Teva Sells Record $5 Billion of Sustainability-Linked Bonds

 Teva Pharmaceutical Industries Ltd., one of the largest generic-drugmakers in the world, sold a record $5 billion in bonds tied to environmental, social and governance targets.

The company, through its finance units, raised the funds in U.S. dollar and euro denominated bonds on Tuesday after the offering was upped by $1 billion, according to a person with knowledge of the matter. The longest portion of the four-part deal, a euro-denominated 8.5-year security, yields 4.375%, after initially being marketed in the high 4% area, the person said.

“The upsizing of the issuance is a testament to the demand for ESG-linked bonds,” Bloomberg Intelligence analyst Mike Holland said in a telephone interview Tuesday. “It certainly doesn’t hurt that this deal is wrapping up on the same day that Teva, along with J&J and Endo, have their first win in California.”

Superior Court Judge Peter Wilson in Santa Ana on Monday rejected claims that units of J&J, Teva, Endo International Plc and Abbvie Inc.’s Allergan Plc duped doctors and patients about the addictiveness of opioid painkillers and created a so-called “public nuisance” tied to the medications.

Proceeds from the bond sale together with cash on hand will fund a $3.5 billion tender offer announced last week for a series of notes maturing through 2024, according to a statement. Proceeds will also be used to pay back outstanding debt upon maturity or earlier redemption and for general corporate purposes.

“The company has been guiding for a large liability management exercise for some time but concerns around litigation risks had thrown a wrench in the gears for them to be able to do a regular bond financing,” said Holland.

https://finance.yahoo.com/news/teva-sell-record-5-billion-152310124.html

NRx: Favorable Safety Report in NIH Sponsored Study in Patients with Life-Threatening COVID

 After Review of More than 300 Enrolled Patients in ACTIV-3b Critical Care Study, No New Safety Concerns Raised by Independent Data Safety Monitoring Board; Study Cleared to Continue Enrollment to Target 640 Patients

- ACTIV-3b Critical Care Study is Evaluating ZYESAMI® (aviptadil) and Remdesivir, in Critical COVID-19 Patients, as Monotherapy and in Combination Against Placebo

- ACTIV-3b Critical Care is a Public-Private Partnership Sponsored by the US National Institutes of Health to Treat COVID-19

https://finance.yahoo.com/news/nrx-pharmaceuticals-announces-favorable-safety-150400241.html

Ocugen Nov. 9 call on Q3 results, business update

 Ocugen, Inc. (NASDAQ: OCGN), a biopharmaceutical company focused on discovering, developing, and commercializing gene therapies to cure blindness diseases and developing a vaccine to save lives from COVID-19, today announced that it will host a conference call to discuss its third quarter 2021 financial results and provide a business update at 8:30 a.m. ET on Tuesday, November 9, 2021.

Ocugen will issue a pre-market earnings announcement on the same day. Investors are invited to participate on the call using the following details:

• Dial-In Number: (844) 873-7330 (U.S.) or (602) 563-8473 (international)

• Conference ID: 8198297

• Webcast: Available in the “Investors” section of the Ocugen website and archived for approximately 45 days following the call

https://finance.yahoo.com/news/ocugen-host-conference-call-tuesday-220800538.html

S.Korean Teens Drive up COVID-19 Cases Ahead of Full School Reopening

 South Korea said on Wednesday it would ramp up COVID-19 testing at schools after a sharp rise of infections among children, weeks ahead of a plan to fully reopen schools nationwide.

The surge comes as new social distancing rules aimed at a phased return to normal came into effect on Monday as a part of the country's plan to gradually move toward living with COVID-19 on the back of high vaccination rates.

South Korea has fully vaccinated nearly 90% of its adult population but only began inoculating children aged between 12 and 17 in recent weeks, administering just 0.6% of the age group with both doses so far.

"There is a growing concern as the frequency of new cluster outbreaks has been increasing, centred on educational facilities such as private tuition centres and schools," Interior and Safety Minister Jeon Hae-cheol said.

The government would expand the use of portable polymerase chain reaction (PCR) diagnostic tests for COVID-19 in schools in Seoul and neighbouring regions, and mobilise more virus-prevention personnel in overcrowded schools, he said.

South Korea plans to fully reopen schools nationwide from Nov. 22.

The country reported 2,667 new cases for Tuesday, an increase of more than 1,000 from the day earlier. Nearly one fourth of the new cases were found in teenagers, officials said.

"The teenagers spend a lot of time in communal living such as schools and tuition centres and they are also active in social activities," Son Young-rae, a senior health ministry official, told a briefing.

"We believe that the risk of infection will inevitably rise and the confirmed cases will continue to surge stemming from these teenagers."

South Korea has not seen a noticeable increase in seriously ill cases among teens, with just one out of 378 severe COVID-19 patients being treated in hospitals. South Korea has also reported a relatively low mortality rate of 0.78%.

Vaccination for the 12-17 age group began in October, using Pfizer/BioNTech, shots.

https://www.usnews.com/news/world/articles/2021-11-03/south-korean-teens-drive-up-covid-19-cases-ahead-of-full-school-reopening

China COVID-19 cases spike ahead of Communist Party conclave

 China’s new locally transmitted COVID-19 cases spiked to a near three-month high and tighter curbs to contain the spread are expected in the capital Beijing in the run-up to a key gathering of the highest-ranking members of the Communist Party next week.

The National Health Commission confirmed on Wednesday 93 new local symptomatic cases for Nov. 2, up from 54 a day earlier and the highest daily count since Aug. 9 at the peak of China’s last major outbreak.

Beijing reported eight new local infections, the most since Jan. 19.

While the new cases accrued each day by the Chinese capital city since late October have remained very modest compared to outside of China, the country’s zero-tolerance policy has meant the imposition of strict measures to contain the spread of the virus at all costs.

Temperature screening has been set up at entrances of shopping malls, supermarkets, hotels, cinemas and subway stations, while a legion of personnel on the ground check the health codes of visiting individuals on their mobile phones.

Beijing authorities have also repeatedly told residents to refrain from traveling out of the city, postpone weddings, simplify funeral arrangements, and cut back on all non-essential gatherings.

Of the flights scheduled on Wednesday at Beijing Daxing Airport, 60.4% have been cancelled as of the morning, while 49.8% of flights at Beijing Capital Airport have been scrapped.

The rise in Beijing infections comes as the 300-plus members of the Communist Party’s Central Committee prepare to gather in a major closed-door meeting on Nov. 8-11. It will be the committee’s sixth and penultimate so-called plenum of its five-year term before the next big Party Congress in 2022.

At the plenum, President Xi Jinping is expected to push through a resolution that will cement his authority and legacy and strengthen his case for a precedent-breaking third term starting next year.

Outside of Beijing, new local infections were reported in the north, northeast and northwest in provinces and areas including Heilongjiang, Hebei, Gansu, Inner Mongolia, Ningxia and Qinghai.

New cases were also seen the southwest of China, in the municipality of Chongqing as well as the provinces of Sichuan and Yunnan.

The southern province of Jiangxi reported two new cases.

Inclusive of cases imported from overseas, China reported 109 new confirmed infections for Nov. 2 compared with 71 a day earlier.

As of Nov. 2, mainland China had 97,423 confirmed cases.

https://newsinfo.inquirer.net/1509842/china-covid-19-cases-spike-ahead-of-communist-party-conclave

AbbVie preps filings after ABBV-951 tops oral Parkinson’s drugs in trial

 AbbVie has reported that a subcutaneous infusion of Parkinson’s disease candidate ABBV-951 was more effective than standard oral therapy in a phase 3 trial, paving the way for regulatory filings.

ABBV-951 is based on foslevodopa and foscarbidopa – delivered via a subcutaneous device once a day – with the aim of providing full 24-hour control of Parkinson’s symptoms that can’t be achieved easily with oral dosing of levodopa and carbidopa.

The head-to-head trial showed that patients taking ABBV-951 had a statistically significant increase in “on” time without dyskinesia – in other worlds period where the muscle symptoms associated with Parkinson’s were controlled without involuntary, uncontrolled movements – at 12 weeks.

There was also a reduction in “off” hours, when Parkinson’s symptoms re-emerge, which tend to get longer as the disease progresses, and the tolerability of subcutaneous delivery was generally good with only mild or moderate side effects, according to AbbVie.

If approved, ABBV-951 could be an alternative to oral therapy – whose efficacy tends to fall off over time – as well as sustained delivery approaches such as AbbVie’s own Duopa, a form of carbidopa/levodopa delivered in gel form via a gastric tube and pump that requires a surgical procedure.

Duopa is generally reserved for use in people with advanced Parkinson’s disease who are still responding well to levodopa-based therapy, but despite its limitations still manages to bring in around $500 million a year. AbbVie sees ABBV-951 as an approach that could significantly expand that market.

In the study, the increase in “on” time without dyskinesia at week 12 was 2.72 hours for ABBV-951 versus 0.97 hours for oral levodopa/carbidopa, with decreases in “off” time of 2.75 hours and 0.96 hours, respectively.

“Patients need more therapeutic options to control their symptoms and troublesome dyskinesia for this debilitating disease,” said Jason Aldred, of the University of Washington, a principal investigator of the study.

“These data are promising and demonstrate positive results on a key endpoint used to assess efficacy of treatments for patients with advanced Parkinson’s,” he added.

AbbVie said full results from the phase 3 study – called M15-736 – will be presented at a future medical meeting or submitted for publication in a peer-reviewed journal.

https://pharmaphorum.com/news/abbvie-preps-filings-after-abbv-951-tops-oral-parkinsons-drugs-in-trial/

Centessa claims a place in the antitrypsin deficiency pipeline

 Vertex lost $6bn in market cap in June after failing in its second attempt in alpha-1 antitrypsin deficiency. Meanwhile, Arrowhead has more than doubled in value, to $6.7bn, since its RNAi approach to the rare disease first showed promise.

There is always more than one driver behind a company’s valuation, of course, but these two examples help illustrate the substantial potential that investors see in a successful AATD treatment. There are only a handful of projects in clinical development, and Arrowhead remains in pole position, though approaching readouts from the likes of Mereo and Inhibrx could firm up the pipeline.

Centessa claimed to join that queue yesterday with the first look at clinical data on its phase 1 project ZF874. A liver toxicity signal means that investors remain to be convinced, however, and for now the biggest bets are being placed on more advanced assets. 

Current market

AATD is an inherited condition causing no or very low levels of a protective enzyme inhibitor, alpha 1 antitrypsin. In its natural form AAT, which is made in the liver, protects the lungs from damage. This means that AATD patients, particularly those who inherit two copies of the malfunctioning gene, are at heightened risk of developing lung diseases like emphysema.

In the liver, mutated or misfolded versions of AAT, sometimes called Z-AAT, build up, causing progressive damage and in rare cases requiring liver transplant. There are no specific treatments available for liver manifestations, although AAT augmentation therapy has been developed for those with severe lung disease.

That treatment involves harvesting normal AAT from blood plasma for infusion, though its benefits have been long debated, and it is not available in all countries. This has not hindered a billion-dollar market, however; it is worth noting that AAT augmentation products are very costly.

Grifols is the dominant player here thanks to a product it acquired with the US biotech Talecris a decade ago; Takeda has a presence thanks to its Shire purchase, which it in turn gained it via Baxter. This explains the Japanese pharma company’s ongoing interest, which last year included cornering certain rights to Arrowhead’s project for $300m up front.

It seems that, should new approaches to AATD make it to market, Grifols has the most to lose.

 Prolastin-C (Grifols): $857m

In terms of the pipeline, RNAi approaches are the most advanced, although these are primarily directed at the liver problems caused by AATD. Arrowhead’s ARO-AAT is considered most promising for now, based on small cuts of data that have been released this year from an ongoing, open-label phase 2 study.

The latest update will emerge at the AASLD meeting this coming weekend. The project, also called TAK-999, works by knocking down production of the mutated Z-AAT protein in the liver. Like most work in this space the focus here is on patients with a homozygous PiZZ mutation, who are most likely to develop severe complications of AATD.

The newly released AASLD abstract describes mean reductions of Z-AAT in the liver of 80-89%, over two cohorts of 16 patients in total, measured at 24 and 48 weeks. Signals of improving liver function and fibrosis have also been seen.

Some analysts reckon ARO-AAT could reach the US in 2022. A more rigorous phase 2 trial called Sequoia is fully enrolled, and should also start generating data next year; how quickly the FDA is prepared to move here is a big question for Arrowhead investors.

Coming behind is Dicerna’s similar RNAi therapy belcesiran, though so far only early results in 18 patients have been reported. These were promising, however, and a larger phase 2 trial, Estrella, has already begun. Alnylam has an option over ex-US rights but, unless a clear safety or efficacy advantage is seen, Dicerna needs to bring on a larger partner if belcesiran is to be considered real competition to Takeda and Arrowhead.

The AATD pipeline
Project	Company	Mechanism	Details
Phase II
TAK-999	Arrowhead/Takeda	RNAi therapeutic	Ph2 Sequoia fully recruited; awaiting plans for pivotal development/filing
Belcesiran	Dicerna (Alnylam option)	RNAi therapeutic	Ph2 Estrella study recruiting
Alvelestat	Mereo (from Astrazeneca)	Neutrophil elastase inhibitor	Ph2 data due by YE 2021 (targeting lung manifestations only)
Phase I
INBRX-101	Inhibrx	Recombinant AAT fusion protein	Ph1 data reported Oct 2021; next update expected H1 2022
ZF874	Centessa	Small-molecule AAT inhibitor	Initial ph1 data reported Nov 2021
Preclinical
AAT gene therapy	Intellia Therapeutics	Crispr/Cas-9 gene therapy	Preclinical work ongoing
AAT research programme	Vertex Pharmaceuticals	AAT correctors	Next-gen programmes to enter clinic in 2022
APB-101	Apic Bio	AAT gene therapy	IND enabling studies ongoing
KB408	Krystal Biotech	Gene therapy	Preclinical data presented Oct 2021
Source: Evaluate Pharma & company statements.

The other mid-stage contender is Mereo, which is aiming at patients with AATD lung disease. Its project, alvelestat, is proposed to work by inhibiting the lung-damaging neutrophil elastase enzyme, a role normally played by AAT.

A phase 2 trial that should yield data before the end of the year primarily measures reductions in desmosine, a biomarker of neutrophil elastase activity. A larger phase 3 trial looking at harder endpoints is a likely next step.

Back further in the pipeline are Inhibrx and Centessa, both of which claim to have the solution for both liver and lung manifestations of AATD.

Centessa

Lying behind Centessa’s efforts is a belief that the disease can be treated by prompting the faulty AAT protein to fold correctly. ZF874 is a pharmaceutical chaperone that, as the company describes it, acts as a molecular patch. Clinical proof of mechanism was claimed yesterday from data in three patients – levels of functional AAT returned to normal in the two who received ZF874.

A toxicity signal in one patient removed the shine, however, and the company’s insistence that a way forward could be found by changing the dosing schedule failed to impress. Centessa’s shares dropped 19% on the update. 

Finally, Inhibrx is pursuing arguably the most straightforward approach with its recombinant AAT-Fc fusion protein, INBRX-101. This could offer a more convenient and cost effective option over AAT augmentation therapy and, according to Inhibrx, complement RNAi approaches.

Shares in the company have advanced 68% since the first look at phase 1 data were released in October. The next update, which will concern a larger patient cohort, is due in the first half of 2022; the attention of bigger players already present in AATD has presumably already been piqued.

That will likely include CSL and Grifols. True, several gene therapies are in preclinical development, but it is easy to understand how INBRX-101 might feel like a surer bet for those with market share to lose.

https://www.evaluate.com/vantage/articles/news/trial-results/centessa-claims-place-antitrypsin-deficiency-pipeline