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After Clinical Setbacks, Theravance Axes 75% of Workforce and Refocuses on Respiratory Drugs

The job reduction was announced the same day that Theravance acknowledged that its wholly-owned symptomatic neurogenic orthostatic hypotension (nOH) candidate ampreloxetine (TD-9855) failed the Phase III Study 0169 (NCT03750552) by missing its primary…

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Theravance chairman and CEO Rick E. Winningham

Intent on bouncing back from a pair of later-phase clinical trial failures, Theravance Biopharma said it will eliminate about 75% of its workforce—270 jobs—and slash its R&D budget next year through a restructuring that will refocus the company on respiratory drugs.

Theravance said approximately 75% of the job cuts are expected to be completed in November, and the rest in February 2022. The company estimated that the layoffs would cost it approximately $10 million to $12 million through the first quarter of 2022, in both cash and accelerated vesting of equity awards for severance and other costs—but would ultimately save Theravance approximately $165 million in operating expenses next year.

The job reduction was announced Wednesday, the same day Theravance acknowledged that its wholly-owned symptomatic neurogenic orthostatic hypotension (nOH) candidate ampreloxetine (TD-9855) failed the Phase III Study 0169 (NCT03750552) by missing its primary endpoint of improvement in OHSA #1 in patients receiving the drug for four weeks compared to placebo. OHSA #1—part of the 0–10 scale Orthostatic Hypotension Questionnaire—measures patients’ dizziness, lightheadedness, feeling faint, or feeling like they might blackout.

Study 0169 (NCT03750552) was a four-week, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of ampreloxetine compared to placebo in 195 patients with symptomatic nOH. Theravance said it will determine “appropriate” next steps for two other clinical trials assessing ampreloxetine: Study 0170, which is assessing the drug in treating symptomatic nOH in patients with primary autonomic failure (NCT03829657; more than 75% enrolled) and Study 0171 (NCT04095793), a Phase III open-label extension study in patients with primary autonomic failure.

Last month Theravance acknowledged that izencitinib (TD-1473), a norepinephrine reuptake inhibitor being co-developed with Johnson & Johnson’s Janssen Biotech, failed a Phase IIb/III trial in patients with ulcerative colitis by missing its primary endpoint: A change in the total Mayo score at week eight, relative to placebo. Izencitinib also failed a key secondary endpoint of clinical remission at week 8, relative to placebo. Based on the disappointing topline results, Theravance said it would minimize future expenses associated with the program.

Theravance once envisioned izencitinib as a competitor to Janssen’s Stelara® (ustakinumab), AbbVie’s multi-indication blockbuster Humira® (adalimumab), and a newer rival, Zeposia® (ozanimod), which won FDA approval in May and is being marketed by Bristol-Myers Squibb’s Celgene subsidiary.

“Given the recent results from our late-stage development programs, we have made the difficult but necessary decision to focus our resources on our most promising respiratory programs and reduce the size of the organization,” Theravance chairman and CEO Rick E. Winningham said in a statement. “I am confident these actions will help us to continue making transformational medicines aimed at improving the lives of patients suffering from serious respiratory illnesses while creating value for our shareholders.”

Incorporated in the Cayman Islands, Theravance became a tax resident of Ireland in 2015, and has a U.S. subsidiary based in South San Francisco, CA.

“Major disappointment”

Investors responded to Theravance’s planned restructuring and ampreloxetine’s clinical setback with a stock selloff that sent the company’s shares falling 15%, to $6.84 at the close of trading Wednesday from Tuesday’s closing price of $8.04.

“This comes as a major disappointment compared to our expectations,” Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, wrote Wednesday in a research note.

As part of its restructuring, which it calls “A New, Focused Theravance Biopharma,” the company said it will pivot toward respiratory drugs—a shift dismissed by Porges: “We expect this will be of little interest to most investors.”

The only two exceptions will be izencitinib’s ongoing Phase II Crohn’s disease Study 0157 (NCT03758443), set to read out results in late fourth quarter 2021 or early first quarter 2022—and ampreloxetine’s Study 0170.

The failure of izencitinib in UC [ulcerative colitis]  lowers our confidence ahead of the readout of data from the Phase II study in Crohn’s,” Brian P. Skorney, senior research analyst with Baird, wrote August 24 in a research note.

“In our view, UC was always the more reasonable indication and Crohn’s more of a Hail Mary. JAK [Janus kinase] inhibition has been much more demonstrably effective in UC than Crohn’s. Additionally, we think the nature of the disease makes a gut-restricted option less likely to work in Crohn’s compared to UC,” Skorney explained. “As such, we expect the data will not support continued development of izencitinib in Crohn’s, as well.”

Theravance’s respiratory pivot starts with its new, most advanced pipeline candidate nezulcitinib (TD-0903), an inhaled drug initially being developed for acute lung injury. Nezulcitinib is a lung-selective, nebulized pan-JAK inhibitor designed for delivery by nebulizer into patients’ lungs when the oxygen in their bloodstream begins to drop.

In June, nezulcitinib showed mixed results in a Phase II study (NCT04402866) that assessed the drug in 235 hospitalized patients with confirmed COVID-19 associated acute lung injury and impaired oxygenation. The randomized, double-blind, placebo-controlled study did not meet the primary endpoint: number of respiratory failure-free days (RFDs) from randomization through Day 28 in the intent-to-treat (ITT) population. However, nezulcitinib showed a favorable trend in improvement when compared to placebo in 28-day all-cause mortality rate.

Under its previous name of TD-0903, Theravance had envisioned the drug as a COVID-19 candidate; it is among more than 300 candidates listed in GEN’s COVID-19 Drug & Vaccine Tracker.

“Putting the brakes on”

In February, Theravance trumpeted the drug’s positive results in a Phase II trial. All three doses studied in the placebo-controlled trial generated high percentages of patients who were alive and free of respiratory failure 28 days after once-daily treatment administered over seven days. Among the six patients who received the highest dose (10 mg), all six were alive and respiratory failure-free on day 28. Similar positive results also occurred in 86% (six of seven patients) receiving the 3 mg dose, and 83% (five of six patients) receiving the 1 mg dose.

‘We’re trying to put the brakes on that hyperinflammatory stage,” Winningham told GEN Edge last winter. “I think if TD-0903 is successful in COVID, it’s a real game-changer for the program, and for inhaled JAK inhibition overall.”

Porges was among analysts who enthused over nezulcitinib earlier this year: “This program has tended to be disregarded by investors, but the dose-dependent improvement in outcomes seen in the small trial offer tantalizing hints of real activity and benefit, and are likely to garner considerable attention in coming days.”

Theravance’s two marketed drugs carry respiratory indications: Yupelri®, an inhaled maintenance treatment for chronic obstructive pulmonary disease (COPD) co-developed with Mylan (since merged with Pfizer’s Upjohn division to form Viatris); and Trelegy Ellipta® (fluticasone/umeclidinium/vilanterol), which is indicated for COPD and asthma, and was developed by Theravance’s predecessor company Theravance Inc. with Glaxo Group, whose affiliates include GlaxoSmithKline (GSK).

During the second quarter, Trelegy generated $405 million in net sales and Yupelri, $42 million. Theravance cited Bloomberg estimates from a consensus of analysts that Trelegy is on track to reach global peak sales of $3 billion and Yupelri, more than $400 million in U.S. peak sales.

Theravance is entitled to 35% of profits and losses on Yupelri (the rest goes to Viatris), as well as tiered royalties of 5.5% to 8.5% paid by GSK on worldwide net sales of Trelegy Ellipta, which won FDA approval in 2017. However, Theravance is enmeshed in a legal dispute over the royalties with Theravance’s predecessor, which renamed itself Innoviva in 2016.

“Short of announcing an outright sale of the two tangible assets (Trelegy royalties and Yupelri profit share), investors are unlikely to see any opportunity for realization of their value, and to expect continued value destruction in terms of capital allocation,” Porges warned. “TBPH’s access to Trelegy is at risk given their ongoing litigation with Innoviva, and the company has lost all credibility with respect to its R&D investments.”

Theravance’s restructuring will also include drastic cuts in two key areas of corporate spending.

As part of its restructuring, Theravance said its R&D budget will be trimmed this year from between $195 million to $225 million as originally forecast to investors, to between $180 million and $190 million according to updated guidance.

In 2022, however, Theravance’s R&D budget will be chopped to between $55 million to $65 million, the company stated in a preliminary guidance to investors.

Also to be chopped next year is Theravance’s spending on selling, general, and administrative (SG&A) expenses, to between $30 million and $40 million, from a projected $70 million to $80 million in 2021—down from the company’s initial guidance of $80 million to $90 million.

The post After Clinical Setbacks, Theravance Axes 75% of Workforce and Refocuses on Respiratory Drugs appeared first on GEN - Genetic Engineering and Biotechnology News.

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Biden Suffers Worst Approval Ratings Plunge Of Any President Since World War II 

Biden Suffers Worst Approval Ratings Plunge Of Any President Since World War II 

President Biden’s job approval rating has fallen the most since the start of his term than any other president since World War II. 

A new Gallup poll was…

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Biden Suffers Worst Approval Ratings Plunge Of Any President Since World War II 

President Biden's job approval rating has fallen the most since the start of his term than any other president since World War II. 

A new Gallup poll was released Friday, polling Americans between Oct. 1-19 shows Biden's approval rating plunged from 56% in Q1 to 44.7% in Q3, a whopping 11.3 percentage points that any president hasn't seen in over 75 years. 

"Biden began his term with relatively solid approval ratings, ranging between 54% and 57% from January through June. His approval dropped to 50% in July and 49% in August as coronavirus infections surged in the U.S. The chaotic U.S. withdrawal from Afghanistan in late August, which included the deaths of more than a dozen U.S. military personnel in a terrorist attack at the Kabul airport, was likely the reason Biden's September job approval rating fell further to 43%," Gallup said. 

We noted in June that Gallup data showed Biden's "honeymoon period" was over and said if the president cannot "tame inflation" could result in further rating declines. And, oh boy, were we right...

Biden also faces an increasing disillusionment among Americans that he can't fix the border crisis, snarled supply chains, high gas prices, soaring inflation, consumer goods shortages, and the coronavirus pandemic, among a whole list of other things. 

His ratings suggest no improvement in Democrat support, declining support among Independents, and only 4% of Republicans polled approve of the job he's done - that figure is likely to go to zero if things don't turn around for the president. 

The 88% partisan gap in job approval is extraordinarily high considering Biden campaigned on "unity." During his inauguration, he said: 

"We can join forces, stop the shouting and lower the temperature. For without unity there is no peace, only bitterness and fury. No progress, only exhausting outrage. No nation, only a state of chaos. This is our historic moment of crisis and challenge, and unity is the path forward."

While Democrats are desperately trying to salvage their $3.5 trillion Build Back Better infrastructure plan, Americans are increasingly becoming confused about what exactly that means and how that will affect them. Repbulicans have requested the president to fix broken supply chain before more social spending. 

Souring support suggests Democrats could be on track to lose big in next year's midterms. 

Tyler Durden Sat, 10/23/2021 - 14:00

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Fauci Funded ‘Cruel’ Puppy Experiments Where Sand Flies ‘Eat Them Alive’; Vocal Cords Severed

Fauci Funded ‘Cruel’ Puppy Experiments Where Sand Flies ‘Eat Them Alive’; Vocal Cords Severed

While recent attention has been focused on Dr. Anthony Fauci’s National Institutes of Health funding the genetic manipulation of bat coronaviruses..

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Fauci Funded 'Cruel' Puppy Experiments Where Sand Flies 'Eat Them Alive'; Vocal Cords Severed

While recent attention has been focused on Dr. Anthony Fauci's National Institutes of Health funding the genetic manipulation of bat coronaviruses in the same town as the bat coronavirus pandemic emerged, a bipartisan group of lawmakers have demanded answers over 'sick' experiments on drugged puppies, according to The Hill.

"Our investigators show that Fauci’s NIH division shipped part of a $375,800 grant to a lab in Tunisia to drug beagles and lock their heads in mesh cages filled with hungry sand flies so that the insects could eat them alive," writes nonprofit organization the White Coat Waste Project. "They also locked beagles alone in cages in the desert overnight for nine consecutive nights to use them as bait to attract infectious sand flies."

As The Hill's Christian Spencer writes:

The White Coat Waste Project, the nonprofit organization that first pointed out that U.S. taxpayers were being used to fund the controversial Wuhan Institute of Virology, have now turned its sights on Anthony Fauci on another animal-testing-related matter — infecting dozens of beagles with disease-causing parasites to test an experimental drug on them.

House members, most of whom are Republicans, want Fauci to explain himself in response to allegations brought on by the White Coat Waste Project that involve drugging puppies.

According to the White Coat Waste Project, the Food and Drug Administration does not require drugs to be tested on dogs, so the group is asking why the need for such testing. 

White Coat Waste claims that 44 beagle puppies were used in a Tunisia, North Africa, laboratory, and some of the dogs had their vocal cords removed, allegedly so scientists could work without incessant barking. -The Hill

The concerned lawmakers are led by Rep. Nancy Mace (R-SC), who said in a letter to the NIH that cordectomies are "cruel" and a "reprehensible misuse of taxpayer funds." Mace is joined by reps Cindy Axne (D-Iowa), Cliff Bentz (R-Ore.), Steve Cohen (D-Tenn.), Rick Crawford (R-Ark.), Brian Fitzpatrick (R-Pa.), Scott Franklin (R-Fla.), Andrew Garbarino (R-N.Y.), Carlos Gimenez (R-Fla.), Jimmy Gomez (D-Calif.), Josh Gottheimer (D-N.J.), Fred Keller (R-Pa.), Ted Lieu (D-Calif.), Lisa McClain (R-Mich.), Nicole Malliotakis (R-N.Y.), Brian Mast (R-Fla.), Scott Perry (R-Pa.), Bill Posey (R-Fla.), Mike Quigley (D-Ill.), Lucille Roybal-Allard (D-Calif.), Maria E. Salazar (R-Fla.), Terri Sewell (D-Ala.), Daniel Webster (R-Fla.) and Del. Eleanor Holmes Norton (D-D.C.) via The Hill.

How will Fauci spin this?

Tyler Durden Sat, 10/23/2021 - 15:00

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COVID-19 pandemic shifted patient attitudes about colorectal cancer screening

Key takeaways Credit: American College of Surgeons Key takeaways A survey of adults eligible for colorectal cancer screening patterns found a preference for at-home fecal occult blood testing (FOBT) versus colonoscopy during the COVID-19 pandemic. Survey.

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Key takeaways

Credit: American College of Surgeons

Key takeaways

  • A survey of adults eligible for colorectal cancer screening patterns found a preference for at-home fecal occult blood testing (FOBT) versus colonoscopy during the COVID-19 pandemic.
  • Survey respondents reported less use of colonoscopy during the pandemic compared to pre-pandemic levels, with factors related to both COVID-19 infection concerns and the financial strain of having copays.
  • FOBT shows potential as an alternative to screening colonoscopy to improve access to colorectal cancer screening in the context of COVID-19 safety and economic concerns.

CHICAGO: The impact of the COVID-19 pandemic on patients’ willingness to keep appointments for non-COVID-19 illnesses has been well documented, but a team of researchers at Virginia Commonwealth University report that for people hesitant to come into the hospital or an outpatient center to get a colonoscopy, home-administered fecal occult blood tests (FOBT) may provide a useful workaround tool. About 30 percent more survey respondents completed home-based test during the pandemic than before.

Kristine Kenning, MD, MS, presented findings from a survey of adults age-eligible for screening at the virtual American College of Surgeons (ACS) Clinical Congress 2021. “The key message from our findings is that barriers to screening have increased during the pandemic, and we have to find a way to work with the community to increase those rates,” said Dr. Kenning, chief general surgery resident at Virginia Commonwealth University (VCU) School of Medicine, Richmond. “Our study found that people are compliant with, and willing to do, home-based fecal occult blood testing. This test provides a very important way for us to increase screening for colorectal cancer.”

The American College of Gastroenterology clinical guidelines recommend colonoscopy for colorectal cancer evaluation and following a positive FOBT with a colonoscopy.1 About 148,000 cases of colorectal cancers are newly diagnosed in the United States each year, the American Cancer Society reports, and they account for 53,000 deaths.2

About the survey

The cross-sectional survey involved 765 people age 50 years and older. Dr. Kenning and colleagues found that their respondents reported a higher completion of stool tests pre-COVID than the American Cancer Society reported,2 32 percent vs. 11 percent. During the pandemic, 50 percent of respondents said they completed the FOBT. By contrast, 44 percent of survey respondents who said they had colon screening during the pandemic underwent a colonoscopy. This practice appears to demonstrate substitution of stool-based testing for colonoscopy, Dr. Kenning noted. 

“Our study looked at attitudes toward colorectal cancer screening and how they were impacted during the pandemic, both related to concerns about the pandemic as well as to economic impacts,” senior author Emily B. Rivet, MD, MBA, FACS, said. “What we learned is that fecal occult blood testing was seen by patients as a viable alternative to conventional screening colonoscopy.” Dr. Rivet is an associate professor in the department of surgery, division of colorectal surgery, and an affiliated professor of internal medicine at VCU School of Medicine.

Patient concerns about copays

Notably, a greater percentage of respondents indicated being unemployed during the pandemic than the year prior: 7.4 vs. 2.6 percent. In addition, 41 percent of respondents expressed concerns about copays; 57.6 percent of those respondents said this was a factor for delaying screening. Dr. Kenning noted that she is working with Carrie Miller, PhD, MPH, the principal investigator of the larger survey, on a follow-up assessment of the pandemic-related impact on attitudes toward colorectal cancer screening. Dr. Miller is post-doctoral fellow with VCU’s department of health behavior and policy.

Other screening delays

Copays were not the only deterrent to getting scheduled colorectal screenings during the pandemic, the study found. Almost two-thirds of respondents—65.9 percent—confirmed concerns about COVID-19 exposure when scheduling colonoscopies; and 59 percent of them said this caused them to delay their screening. 

To address those concerns, respondents endorsed that being offered protective equipment (gloves and masks), visits to smaller offices, or weekend screening appointments would increase their likelihood of following through with the colonoscopy; respectively, 30.7 percent for each of the two former factors and 19.7 percent for weekend screening. However, 48.1 percent of respondents said they were willing to do an at-home FOBT as an alternative to colonoscopy, among whom 93 percent indicated they would be willing to undergo a follow-up colonoscopy if the FOBT was positive. 

Lessons learned from the pandemic

“Even pre-pandemic, the rates for colorectal screening in the United States were very far from 100 percent, so I think the lessons that we are learning from this pandemic and working with patients to find alternatives to what the conventional approaches have been in the past are going to be applicable to care moving forward. This approach applies even if we do eventually enter a post-pandemic state, which is, of course, what we are all hoping for,” Dr. Rivet said.

Dr. Kenning said the survey results show that there is still much work to do to improve colorectal screening. “Colorectal cancer screening has decreased significantly during the pandemic and still hasn’t improved to the rate that it was before,” Dr. Kenning said. “Making sure that we’re offering all of the options to patients is very important so that, whatever form of screening they’re comfortable with, they’ll start down that pathway in order to get the screening they need.”

The survey results also underscore the need to tailor colorectal cancer screening to each patient’s concerns and needs, Dr. Rivet said. “It’s important to have a conversation about all of these different alternatives and what the different positives and negatives are,” she said.

Study coauthors are Dr. Miller and Bernard F. Fuemmeler, PhD, MPH, also with the department of health behavior and policy at VCU; and Jaime L. Bohl, MD, FACS, with the department of surgery at VCU.

“FACS” designates that a surgeon is a Fellow of the American College of Surgeons.

The study authors have no relevant financial relationships to disclose. The survey was funded as part of a larger survey led by Dr. Miller on colorectal cancer and funded, in part, through support of an institutional training grant awarded by the National Cancer Institute (T32CA093423).

Citation: Kenning K. et al, COVID-19 Pandemic Impact on Colorectal Cancer Screening. Scientific Forum Presentation. American College of Surgeons Clinical Congress 2021.

______________ 

  1. Shaukat A, Kahi C, Burke CA, Rabeneck L, Sauer BG, Rex DK. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Amerc J Gastroenterol. 2021;116(3):458-479. doi: 10.14309/ajg.0000000000001122
  2. American Cancer Society. Colorectal Cancer Facts & Figures 2020-2022. Atlanta: American Cancer Society; 2020:22. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-facts-and-figures-2020-2022.pdf 

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About the American College of Surgeons
The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and improve the quality of care for all surgical patients. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has more than 84,000 members and is the largest organization of surgeons in the world. For more information, visit www.facs.org.


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