A broader use for Regeneron’s Covid-19 antibody combo

 Having earlier failed with its antibody combo in the sickest hospitalised Covid-19 patients Regeneron yesterday claimed an important success. This came courtesy of the UK’s Recovery trial, which has backed the treatment thanks to being large enough and looking primarily at patients failing to mount an immune response of their own.

The result could see the US emergency use authorisation for Regeneron’s combo extended, as this currently covers only non-hospitalised patients. However, such a move would likely call for patients presenting in hospital with Covid-19 first to be tested for seropositivity, to weed out those who are already mounting their own immune response.

This is key to the findings in this cohort of the Recovery trial, which randomised 9,785 people hospitalised with Covid-19 to receive either Regeneron’s casirivimab plus imdevimab with standard of care, or standard of care alone.

Though these were all-comers in terms of serostatus, the primary analysis concerned only those seronegative at baseline, amounting to 3,153 of those enrolled. 5,272 were seropositive, meaning that they were producing their own antibodies against the coronavirus, and the remainder’s serostatus was unknown.

It was in the primary, seronegative, population that Regeneron’s combo scored on Recovery’s primary endpoint of all-cause mortality at 28 days: with median survival not reached for either arm, a landmark analysis showed 76% survival at 28 days with casirivimab plus imdevimab, versus 70% for standard care.

This amounted to a 20% reduction in risk of death at any point in the 28 days (p=0.001). The University of Oxford, Recovery’s sponsor, said this amounted to six fewer deaths for every 100 seronegative patients treated with the antibody combination – a result that seems strong enough to back authorisation in this setting.

Smart statistical decision

The decision to focus primarily on seronegatives was taken after a smaller phase 1/2 trial in hospitalised Covid-19 patients suggested a benefit in this subgroup, though only in terms of viral load, which was reduced significantly versus placebo at day five, while no effect was seen in seropositives.

A sequential analysis in Recovery also looked at all-comers, and found no statistically significant effect on 28-day mortality, which was 20% for the combo versus 21% for standard care (p=0.17). Moreover, specifically in seropositives there was a 9% greater risk of death across the 28 days for the combo versus control.

It seems rational that patients unable to mount their own immune response would benefit most from an antibody treatment, and those who do mount a response would logically skew any benefit by improving survival in the control as well as the active group.

Source: Recovery investogators & Medrxiv preprint server.

Yesterday’s positive result owes much to smart statistical decision-making, based on previous experience. That experience included an earlier setback in Regeneron’s hospitalised patients trial, in which cohorts with the sickest patients were halted owing to a negative risk/benefit profile.

Based on that result it came as a surprise that a week later an advisory committee recommended the continuation of Recovery cohorts in all hospitalised patients – a decision vindicated by yesterday’s readout.

Regeneron might thus be putting clear blue water between casirivimab/imdevimab and competitor MAbs from Lilly and Astrazeneca. While Astra’s AZD7442 yesterday failed in the post-exposure prophylaxis setting, Lilly and Regeneron have both shown encouraging clinical data in prevention of Covid-19 infection among at-risk individuals.

But Regeneron appeared to pull ahead in prevention, with positive pivotal data in April, and yesterday a preprint of the same study, but focusing on 314 asymptomatic patients, found that casirivimab/imdevimab prevented progression to symptomatic disease by 31.5% versus placebo (p=0.0380). Nevertheless, prophylaxis might remain a mere curiosity if antibodies have to be administered in a hospital.

This gives additional importance to the Recovery readout. Dr Martin Landray, one of Recovery’s authors, has suggested a scenario whereby a Covid-19 patient presenting in hospital is first tested for serostatus; if they have antibodies of their own there is no need to give them more, but if they do not then giving them the Regeneron combo cuts chances of death by a fifth.

All that needs to happen now is for casirivimab/imdevimab to be authorised additionally for this use, and for medical practice to include seropositivity testing.

Selected Regeneron MAb combo data in hospitalised Covid-19
Trial	Design	Result
Hospitalised patients	Four cohorts (low-flow oxygen/no oxygen/high-flow oxygen/mechanical ventilation)	30 Oct 2020 - high-flow oxygen & mechanical ventilation cohorts halted on IDMC advice
		29 Dec 2020 - treated seronegative low-flow oxygen patients showed viral load reduction vs placebo
Recovery	Seropositive, seronegative and serostatus unknown patients	15 Jun 2021 - primary analysis in seronegatives shows stat sig reduction in 28-day mortality
		15 Jun 2021 - seropositives and all-comer analyses show no effect on 28-day mortality https://www.evaluate.com/vantage/articles/news/trial-results/broader-use-regenerons-covid-19-antibody-combo

Clearside’s long-acting eye project shows promise

 The wet age-related macular degeneration market is dominated by Regeneron and Bayer’s monthly injection Eylea, but other groups are trying to get a piece of the action by developing longer-lasting options. Clearside Medical is the latest to join the pack, with promising phase 1 data on CLS-AX sending the company’s stock up 38% yesterday.

Still, these results came in just six patients, and Clearside is a long way from proving that CLS-AX’s effect is as durable as it hopes. The company is already pushing the dose higher, but Clearside will need something special to set it apart from the rest of the long-acting pipeline, which includes gene therapies and high-dose Eylea.

Oasis

Stifel analysts believe that CLS-AX, a suprachoroidal pan-VEGF inhibitor, has shown “stand-out differentiation” based on the early results from the Oasis trial. The data reported yesterday involved the lowest planned dose of the asset, 0.03mg.

The trial is primarily evaluating safety, and Clearside said there were no signs of toxicity including inflammation, vasculitis, or intraocular pressure increases.

But it is efficacy data that will have got investors excited. Before enrolling into Oasis, patients had been on standard of care anti-VEGF therapy such as Eylea. At the start of the trial they received 2mg of Eylea, the approved dose, and were assessed after a month. Patients’ vision, measured using best-corrected visual acuity, was on average stable, with a mean decrease of 0.2 letters.

Patients then received 0.03mg of CLS-AX. After a month, five of six patients showed an improvement in their vision; overall, the mean increase was 4.7 letters.

Source: Company presentation

Still, CLS-AX will need to keep showing this effect over a longer time period, and Clearside hopes for durability of six to 12 months.

Here the jury is still out. Only two of the six CLS-AX-treated patients went three months without needing Eylea, although these did continue to show an increase in BCVA, of five to seven letters. The four remaining patients received Eylea after two months.

Clearside now plans to start a second cohort of Oasis, dosing CLS-AX at 0.1mg. There is also scope for a third cohort, at 0.3mg.

If the group can show a long-lasting effect with the higher doses it might have a contender on its hands. But there are plenty of others also trying to get into the long-acting AMD arena.

Selected long-acting projects in development for wet AMD
Project	Company	Description	Dosing interval	Trial(s)
KSI-301	Kodiak Sciences	Intravitreal VEGF-A inhibitor	12, 16 & 20 weeks	Ph2/3 Dazzle, completes Nov 2021
Eylea	Regeneron/Bayer	Intravitreal VEGF-A inhibitor	Every 12 & 16 weeks	Ph3 Pulsar, completes Jul 2022
RGX-314 Subretinal	Regenxbio	Subretinal AAV8 anti-VEGF gene therapy	One-time therapy	Ph2/3 Atmosphere completes Mar 2023; 2nd pivotal study to start H2 2021
RGX-314 Suprachoroidal	Regenxbio	Suprachoroidal AAV8 anti-VEGF gene therapy	One-time therapy	Ph2 Aaviate, data due Q3 2021
GB-102	Graybug Vision	Microparticle depot formulation of pan-VEGF inhibitor	Every 6 months	Ph2 Altissimo reported disappointing data Mar 2021
CLS-AX	Clearside Biomedical	Suprachoroidal pan-VEGF inhibitor	Every 6-12 months	Ph1/2 Oasis, cohort 1 data reported
EYP-1901	Eyepoint Pharmaceuticals	Intravitreal sustained delivery system with VEGF inhibitor	Every 6 months	Ph1 Davio, interim data due Q4 2021
OTX-TKI	Ocular Therapeutix	Intravitreal implant, pan-VEGF inhibitor	Every 6 months or longer	Ph1 US trial to start mid-2021; OUS ph1 completes Nov 2021
ADVM-022	Adverum Biotechnologies	Intravitreal AAV.7m8 anti-VEGF gene therapy	One-time therapy	Ph1 Optic in wet AMD; ph2 Infinity in DME unblinded after serious adverse event
4D-150	4D Molecular Therapeutics	Intravitreal R100 vector (AAV) anti-VEGF/PlGF gene therapy	One-time therapy	Ph1/2 to start  H2 2021
Source: Evaluate Pharma, clinicaltrials.gov & Stifel.

Some of these projects are longer acting than others. At the more frequent end of the spectrum, Regeneron and Bayer are trialling a high 8mg dose of Eylea in an attempt to push injections out to every 12 or 16 weeks. A 2mg dose of the therapy is currently given every month or every two months, after an initial loading period. 

At the other end of the scale, gene therapies offer the promise of a once-and-done treatment. However, this field took a blow with a recent toxicity scare with Adverum’s ADVM-022 in diabetic macular oedema; the project is also being developed for wet AMD.

Regenxbio has a competing gene therapy, RGX-314, which it is developing for subretinal and the less invasive suprachoroidal delivery; the latter project uses Clearside’s microinjector technology.

In short, the competition is fierce and Clearside has a long way to go. Perhaps reality began to sank in for investors today – shares were off 10% this morning.

https://www.evaluate.com/vantage/articles/news/trial-results/clearsides-long-acting-eye-project-shows-promise

Altimmune: Positive Interim Data From ALT-801 Phase 1 Trial In Overweight, Obese Volunteers

 

• Weight loss of 5.4% achieved at 6 weeks of treatment with 1.8 mg once weekly dose, surpassing the 2% pre-established treatment target
• Ascending multi-dose regimen well-tolerated without necessity for dose titration
• Trial continuing with 12-week data expected in Q3 2021
• Company plans to file an additional IND and initiate an obesity program in 2021
• Altimmune to host a conference call today at 8:30 a.m. ET

GAITHERSBURG, Md., June 16, 2021 (GLOBE NEWSWIRE) — Altimmune, Inc. (Nasdaq: ALT), a clinical-stage biopharmaceutical company, today announced results from a prespecified 6-week interim analysis of its ongoing 12-week, Phase 1, placebo-controlled, single and multiple ascending dose trial of ALT-801, an investigational GLP-1/glucagon dual receptor agonist, in healthy overweight and obese volunteers. The study is currently being conducted in Australia under a clinical trial application.

The interim data showed a mean weight loss of 5.4% was achieved by Week 6 with a once weekly ALT-801 dose of 1.8 mg administered subcutaneously (sc) compared to a weight gain of 0.9% in the placebo group (net change from placebo of 6.3%, p < .0001), surpassing the pre-established treatment target of 2% weight loss. All but one subject who received the 1.8 mg sc dose achieved at least 3% weight loss by Week 6. A lower dose cohort that received a weekly 1.2 mg sc dose achieved a mean weight loss of 1.8% (net change from placebo of 2.7%, p < .05) at the same time point. ALT-801 was well-tolerated without dose titration, with transient nausea rates of 14.3% at the 1.2 mg dose and 22.2% at the 1.8 mg dose, and no reports of vomiting, diarrhea or constipation at either dose. All nausea events at the 1.8 mg dose were mild in severity. Gastrointestinal adverse events have required other GLP-1 based agents to dose titrate over 16 to 20 weeks to maintain adequate tolerability.

“These data are encouraging considering that only a 2% weight loss was targeted at 6 weeks of treatment and that nausea rates were low, without emesis, which is particularly notable in the absence of dose titration,” commented Stephen Harrison, MD, Visiting Professor of Hepatology, University of Oxford, and Medical Director, Pinnacle Research. “The high degree of weight loss, the very good safety and tolerability profile, and the absence of dose titration with short treatment duration is very favorable for ALT-801 and makes it an attractive candidate among the GLP-1 class of drugs. Based on the relationship between weight loss and liver fat reduction, and NASH resolution observed in other studies, ALT-801 appears to be a promising therapeutic candidate for both obesity and NASH.”

Because the recruited study population was young (mean age 29.8 years) and non-diabetic, the proportion of subjects with MRI-PDFF greater than 10% was insufficient to perform an analysis of liver fat reduction in this population. Consequently, the Company plans to expand the enrollment criteria and conduct a separate 12-week Phase 1b study of diabetic and non-diabetic subjects with non-alcoholic fatty liver disease (NAFLD) in the United States, which is anticipated to commence in Q3 2021, and to initiate a 52-week biopsy-driven NASH trial in Q1 2022. The expansion of enrollment criteria to diabetic and older subjects will accelerate the recruitment of the target NAFLD population and mirror the anticipated study population in the 52-week trial.

The ALT-801 Phase 1 trial is currently progressing through higher dose cohorts, and the Company plans to report the results following 12-weeks of dosing in Q3 2021. Based on these latest results, Altimmune now plans to file a second IND in obesity in Q3 2021 to supplement its ongoing NASH program.

https://biobuzz.io/altimmune-announces-positive-interim-data-from-alt-801-phase-1-trial-in-overweight-and-obese-volunteers/

CVS accidentally exposed 1B record data, including searches for meds, COVID vax

 

• In March, a cybersecurity researcher discovered a CVS database including 1 billion data points.

• It contained searches for COVID-19 vaccines and medications, the researcher said on Website Planet.

• Researcher Jeremiah Fowler told Forbes CVS took the data set down within one day of him notifying the firm.

A dataset containing 1 billion data points from CVS customers, including searches for medications and COVID-19 vaccines made on CVS.com, was inadvertently posted online.

Cybersecurity researcher Jeremiah Fowler discovered a non-password protected database belonging to CVS Health on March 31. Fowler posted his findings on Website Planet.

The data consisted of searches for medications, COVID-19 vaccines, and other CVS products, Fowler reported. Some searches contained email addresses and "Visitor IDs" that could have matched searches with personal identifying information.

Fowler told Forbes he did not download the full dataset for ethical reasons, as he did not want to collect personal data. The researcher added CVS took down public access to the database within one day of Fowler notifying them.

"The bad part about this finding was just how big it was," Fowler told Forbes in an interview. "In a small sampling of records there were emails from all major email providers."

CVS told Insider the firm determined the database, which was hosted by a third-party vendor, did not contain personal information of customers, members or patients. The firm worked with the vendor to quickly take down the database.

"We've addressed the issue with the vendor to prevent a recurrence and we thank the researcher who notified us about this matter," a CVS spokesperson said in a statement.

https://news.yahoo.com/cvs-inadvertently-leaked-database-containing-140747153.html

Biogen's Aduhelm is already generating enthusiasm among doctors: survey

 Biogen’s Aduhelm may have stirred up controversy after its landmark FDA approval, but some Alzheimer’s disease doctors are tabling the many unanswered questions as they appear ready to prescribe the drug.

Doctors have shown strong interest in prescribing Aduhelm for about 35% of early-stage Alzheimer’s patients with mild cognitive impairment, Jefferies analysts found after surveying 50 U.S. neurologists or psychiatrists who currently treat about 12,000 Alzheimer’s patients.

The rate suggests “good planned uptake” of the med compared with Wall Street’s expectations, the Jefferies team noted. If that enthusiasm pans out in the long run, it could mean at least 300,000 patients taking the drug, or $10 billion to $15 billion in peak Aduhelm from U.S. sales alone, which is above consensus estimates of around $7 billion to $8 billion, the team said.

The FDA has blessed Aduhelm with a broad label that allows doctors to use it in a wide range of patients. Investigators only studied the drug in mild Alzheimer’s patients who tested positive for beta amyloid plaques, which the drug was designed to target, but the label doesn’t restrict Aduhelm’s use based on either a patient’s clinical stage or biomarkers.

In the survey, doctors told Jefferies analysts they’d only require beta amyloid screening in about 60% of their patients. The number is lower than expected and “points to docs wanting to get [patients] on,” the analysts noted. Plus, docs also expressed interest in treating about 10% to 20% of patients that have late stages of the disease.

Still, given the launch hasn’t even started, many uncertainties remain. While the FDA didn't impose any restrictions, a “leading neurologist” who oversees over 1,000 Alzheimer’s patients at his center expects commercial and federal payers will set some limits, the analysts wrote. The expert figured some payers will restrict use around the beta amyloid biomarker and disease severity, the Jefferies team said in a note Saturday.

To the leading expert, demand may vary among physicians based on how they see the drug’s benefits and risks. The doctor has participated in many Alzheimer’s drug trials, including one of the two Aduhelm phase 3 trials Biogen used for its FDA filing.

During the survey, a third of physicians said they’re concerned about payer coverage. Still, the Jefferies team figures reimbursement likely won’t be an issue, at least for Medicare. The Alzheimer’s expert believes Medicare will likely also pay for the beta amyloid test to screen patients.

Another potential hurdle? A quarter of surveyed doctors believe patient access to physicians, screening and infusion centers will pose challenges. The response at least suggests strong demand for Aduhelm, Jefferies pointed out.

Meanwhile, one of the major side effects of Aduhelm is amyloid-related imaging abnormalities, or ARIA, which involves swelling of the brain. To monitor for ARIA, the FDA label currently requires MRI scans prior to infusions at Month 7 and Month 12 of treatment with Aduhelm. The Alzheimer’s expert plans to do more frequent tests despite already constrained MRI machine capacity. Nevertheless, he thinks he can treat 100 patients within the next 12 months and 200 over a couple of years, the analysts wrote.

Biogen has said it can start delivering Aduhelm to about 1,000 infusion centers within weeks. For these centers, the expert pointed out that Medicare’s 6% reimbursement surplus on top of the drug’s average sales price could benefit doctors economically.

https://www.fiercepharma.com/pharma/biogen-s-aduhelm-despite-controversy-could-see-10b-to-15b-u-s-sales-alzheimer-s-doctors

EU Approval of Russia's Sputnik V Vaccine Delayed

 European Union approval of Russia's Sputnik V coronavirus vaccine will be delayed because a June 10 deadline to submit data was missed, two people familiar with the matter told Reuters, diminishing the shot's prospects in the EU's pandemic response.

One of the sources, a German government official, said the failure to provide the necessary clinical trial data to the EU medicines watchdog would postpone any go-ahead in the bloc until at least September.

"Approval of Sputnik will be delayed probably until September, maybe until the end of the year," the official said, speaking on condition of anonymity.

The European Medicines Agency (EMA) had previously been expected to conclude its review of the Russian vaccine and issue a decision in May or June.

A second source said the June 10 cut-off date not been met and that EMA had given the vaccine's developer, Russia's Gamaleya Institute, another week to file the required data.

The Russian Direct Investment Fund (RDIF), which markets the vaccine, said the EMA review was on track.

"All of the information on the Sputnik V vaccine clinical trials has been provided and GCP (General Clinical Practice) review has been completed with positive feedback from the European Medicines Agency," RDIF said.

"While it is up to EMA to decide on the timing of the approval procedure, the Sputnik V team expects the vaccine approval with the next two months," it added.EMA was not immediately available for comment.

German Chancellor Angela Merkel's government has held talks to buy Sputnik V but has made any purchase contingent on EMA approval.

Frustrated by a sluggish immunisation campaign, some regional German states including Bavaria earlier this year flagged interest in placing orders for Sputnik V but vaccination has since picked up speed.

Slovakia became the EU's second country after Hungary to start inoculating people with Sputnik V this month, despite lack of EU approval.

https://www.usnews.com/news/top-news/articles/2021-06-16/eu-approval-of-russias-sputnik-v-vaccine-delayed-sources-say

EU Says J&J to Miss Vaccine Supply Target in Second Quarter

 Johnson & Johnson is expected to miss its COVID-19 vaccine supply target to the European Union for the second quarter after millions of doses were banned for use in Europe over safety concerns, an EU Commission spokesman said.

The setback could cause new delays in the bloc's vaccination drive, although the EU now relies mostly on the Pfizer-BioNTech shot to inoculate its population. More than half of adults in the EU have so far received at least one shot.

The European drugs regulator last week said J&J doses sent to Europe from an Emergent factory in the United States would not be used as a precaution after a case of contamination with substances used for AstraZeneca shots, which are also manufactured in that factory.

EMA said in a statement to Reuters that 17 million doses had been forbidden from being used in the bloc after that decision.

"Following the non-release of these batches, the company is not expected to be in a position to deliver 55 million doses by the end of this quarter," the EU commission spokesman said on Wednesday.

The EU has ordered a total of 200 million doses from J&J, of which 55 million were to be delivered by the end of June. The company has so far delivered around 12 million shots of its single-dose vaccine.

The spokesman declined to say how many doses J&J was now expected to deliver by the end of June.

"The member states and the Commission have voiced their strong concerns regarding this shortfall," he told a news conference, adding that the EU continued to work with the company "towards the delivery of the agreed doses overall in this and following quarters".

Despite the possible delays that this may cause, the spokesman said the EU remained on track to meet its target of immunizing 70% of its adult population this summer.

"Johnson & Johnson remains committed to supplying 200 million doses of its COVID-19 vaccine to the European Union, Norway and Iceland and will continue to update the European Commission and member states in a timely manner as we refine delivery timelines," a spokeswoman for J&J said in a statement.

EMA approval of Russia's Sputnik V vaccine, meanwhile, has been delayed because a June 10 deadline to submit data was missed, sources have told Reuters. The head of Russia's RDIF sovereign wealth fund said on Wednesday it expected the vaccine to be approved by the EU within two months.

https://www.usnews.com/news/world/articles/2021-06-16/eu-says-j-j-to-miss-vaccine-supply-target-in-second-quarter