Capsaicin Injection Improves Knee Osteoarthritis Pain

Highly purified synthetic trans-capsaicin (CNTX‐4975) injected directly into the joint reduced pain in chronic knee osteoarthritis (OA), data from the open-label phase III VICTORY-3 trial showed.

People with bilateral knee OA pain who received the investigational treatment had less pain when walking in as early as 3 days and the effect was maintained for 8 weeks, reported Randall Stevens, MD, of Centrexion Therapeutics in Boston, at the American Society of Interventional Pain Physicians (ASIPP) virtual meeting.

The findings supported those of the phase II TRIUMPH study, which showed that a single 1-mg injection of CNTX-4975 provided a significant (P<0.0001) and clinically meaningful reduction in chronic, moderate-to-severe OA knee pain, with effects persisting for up to 24 weeks.

Because intraarticular capsaicin injection produces short-term procedural pain, VICTORY-3 aimed to assess different ways to administer CNTX-4975, in addition to looking at the drug’s clinical benefit on bilateral knee pain.

Earlier reports showed that cooling the knee with a circumferential wrap — either a circulating ice water wrap or an ice gel pack wrap — reduced intra-articular temperature much better than an ice bag on the knee, Stevens said. “The result was the short-lived post-injection pain was cut by 50%, compared to an ice bag,” he told MedPage Today.

VICTORY-3 showed that “either method of circumferential cooling wrap — ice water or gel-based — was equivalent in effect to each other,” he added. “It also showed that using two needles to inject lidocaine and capsaicin, separated by 30 minutes, was no better than cooling and using one needle to inject first lidocaine, then capsaicin, to manage post-injection pain.”

Capsaicin products currently are used in topical applications to treat OA, including an 8% capsaicin patch, Stevens noted.

CNTX-4975 works by targeting the capsaicin receptor (TRPV1) to selectively inactivate local pain fibers transmitting signals to the brain, providing pain relief that may last for months until the ends of the fibers regenerate. The compound has a short half-life and is cleared from the body within 24 hours.

Pain from knee OA “may be effectively and safely managed with this new investigational compound, CNTX‐4975, and is thought to be mediated by sustained desensitization of nociceptors,” observed Jack Cush, MD, of Baylor University Medical Center in Dallas, who wasn’t involved with the research.

In the 8-week VICTORY-3 study, 848 people with moderate to severe OA knee pain received unilateral or bilateral CNTX-4975 1 mg intra-articular injections. About 60% of participants were female. The average age of participants was about 63 and mean BMI was 31.3. Most had bilateral radiographic OA (81.7%) and index knee Kellgren-Lawrence grades 2–4 (87.4%).

A total of 523 participants had bilateral pain and received bilateral capsaicin intra-articular injections: 427 received injections in both knees, and 96 did not receive an injection in the non-index knee. Mean baseline scores for pain with walking were 7.4 in the index knee and 6.1 in the non-index knee on the 10-point Numerical Pain Rating Scale (NPRS), where 0 represents no pain and 10 represents worst pain ever.

Reductions in pain with walking after CNTX-4975 injections were seen as early as day 3 for the index knee (LS mean change from baseline in NPRS score -4.21, 95% CI -4.41 to -4.01, P<0.0001) and day 8 plus 3 days for the non-index knee (LS mean -3.84, 95% CI -4.02 to -3.65, P<0.0001). Improvements were maintained at week 8 for both knees.

All cooling and administration regimens evaluated in VICTORY-3 were clinically acceptable based on pain and satisfaction scores, Stevens said.

“A single intra-articular injection of CNTX-4975 1 mg into each knee with moderate to severe OA pain may provide a valuable new option for fast and long-lasting relief,” he noted.

Pivotal phase III trials of CNTX-4975 are using a proprietary aqueous formulation in a pre-filled syringe of capsaicin, he added. VICTORY-1 is a 52-week double-blind trial with a single dose at day 1 for painful knee OA; VICTORY-2 is a 52-week double-blind trial with a first dose at day 1 and second dose at week 26.

Adverse events in VICTORY-3 were not reported at ASIPP, but in TRIUMPH, treatment‐emergent adverse events were similar in placebo and CNTX‐4975 groups. CNTX-4975 has been granted FDA fast track designation for treating moderate-to-severe pain associated with knee OA.

Disclosures

The study was sponsored by Centrexion Therapeutics.

Stevens disclosed holding stocks in Centrexion Therapeutics.

Primary Source

American Society of Interventional Pain Physicians

Source Reference: Stevens R, et al “Intra-articular CNTX-4975 for OA pain: Comparison of 5 treatment regimens” ASIPP 2020.

https://www.medpagetoday.com/meetingcoverage/asipp/88481

Biotech week ahead, Sept. 8

After remaining steady in the first three sessions of the week ended Sept. 4, biotech stocks pulled back along with the broader market in a tech-induced sell-off. Barring anything COVID-19-related, the news flow was fairly light ahead of the Labor Day holiday.

Amarin Corporation plc AMRN 5.7% took a severe beating after losing a patent appeal related to its synthetic fish oil pill Vascepa. The stock lost over 40% during the week, attributable primarily to the adverse ruling and to a smaller extent to the market sell-off.

Here are the key catalysts for the unfolding week.

Conferences

• Citi’s 15th Annual BioPharma Conference: Sept. 8-11
• Wells Fargo 2020 Virtual Healthcare Conference: Sept. 9-10
• Baird 2020 Global Healthcare Conference: Sept. 9-10
• BTIG Virtual Biotechnology Conference: Sept. 10-11
• 66th Annual Meeting of the American Rhinologic Society, or ARS, (virtual event): Sept. 10-12
• International Gynecologic Cancer Society, or IGCS, xDigital Annual Global Meeting: Sept. 10-13
• 2020 Psych Congress (virtual event): Sept. 10-13
• MDS Virtual Congress 2020: September 12–16
• MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting: Sept. 11-13

PDUFA Dates

The FDA is set to rule on Mallinckrodt PLC’s MNK 4.95% NDA for terlipressin that is being evaluated for treating hepatorenal syndrome type 1. (Saturday)

Clinical Readouts/Presentations

Standalone Releases:

Applied Genetic Technologies Corp AGTC 0.69% said it will present an update on its planned Phase 2/3 X-Linked Retinitis Pigmentosa clinical trial design, a re-analysis of dose Groups 2 and 4 data, and new preliminary visual sensitivity data from Group 5. (Wednesday)

MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting Presentations:

Johnson & Johnson’s JNJ 0.56% Janssen unit: additional data on the effect of treatment with ponesimod versus teriflunomide on disability measures in patients with relapsing multiple sclerosis.

Roche Holdings AG’s RHHBY 0.07% Genentech unit: New analyses from the two-year open-label Phase 3b CASTING study of Ocrevus in patients with relapsing-remitting multiple sclerosis, and new data from the SAkura Phase 3 studies of Enspryng in neuromyelitis optica spectrum disorder.

Atara Biotherapeutics Inc ATRA 0.94%: New 12-month data from all four cohorts in the Phase 1a study of ATA188 for the treatment of progressive forms of multiple sclerosis. (Friday)

ARS Meeting Presentations:

VERONA PHARMA P/S ADR VRNA 2.09% and Ligand Pharmaceuticals Inc. LGND 0.34%: new subgroup analysis from Phase 2b trials with nebulized ensifentrine in chronic obstructive pulmonary disease. (Tuesday)

Lyra Therapeutics Inc LYRA 4.89%: Poster presentation for lead asset LYR-210 for the treatment of chronic rhinosinusitis.

IGCS Presentations:

Sutro Biopharma IncSTRO 3.54%: updated data from the Phase 1 study of STRO-002, its FRα-targeting antibody-drug conjugate, in ovarian cancer; The company will hold a conference call Wednesday to discuss the updated data.

MDS Virtual Congress Presentations:

Neurocrine Biosciences, Inc. NBIX 0.64%: new Phase 3 data analyses of Ongentys capsules as an add-on therapy to levodopa/carbidopa in patients with Parkinson’s disease experiencing motor “off” episode and new Phase Ib data of an investigational gene therapy, NBIb-1817 in advanced Parkinson’s disease.

Voyager Therapeutics Inc VYGR 2.89%: 24-month results from the PD-1102 trial evaluating its investigational gene therapy VY-AADC in advanced Parkinson’s disease. (Friday)

Earnings

Applied Genetic Technologies (Wednesday before the market open)

MEI Pharma Inc MEIP 1.6% (Wednesday after the close)

IPO Quiet Period Expiry

CureVac BV CVAC 11.47%

https://www.benzinga.com/general/biotech/20/09/17389314/the-week-ahead-in-biotech-focus-on-mallinckrodt-fda-decision-conference-presentations

Korea may produce Russian vaccine in November

Russia has selected South Korea as the place to produce its COVID-19 vaccine for the Asian market, according to the head of the world’s largest country’s sovereign wealth fund.

Russian Direct Investment Fund (RDIF) CEO Kirill Dmitriev told The Korea Times in a recent interview that his country has begun procedures to supply South Korea with the world’s first registered vaccine against the coronavirus within a couple of months.

“South Korea can be a great partner to produce Sputnik V,” he said.

“We are in talks with two major Korean pharmaceutical companies, which have production capabilities, to produce the vaccine in South Korea and potentially supply it not only in Korea but also to export it to other countries in Asia.”

Korea has already been mentioned as a potential production base for COVID-19 vaccines developed by several countries, since SK Bioscience signed agreements with AstraZeneca and Novavax to produce their vaccines here. Samsung Biologics joined hands with GlaxoSmithKline (GSK) to produce its medicine for COVID-19.

Dmitriev did not disclose the names of the Korean drugmakers he has contacted, but he noted those companies may start producing the vaccine here as soon as November, if they get approval from the Korean authorities.

“We aim to make it available for use in countries globally and to create strategic partnerships for vaccine production in all parts of the world, including South Korea,” he said.

“We believe that the registration of Sputnik V in Russia is a milestone in global efforts to protect people around the world against coronavirus.”

RDIF has made investments in the Nikolai Gamaleya National Center of Epidemiology and Microbiology, so that the state-run research institute can develop the vaccine named after the world’s first satellite that the Soviet Union launched in 1957.

Moscow granted regulatory approval to the vaccine in August, after less than two months of human testing without a phase 3 trial.

In Europe and North America, this has caused concerns over its safety, despite Russian President Vladimir Putin’s announcement that the vaccine had been administered to one of his daughters. A recent survey by the Russian Public Opinion Research Center showed 52 percent of Russians were not prepared to be vaccinated with Sputnik V, according to Tass.

Having confirmed that he and his family had been vaccinated, however, Dmitriev dismissed concerns, emphasizing the vaccine uses a proven platform based on human adenoviral vectors.

“Nowadays, this is the safest mechanism for introducing the genetic code of the virus spike into the human body, and it has been thoroughly studied not only in Russia but also abroad,” he said.

“Clinical trials of the vaccine against coronavirus have demonstrated that 100 percent of volunteers developed immunity within 21 days. After the second vaccination, the immunity response was boosted further and provided for long-lasting immunity.”

According to the CEO, the post-registration trials involve more than 40,000 people in Russia, the Middle East and other countries.

“This vaccine will not only protect people, but it will also help the global economy recover faster,” Dmitriev said.

“We believe in the necessity of international cooperation in fighting the pandemic and welcome cooperation between our countries, which would lead to more efficient collaboration in the joint fight against the common enemy.”

Partnership with KIC

After the outbreak of the disease, Russia also tried to take the lead in cooperation among international sovereign wealth funds, including the Korea Investment Corporation (KIC).

RDIF hosted a teleconference of sovereign wealth funds in April to discuss countermeasures against COVID-19 and to share investment strategies.

In addition to KIC CEO Choi Hee-nam, the participants included representatives from the China Investment Corporation, Singapore’s GIC and Temasek, the United Arab Emirates’ Mubadala Investment Company, the Public Investment Fund of Saudi Arabia, the U.S. International Development Finance Corporation, France’s Bpifrance and the Japan Bank for International Cooperation. Bridgewater founder Ray Dalio and EQT Partners co-head Marcus Brennecke also joined the meeting.

“During our regular calls, we discussed with partners the most advanced technologies to fight the virus, which included testing systems, drugs and vaccines, as well as the best way to resume economic activity,” Dmitriev said.

He reaffirmed the RDIF’s strong ties with the KIC, with which it agreed in 2013 to raise a $500 million investment fund. When Deputy Prime Minister and Finance Minister Hong Nam-ki visited Russia in September 2019, the RDIF also promised to create a $1 billion investment fund with Korea.

“Together with our partners from the KIC, we are evaluating a number of joint investment opportunities with Korean partners in the chemical, telecommunications, biotech, healthcare and finance industries,” Dmitriev said. “Seven projects totaling $500 million are in the final stage.”

http://m.koreatimes.co.kr/pages/article.asp?newsIdx=295501

A negative COVID-19 test does not mean recovery

Eight months into the global pandemic, we’re still measuring its effects only in deaths. Non-hospitalized cases are loosely termed ‘mild’ and are not followed up. Recovery is implied by discharge from hospital or testing negative for the virus. Ill health in those classed as ‘recovered’ is going largely unmeasured. And, worldwide, millions of those still alive who got ill without being tested or hospitalized are simply not being counted.

Previously healthy people with persistent symptoms such as chest heaviness, breathlessness, muscle pains, palpitations and fatigue, which prevent them from resuming work or physical or caring activities, are still classed under the umbrella of ‘mild COVID’. Data from a UK smartphone app for tracking symptoms suggests that at least one in ten of those reporting are ill for more than three weeks. Symptoms lasting several weeks and impairing a person’s usual function should not be called mild.

Defining and measuring recovery from COVID-19 should be more sophisticated than checking for hospital discharge, or testing negative for active infection or positive for antibodies. Once recovery is defined, we can differentiate COVID that quickly goes away from the prolonged form.

I had COVID symptoms of fever, cough, gastrointestinal upset, chest and leg pains in late March. But at that time, non-hospitalized patients were not tested. Since then, I have had bad days with some symptoms, then OK days, then worse days of exhaustion, making me regret what I did on the OK days, such as taking a short walk.

This is a difficult time for me as a public-health academic engaged in pandemic action while struggling with this strange pattern of illness. I don’t know what it means for my long-term health, which is concerning as a mother caring for young children.

One consolation is knowing that I am not alone. There are many others who have not regained their previous health, even months after their initial symptoms. Among them, fluctuating symptoms like mine are common.

Although clinicians and researchers have an idea of who is at increased risk of dying from COVID, we don’t know who is more likely to experience prolonged ill health following symptomatic, or even asymptomatic, infection. The idea of accepting certain levels of infection to run through society, while protecting the vulnerable, becomes meaningless without considering health and productivity as outcomes alongside death.

Research that follows COVID patients after discharge from hospital is starting. But there is still a gap in quantifying and characterizing COVID-related illness in those not hospitalized. The consequences of failing to do so are significant. Some people, especially the young and healthy, might not see a need to follow preventive measures, because they expect only a few days of flu-like symptoms at the worst. Sick people might not get the support they need, and the true human and economic costs of the pandemic will not be correctly estimated.

As long as ‘long COVID’ is labelled as anecdotal, it will not be taken seriously, and public communication will neglect it. We need to quantify it properly and accurately. We must measure recovery in those not presenting with severe disease at the outset.

Let us start simple. With other common viral illnesses, such as flu, we would expect recovery to mean going back to pre-infection levels of functionality and quality of life. This means we must follow up all patients with confirmed (by test) or highly probable (by symptoms) COVID and find out whether they have returned to their previous normal within a specified time from the onset of their symptoms.

The ‘recovery’ definition must include duration, severity and fluctuation of symptoms, as well as functionality and quality of life. Everyone who is symptomatic would remain a ‘case’ until they fulfilled the recovery criteria or died. This is basic bread-and-butter epidemiology. We just need to apply it to this pandemic.

To do so, we must also define who had the infection in the first place. When testing is absent or inaccurate, physicians must be provided with universal and simple criteria for what constitutes clinical COVID. A good starting point are the studies characterizing typical symptoms on a population level.

Measuring recovery is not an easy ask with health and surveillance systems already struggling to cope. It makes sense to set up disease registers, akin to cancer registries, to track people over time and record their condition. This could be done through quick monthly, and subsequently annual, check-ups with health-care providers. If national registers are not quickly forthcoming, local ones could be started.

For surveillance, public-health agencies must prioritize agreement on criteria for a definition of recovery, and on the structures in which these criteria could be implemented. We must overlay research on surveillance with studies of the characteristics of those experiencing prolonged ill health. We must learn to identify and protect the most vulnerable.

The narrow narrative of death as the only bad outcome from COVID needs broadening to include people becoming less healthy, less capable, less productive and living with more pain. For that, we’ll need better surveillance. The essential first step is getting clear and universal definitions for recovery and COVID severity.

Nisreen A. Alwan is an associate professor of public health at the University of Southampton, UK.

https://www.nature.com/articles/d41586-020-02335-z

‘One vaccine isn’t enough’: Mexico aims for its own coronavirus jab

Mexico is working to produce its own COVID-19 vaccines and could have one ready by next spring, according to a researcher coordinating local efforts amid a global race to tame a disease that has infected over 26.75 million people worldwide.

Esther Orozco, coordinator of the scientific group that represents Mexico at the Coalition for Epidemic Preparedness Innovations, said research based on a virus that transmits the avian Newcastle disease is the most viable candidate to produce the first vaccine in Mexico.

Orozco said the vaccine, developed by the private firm Laboratorio Avimex with researchers from Mexico’s main public university, UNAM, and the Mexican Social Security Institute, is ready to start the first phase of testing with humans.

“They are advanced,” Orozco told Reuters in an interview. “I think it’s going to be ready by spring or the start of summer.”

She said the Avimex vaccine trials will begin with “dozens of humans.” A second stage will see “hundreds of patients” before thousands of volunteers take part in final Phase 3 studies.

Avimex, normally dedicated to the manufacture of vaccines and pharmaceutical products for animals, did not respond to a request for comment.

Mexico has launched a global effort to build diplomatic and commercial alliances to ensure it receives the approximately 200 million vaccine doses it estimates it will need for a disease that has infected more than 623,000 people and killed at least 66,851 in Latin America’s second-largest economy.

Mexico will take part in clinical trials of Italian and Russian vaccines, and has also struck a deal to produce pharmaceutical firm AstraZeneca Plc’s (AZN.L) vaccine.

In addition, it is looking to participate in phase 3 trials with French drugmaker Sanofi (SASY.PA), Johnson & Johnson’s (JNJ.N) Janssen unit and Chinese companies CanSino Biologics Inc (6185.HK) and Walvax Biotechnology Co Ltd (300142.SZ), all of which have agreed to guarantee access to their vaccines if successful.

Orozco said the Mexican vaccine will arrive “later” than leading foreign candidates. But she noted that 7.5 billion people on the planet will need to be inoculated, and the number of vaccines may be double that figure if two doses are needed.

“The world is going to need much more than one vaccine,” she said. “Our hope is that Mexico is a part of this even if we’re not the first to cross the finish line.”

https://www.reuters.com/article/us-health-coronavirus-mexico-vaccine/one-vaccine-isnt-enough-mexico-aims-for-its-own-coronavirus-fix-idUSKBN25X0IH

Nothing to see: COVID origins off-limits as China’s Wuhan touts recovery

The Huanan seafood market in the Chinese city of Wuhan, believed by many to be the origin of the COVID-19 pandemic, is sealed behind a blue perimeter fence. A large team of security staff chases away anyone who lingers.

“We are just doing our job,” said a guard in black who ordered a Reuters reporter to delete footage recorded near the market’s main gates. He identified himself as a worker from the city government’s epidemic prevention and control team.

Foreign journalists were invited on an official tour to report on Wuhan’s efforts to rebuild its economy after the months-long trauma of COVID-19. The official message: the “heroic city” is back to normal and back in business, its schools and tourist sites reopened and its enterprises running at full capacity.

“No other place is as safe as this,” said Lin Songtian, president of the Chinese People’s Association for Friendship with Foreign Countries, a state-backed group that helped organise the tour.

The location of more than 80% of the country’s COVID-19 deaths, the central Chinese city on the banks of the Yangtze river has reported no cases of local transmission since May, and most of the stringent controls imposed during a two-month lockdown have been relaxed.

But Wuhan was accused of acting too slowly in the early stages of the outbreak amid fears of disrupting the economy or displeasing China’s leadership in Beijing. Critics say media censorship and the silencing of whistleblowers gave the virus more time to spread undetected.

Wuhan remains reluctant to allow light to be shed on the origins of a pathogen that has killed nearly 900,000 people worldwide.

The city still restricts access to locations like the Huanan market, which was linked to the first identified cluster of infections in December.

At another wholesale market in the far north of city, which is open to the public, Reuters was tailed by security staff and deterred from speaking to stallholders and traders.

“If you don’t allow people to visit these places, you give people the impression you have something to hide,” said Yanzhong Huang, senior fellow at the Council on Foreign Relations in Washington who studies the politics behind China’s health issues.

ORIGINS

China rejects conspiracy theories surrounding the coronavirus, including claims without evidence that a specialist virology institute in Wuhan manufactured it. But many unanswered questions remain about the origins of COVID-19 and the role played by the trade in exotic wildlife in Wuhan.

Though authorities closed the Huanan market in January, there is a growing scientific consensus that the virus did not originate there. Some studies suggest it was already in circulation by the time it reached the market, with more than one transmission route.

“I agree with the general idea that the virus jumped into a human before the Wuhan market,” said David Irwin, professor of medicine and pathobiology at the University of Toronto. “They may have been a trader that had been exposed either directly to the virus in a host animal or interacted with farmers or other traders outside of Wuhan.”

China has shown little appetite for an international enquiry into the origins of COVID-19 or for allowing more scrutiny of its efforts in the early stages of the outbreak, preferring to focus on the country’s rapid economic and psychological recovery.

“There is no doubt that China has been very successful in containing the virus, so why can’t they be more open?” said Huang. “If you want to dispel those myths… you don’t need to worry about people visiting the market or even the virus institute.”

https://www.reuters.com/article/us-health-coronavirus-china-wuhan/nothing-to-see-covid-origins-off-limits-as-chinas-wuhan-touts-recovery-idUSKBN25X08E