Novartis looks to former neuro glories

 When it comes to neuropsychiatric drugs, Novartis peaked in 2011. In that year sales of its therapies that broadly fall into the categories of cognitive, mood and movement disorders topped $3bn; since then these revenues have fallen dramatically. But the company appears to be getting back into this area judging by its latest deal, in which it bought Cadent Therapeutics for $210m up front. Cadent’s pipeline encompasses CAD-9303, an NMDAr positive allosteric modulator scheduled to enter phase II trials in schizophrenia next year, and CAD-1883, a modulator of SK channels, whose phase II trial in spinocerebellar ataxia is currently on hold owing to the Covid-19 pandemic. Cadent is also developing MIJ821, a phase II-stage NMDAr negative modulator which was licensed to Novartis in 2015 by Luc Therapeutics, one of the two companies from which Cadent was subsequently formed. Other than MIJ821 Novartis’s own pipeline contains just one clinical-stage neuropsychiatric project, LMI070, an SMN2 gene splicing modulator in phase II for depression. Still, Novartis is big in multiple sclerosis, with Kesimpta and Mayzent forecast to sell nearly $3.4bn between them in 2026, EvaluatePharma consensus shows. Perhaps the Swiss firm believes its MS salesforce can handle its new CNS therapies, too.

 Ritalin (ADHD): 143

https://www.evaluate.com/vantage/articles/news/snippets/novartis-looks-former-neuro-glories

Entresto set for big sales hike after FDA panel endorsement

 Novartis’ Entresto is on course to become the first drug to be approved in the US for a form of heart failure that is notoriously hard to treat effectively, despite missing the mark in a phase 3 trial.

An FDA advisory committee 12 to 1 in favour of approving Entresto (sacubitril/valsartan) for heart failure with preserved ejection fraction (HFpEF), which accounts for around half of all heart failure cases but proves highly resistant to drug treatment. In HFpEF, the heart muscles pump normally but the organ is too stiff to fill properly.

Entresto is already approved to treat heart failure with reduced ejection fraction (HFrEF), caused by the heart muscles not pumping effectively, and has revitalised the treatment of patients with this form since its launch in 2015.

After a slow start, it has grown to become a $1.7 billion product last year, and that represented a surge from around $1 billion in 2018 revenues.

Analysts have predicted that approval in HFpEF – which affects around 3 million people in the US alone – could more than double Entresto’s sales, perhaps driving them as a high as $5 billion a year. There’s also plenty of upside in HFrEF as three out of four eligible patients are still not being treated with the drug, according to Novartis.

The prospect of adding HFpEF to Entresto’s label looked shaky last year however, when the drug missed its primary objective in the phase 3 PARAGON-HF trial.

The 4,822-patient study missed statistical significance for a composite primary endpoint of reducing cardiovascular death and total heart failure hospitalisations by 13% compared with valsartan alone, but only by a whisker, and Novartis has been upbeat since about the chances of approval.

The published data from the study suggested that the drug performed better in women, people with structural abnormalities in the left ventricles of their hearts, and those with very low ejection fractions – the amount of blood pushed out of the heart each beat.

The positive vote by FDA advisors came after the FDA reviewer acknowledged the narrow miss for statistical significance and pointed to the pressing need for a drug treatment for HFpEF.

The agency’s own expert said that “various pre-specified and post-hoc analyses suggest that sacubitril/valsartan compared to valsartan reduces HF events” in HFpEF, and of course Entresto’s long track record of safety stands in its favour.

While the FDA doesn’t have to follow its advisory committee’s advice it generally does, and Novartis is now eyeing approval of Entresto in HFpEF in the first quarter of 2021.

The main question now is exactly how the FDA will word the label if it approves the drug, with panellists debating the use of ejection fractions percentages to guide treatment with little agreement.

PARAGON-HF in included patients with left ventricular ejection fraction (LVEF) of 45% or more, but earlier studies have suggested the drug can have a benefit in people with scores below 40%.

https://pharmaphorum.com/news/entresto-set-for-big-sales-hike-after-fda-panel-endorsement/

Macrogenics gets to market, but what comes next?

 In the end, perhaps Macrogenics never needed to talk up a supposedly stronger responding subgroup in Sophia, margetuximab’s breast cancer trial. The Her2-targeting drug, now branded Margenza, was granted an all-comers label by the FDA yesterday in late-line metastatic disease. No mention was allowed on the label of data in carriers of the F-allele, a group of patients in which the company claimed Margenza works better than Herceptin. That has not been definitively proven and it is not inconceivable that Macrogenics will give up on this and try to make the most of the label it has won. With the Her2-targeting space very competitive – Astrazeneca’s Enhertu and Seagen’s Tukysa have both seen strong launches – and Margenza carrying two black box warnings, this will be no easy task. Sales forecasts show that Margenza is not expected to make big waves, although should Sophia unexpectedly yield an overall survival benefit at the final readout next year, opinions could shift. In any case it is the remainder of Macrogenics’ pipeline that investors are watching. The first readout of the Mahogany trial early next year is the next big event, with a number of other assets following behind.

Margenza and beyond: a selection of Macrogenics' trials
Trial and setting	Regimens tested	Details
Sophia: Metastatic, refractory Her2+ breast cancer	Margenza + chemo vs Herceptin vs chemo	Final overall survival readout due H2'21
Mahogany; 1L Her2+ gastric cancer	Margenza + retifanlimab (anti-PD-1); + tebotelimab (anti-PD-1xLag-3 bispecific); vs Herceptin + chemo	First read out due from cohort A (Her2+PD-1) in H1'21, and decision on whether to expand enrollment for registrational purposes.
Margot: Stage II-III Her2+ breast cancer	Margenza + Perjeta + paclitaxel vs Herceptin + Perjeta + paclitaxel	Academic trial, started July 2020.
Refractory, metastatic solid tumours	MGD013 (tebotelimab, anti-PD-1xLag-3 bispecific) +/- Margenza	Basket study primarily of MGD013; expansion cohorts added recently in late-line breast and gastric.
Source: clinicaltrials.gov, company statements.

 Perjeta (Roche): $5 265m

https://www.evaluate.com/vantage/articles/news/snippets/macrogenics-gets-market-what-comes-next

Novo takes the plunge in Alzheimer’s

 Is Novo Nordisk brave or foolhardy? The company’s decision to take its oral GLP-1 analogue Rybelsus into pivotal trials in Alzheimer’s next year is certainly bold – especially given the recent failure of the Elad trial of the similarly acting Victoza, and a flop this week from VTV Therapeutics, another proponent of the Alzheibetes hypothesis.

During a conference call yesterday, Novo execs were keen to point out that Elad was only part of the puzzle, and put forward a host of other data supporting its move. With academics calling for further investigation of the GLP-1s in Alzheimer’s, Novo has stepped up to the plate, and the gamble is probably one that the Danish group can afford to take.

What cost?

Executives would not give a definitive figure for the cost of the two trials that are set to begin in the first half of next year and will enrol a total of 3,700 early Alzheimer’s patients between them. But the company’s chief financial officer, Karsten Munk Knudsen, said this would equate to a mid-single-digit percentage of Novo's total R&D budget over the next few years.

Novo plans to up its investment in research over this period; however, using last year’s R&D spend of $2bn as a rough guide would put the cost of the studies at around $100m.

An analysis by Evaluate Omnium, based on the costs of previous Alzheimer’s and Rybelsus trials, puts the figure higher, at around $350m.

Either way, this will not break the bank for Novo. And the group believes that it has reasons for optimism here despite the failure of Elad, an academic-led study of Victoza, Novo’s once-daily injectable GLP-1 (CTAD 2020 – Elad fails, but GLP-1s could still have a future in Alzheimer’s, November 6, 2020).

Martin Holst Lange, senior vice-president of global development, noted that the Covid-19 pandemic had led to some missing data in Elad that might have affected the results. He added that Elad, which enrolled patients with mild Alzheimer’s, covered a different population to the one Novo will evaluate in its phase III trials, which will encompass both mild cognitive impairment and early Alzheimer’s.

He then pointed to a body of evidence that, Novo believes, supports its decision. Perhaps most intriguingly, a post-hoc analysis of the group’s cardiovascular outcomes studies of its various GLP-1s found a 53% lower risk of dementia in patients receiving the drugs versus those on placebo.

Source: Company presentation

This analysis does not have the rigour of a prospective clinical trial, and Novo’s other supporting data come from real-world registries and animal studies. It is surprising that the group is going straight into pivotal development without testing its hypothesis in a smaller phase II trial.

Perhaps time is of the essence. The two trials will take three to four years to complete, executives said yesterday. And other diabetes drug developers might also want to get in on the act. The most obvious would be Lilly, which has an injectable GLP-1 in the shape of Trulicity, and also an interest in Alzheimer’s.

Clinicaltrials.gov does not reveal any ongoing studies of Trulicity in Alzheimer’s. But a post-hoc analysis of the Rewind trial of Trulicity found a 14% decrease in cognitive impairment in those receiving the drug.

GLP-1s have shown a “multitude of activities” that might be relevant in Alzheimer’s, according to Novo’s chief scientific officer, Mads Krogsgaard Thomsen, from metabolic and blood flow improvements to anti-inflammatory effects.

VTV flops again

However, another company banking on a connection between Alzheimer’s and diabetes has fallen short for a second time. After hours on Tuesday, VTV Therapeutics’ Rage inhibitor azeliragon flunked the phase II Elevage study in patients with mild Alzheimer’s plus type 2 diabetes.

The asset had already crashed in a pivotal trial in Alzheimer’s without diabetes two years ago. The latest failure sent VTV's stock down 23% yesterday.

Novo saw a better reaction from the market to its news, with its shares climbing 3% yesterday. The consensus seems to be that studying Rybelsus in Alzheimer’s is a risk worth taking.

https://www.evaluate.com/vantage/articles/news/corporate-strategy/novo-takes-plunge-alzheimers

COVID vaccine is bonanza for digital supply chain tracking industry

 More than half of vaccines go to waste globally every year because of temperature control, logistics and shipment-related issues.

Logistical hurdles are a significant risk for efforts to rapidly distribute COVID-19 vaccines, but they have resulted in booming business for companies such as private California-based Cloudleaf, Germany’s SAP SE and others that sell technology for monitoring shipments from factory freezer to shot in the arm.

Cloudleaf, backed by Intel Capital, the venture arm of chipmaker Intel Corp, uses sensors attached to material containers to track the location, temperature, humidity, vibration and acceleration.

The sensors send data to the cloud, where an artificial intelligence algorithm can predict if action is needed to prevent a product from becoming exposed to temperatures outside the recommended range, known as excursions.

Cloudleaf Chief Executive Mahesh Veerina said orders have jumped 500% this year. To keep pace, the company had to expand its workforce and increase capital spending by as much as 80%. He expects a similar growth in capital spending in 2021.

“I have CEOs calling and saying ‘Hey, can we get this up in the next 4-5 weeks’?” Veerina said.

The booming business has also increased the need for fresh capital. Cloudleaf has raised millions of dollars this year and has plans to raise “very significant” amounts of capital next year too, Veerina said.

Pfizer Inc and German partner BioNTech’s vaccine must be shipped and stored at ultra-cold temperatures or on dry ice and can only last at standard refrigerator temperatures for up to five days.

In contrast, Moderna Inc’s vaccine, which is expected to receive U.S. regulatory authorization as soon as Friday, can be kept in a regular refrigerator for up to a month.

These varying requirements have increased the risks of logistical mishaps.

A quarter of all vaccines are degraded by the time they arrive at their destination due to incorrect shipping procedures, according to the International Air Transport Association. Losses associated with temperature excursions in the healthcare industry are estimated at about $35 billion annually.

Given the scale and the magnitude of the COVID-19 vaccine rollout, the losses could be significantly higher in 2021, analysts said.

At least two trays of COVID-19 vaccine doses delivered in California needed to be replaced after their storage temperatures dipped below minus 80 Celsius (minus 112 Fahrenheit), U.S. Army General Gustave Perna said on Wednesday.

Blockchain and sensor-enabled cold chain monitoring tools can help reduce the losses as well as mitigate the risks of theft or counterfeiting of the vaccines.

Moderna is using SAP’s digital solutions to help serialize and distribute its vaccine. The applications are designed to prevent counterfeit medicines and enable collaboration with contract manufacturers and wholesalers.

BOOMING DEMAND

Similarly, Israeli startup Varcode, which makes smart tags that measure time and temperature, and can track and trace products throughout the supply chain, has seen a multifold jump in orders.

Before the pandemic, the orders for Varcode’s tags would range between 100,000 to 1 million units. Since the middle of this year, Chief Executive Joe Battoe said some of the companies involved in the vaccine distribution have been asking for billions of tags. This, in turn, has led to a 200% increase in Varcode’s capital spending this year.

Battoe said the pandemic had “been good for our business.”

Varcode’s low-cost cloud-based, blockchain-enabled technology not only sends out alerts when a product goes outside its prescribed temperature range, but also captures the cumulative time that the product has been outside of the temperature range.

Its smart tags are serialized and need just a smart phone to scan them. Every scan leaves a digital trail, reducing the risks of theft or counterfeiting.

The tags can track individual vials, making them a better fit for the vaccine distribution in small and rural areas which may require fewer than the minimum order of doses.

Varcode’s tags are produced in Israel. The soaring demand, however, has prompted Varcode to invest in a unique printer and an applicator that would generate the tags on site where the vaccines are being manufactured and apply them to carts going down the conveyor belt in real time.

Battoe reckons the $5 billion global cold chain monitoring technology market could grow 50% next year, thanks to the vaccine rollout.

“I don’t think we would be garnering the attention ... had it not been for the scale and the sensitivity of these vaccines,” Battoe said.

https://www.reuters.com/article/health-coronavirus-tech-supplychain-focu/covid-vaccine-is-bonanza-for-digital-supply-chain-tracking-industry-idUSKBN28R1EX