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Wednesday, March 31, 2021

Brazilian hospital operator Care files for IPO

Brazilian hospital chain Care has filed for an initial public offering of roughly 790.5 million reais ($139.42 million), amid a dealmaking boom in Brazil's healthcare sector, according to a securities filing on Wednesday.

Care's plans for an IPO follows a raft of share offerings by hospital operators. Rede D'Or successfully concluded in December a 11.4 billion reais IPO and rivals such as Kora Saude Participacoes and Dasa are expected to conclude share offerings in the coming weeks.

Rising demand for services and an aging population have fueled deals in Brazil's healthcare sector, as Reuters reported earlier.

Hospital Care and its shareholders plan to sell at least 31 million shares between 22.50 reais and 28.50 reais. If overallotments are sold, the offering may increase by 35%. The price will be set on April 20.

The hospital operator has among its shareholders Brazilian private equity firm Crescera and Elie Horn, the founder of homebuilder Cyrela.

It operates 11 hospital, with 1,206 beds, and also sells healthcare plans, in a business model similar to Hapvida and Notre Dame Intermedica.

Itau BBA, BTG Pactual, Bank of America, XP, Safra and UBS BB will manage the offering.

J&J Says Covid-19 Vaccine Batch Didn't Meet Quality Standards

 Johnson & Johnson said one batch of its new Covid-19 vaccine didn't meet quality standards at a contract manufacturer, and the doses weren't distributed.

J&J said Wednesday the batch never advanced to the filling and finish stages of its manufacturing process, and that the quality lapse wouldn't affect its ability to supply the U.S. with 100 million doses by the end of May.

J&J didn't disclose the nature of the quality lapse or how many doses were affected, but said it arose from quality checks during the start-up phase of manufacturing. The company said it shared information about the issue with the U.S. Food and Drug Administration.

The FDA is investigating, according to a person familiar with the matter.

The New York Times reported Wednesday that the J&J doses were ruined due to an accidental mix-up of ingredients at Emergent BioSolutions Inc., the contract manufacturer working with J&J. The Times reported that about 15 million doses were ruined.

Emergent declined to comment.

J&J's vaccine was the third to be authorized for use against Covid-19, after shots from Pfizer Inc. and its partner BioNTech SE and from Moderna Inc. Health authorities especially welcomed the addition of the J&J vaccine because it requires just one dose and is easier to store.

Supplies in the U.S. were expected to increase as J&J's manufacturing network ramped up production, accelerating a mass vaccination campaign that has been gaining steam.

J&J said it is providing additional experts in manufacturing, technical operations and quality to be on-site at Emergent to oversee all manufacturing of the J&J vaccine there.

Emergent, a contract manufacturer based in Gaithersburg, Md., has been making the main ingredient for J&J's vaccine at an Emergent plant in Baltimore.

At the same plant, Emergent also makes the main ingredient for AstraZeneca PLC's Covid-19 vaccine, which hasn't yet been authorized for use in the U.S.

J&J's own plant in the Netherlands has been making the main ingredient for the initial U.S. supply of its vaccine -- including the nearly four million doses that were distributed immediately after it was authorized in late February.

J&J said it was able to meet a target of delivering a total of 20 million vaccine doses by the end of March. The company said it expects to deliver an additional 24 million doses in April, and plans to have delivered a total of 100 million by the end of May.

Innate immune deficiencies in patients with COVID-19

 Marine Peyneau, Vanessa Granger, Paul-Henri Wicky, Dounia Khelifi-Touhami, Jean-Francois Timsit, Francois-Xavier Lescure, Yazdan Yazdanpanah, Alexy Tran-Dihn, Philippe Montravers, Renato Monteiro, Sylvie Chollet-Martin, Margarita Hurtado-Nedelec, 

Luc de Chaisemartin

T Cells Recognize Recent SARS-CoV-2 Variants

 When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination. 

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response.  CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells. 

In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.    

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.  

AD Redd et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infectious Diseases DOI: 10.1093/ofid/ofab143 (2021).

Anthony S. Fauci, M.D., NIAID Director and Chief, Laboratory of Immunoregulation, is available to comment on this research. Dr. Andrew Redd, staff scientist in the Laboratory of Immunoregulation, is also available.

This work was supported in part by NIAID grants R01AI120938, R01AI120938S1 and R01AI128779 and by National Heart Lung and Blood Institute grant 1K23HL151826-01.

J&J Covid Vax Distribution Delayed by U.S. Factory Mix-up: NYT

 --A mix-up at a U.S. factory will delay distribution of the Johnson & Johnson Covid-19 vaccine, the New York Times reported.

--The NYT said that workers at the Baltimore plant had accidentally conflated the vaccine's ingredients weeks ago and ruined about 15 million doses of Johnson & Johnson's vaccine.

--The plant is run by Emergent BioSolutions, a manufacturing partner to Johnson & Johnson and AstraZeneca PLC, the NYT said.

--Johnson & Johnson vaccine doses currently being delivered and used nationwide were produced in the Netherlands and are not affected, the NYT reported, adding that all further shipments of the Johnson & Johnson vaccine were supposed to have come from the Baltimore plant and are now in question while the quality control issues are sorted out.

In after-hours trading, Johnson & Johnson shares were down 0.33% at $163.81, while Emergent Solutions' stock was down 4.85% at $88.40.

Experimental antibodies for Parkinson's, Alzheimer's may cause harmful inflammation

 A team led by scientists at Scripps Research has made a discovery suggesting that experimental antibody therapies for Parkinson's and Alzheimer's have an unintended adverse effect--brain inflammation--that may have to be countered if these treatments are to work as intended.

Experimental antibody treatments for Parkinson's target abnormal clumps of the protein alpha-synuclein, while experimental antibody treatments for Alzheimer's target abnormal clumps of amyloid beta protein. Despite promising results in mice, these potential treatments so far have not seen much success in clinical trials.

"Our findings provide a possible explanation for why antibody treatments have not yet succeeded against neurodegenerative diseases," says study co-senior author Stuart Lipton, MD, PhD, Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research.

Lipton, also a clinical neurologist, says the study marks the first time that researchers have examined antibody-induced brain inflammation in a human context. Prior research was conducted in mouse brains, whereas the current study used human brain cells.

The study will appear in the Proceedings of the National Academy of Sciences of the United States of America during the week of March 29.

An approach that may need tweaking

Neurodegenerative diseases such as Alzheimer's and Parkinson's afflict more than 6 million Americans. These diseases generally feature the spread of abnormal protein clusters in the brain, with different mixes of proteins predominating in different disorders.

An obvious treatment strategy, which pharmaceutical companies began to pursue in the 1990s, is to inject patients with antibodies that specifically target and clear these protein clusters, also called aggregates.

The aggregates have included not only the large clusters that pathologists observe in patients' brains at autopsy, but also the much smaller and harder-to-detect clusters called oligomers that are now widely considered the most harmful to the brain.

Exactly how these protein clusters damage brain cells is an area of active investigation, but inflammation is a likely contributing factor. In Alzheimer's, for example, amyloid beta oligomers are known to shift brain immune cells called microglia to an inflammatory state in which they can damage or kill healthy neurons nearby.

Surprise finding

Lipton and colleagues were studying alpha synuclein oligomers' ability to trigger this inflammatory state when they encountered a surprise finding: While the oligomers on their own triggered inflammation in microglia derived from human stem cells, adding therapeutic antibodies made this inflammation worse, not better. The team traced this effect not to the antibodies per se but to the complexes formed with antibodies and their alpha synuclein targets.

Amyloid beta aggregates often co-exist with the alpha synuclein aggregates seen in Parkinson's brains, just as alpha synuclein often co-exists with amyloid beta in Alzheimer's brains.

In the study, the researchers added amyloid beta oligomers to their mix, mimicking what would happen in a clinical case, and found that it worsened inflammation. Adding anti-amyloid beta antibodies worsened it even further. They found that both alpha synuclein antibodies and amyloid beta antibodies made inflammation worse when they successfully hit their oligomer targets.

Lipton notes that virtually all prior studies of the effects of experimental antibody treatments were done with mouse microglia, whereas the key experiments in this study were done with human-derived microglia--either in cell cultures or transplanted into the brains of mice whose immune system had been engineered to accommodate the human microglia.

"We see this inflammation in human microglia, but not in mouse microglia, and thus this massive inflammatory effect may have been overlooked in the past," Lipton says.

Microglial inflammation of the kind observed in the study, he adds, could conceivably reverse any benefit of antibody treatment in a patient without being clinically obvious.

Lipton says that he and his colleagues have recently developed an experimental drug that may be able to counter this inflammation and thereby restore any benefit of antibody treatment in the human brain. They are actively working on this now.


The lead author of the study was Dorit Truder, PhD, a postdoctoral fellow in the Lipton laboratory. Other senior authors were Rajesh Ambasudhan, PhD, an adjunct assistant professor at Scripps Research; Michael Karin, PhD, a professor at the UC San Diego School of Medicine; and Nicholas Schork, PhD, a professor at the Translational Genomics Institute in Phoenix and adjunct professor at UC San Diego and Scripps Research.

"Soluble α-synuclein/antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia" was co-authored by Dorit Trudler, Kristopher Nazor, Yvonne Eisele, Titas Grabauskas, Nima Dolatabadi, James Parker, Abdullah Sultan, Zhenyu Zhong, Marshal Goodwin, Yona Levites, Todd Golde, Jeffery Kelly, Michael Sierks, Nicholas Schork, Michael Karin, Rajesh Ambasudhan and Stuart Lipton.

The work was supported by the National Institutes of Health (R01 NS086890, RF1 AG057409, R01 AG056259, R01 DA048882, DP1 DA041722, R01 AI043477).

Aptevo Reports 2020 Results, Business Update

 Advances Phase 1/1b Study of APVO436 for Treatment of Acute Myeloid Leukemia and High-Grade Myelodysplastic Syndrome; Enrollment in Cohort 10 Ongoing

Completes Sale of RUXIENCE Royalty Payments for Up Front Plus Milestone Payments of up to $67.5 million; Amends Non-Dilutive Term Loan Agreement

FDA OKs Sanofi Sarclisa combo for relapsed or refractory multiple myeloma


  • Sarclisa regimen reduced risk of disease progression or death by 45% compared to standard of care in patients who had relapsed after one to three prior therapies

  • While the median progression free survival (PFS) for Sarclisa combination therapy is not yet reached, consistent improvement in PFS is seen across patient subgroups

  • This is the second FDA approval for Sarclisa in combination with standard of care backbone therapies

Mixed Results in Phase 1/2 of BioXcel Treatment for Opioid Withdrawal Symptoms

 BioXcel Therapeutics, Inc. (“BioXcel” or the “Company”) (NASDAQ: BTAI), a clinical-stage biopharmaceutical company utilizing artificial intelligence approaches to develop transformative medicines in neuroscience and immuno-oncology, today announced topline results from its Phase 1b/2 proof-of-concept RELEASE study of BXCL501, the Company’s proprietary, orally dissolving thin film formulation of dexmedetomidine, for the treatment of opioid withdrawal symptoms.

The study met its primary safety endpoint across multiple doses given twice-daily over seven days. BXCL501 was generally well tolerated, with no severe or serious adverse events reported, and dose dependent exposures were observed across all doses evaluated (30 mcg, 60 mcg, 90 mcg, 120 mcg, 180 mcg and 240 mcg).

With respect to retention, a secondary endpoint, the study showed that patients in multiple dose cohorts treated with BXCL501 had numerical improvements in retention rates, a key goal of opioid withdrawal treatment. The 120 mcg and 180 mcg dose groups showed 42% and 52% rates of retention at Day 6 of BXCL501 treatment, respectively, versus 24% for placebo, though observations were not statistically significant. The results also showed that of the 87% of patients who had fentanyl in their systems upon entry, greater than 50% remained fentanyl positive following the morphine stabilization phase of 5 days. Consequently, withdrawal symptoms were not equivalent across various dose cohorts indicating morphine did not normalize withdrawal symptoms. Improvements were not observed in the severity of opiate withdrawal as measured by the Short Opiate Withdrawal Scale of Gossop (“SOWS-Gossop”) or the Clinical Opiate Withdrawal Scale (“COWS”). The Company believes that the high fentanyl prevalence and lack of normalization observed in study subjects could have confounded these results and made them difficult to interpret.

“We’re encouraged that the RELEASE study helped us to identify a dose range that was generally well tolerated and resulted in numerical improvements in retention in this patient population," commented Reina Benabou, M.D., Ph.D., Senior Vice President & Chief Development Officer.  "We’ll continue to analyze these results in collaboration with our advisors regarding potential next steps for this important indication.”

Akebia tries for FDA approval of anemia drug after mixed data


  • Akebia Therapeutics is taking a chance on its closely watched pill for anemia, announcing Tuesday the submission of an application for approval to the Food and Drug Administration despite mixed study data disclosed last fall that lowered expectations for the drug. 
  • In two Phase 3 studies, Akebia's experimental drug matched the approved injection Aranesp in raising and sustaining hemoglobin levels among trial participants with anemia due to their chronic kidney disease. But the pill, called vadadustat, appeared worse than Aranesp on a measure of heart safety, with a greater risk of major adverse cardiovascular events. 
  • Akebia said then the company still intended to ask the FDA for approval, citing the totality of the data from those and other studies. But analysts who follow the company were more skeptical the drug could obtain a clearance for a broad patient population that includes both dialysis and non-dialysis patients. 

For several years now, Akebia has been chasing rival anemia drug developer Fibrogen, which appeared to be ahead in its development of a similar acting treatment and would-be competitor to vadadustat. 

Fibrogen applied for FDA approval last year, only to have a potential December decision delayed until March. Then, at the beginning of the month, the company and its investors were taken by surprise when the agency indicated it would call an advisory committee meeting to review Fibrogen's drug. 

At least twice before, Fibrogen claimed, the FDA had indicated it wouldn't convene a panel, making the last-minute communication an unexpected and potentially costly twist. No date has yet been set, and the FDA has now missed its March 20 goal. The company has not issued any update.

Now that Akebia has submitted its application, the FDA may seek to convene an advisory committee meeting covering both drugs, wrote Christopher Raymond, an analyst at Piper Sandler, in a note to clients. 

Both drugs are designed to replace current injectable therapies with a more convenient pill option. They are known as HIF-PH inhibitors and work by promoting red blood cell production in a way that mimics the body's response to low-oxygen environments.

Studies have shown both pills can match the efficacy of injectable drugs. But their safety, particularly for the heart, has become a key concern, especially following Akebia's results last year. Those findings could make the approval case for both drugs harder to regulators, given both are meant to be at least as safe, if not safer, than the injectable medicines like Aranesp that are already tied to potential heart problems. 

Akebia's submission came one to two months ahead of expectations, and the company indicated it did not include in its filing a priority review voucher. Such vouchers are a kind of a regulatory fast-pass and can be used to shorten FDA review times by four months. 

In early 2020, Akebia had struck a deal with partner Vifor Pharma to hold onto a voucher Vifor bought for about $100 million. The agreement specified the companies would either use it on vadadustat or resell it and share the proceeds. 

But the delay facing rival Fibrogen, and resulting uncertainty on the FDA's view of HIF-PH blockers, may have weakened the case for seeking a speedier review. Once a rare commodity, vouchers are now more common but can still fetch around $100 million in a sale. 

The FDA now has 60 days to determine whether Akebia's application is complete and ready for an official review.

FDA advisers reassert case against approval of Biogen Alzheimer's drug

 One of the most important decisions in the history of the Food and Drug Administration is quickly approaching. By early June, the agency should have a verdict on whether to approve aducanumab, a potentially first-of-its-kind treatment for Alzheimer's disease that became a major source of hope and controversy over the last two years.

Aducanumab is meant to the slow the cognitive decline that Alzheimer's patients experience by combating what many believe to be the root cause of disease. Such a treatment would be in high demand, given Alzheimer's care has been limited to medications that alleviate symptoms rather than change the disease's course. However, the data supporting aducanumab have come under intense scrutiny, leaving many doctors and researchers on the fence about its seeming benefit.

In November, the FDA convened a group of experts who advise the agency about brain drugs, and asked them whether there was enough positive evidence to say aducanumab works. Their answer was resoundingly negative, with all but one member voting against the drug.

While the FDA typically follows the recommendations of its advisers, it isn't required to. The agency is under immense pressure to clear more Alzheimer's treatments. And with certain high-ranking members of the FDA taking a favorable view of aducanumab, it's possible the drug may still be approved.

Perhaps that's why, on Tuesday, three of those FDA advisers rehashed their arguments against aducanumab in an editorial published in JAMA. The authors were Caleb Alexander, a professor of epidemiology and medicine at Johns Hopkins University; Aaron Kesselheim, a professor of medicine at Harvard Medical School; and Scott Emerson, a professor emeritus of biostatistics at the University of Washington.

The three were among the most vocal committee members in criticizing Biogen's case for aducanumab at the November meeting.

In their editorial, Alexander, Emerson and Kesselheim noted how the two large, near-identical clinical trials meant to prove aducanumab's merit showed very different results. One found patients who received a high dose for a long enough period of time did significantly better on a cognitive test than patients who received placebo. The other had the opposite outcome.

The authors called out the after-the-fact analyses that aducanumab's developer, Biogen, used to explain the disparate results. Namely, they took issue with how these "post hoc" analyses essentially presumed the positive study was reliable and the negative study was more a fluke, even though the consistent failure of drugs that work like aducanumab would suggest otherwise.

"In short, while post hoc analyses are useful for generating interesting hypotheses to be tested in future trials, the post hoc analyses regarding aducanumab provided limited information useful in deciding the benefit of this new drug and these post hoc analyses should not be the basis for FDA approval," they wrote.

The authors also detailed the close working relationship between the FDA and Biogen to analyze the clinical trial data. This "unusual degree of collaboration ... has been criticized as having potentially compromised the FDA's objectivity" in reviewing the drug, according to the three advisers.

While the authors acknowledged the dire need for safe and effective Alzheimer's drugs, and commended Biogen for running two large, valuable clinical trials, they ultimately see "no persuasive evidence to support approval of aducanumab at this time." FDA statisticians, ahead of the November advisory committee meeting, drew similar conclusions.

Though the arguments brought up in the JAMA article aren't new, "the decision by these authors to reiterate these points speaks to the degree to which they strongly believe that an aducanumab [rejection] is the correct decision here," wrote Brian Skorney, an analyst at Baird who's been critical of aducanumab and its approval odds.

The advisory committee members "clearly want FDA to remember what they said and not allow the long time frame between the meeting and the new [review deadline] to diminish their conclusions," Skorney added in his March 30 note to clients.

Macron orders COVID-19 lockdown across all of France, closes schools

 President Emmanuel Macron on Wednesday ordered France into its third national lockdown and said schools would close for three weeks as he sought to push back a third wave of COVID-19 infections that threatens to overwhelm hospitals.

With the death toll nearing 100,000, intensive care units in the hardest-hit regions at breaking point and a slower-than-planned vaccine rollout, Macron was forced to abandon his goal of keeping the country open to protect the economy.

“We will lose control if we do not move now,” the president said in a televised address to the nation.

His announcement means that movement restrictions already in place for more than a week in Paris, and some northern and southern regions, will now apply to the whole country for at least a month, from Saturday.

Departing from his pledge to safeguard education from the pandemic, Macron said schools will close for three weeks after this weekend.

Macron, 43, had sought to avoid a third large-scale lockdown since the start of the year, betting that if he could steer France out of the pandemic without locking the country down again he would give the economy a chance to recover from last year’s slump.

But the former investment banker’s options narrowed as more contagious strains of the coronavirus swept across France and much of Europe.

For school-children after this weekend, learning will be done remotely for a week, after which schools go on a two-week holiday, which for most of the country will be earlier than scheduled.

Thereafter, nursery and primary pupils will return to school while middle and high school pupils continue distance learning for an extra week.

“It is the best solution to slow down the virus,” Macron said, adding that France had succeeded in keeping its schools open for longer during the pandemic than many neighbours.


Daily new infections in France have doubled since February to average nearly 40,000. The number of COVID-19 patients in intensive care has breached 5,000, exceeding the peak hit during a six-week-long lockdown late last year.

Bed capacity in critical care units will be increased to 10,000, Macron said.

The new lockdown risks slowing the pace of France’s economic recovery from last year’s slump. It will force the temporary closure of 150,000 businesses at a cost of 11 billion euros ($12.89 billion) per month, the finance ministry said

The set-back for France, the euro zone’s second-largest economy, may also dampen Europe’s hopes of bouncing back swiftly from the pandemic, in the way that the U.S. and Chinese economies are doing.

France’s new lockdown underlines the cost of the European Union’s slow rollout of anti-COVID vaccines.

Neighbouring Britain, which finalised its divorce with the bloc on Jan. 1., has inoculated nearly half its population against the coronavirus and is re-opening its economy just as France hunkers down once again.

Macron said the vaccine campaign needed to be accelerated. Mired early on in red tape and slowed by supply shortages, it is only now finding its stride three months in, with just 12% of the population inoculated.

Bringing the calendar forward, Macron said people in their sixties would be eligible for a shot from mid-April and those in their fifties a month later. A goal of 30 million adults inoculated by mid-June remained the target, he said.

Seeking to offer hope, Macron said the April lockdown and a swifter vaccination campaign would allow the slow re-opening of the country from mid-May, starting with museums and the outdoor terraces of bars and restaurants, albeit under strict rules.

“We can see a way out of this crisis,” Macron said.

Delcath Adds Information on FOCUS Trial Power Calculation

 20.1% Lower Bound of Preliminary ORR Analysis Exceeds Required 8.3% Threshold

Delcath Systems, Inc. (NASDAQ: DCTH), an interventional oncology company focused on the treatment of primary and metastatic cancers of the liver, today provided additional information regarding the power calculation for the Phase 3 FOCUS trial of HEPZATO KIT (melphalan hydrochloride for injection/hepatic delivery system) in patients with liver dominant metastatic ocular melanoma (mOM).

In the summer of 2018, the Company amended the protocol for the FOCUS trial to a single arm design. In consultation with FDA, the FOCUS single arm trial was powered to demonstrate a superior Overall Response Rate (ORR) versus checkpoint inhibitors, one of the few mOM treatment categories with a significant amount of peer reviewed publications.

A point estimate of 21.0% ORR was calculated as the requirement to demonstrate superiority over the checkpoint inhibitors given the planned trial size and this threshold was shared with investors. The checkpoint inhibitor ORR was calculated based on a meta-analysis covering 16 different publications and 476 patients. The pooled overall response rate was 5.5% with a 95% Confidence Interval of 3.6% - 8.3%. To achieve statistical significance at a 95% Confidence Interval the lower bound of the ORR for HEPZATO needs to exceed the 8.3% upper bound of the meta-analysis. A preliminary analysis of 87% of enrolled patients analyses by the Independent Review Committee yielded an ORR of 29.2% [95% CI: 20.1, 39.8] in the Intent to Treat population, which substantially exceeds the 21.0%-point-estimate requirement. For further clarity, since the 20.1% lower bound exceeds the 8.3% upper bound of the meta-analysis the predefined success threshold was met. Further detail is available on the events and presentations section of the company website.

TG Therapeutics completes FDA filing for Roche challenger in CLL

 TG Therapeutics has completed its rolling FDA filing for its U2 combination therapy consisting of the antibody ublituximab with the oral drug Ukoniq (umbralisib) as a treatment for chronic lymphocytic leukaemia (CLL).

The US pharma is mounting a challenge to Roche, which markets an antibody therapy, Gazyvaro (obinutuzumab) in advanced CLL.

Like Gazyvaro, ublituximab targets a receptor known as CD-20 that is over-expressed on the surface of malignant B-cells that cause the disease, but adds umbralisib, an oral inhibitor of PI3K-delta and CK1-epsilon.

This adds to the potency of the medication by interfering with receptors that play an important role cell proliferation and survival, and regulate protein translation in cancer cells.

TG Therapeutics began a rolling filing with the FDA for the combination in December, following a $275 million fundraiser to bankroll late development and launch after supportive trial findings announced at the American Society of Hematology conference late last year.

The filing includes the UNITY-CLL phase 3 trial, a randomised study comparing the U2 combination therapy with an active control arm in which patients received Roche’s Gazyvaro plus chlorambucil chemotherapy in both treatment-naïve patients and those with relapsed/refractory disease.

The FDA had previously given the combination Fast Track designation, which allowed extra support to hasten development, as well as orphan drug development.

The trial met its primary endpoint of superior progression-free survival (PFS) for the U2 combination compared to the control arm to support the submission of the U2 combination in CLL.

Patients were randomly placed into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and the active control arm.

A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms.

The trial continued recruitment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil.

About 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory.