mg).2,3

“The FDA approval of Orladeyo fulfills a promise BioCryst made to HAE patients that we were committed to helping them achieve the dream of an oral, once-daily medicine to prevent and reduce the burden of their attacks,” said Jon Stonehouse, president and chief executive officer of BioCryst.

“Thank you to the HAE patients who participated in our clinical trials, to the investigators around the world who conducted these trials, to the HAEA for their patient advocacy and to our employees who never forgot that patients were waiting. We will stay focused on enabling access and providing personalized support to HAE patients and physicians,” Stonehouse added.

https://en.wikipedia.org/wiki/Berotralsta

FDA Approves Orladeyo (berotralstat) as the First Oral, Once-Daily Therapy to Prevent Attacks in Hereditary Angioedema Patients

Oral Azacitidine Benefits Some Older Adults With AML

In continuation of my update on azacitidine 

For older patients with acute myeloid leukemia (AML) who are in remission after chemotherapy, those receiving maintenance therapy with the oral formulation of azacitidine (CC-486) versus placebo had longer overall and relapse-free survival, according to a study published in the Dec. 24 issue of the New England Journal of Medicine.

Andrew H. Wei, M.B., B.S., Ph.D., from Monash University in Melbourne, Australia, and colleagues conducted a phase 3 randomized trial of CC-486 as maintenance therapy for patients with AML in first remission after intensive chemotherapy. A total of 472 patients aged 55 years and older who were in complete remission and were not candidates for hematopoietic stem cell transplantation were randomly assigned to receive either CC-486 or placebo once daily for 14 days per 28-day cycle (238 and 234 patients, respectively).

The researchers observed significantly longer median overall survival from the time of randomization with CC-486 versus placebo (24.7 versus 14.8 months). The corresponding median relapse-free survival was also significantly longer (10.2 versus 4.8 months). In most subgroups defined according to baseline characteristics, similar benefits of CC-486 were seen with respect to overall and relapse-free survival. During CC-486 treatment, overall health-related quality of life was preserved.

"Despite demonstrable survival advantages with CC-486 maintenance therapy, the risk of eventual relapse and death from AML remains problematic," the authors write. "Whether CC-486 may benefit patients with AML when it is used in other clinical contexts requires further investigation."

The study was funded by Celgene (a wholly owned subsidiary of Bristol Myers Squibb), which manufactures azacitidine.

https://en.wikipedia.org/wiki/Azacitidine

Oral Azacitidine Benefits Some Older Adults With AML 

Drug discovery study identifies promising new compound to open constricted airways

Despite the progress made in managing asthma and chronic obstructive pulmonary disease (COPD), poorly controlled symptoms for both respiratory diseases can lead to severe shortness of breath, hospitalizations or even death.

"Only about 50 percent of asthmatics, and an even lower percentage of people with COPD, achieve adequate control of lung inflammation and airway constriction with currently available medications," said Stephen Liggett, MD, vice dean for research at the University of South Florida Morsani College of Medicine and a USF Health professor of medicine, molecular pharmacology and physiology, and biomedical engineering. "So, we're clearly missing something from our drug armamentarium to help all these patients."

Dr. Liggett's laboratory has discovered several subtypes of bitter taste receptors (TAS2Rs) -- G protein-coupled receptors expressed on human smooth airway muscle cells deep inside the lungs. In asthma and COPD, tightening of smooth muscles surrounding bronchial tubes narrows the airway and reduces air flow, and Dr Liggett's lab found that these taste receptors open the airway when activated. They are now looking for new drugs to treat asthma and other obstructive lung diseases by targeting smooth muscle TAS2Rs to open constricted airways.

A promising bronchodilator agonist rises to the top

In a preclinical study published Nov. 5 in ACS Pharmacology and Translational Science, Dr. Liggett and colleagues identified and characterized 18 new compounds (agonists) that activate bitter taste receptor subtype TAS2R5 to promote relaxation (dilation) of human airway smooth muscle cells. The cross-disciplinary team found 1,10 phenanthroline-5,6-dione (T5-8 for short) to be the most promising of several lead compounds (drug candidates). T5-8 was 1,000 times more potent than some of the other compounds tested, and it demonstrated marked effectiveness in human airway smooth muscle cells grown in the laboratory.

For this drug discovery project, Dr. Liggett's laboratory collaborated with Jim Leahy, PhD, professor and chair of chemistry at the USF College of Arts and Sciences, and Steven An, PhD, professor of pharmacology at the Rutgers Robert Wood Johnson Medical School.

In an extensive screening conducted previously, another research group identified only one compound that would bind to and specifically activate the TASR5 bitter taste receptor -- although apparently with limited effectiveness. Using this particular agonist (called T5-1 in the paper) as a starting point, the team relied on their collective disciplines to devise new activators, aiming for a much better drug profile for administration to humans.

"The two key questions we asked were: 'Is it possible to find a more potent agonist that activates this receptor?' and 'Is it feasible to deliver by inhalation given the potencies that we find?'" said Dr. Liggett, the paper's senior author. "T5-8 was the bronchodilator agonist that worked best. There were a few others that were very good as well, so we now have multiple potential new drugs to carry out the next steps."

The researchers developed screening techniques to determine just how potent and effective the 18 compounds were. A biochemical test assessed how well these new agonists activated TAS2R5 in airway smooth muscle cells isolated from non-asthmatic human donor lungs. Then, the researchers validated the effect on airway smooth muscle relaxation using a technique known as magnetic twisting cytometry, pioneered by Dr An.

"Team science" solves a structural problem

"The biggest challenge we faced was not having a 3-D crystal structure of TAS2R5, so we had no idea exactly how agonist T5-1 fit into this mysterious bitter taste receptor," Dr. Liggett said. "By merging our strength in receptors, pharmacology, physiology, and drug development, our team was able to make the breakthrough."

T5-8 was superior to all the other bronchodilator agonists screened, exhibiting a maximum relaxation response (50%) substantially greater than that of albuterol (27%). Albuterol belongs to the only class of direct bronchodilators (beta-2 agonists) available to treat wheezing and shortness of breath caused by asthma and COPD. However, this drug or its derivatives, often prescribed as a rescue inhaler, does not work for all patients and overuse has been linked to increased hospitalizations, Dr. Liggett said. "Having two distinct classes of drugs that work in different ways to open the airways would be an important step to help patients optimally control their symptoms."

The ACS Pharmacology paper highlights the importance of translational research in bridging the gap between laboratory discoveries and new therapies to improve human health, he added. "This study yielded a drug discovery that successfully meets most of the criteria needed to advance the compound toward its first trial as a potential first-in-class bronchodilator targeting airway receptor TAS2R5."

https://pubs.acs.org/doi/10.1021/acsptsci.0c00127

Drug discovery study identifies promising new compound to open constricted airways  

New drug form may help treat osteoporosis, calcium-related disorders

A novel form of a drug used to treat osteoporosis that comes with the potential for fewer side effects may provide a new option for patients.

The work is supported by the National Institutes of Health and is published in Biophysical Journal.

Purdue University innovators developed a stabilized form of human calcitonin, which is a peptide drug already used for people with osteoporosis. Researchers at Purdue created a prodrug form of the peptide hormone to increase its effectiveness as an osteoporosis treatment.

In humans, calcitonin is the hormone responsible for normal calcium homeostasis. When prescribed to osteoporosis patients, calcitonin inhibits bone resorption, resulting in increased bone mass.

Unfortunately, human calcitonin undergoes fibrillation in aqueous solution, leading to reduced efficacy when used as a therapeutic. As a substitute, osteoporosis patients are prescribed salmon calcitonin. It does not fibrillate as rapidly but suffers from low potency and the potential for several adverse side effects.

"The technology can help make these calcitonin drugs safer and more effective," said Elizabeth Topp, a Purdue professor of physical and industrial pharmacy. "Our approach will increase the therapeutic potential of human calcitonin, promising a more effective option to replace salmon calcitonin for osteoporosis and related disorders."

To decrease the fibrillation propensity and increase the therapeutic benefit of human calcitonin, Purdue researchers phosphorylated specific amino acid residues.

"Many promising new peptide drugs tend to form fibrils," Topp said. "This technology provides a way to stabilize them in a reversible way so that the stabilizing modification comes off when the drug is given to the patient."

New drug form may help treat osteoporosis, calcium-related disorders  

Sitagliptin Promising Addition for Preventing Acute GVHD

In continuation of my updates on sitagliptin 

For patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation, sitagliptin combined with tacrolimus and sirolimus results in a low incidence of grade II to IV acute graft-versus-host disease (GVHD) by day 100, according to a study published in the Jan. 7 issue of the New England Journal of Medicine.

Sherif S. Farag, M.D., Ph.D., from the Indiana University School of Medicine in Indianapolis, and colleagues conducted a phase 2 clinical trial to examine the reduction in incidence of grade II to IV acute GVHD from 30 percent to no more than 15 percent by day 100 with sitagliptin plus tacrolimus and sirolimus. Thirty-six patients received myeloablative conditioning followed by mobilized peripheral-blood stem cell transplants from matched related or unrelated donors.

The researchers found that by day 100, acute GVHD occurred in two of 36 patients. The incidence of grade II to IV GVHD and of grade III or IV GVHD was 5 and 3 percent, respectively. At one year, nonrelapse mortality was zero. The one-year cumulative incidence of relapse was 26 percent, and for chronic GVHD, it was 37 percent. At one year, GVHD-free, relapse-free survival was 46 percent. Toxic effects were similar to those seen in patients undergoing allogeneic stem cell transplantation.

"Inhibition of dipeptidyl peptidase 4 should be further investigated in randomized trials that compare sitagliptin with current standard GVHD prophylaxis regimens," the authors write.

https://en.wikipedia.org/wiki/Sitagliptin

Statins May Protect Heart From Chemo for Early Breast Cancer

In continuation of my update on statins 

For women with early breast cancer treated with anthracyclines, statin exposure is associated with a lower risk for hospital presentation for heart failure, according to a study published online Jan. 6 in the Journal of the American Heart Association.

Husam Abdel-Qadir, M.D., Ph.D., from the Women's College Hospital in Toronto, and colleagues conducted a retrospective cohort study involving women aged 66 years and older without prior heart failure who received anthracyclines or trastuzumab for newly diagnosed early breast cancer. Using propensity scores, statin-exposed and unexposed women were matched in a 1:1 ratio. Data were included for 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women.

The researchers found that the five-year cumulative incidence of heart failure hospital presentations after anthracyclines was 1.2 percent (95 percent confidence interval [CI], 0.5 to 2.6 percent) and 2.9 percent (95 percent CI, 1.7 to 4.6 percent) in statin-exposed and unexposed women, respectively (P = 0.01). In the anthracycline cohort, the cause-specific hazard ratio associated with statins was 0.45 (95 percent CI, 0.24 to 0.85; P = 0.01). The five-year cumulative incidence of heart failure hospital presentations after trastuzumab was 2.7 percent (95 percent CI, 1.2 to 5.2 percent) and 3.7 percent (95 percent CI, 2.0 to 6.2 percent) in statin-exposed and unexposed women, respectively (P = 0.09), with a cause-specific hazard ratio associated with statins of 0.46 (95 percent CI, 0.20 to 1.07; P = 0.07).

"This study does not conclusively prove statins are protective," Abdel-Qadir said in a statement. "However, this study builds on the body of evidence suggesting that they may have benefits."

Alzheimer's disease drug may help fight against antibiotic resistance

In continuation of my update on PBT2

Researchers from The University of Queensland, The University of Melbourne and Griffith University have discovered that the drug called PBT2 is effective at disrupting and killing a class of bacteria -- known as Gram-negative bacteria -- that cause infections such as pneumonia, bloodstream infections and meningitis.

UQ's Professor Mark Walker said the metal transport drug may offer a last line of defence against some of the world's most difficult to treat superbugs.

"The emergence of antibiotic-resistant superbugs is an urgent threat to human health, undermining the capacity to treat patients with serious infection," Professor Walker said.

"Alternative strategies to treat such multi-drug resistant bacteria are urgently needed.

"Led by UQ's Dr David De Oliveira, our team hypothesised that, by using this experimental Alzheimer's treatment to disrupt the metals inside these bacteria, we would also disrupt their mechanisms of antibiotic resistance.

"This was shown to be the case, with the Alzheimer's drug -- combined with the antibiotic polymyxin -- successfully tackling antibiotic-resistant superbugs like Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli."

Griffith University's Professor Mark von Itzstein AO from the Institute for Glycomics said the new treatment was effective, and offered a range of other benefits.

"Based on its use as an experimental Alzheimer's treatment, there's been a significant amount of solid science done on this drug already," Professor von Itzstein said.

"We know, for example, that clinical studies of PBT2 show that it is safe for use in humans.

"And, given that we've been able to combine it with the antibiotic polymyxin to treat polymyxin-resistant bacteria, we may be able to make other now-ineffective antibiotics become effective again for treating infectious diseases.

"This could resharpen, so to speak, some of the weapons we thought we'd lost in our fight against antibiotic-resistant bacteria."

The University of Melbourne's Associate Professor Christopher McDevitt, from the Peter Doherty Institute for Infection and Immunity (Doherty Institute), said the drug had already proved effective beyond the petri dish.

"Animal studies show that the combination of polymyxin and PBT2 kills polymyxin-resistant bacteria, completely clearing any infection," Associate Professor McDevitt said.

"Hopefully in the not-too-distant future people will be able to access this type of treatment in the clinic.

"New techniques are critical in addressing this building threat to human health, and this treatment is an additional weapon in our arsenal to fight the accelerating threat of antibiotic resistance.

"If these new solutions aren't developed, it's estimated that by 2050, antimicrobial-resistant bacteria will account for more than 10 million deaths per year.

"This new treatment could help turn the tide on antibiotic resistance."

https://en.wikipedia.org/wiki/PBT2

Lorlatinib Superior to Crizotinib for ALK-Positive NSCLC

In continuation of my update on lorlatinib and  crizotinib

                                                                 lorlatinib

                                                               crizotinib

Among patients with previously untreated advanced ALK-positive non-small cell lung cancer (NSCLC), progression-free survival is significantly longer for those who receive first-line therapy with lorlatinib versus crizotinib, according to a study published in the Nov. 19 issue of the New England Journal of Medicine.

Alice T. Shaw, M.D., Ph.D., from the Massachusetts General Hospital Cancer Center in Boston, and colleagues conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who were previously untreated for metastatic disease.

The researchers found that 78 and 39 percent of patients in the lorlatinib group and crizotinib group, respectively, were alive without disease progression at 12 months (hazard ratio for disease progression or death, 0.28). An objective response occurred in 76 and 58 percent of those in the lorlatinib and crizotinib groups, respectively. Among those with measurable brain metastases, an intracranial response occurred in 82 and 23 percent, respectively; an intracranial complete response occurred in 71 percent of those who received lorlatinib. Hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects were the most common adverse events associated with lorlatinib. Compared with crizotinib, lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels; 72 versus 56 percent).

"Among patients with previously untreated, advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival, a higher overall and intracranial response, and better quality of life than those who received crizotinib," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Pfizer, which manufactures lorlatinib and funded the study.

https://en.wikipedia.org/wiki/Lorlatinib

https://en.wikipedia.org/wiki/Crizotinib

New effective and safe antifungal isolated from sea squirt microbiome

The new molecule was discovered in the microbiome of a sea squirt from the Florida Keys as part of an effort to identify novel antimicrobials from understudied ecosystems. Scientists named the antifungal turbinmicin, after the sea squirt from which it was isolated, Ecteinascidia turbinate.

Disease-causing fungi continue to evolve resistance to the small number of drugs available to thwart them. As a result, more people are dying from previously treatable diseases, such as candidiasis or aspergillosis, which are caused by common fungi that sometimes turn virulent. Identifying compounds like turbinmicin is key to developing new and effective drugs. However, while turbinmicin is a promising drug candidate, additional study of the molecule and extensive preclinical research must be performed before a new drug can become available.

A collaboration of chemists, biologists, and physicians from UW-Madison published their findings Nov. 19 in the journal Science. The discovery of turbinmicin is the most tangible output yet of the group's five-year, $30 million grant from the National Institutes of Health to glean useful new antimicrobial drugs from bacteria living in overlooked environments.

The majority of existing antimicrobials were isolated from soil-dwelling bacteria. As scientists continued probing these bacteria for new drugs, they often turned up the same molecules over and over again.

"Bacteria in particular are rich sources of molecules. But a lot of the terrestrial ecosystems have been pretty heavily mined for drug discovery," says Tim Bugni, a professor in the UW-Madison School of Pharmacy who led the turbinmicin project. "There's immense bacterial diversity in the marine environment and it's barely been investigated at all."

To correct for that oversight, Bugni partnered with UW School of Medicine and Public Health infectious disease professor David Andes, UW-Madison bacteriology professor Cameron Currie, and their colleagues to search neglected ecosystems. Specifically, they sought to discover novel bacteria from marine animals and then screen them for new kinds of antimicrobial compounds.

To identify turbinmicin, the research team began by collecting ocean-dwelling invertebrates from the Florida Keys between 2012 and 2016. From these animals, they identified and grew nearly 1,500 strains of actinobacteria, the same group of bacteria that has produced many clinical antibiotics. Using a screening method, they prioritized 174 strains to test against drug-resistant Candida, an increasingly prominent and dangerous disease-causing fungus. Turbinmicin stood out for its effectiveness.

"Candida auris in particular is pretty nasty," says Bugni. Nearly half of patients with systemic Candida infection die. "The Candida auris strain we targeted in this paper is resistant to all three classes" of existing antifungals.

The researchers tested purified turbinmicin against a slate of 39 fungi isolated from patients. These strains both represented diverse species and encompassed all the known ways that fungi have evolved resistance to existing drugs. In lab experiments, turbinmicin halted or killed nearly all fungal strains at low concentrations, indicating a potent effect.

Similar experiments in mice infected with drug-resistant strains of Candida auris and Aspergillus fumigatus also demonstrated turbinmicin's ability to attack resistant fungi. Because fungi and animals are closely related, and thus share similar cellular machinery, antifungals can prove toxic to animals as well. Yet, turbinmicin did not show toxic side effects in mice, even at concentrations 1000 times higher than the minimum dose. The effective dose would work out to tens of milligrams for an average-weight adult, less than for many other antibiotics.

Based on experiments in yeast led by UW-Madison genetics professor Anjon Audhya, turbinmicin appears to target the cellular packaging and organizational system of fungi. Turbinmicin blocks the action of the protein Sec14p, with the end result that yeast like Candida cannot bud to reproduce. Other kinds of fungi, when exposed to turbinmicin, may have a difficult time shuttling cellular contents around to grow.

The researchers have submitted a patent for turbinmicin and have now turned their attention to improving the molecule by making small alterations to its structure that could increase its effectiveness as a drug. The discovery of turbinmicin also serves as a proof-of-concept for the collaboration's efforts to explore new ecosystems and screen thousands of candidates to identify new, effective antimicrobial candidates.

"Now we have the tools to sort through candidates, find promising strains and produce molecules to do animal studies," says Bugni. "That's the key for targeting multi-drug resistance: you need unique molecules."

https://science.sciencemag.org/content/370/6519/974

Xofluza Approved for Postexposure Prevention of Flu

In continuation of my update on Baloxavir marboxil (BXM)

The approved indication for Xofluza (baloxavir marboxil) has been expanded to include postexposure prevention of influenza for those who may have come in contact with someone who has the flu, the U.S. Food and Drug Administration announced Monday.

Xofluza was approved in 2018 to treat uncomplicated flu in patients 12 years and older who are symptomatic for no more than two days. The drug was previously only available in a tablet form but is now available in granule form for mixing in water.

The expanded approval decision was based on data from the Phase III BLOCKSTONE study, a randomized, double-blind, controlled trial of 607 individuals ages 12 years and older who were exposed to a household member with the flu. Individuals were randomly assigned to receive either a single dose of Xofluza (303 individuals) or placebo (304 individuals). One percent of those who received Xofluza compared with 13 percent who received placebo were infected with influenza and presented with fever and at least one respiratory symptom over 10 days. These data were published in the New England Journal of Medicine in July.

The most commonly reported side effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

"This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic," Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA Center for Drug Evaluation and Research, said in an agency news release. "Americans will have to be more vigilant than ever as these viruses spread concurrently."

https://en.wikipedia.org/wiki/Baloxavir_marboxil

Researchers identify three drugs as possible therapeutics for COVID-19

In continuation of my update on Amodiaquine and nebivolol

amodiaquine

Zuclopenthixol

Nebivolol

Based on virtual and in vitro antiviral screening that began in the earlier months of the COVID-19 pandemic, the researchers led at UTHSC by Colleen Jonsson, PhD, identified zuclopenthixol, nebivolol, and amodiaquine as promising therapeutics for the virus in its early stages.

Dr. Jonsson is a professor and the Endowed Van Vleet Chair of Excellence in Virology in the College of Medicine at UTHSC. She also directs the UTHSC Regional Biocontainment Laboratory (RBL), where this research was conducted. The university's RBL is one of roughly a dozen federally funded labs authorized to safely study contagious pathogens.

In a paper published in ACS Pharmacology & Translational Science, the researchers propose the drugs as possible candidates for testing in future clinical trials to improve immune response to the virus. Amodiaquine is an older antimalarial, zuclopenthixol is an antipsychotic, and nebivolol is a blood pressure medication.

"Particularly in the context of this pandemic, there is a stringent need for high-quality studies that can provide critical knowledge concerning the COVID-19 disease and reliable treatment proposals," the paper states. "With these caveats in mind, we conceived a computational workflow that included independent in vitro validation, followed by assessing emerging candidates in the context of available clinical pharmacology data with the aim of proposing suitable candidates for clinical studies for early stage (incubation and symptomatic phases) patients infected by SARS-CoV-2."

"Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection," the researchers wrote.

Comparing the drugs to hydroxychloroquine, the anti-malarial drug most-frequently studied in clinical trials for use as a COVID-19 therapeutic, the researchers examined 4,000 approved drugs and found these three to act similarly to the hydroxychloroquine, and in some cases, more safely. The research indicates they may also improve efficacy when combined in lower doses with remdesivir, an anti-viral given an emergency use authorization by the United States Food and Drug Administration as a therapeutic for COVID-19.

"Think of it as a whack-a-mole game," said Tudor Oprea, MD, PhD, professor of Medicine and Pharmaceutical Sciences, chief of the UNM Division of Translational Informatics, and corresponding author on the paper. "Instead of having one hammer, you have two hammers, which is more effective. We're trying to give the scientific community two hammers, instead of one."

Dr. Jonsson added, "This is a very exciting discovery and we are following up on the potential use of zuclopenthixol, nebivolol, and amodiaquine in additional research studies."

https://en.wikipedia.org/wiki/Amodiaquine

https://en.wikipedia.org/wiki/Zuclopenthixol

https://en.wikipedia.org/wiki/Nebivolol

Researchers identify three drugs as possible therapeutics for COVID-19

FDA Approves Zokinvy (lonafarnib) for Hutchinson-Gilford Progeria Syndrome and Processing-Deficient Progeroid Laminopathies

Eiger BioPharmaceuticals, Inc. (Nasdaq:EIGR), focused on the development and commercialization of targeted therapies for serious rare and ultra-rare diseases, announced  the U.S. Food and Drug Administration (FDA)  approval of  Zokinvy (lonafarnib) for the treatment of Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria) and processing-deficient Progeroid Laminopathies (PL).  

Progeria and Progeroid Laminopathies are separate and distinct ultra-rare, genetic, premature aging diseases that accelerate mortality in young patients.  Disease manifestations include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular disease and stroke.  Untreated children with Progeria die of heart disease at an average age of 14.5 years.  There are 20 children and young adults with Progeria and PL identified and followed in the U.S.  

Zokinvy is a disease-modifying agent that has demonstrated a statistically significant survival benefit in children and young adults with Progeria.  In patients with Progeria, Zokinvy reduced the incidence of mortality by 60% (p=0.0064) and increased average survival time by 2.5 years.  The most commonly reported adverse reactions were gastrointestinal (vomiting, diarrhea, nausea), and most were mild or moderate (Grade 1 or 2) in severity.  Many Progeria patients have received continuous Zokinvy therapy for more than 10 years.

The increase in survival observed with Zokinvy was derived from two open-label clinical trials (N=62) conducted at Boston Children's Hospital.  The survival analysis compared Zokinvy-treated versus Zokinvy-naïve subjects with Progeria born in or after 1991, by age, gender, and geographic location. Zokinvy-naïve patients originated from a separate natural history study (n=81) conducted by The Progeria Research Foundation.

With this approval, the FDA issued a Rare Pediatric Disease Priority Review Voucher (PRV) to Eiger.  The Rare Pediatric Disease Priority Review Voucher program is designed to encourage development of new drugs and biologics for the prevention or treatment of rare pediatric diseases.  Eiger plans to sell the PRV and under the terms of the Collaboration and Supply Agreement with the Progeria Research Foundation (PRF) will share the proceeds equally with PRF.

"The FDA approval of Zokinvy is the result of a pioneering partnership between Eiger BioPharmaceuticals and PRF to bring the first approved therapy to children, young adults and families living with this devastating disease," said David Cory, President and CEO of Eiger.  "We are very proud that the first drug approval at Eiger confers a survival benefit to patients with one of the most ultra-rare, and ultimately fatal, pediatric diseases.  We are extremely grateful to all the children, young adults and their families who have made this possible through participation in the Zokinvy clinical trials."

"The approval of this breakthrough therapy is a critical milestone for the Progeria community and also for Eiger," said Thomas Dietz, PhD, Chairman of the Board at Eiger.  "The Eiger Board congratulates and commends the management team for their incredible dedication leading the company through its first NDA filing and approval, a major accomplishment for Eiger."

PRF Medical Director, Leslie Gordon, MD, PhD, added, "Shortly after our son, Sam, was diagnosed with Progeria, my family and I founded The Progeria Research Foundation to find the cause, treatments, and cure for all children with this fatal disease.  This first approved medication is a truly incredible milestone for the Progeria community as we forge ahead toward finding the cure.  We are thrilled to have Eiger as a partner in bringing Zokinvy to the approval finish line, and for their commitment to ensuring patient access to Zokinvy moving forward."

In support of the patient and healthcare provider community, Eiger is launching our dedicated service center, Eiger OneCare™.  This specialized team will offer personalized support, financial assistance, and access to Zokinvy, all designed for Progeria and processing-deficient Progeroid Laminopathy patients.  Eiger OneCare™ will be available Monday through Friday from 9 AM to 5 PM Eastern Time at 1-833-MYEIGER (1-833-693-4437).

https://en.wikipedia.org/wiki/Lonafarnib

FDA Approves Zokinvy (lonafarnib) for Hutchinson-Gilford Progeria Syndrome and Processing-Deficient Progeroid Laminopathies