Mexico said on Thursday that it plans to take part in stage 3 trials of the Russian coronavirus vaccine in October, part of the nation’s efforts to secure supplies of possible future COVID-19 vaccines.
Foreign Minister Marcelo Ebrard said that if the Mexican regulator permits it, the Russian vaccine can be brought to Mexico and several thousand volunteers will “test that vaccine in our country as close as next month”.
Ebrard has previously said that 2,000 Mexican volunteers would take part in clinical trials of Russia’s “Sputnik V” vaccine.
The race to produce a vaccine has become a contest for influence and prestige among major powers, while developing economies are trying to ensure a fair distribution of the medicines.
Mexico has engaged in a diplomatic push to forge COVID-19 vaccine alliances across a wide ideological spectrum of countries from France to Cuba as a World Health Organization (WHO) vaccine initiative is expected to fall short of its needs.
This technical report addresses a pressing issue in the trajectory of the coronavirus outbreak; namely, the rate at which effective immunity is lost following the first wave of the pandemic. This is a crucial epidemiological parameter that speaks to both the consequences of relaxing lockdown and the propensity for a second wave of infections. Using a dynamic causal model of reported cases and deaths from multiple countries, we evaluated the evidence models of progressively longer periods of immunity. The results speak to an effective population immunity of about three months that, under the model, defers any second wave for approximately six months in most countries. This may have implications for the window of opportunity for tracking and tracing, as well as for developing vaccination programmes, and other therapeutic interventions.
AnPac Bio-Medical Science (NASDAQ:ANPC) surges 28% premarket on the heels of positive results from a successfully completed multi-year lung cancer prognosis and recurrence study in collaboration with a major hospital in China.
The study began in 2014 with the enrollment and completed all follow-up and testing in 2020. Approx. 1,000 confirmed lung cancer patients were tested using AnPac Bio’s cancer differentiation analysis (CDA) technology.
Initial results indicate that CDA technology could act as a viable tool for measuring and evaluating lung cancer treatment, efficacy and recurrence following remission.
A summary of the results from the study are as follows:
CDA values are statistically different between complete response (CR) patient group and stable disease patient group, and between CR group and progressive disease group, indicating that CDA could be used for cancer prognosis.
Patient groups with higher CDA values (higher cancer risk or progression) have statistically lower five-year survival probability than patient groups with lower values which shows that CDA values could be a good indicator predicting the outcome of a treatment (survival probability).
In a number of cases, CDA values increased ahead of the onset of the cancer’s recurrence, indicating that the technology could potentially be used as a recurrence monitor.
Why companies may choose to not submit their drugs to NICE and keep them off routine commissioning – a trend that appears to be on the rise.
Appraisal of a treatment by the National Institute for Health and Care Excellence (NICE) is voluntary; companies can simply choose not to submit, resulting in a statement from NICE that the appraisal was terminated due to non-submission.
Yet this will have consequences because non-submission is looked upon dimly by the biggest buyer of specialised medicines, NHS England. Their policy is clear; their default position is not to routinely commission the treatment. Yet it is clear that companies choose not to submit to NICE, that raises questions; why and so what?
Rise in non-submissions
NICE first saw companies choosing not to submit in 2008/9 and since then more and more have taken this option. In 2019/20 close to 1 in 5 of NICE’s recommendations was a non-submission.“Companies may simply be putting the UK further down the priority list due to Brexit. The referendum was held in June 2016; it does look like non-submissions have been going up since then”
In total, there were 54 non-submission recommendations from NICE from 2008/09 to 2019/20. The reasons for non-submission are of course not clear from NICE’s data – they will only be known by the companies involved.
The companies who have chosen to not to submit – at least at the time and in the indication being looked at by NICE and based upon the company name identified as supplying the treatment in the Electronic Medicines Compendium (EMC) – include (number of non-submission recommendations in brackets):
Amgen (3)
Bausch & Lomb (2)
Bayer (1)
BMS (2)
Boehringer Ingelheim (1)
Celgene (2)
Chiesi (1)
Eli Lilly (1)
Gilead (3)
Ipsen (1)
Janssen-Cilag (6)
Merck Serono (1)
MSD (3)
Novartis (5)
Pfizer (2)
Roche (7)
Takeda (1)
In 12 non-submissions, the company could not be identified because either there were several names in the EMC (likely because the treatment is now off patent) or were not found.
NICE introducing charges for appraisals was seen as a potential driver of non-submissions by companies according to consultants at Athena Market Access Solutions and Tolley Health Economics, in advance of their introduction. This was a concern particularly for smaller companies who may find the charges prohibitive (which in 2019/20 ranged from £22,000 to £215,000).
NICE introduced charges on the 1 April 2019. Since then there have been 10 non-submissions, but all but one of the treatments are from companies who are listed in the top 100 by revenue for 2019. This perhaps suggests that fees for small companies aren’t likely to be driving non-submissions (so far). It could also be a function of whether small company treatments are invited for appraisal; that’s something that needs more data mapping to know.
It is possible to look at some of the features of the treatments which perhaps help explain non-submissions. Of the 54 treatments, 24 (44%) are for conditions categorised as rare by Orphanet. Seventy-eight per cent are in the antineoplastic and immunomodulating agents (many of which are cancer) according to WHO’s ATC classification.
Whilst the underpinning evidence to support use of these treatments for rare conditions has not been looked at – this would after all be what NICE would have wanted to have seen if companies had submitted – it is not a stretch to think that there could be challenges in the robustness of the clinical evidence base. The challenges could be, for example, small sample sizes in trials, or single arm trials, given that many of the treatments are for rare conditions.
What could also be a factor – with the limited ability to offer different prices for different indications and/or use in combination – is the potential for companies to prefer to forgo an indication and/or combination use because it’s going to compromise revenues.
In essence, if a company has already launched and secured approval, but needs a lower price in another indication/combination, they would need to lower the price for all use under current rules.
Whilst it’s hard to know if this is the case, there are 54 non-submissions for 44 treatments that in total – including non-submissions – have 162 recommendations. This suggests that there are products that have been put through appraisal in another circumstance – be that in another position in the pathway, indication or combination – but where companies have decided not to submit in another.
It’s also true that it could be a function of the anticipated finding from NICE; NICE committees are guided not just by the clinical evidence but the value for money too. Depending upon the price being sought and the wider costs and cost offsets, companies could anticipate that they would not be able to meet NICE’s cost-effectiveness thresholds.
Of course, Brexit could play a role and companies may simply be putting the UK further down the priority list when it comes to securing market access. The referendum to leave the EU was held in June 2016; it does look like non-submissions have been going up since then.
Does it matter?
There are different schools of thought about whether non-submissions are an issue, at least from an NHS perspective. If treatments are simply not that clinically effective then arguably it’s not a big concern. If they aren’t cost-effective – at prevailing thresholds – that could be argued to mean that other, more cost-effective treatments that can generate more health for scarce NHS pounds can be bought. If it’s due to inflexible pricing rules that don’t allow for the commercial drivers it’s arguably more of an issue as there is the potential for health to be generated cost-effectively – although the counter argument to this is affordability, as different prices for different indications could add more spend to the system overall.
For NICE, non submissions are a double-edged sword; less to do, yet since they charge companies for appraisals, it also means less income. Charges are, to a degree, predicated on volumes of expected number of appraisals with fixed costs spread across appraisal activity. If NICE does far less than it expects it’s not going to successfully recoup costs. This could change charges in the future too.
From a company perspective, it does seem that companies are willing to forgo a NICE appraisal, and perhaps it doesn’t affect their reputation.
Yet, if you are the patient, it must surely be frustrating that something that could help you, and that has been approved by the regulator, isn’t going to be easily available. It means you have limited options to access the treatment, be that paying privately, relying on a clinician to apply for exceptional funding, or seeking access perhaps via ongoing trials or compassionate use from the company.
Of course, whether an issue is important enough to address also relies on the scale of the problem. It certainly looks like non-submissions are on the rise so we might expect more discussion on the issue and potential solutions – one of which could be a genuine openness to indication-based pricing – to be pushed for in the future.
Cardiac safety threatens to derail the company’s new anaemia pill, but should rival Fibrogen be celebrating?
Safety concerns have long haunted Akebia’s oral anaemia project, vadadustat, and yesterday those fears materialised. The pill demonstrated worse cardiac safety than the epo agent Aranesp in two crucial chronic kidney disease studies, a finding that could wreck vadadustat’s chances of approval.
This is clearly a disaster for Akebia, which lost three-quarters of its market cap on the assumption that vadadustat is over, even if it does manage to limp onto the market. Fibrogen is already considered the leader in this field as the developer of a more advanced HIF-PH inhibitor, roxadustat, and the removal of a close rival could prove advantageous. But this company’s stock also fell yesterday, suggesting that the situation is not that simple.
True, Fibrogen shares did initially rise on the vadadustat news, and then closed down 7% as wider markets retreated. There are reasons for both caution and optimism here.
In terms of plus points, the fact that Fibrogen could have the market to itself, along with marketing partners Astellas and Astrazeneca, is certainly a big one. Glaxosmithkline also has a HIF-PH inhibitor, daprodustat, in pivotal development, but results are unlikely to emerge before 2022.
All contenders are going after two distinct markets: dialysis-dependent patients, and those yet to progress to dialysis. While epo is widely used to treat anaemia in this first group, the known cardiac risks of the class mean very few receive it in the latter setting, where patients are generally less sick.
In its pivotal programme Fibrogen demonstrated that roxadustat was non-inferior to placebo on both efficacy – mean haemoglobin change – and cardiac safety in both groups. The company is certainly not without its critics, with many concerned that roxadustat will not stand up to regulatory scrutiny. But at this point no adcom has been called ahead of a December Pdufa date, and this has been read as a positive sign.
The problem lies in non-dialysis patients. In the Pro2tect trials vadadustat was again pitted against Aranesp, with the former proving non-inferior on the primary efficacy endpoint, mean change in haemoglobin. But on the primary safety endpoint, time to first major adverse cardiac event, a hazard ratio of 1.17 failed to cross the non-inferiority margin of 1.25.
This suggests that patients in the vadadustat arm were at a greater risk of dying or suffering a heart attack or stroke than those taking Aranesp. Given that this margin had been prospectively agreed with the FDA it seems implausible that approval could be considered in these patients.
Approval in dialysis-dependent patients is also surely threatened; however, Akebia still has a broad label in its sights. Full data from the four-trial pivotal programme will be presented at the American Society of Nephrology’s annual meeting in October, and from the “totality of the data” a path forward will emerge, executives insist.
On a conference call “regional and other patient characteristics” were hinted at, to explain the different safety findings between Pro2tect and Inno2vate. Inno2vate enrolment was skewed more to the US, Akebia executives said; it seems that blame might be laid at the feet of different standards of care in other parts of the world.
“When you see the data together you will agree we have a path forward,” chief executive John Butler said. “It’s not a straightforward path forward …. but we believe it supports approval in both dialysis and non-dialysis patients.”
Akebia’s argument thus seems somewhat contradictory, claiming that these indications are distinct, but at the same time that approval can be gained on the “totality of the data”. A meeting with the FDA is planned for later this year, when regulators will have to decide whether any of this holds water.
Class effect?
The implications of all this on Fibrogen are still hard to gauge; vadadustat aside, it is far from assured that roxadustat will get the clean, broad label the company is after. Why vadadustat would fail where roxadustat seemed to succeed also becomes a crucial question.
They are different molecules, of course, and the answer could be this simple; Fibrogen bulls have long argued that roxadustat is better designed and dosed. Trial design is another factor, with roxadustat pitted against placebo and vadadusat versus an active agent. This can also be argued in Fibrogen’s favour, as it is surely harder to demonstrate non-inferior safety against a sugar pill.
But until the FDA’s verdict on roxadustat emerges, it is impossible to rule out fears of a class effect being reflected on any label. It is understandable that some view the Pro2tect finding as increasing the chances of that outcome.
Initiated with a Outperform at Cowen, Alphatec Holdings (ATEC -1.9%) has recorded an impressive 15.6% in the past one month as against a 5.9% gain in the broader index (NYSEARCA:XLK); PT of $12, indicating upside of 110.9% from current levels.
Analyst Joshua Jennings notes that the company’s turnaround story is de-risked but still in the early innings.
He further adds that the company has made major progress in revamping its product portfolio (new product revenue contribution stood at 61% vs. nil in 2Q17), distribution network, and surgeon customer base (revenue from top surgeons +51% in Q2).
Percentage of sales driven by strategic channel stands at 91% vs. 56% in 2Q17.
Upcoming share catalysts and revenue drivers include the launch of the company’s proprietary prone transpsoas technique, which should strengthen investor sentiment, says Jennings.
The U.S. Federal Trade Commission (FTC) has voted 3-1-1 approving a final order settling charges that AbbVie’s (ABBV +0.1%) $63B takeover of Allergan would violate federal antitrust law.
The complaint, filed in May, claimed that the tie-up would likely harm current competition in the exocrine pancreatic insufficiency (EPI) treatment market and future competition in IL-23 inhibitors.
The final order requires the companies to divest Allergan’s EPI meds Zenpep (pancrelipase) and Viokase (pancrelipase tablets, powder) to Nestlé S.A. (OTCPK:NSRGY) and Allergan’s IL-23 inhibitor brazikumab to AstraZeneca (AZN -1.3%).
