People With Advanced AIDS Benefit From Dolutegravir Treatment

 Patients with advanced HIV/AIDS infections had higher proportion of viral suppression with dolutegravir (Tivicay) treatment versus efavirenz (Sustiva) treatment, a researcher reported.

At 48 weeks, 73.9% of the 92 patients assigned to a dolutegravir-based (DTG) regimen achieved viral suppression based on the 200 copies/ml assay versus 47.8% of the 92 patients assigned to a efavirenz-containing (EFV) regimen (P<0.001), according to Carlos Brites, MD, PhD, of the Federal University of Bahia in Salvador, Brazil.

Using the more stringent 50 copies/ml assay, the undetectable threshold was achieved by 65.2% in the DTG group versus 45.7% in the EFV arm (P<0.001), he said in a presentation at the International AIDS Conference (IAC). Brites also reported that 12 patients in the EFV arm died versus with nine in the DTG group, although the difference was not statistically different.

While the World Health Organization (WHO) recommends DTG as a preferred HIV treatment in all populations, Brites said there is limited evidence of how dolutegravir works in a population with advanced AIDS and low CD4-positive cells. "Most of studies on integrase inhibitors efficacy were conducted on healthy patients," Brites and colleagues wrote. "There is scarce information on dolutegravir use in late-presenter HIV patients."

Late-presenter HIV patients are those diagnosed with a CD4 cell count <350/mm³ or an AIDS-defining condition regardless of CD4 cell count, according to the European Late Presenter Consensus Working Group. WHO defines advanced HIV disease as CD4 cell count <200 cells/mm³ or WHO stage 3 or 4 in adults and adolescents.

Brites' group enrolled symptomatic, treatment-naïve, late-presenter HIV patients from AIDS referral centers of five Brazilian cities who had CD4-positive cells counts <50 cells/ml, and had been diagnosed with an AIDS-defining illness. Patients either received DTG with lamivudine (Epivir) and tenofovir (Viread), or EFV with lamivudine and tenofovir.

Mean patient age in the DTG arm was 39.4 and 37.3 in the EFV arm; about 68% were men. The mean baseline CD4-positive cell count was 23 cells/ml. The most frequent AIDS-defining illnesses were esophageal candidiasis, neurotoxoplasmosis, and bacterial pneumonia.

There were 12 patients in the DTG arm who were lost to follow up as were 15 in the EFV arm, but the difference was not statistically significant, Brites reported. He also noted that one person in the DTG arm required antiretroviral modification versus 16 in the EFV arm.

At the end of 48 weeks, 44.6% of patients in the DTG arm had increased their CD4-positive counts to >200 cells/ml threshold versus 29.4% of patients in the EFV arm (P<0.001).

"The use of dolutegravir for treatment of advanced AIDS patients was significantly associated with higher rates of viral suppression at 24 weeks and at 48 weeks," Brites said. "There were less treatment interruptions and changes due to adverse events, and a higher proportion of patients reached a CD4-positive count above 200 cells/ml."

IAC session moderator Chloe Orkin, MD, MBChB, of Queen Mary University of London, told MedPage Today that "we still have people who are presenting late in their disease -- with their first presentation being an AIDS-defining illness.

It's estimated that late presenters account for nearly 40% of all HIV cases in Brazil, 40%-60% of cases in Europe, 72%-83% in Asia, and 35%-89% in Africa, according to a 2021 Pathogens article.

"We need data on how these drugs work when people are very immunosuppressed. It is fantastic that, even in these patients, there is a very good response to treatment with antiretroviral combination therapy," Orkin said.

Disclosures

Brites disclosed relationships with Bristol Myers Squibb (BMS), GlaxoSmithKline, Janssen-Cilag, Merck, and Janssen.

Orkin disclosed multiple relationships with industry including Merck, BMS, and Gilead.

Primary Source

International AIDS Conference

Source Reference: Brites C, et al "Survival in advanced AIDS patients treated with efavirenz or dolutegravir in Brazil: a multicenter, observational study" AIDS 2022.

https://www.medpagetoday.com/meetingcoverage/iac/99989

Where the pandemic could go next

 As the third winter of the coronavirus pandemic looms in the northern hemisphere, scientists are warning weary governments and populations alike to brace for more waves of COVID-19.

In the United States alone, there could be up to a million infections a day this winter, Chris Murray, head of the Institute of Health Metrics and Evaluation (IHME), an independent modeling group at the University of Washington that has been tracking the pandemic, told Reuters. That would be around double the current daily tally.

Across the United Kingdom and Europe, scientists predict a series of COVID waves, as people spend more time indoors during the colder months, this time with nearly no masking or social distancing restrictions in place. 

However, while cases may surge again in the coming months, deaths and hospitalizations are unlikely to rise with the same intensity, the experts said, helped by vaccination and booster drives, previous infection, milder variants and the availability of highly effective COVID treatments.

"The people who are at greatest risk are those who have never seen the virus, and there's almost nobody left," said Murray.

These forecasts raise new questions about when countries will move out of the COVID emergency phase and into a state of endemic disease, where communities with high vaccination rates see smaller outbreaks, possibly on a seasonal basis.

Many experts had predicted that transition would begin in early 2022, but the arrival of the highly mutated Omicron variant of coronavirus disrupted those expectations.

"We need to set aside the idea of 'is the pandemic over?'" said Adam Kucharski, an epidemiologist at the London School of Hygiene and Tropical Medicine. He and others see COVID morphing into an endemic threat that still causes a high burden of disease.

"Someone once told me the definition of endemicity is that life just gets a bit worse," he added.

The potential wild card remains whether a new variant will emerge that out-competes currently dominant Omicron subvariants.

If that variant also causes more severe disease and is better able to evade prior immunity, that would be the "worst-case scenario," according to a recent World Health Organization (WHO) Europe report.

"All scenarios (with new variants) indicate the potential for a large future wave at a level that is as bad or worse than the 2020/2021 epidemic waves," said the report, based on a model from Imperial College of London.

CONFOUNDING FACTORS

Many of the disease experts interviewed by Reuters said that making forecasts for COVID has become much harder, as many people rely on rapid at-home tests that are not reported to government health officials, obscuring infection rates.

BA.5, the Omicron subvariant that is currently causing infections to peak in many regions, is extremely transmissible, meaning that many patients hospitalized for other illnesses may test positive for it and be counted among severe cases, even if COVID-19 is not the source of their distress.

Scientists said other unknowns complicating their forecasts include whether a combination of vaccination and COVID infection – so-called hybrid immunity – is providing greater protection for people, as well as how effective booster campaigns may be.

"Anyone who says they can predict the future of this pandemic is either overconfident or lying," said David Dowdy, an infectious disease epidemiologist at Johns Hopkins Bloomberg School of Public Health.

Experts also are closely watching developments in Australia, where a resurgent flu season combined with COVID is overwhelming hospitals. They say it is possible that Western nations could see a similar pattern after several quiet flu seasons.

"If it happens there, it can happen here. Let's prepare for a proper flu season," said John McCauley, director of the Worldwide Influenza Centre at the Francis Crick Institute in London.

The WHO has said each country still needs to approach new waves with all the tools in the pandemic armory – from vaccinations to interventions, such as testing and social distancing or masking.

Israel's government recently halted routine COVID testing of travelers at its international airport, but is ready to resume the practice "within days" if faced with a major surge, said Sharon Alroy-Preis, head of the country's public health service.

"When there is a wave of infections, we need to put masks on, we need to test ourselves," she said. "That's living with COVID."

https://www.ctvnews.ca/health/coronavirus/living-with-covid-where-the-pandemic-could-go-next-1.6009913

BMS’ plan to move Opdivo into adjuvant RCC gets knocked back

 Bristol-Myers Squibb has revealed that its checkpoint inhibitor combination of Opdivo and Yervoy failed a phase 3 trial as adjuvant (post-surgery) therapy for renal cell carcinoma (RCC), the most common form of kidney cancer.

The disappointing outcome from the CheckMate -914 trial undermines BMS’ hopes of moving PD-1 inhibitor Opdivo (nivolumab) and CTLA4 inhibitor Yervoy (ipilimumab) treatment into earlier-stage cancers.

Opdivo/Yervoy has been approved since 2018 as first-line treatment for patients with intermediate- and poor-risk advanced RCC, and BMS was hoping to extend the use of the regimen into patients with localised RCC tumours that are treatable with surgery.

The new data come from Part A of the CheckMate -914 trial, which involved patients with localised RCC who had full or partial kidney removal surgery and were considered at moderate or high risk of the cancer coming back.

The results showed that Opdivo/Yervoy was no better than placebo at improving disease-free survival, said BMS. Part B of the trial is investigating Opdivo alone versus placebo in this setting and will continue to read out, although now looks likely to disappoint.

It’s a blow to BMS’ particularly as its arch-rival in the PD-1 inhibitor category – Merck & Co – recently scored approval for its drug Keytruda (pembrolizumab) as adjuvant RCC.

“Even with notable progress in the treatment of metastatic renal cell carcinoma, there are still limited treatment options available for patients with localised disease,” said BMS’ Dana Walker, who heads up the drugmaker’s genitourinary cancer development programmes.

She noted that Opdivo and Opdivo/Yervoy have previously been shown in trials to be effective as adjuvant therapy for other cancers, including genitourinary tumours.

That includes bladder cancer for example, where Opdivo was approved last year for use after surgery in patients with muscle-invasive urothelial carcinoma (UC), as well as for oesophageal/gastro-oesophageal cancer and melanoma.

Securing approvals in the adjuvant or neo-adjuvant (pre-surgery) setting is a key strategy for BMS and other checkpoint inhibitor developers, as it allows them to position their drugs as the earliest cancer immunotherapy option in the treatment pathway.

Opdivo and Opdivo/Yervoy have also shown a benefit in clinical trials alongside Exelixis’ tyrosine kinase inhibitor Cabometyx (cabozantinib) as first-line therapy in advanced RCC, while Opdivo proved to be effective as second-line treatment.

BMS said it is also investigating Opdivo and Opdivo plus Yervoy in combination with novel agents targeting alternative immunomodulatory molecules and pathways in RCC.

Meanwhile, other pharma companies are also developing checkpoint inhibitors for adjuvant RCC, including Roche whose Tecentriq (atezolizumab) is in the phase 3 IMmotion010 study, and AstraZeneca which is testing its Imfinzi (durvalumab) alone and in combination with CTLA4 drug tremelimumab in the RAMPART trial.

https://pharmaphorum.com/news/bms-plan-to-move-opdivo-into-adjuvant-rcc-gets-knocked-back/

First monkeypox deaths outside Africa recorded

 Monkeypox has claimed the first lives outside Africa – one in Brazil and another two in Spain – although the World Health organization (WHO) has said the outbreak remains “containable.”

More than 18,000 cases of monkeypox from 78 countries have been reported to the WHO, said WHO director general Tedros Adhanom Ghebreyesus last week, with more than 70% of cases identified in Europe and 25% in the Americas. That is a scale of outbreak never before encountered with the virus.

As of 22 July, there had been five reported deaths among the current outbreak, with around 10% of all cases requiring admission to hospital, mainly to manage the pain caused by the disease. The WHO formally declared monkeypox an emergency last week.

Dr Tedros said however that the outbreak “can be stopped, if communities and individuals inform themselves, take the risks seriously, and take the steps needed to stop transmission and protect vulnerable groups,” he added.

The deaths are a reminder however that even though most monkeypox infections are mild, some can be serious, particularly in vulnerable people.

The Brazilian fatality occurred in a man with lymphoma and a weakened immune system. Details are scant on the Spanish deaths, although one is reported to have been caused by encephalitis, a possible complication of monkeypox infection. Meanwhile, there are unconfirmed reports of a possible death in india.

On Friday, the FDA said it was taking several steps in response to the outbreak, including starting to distribute supplies of manufactured doses of Bavarian Nordic’s Jynneos vaccine, shortly after approving additional capacity to produce the shot.

It has previously also granted “compassionate use” access to Siga Technologies’s antiviral Tpoxx (tecovirimat), which is approved for smallpox but not monkeypox in the US. It is however cleared for both diseases in Europe.

“The FDA has been closely tracking reports of monkeypox transmissions in the US with our federal public health partners and coordinating preparedness efforts accordingly,” said agency chief Robert Califf.

“We understand that while we are still living with COVID-19, an emerging disease may leave people feeling concerned and uncertain, but it’s important to note that we already have medical products in place, specifically an FDA-approved vaccine…and an FDA-cleared diagnostic test.”

Monkeypox causes symptoms similar to but milder than smallpox, typically beginning with fever, headache, muscle aches and exhaustion. It is transmitted to people from various wild animals, such as rodents and primates, and is usually a self-limiting disease with symptoms lasting from two to four weeks.

https://pharmaphorum.com/news/first-monkeypox-deaths-outside-africa-recorded/

US FDA approval tracker: July 2022

 For companies that did not receive approval decisions in July, as expected, investors will hope that the old adage that no news is good news rings true. After the FDA provided proposed labelling in June the wait continues for Axsome’s AXS-05 in major depressive disorder. The verdict was originally scheduled for nearly a year ago and was first delayed by deficiencies. Neither has any update emerged on Akeso and Sino’s anti-PD-1 MAb penpulimab, which had an assumed first-half timing. Beigene, like Akeso, is based in China and review of its own anti-PD-1 MAb tislelizumab was postponed because Covid-related travel restrictions delayed inspections. Several drugs did manage to make it across the FDA line, though, including two dermatology thumbs-ups. Arcutis’s Zoryve, a topical PDE4 inhibitor, is now approved in plaque psoriasis, and Incyte’s Opzelura, a topical version of ruxolitinib, the active ingredient in Jakafi, became the first FDA-approved product for repigmentation in vitiligo.

Notable first-time US approval decisions in July
Project	Company	Indication(s)	2028e sales by indication ($m)	Outcome
AXS-05	Axsome	Major depressive disorder	787	Pending
Zoryve (roflumilast cream)	Arcutis/ Astrazeneca	Plaque psoriasis in patients 12 years of age or older	606	Approved
Lumryz (FT218)	Avadel	Treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy	361	Tentative approval (full approval not expected until Jun 2023, when Jazz's '963 Rems patent expires)
Tislelizumab	Beigene/ Novartis	2nd-line oesophageal squamous cell carcinoma	83	Deferred owing to Covid-19 travel restrictions delaying inspections
Zonisade (zonisamide oral suspension)	Eton	Partial seizures in patients with epilepsy	-	Approved
Ryzneuta	Evive Biotech (private)	Chemotherapy-induced neutropenia	-	Pending (filed May 2021)
SH-111	Shorla Oncology (private)	T-cell leukaemia	-	Pending (filed Apr 2021)
Annik (penpulimab)	Akeso/Sino	3L nasopharyngeal carcinoma	-	Pending (was estimated as H1)
SBI: sales by indication. Source: company releases & Evaluate Pharma.

 

Supplementary and other notable approval decisions in July
Product	Company	Indication (clinical trial)	Outcome
Krystexxa + methotrexate	Horizon	Uncontrolled gout (Mirror)	Approved
Opzelura (ruxolitinib cream)	Incyte	Adolescents and adults with vitiligo (True-V1, True-V2)	Approved
Comirnaty	Pfizer/Biontech	Immunisation to prevent Covid-19 in individuals aged 12-15 years of age (received EUA in May 2021)	Approved
Xalkori	Pfizer	Adult and paediatric patients 1 year of age and older with unresectable, r/r inflammatory ALK-positive myofibroblastic tumours (ADVL0912, A8081013)	Approved
Benlysta	GSK	Children aged 5-17 with active lupus nephritis	Approved
Ronapreve (Regen-Cov)	Regeneron	Treatment of Covid-19 in non-hospitalised patients and as prophylaxis in certain individuals; given EUA in Nov 2020, limited Jan 2022 after emergence of omicron (NCT04425629, NCT04452318)	Review said to be ongoing
Imfinzi + chemo	Astrazeneca	1L biliary tract cancer (Topaz-1)	Pending (Q3)
Enhertu	Astra/Daiichi Sankyo	Unresectable or metastatic NSCLC whose tumours have a Her2 mutation and who have received prior systemic therapy (Destiny-Lung01)	Pending (Q3)
Actemra	Roche	Hospitalised Covid patients; received EUA in Jun 2021 (Empacta, Covacta, Remdacta, Recovery)	Pending (Q3)
Source: company releases & Evaluate Pharma.

 

FDA Covid-19 EUAs
Product	Company	Outcome
Zyesami	NRX Pharmaceuticals	Declined for subgroup of patients with critical Covid-19 at immediate risk of death from respiratory failure despite treatment with approved therapy, including remdesivir
Nuvaxovid	Novavax	Granted for individuals 18 years of age and older (vaccine)
Source: company releases. https://www.evaluate.com/vantage/articles/insights/nme-approvals-snippets/us-fda-approval-tracker-july-2022

Concert Pharma Aces Second Trial in Alopecia

 

• Concert Pharmaceuticals Inc 
  CNCE+7.23%+ Free Alerts
   announced topline results from its second Phase 3 trial, THRIVE-AA2, evaluating CTP-543 in adult patients with moderate to severe alopecia areata, an autoimmune disorder that results in patchy or complete scalp hair loss. 
• The primary efficacy endpoint was met with statistical significance in the 8 mg twice-daily and 12 mg twice-daily dose groups relative to placebo. 
• A statistically significant proportion of patients treated with either 8 mg twice-daily or 12 mg twice-daily of CTP-543 experienced greater scalp regrowth compared to placebo. 
• The proportion of patients achieving a SALT score of 20 or less (meaning 20% or less scalp hair loss) was 38.3% in the 12 mg twice-daily dose group and 33% in the 8 mg twice-daily dose, compared to 0.8% in the placebo group.
• 47% of patients in the 8 mg twice-daily group and 52% in the 12 mg twice-daily group reported being "satisfied" or "very satisfied," compared to 2% of patients in the placebo group. 
• The safety profile seen with CTP-543 in THRIVE-AA2 was consistent with previous studies. 
• Concert plans to submit to FDA marketing application in 1H of 2023.

https://www.benzinga.com/general/biotech/22/08/28290507/concert-pharma-aces-second-trial-for-patchy-hair-loss-hopeful