AHA: AstraZeneca, Moderna shine early light on mRNA potential in heart failure

 Although AstraZeneca and Moderna are archrivals in the COVID-19 vaccine space, the two have an interesting mRNA pact that has been operating largely under the radar.  

For years, the pair has quietly been plugging away using Moderna’s mRNA technology to help patients with heart disease (as well as other diseases), and new midstage data out today offer a glimmer of hope that, outside of infectious disease, this platform could have a broader scope.

We know mRNA players such as BioNTech, Moderna and CureVac are all gunning for influenza and cancer with their tech, having already swiftly proven its worth in treating SARS-CoV-02, but heart failure may be a viable target, too.

Since around 2017, AstraZeneca and the then little-known, pre-IPO and pre-COVID Moderna were working away on several mRNA assets for heart disease.

One of these therapies, AZD8601, encodes for vascular endothelial growth factor (VEGF-A), a protein that induces the growth of blood vessels, and has today in a phase 2a test met its primary endpoint of hitting safety and tolerability in patients with heart failure.

The data, officially released at the American Heart Association Scientific Sessions Monday, were the first from a clinical trial injecting what AZ calls “naked” mRNA directly into the heart of patients undergoing elective coronary artery bypass surgery (CABG).

It works as an mRNA-based therapy, with mRNA formulated in a citrate saline buffer in the absence of lipid encapsulation that encodes for VEGF-A for local administration in patients undergoing CABG. The idea is that it can help the spur the heart to heal after damage.

We don’t know whether it can work on a large commercial scale as, for now, we’re getting a peak at a small study made up of just 11 patients in which seven were treated with AZD8601 and four received placebo injections.

But AZ and partner Moderna said “trends were observed in the three exploratory efficacy endpoints,” namely: left ventricular ejection fraction, NT-proBNP—a biomarker that measures the level of a hormone and is elevated in patients with heart failure—and functional patient reported outcomes compared with placebo.

“Although the data is limited to show significant effect, it provides opportunity for AstraZeneca to move to further trials with AZD8601,” the U.K. Big Pharma said. There are still many questions to be answered,  and deeper tests to be done, but the pair is at least confident enough to move on to the next stage.

“Over one billion heart cells can be lost during a heart attack,” said Mene Pangalos, executive vice president, for biopharmaceuticals R&D at AstraZeneca.

“These early results indicate the potential of mRNA therapeutics in stimulating VEGF-A production to provide reparative and disease-modifying options for patients with heart failure and other ischaemic vascular diseases.”

Novartis’ Entresto is one of the more recent drugs to be approved for heart failure, though the condition, and heart disease in general, remains a major unmet medical need around the world.

https://www.fiercebiotech.com/biotech/aha-astrazeneca-moderna-shine-early-light-mrna-potential-heart-failure

BioMarin's new launch Voxzogo could become a surprise blockbuster: analyst

 After a period of "stagnant" growth at BioMarin—as characterized by one analyst team—the drugmaker could be on the brink of its next big launch. The company's dwarfism drug Voxzogo already has its European approval in hand, and it's due for an FDA decision later this week.

BioMarin management has voiced high expectations for Voxzogo, but investors haven't come around to the med, SVB Leerink analyst Joseph Schwartz wrote to clients on Sunday. After conducting a doctor survey on the medicine and others, the analyst sees "significant opportunity that could revive growth that has been stagnant" for BioMarin.

In August, Voxzogo scored approval in Europe to treat achondroplasia in patients two years and older until their growth plates close, which is typically around 18 years. The med is under review at the FDA, with a decision date set for Saturday, Nov. 20.

Patients with achondroplasia, the most prevalent form of skeletal dysplasia, develop a "short stature and truncated limbs," Schwartz wrote. The condition "may appear cosmetic on the surface," but it's "associated with life-threatening comorbidities that can increase mortality," he added. Doctors consistently see it as a disease with a "huge unmet need."

After SVB Leerink's recent doctor survey, Schwartz and his team believe adoption "could be swift," with about 30% of eligible patients starting on the therapy within a year. The team is projecting $1 billion in peak sales. 

One factor supporting uptake is that patients are "readily identifiable" and most are "born to parents with normal height who are likely more motivated than not to treat their children," the analyst noted. In addition, doctors may want to start treatment quickly while a patient's growth plates are open.

From a "commercial execution standpoint," the company has an "extensive sales force worldwide that could readily execute a global launch from their years of being a commercial company," Schwartz noted. 

But the drug faces some uncertainties. The disease is "fraught with social complexities making the adoption of Voxzogo not very straightforward." With that challenge considered, and because some of other BioMarin launches haven't lived up to management's expectations, some investors remain skeptical, Schwartz wrote.

With all of the factors considered, Schwartz believes there's reason to buy into BioMarin's enthusiasm for Voxzogo. This summer, BioMarin's chief commercial officer Jeff Ajer said the company had teams "in place and well-prepared for what could be BioMarin's largest brand yet."

Aside from BioMarin, other potential achondroplasia treatments are in development at Ascendis Pharma, BridgeBio and Pfizer, Schwartz wrote. 

https://www.fiercepharma.com/pharma/biomarin-s-voxzogo-could-surprise-investors-and-become-a-blockbuster-analyst

Apellis' eye med application on track for next year after FDA OKs inclusion of phase 2 data

 After posting mixed phase 3 readouts in September, Apellis Pharmaceuticals' investigational eye drug pegcetacoplan is poised to hit the FDA's desk in geographic atrophy with a mix of mid- and late-stage data. 

The FDA gave Apellis the OK to use safety and efficacy data from two phase 3 trials, Derby and Oaks, plus the phase 2 Filly trial, when it files the drug for approval in geographic atrophy secondary to age-related macular degeneration in the first half of 2022. The company said it doesn't believe it will need to run any additional studies. 

GA, which is an advanced form of AMD that can lead to vision loss and blindness in older adults, has no FDA-approved treatments. Apellis' drug targets the protein complement component 3, which the company says is the only target that can precisely control complement overactivation, which drives lesion growth.

Pegcetacoplan, the active ingredient in Apellis' rare disease med Empaveli, won approval in May in patients with the rare blood disorder paroxysmal nocturnal hemoglobinuria. 

In written feedback, the FDA told Apellis it doesn't distinguish between trial phases, so long as the studies are adequate and well-controlled. All three trials Apellis plans to use in its application package meet those standards, the agency said, according to Apellis' release. 

Back in September, pegcetacoplan posted a win in the phase 3 Oaks study, where it slashed GA lesion growth by 22% and 16% in patients who received the drug monthly and every-other-month, respectively. In Derby, however, pegcetacoplan only reduced lesions by 12% and 11% in the same patient cohorts. Neither study raised significant safety concerns, although the drug was linked to slightly higher rates of exudation, or emitted fluid. 

Apellis' chief medical officer Federico Grossi, M.D., Ph.D., has pointed to the drug's potential as the first FDA-approved treatment for GA secondary to age-related AMD, which can cause blindness. 

While the "totality of the evidence" bodes well for pegcetacoplan, it was previously unclear whether the FDA would sign off on the addition of the Filly study to Apellis' filing package. The FDA's phase 2 blessing marks "an important de-risking for the submission process," Cantor Fitzgerald analysts wrote in a note to clients Friday. The drug's efficacy across the three related studies sits at around 20% reduction in GA lesion, the analysts said. 

Some 1 million Americans and 5 million people globally suffer from GA. If pegcetacoplan can succeed where others, like Roche's complement-inhibiting drug lampalizumab, have failed, it could be looking at $3 billion in peak sales, Jefferies analysts have predicted.

Earlier this year, Apellis entered the commercial realm when pegcetacoplan scored approval in paroxysmal nocturnal hemoglobinuria (PNH). In that disease, it's challenging Alexion's big-selling Soliris and the company's follow-up Ultomiris.

https://www.fiercepharma.com/pharma/apellis-eye-med-application-track-after-fda-oks-inclusion-phase-2-data

TG cut to Sell from Neutral by Goldman

 Target to $26 from $33

https://finviz.com/quote.ashx?t=tgtx

AHA 2021 – Merck’s oral cholesterol lowerer could heap more misery on Esperion

 Merck & Co might have succeeded where others have failed and developed an oral PCSK9 inhibitor. Data presented at the American Heart Association meeting today, although early, put the cholesterol-lowering abilities of Merck’s project, MK-0616, on a par with injectable PCSK9 MAbs from Amgen and Sanofi/Regeneron and Novartis’s longer-lasting RNAi therapy Leqvio. The results could also represent another nail in the coffin for Esperion; that group has struggled to sell its oral therapy Nexletol, which it had positioned between statins and PCSK9s, arguing a convenience advantage over the latter. However, cholesterol lowering of 15-25% with Nexletol alone, or around 38% when combined with ezetimibe, pales against around 65% LDL-C lowering with Merck’s agent in phase 1. Merck’s Douglas Johns, presenting the MK-0616 results, admitted that larger studies would now be needed. But he added that availability of an oral agent could extend the reach of PCSK9 inhibitors, whose uptake has been limited. Still, one reason for lack of use has been the high cost of the MAbs – Mr Johns told a press briefing that it was too early to talk about MK-0616's price tag, but that this was something Merck was taking “very seriously”. 

LDL lowering with the PCSK9 inhibitors
Product/project	Company	Description	LDL lowering
MK-0616	Merck & Co	Oral PCSK9	~65%
Repatha	Amgen	SC PCSK9 MAb	55%*
Praluent	Sanofi/Regeneron	SC PCSK9 MAb	58%**
Leqvio (inclisiran)	Novartis	SC PCSK9 RNAi therapy	50-52%^
All on top of background statins; Repatha, Praluent & Leqvio data placebo-adjusted; SC=subcutaneous; *Descartes; **Odyssey Long Term; ^Orion-10 & 11. Source: product labels, clinicaltrials.gov & NEJM article. https://www.evaluate.com/vantage/articles/news/snippets/aha-2021-mercks-oral-cholesterol-lowerer-could-heap-more-misery

Philips sinks beneath the foam

 Philips is working hard to get its respiratory technologies back on track, but its efforts have been set back again. After its ventilators were recalled in the summer when the polyester-based polyurethane foam used to quieten them was found to be potentially dangerous the FDA said on Friday that an alternative, silicone-based foam used in one device had failed a safety test.

Shares in the Dutch group are down 12% so far today, and some analysts had warned that other ventilator players could be hit by the controversy since they use similar silicone foam components. In fact the opposite has occurred: Philips’ main respiratory rival Resmed is up 6% in premarket trading, and New Zealand-listed Fisher & Paykel closed up 5%. Philips might have a hard time winning shareholder and customer confidence back. 

The issues started for Philips in June, when it recalled some of its ventilators and sleep apnoea devices. The recall was prompted by the discovery that the polyester-based polyurethane foam used to dampen sound made by the machines, many of which are used as the patient sleeps, can break down in ways that might be dangerous. The foam could degrade into particles which might be ingested or inhaled by the user, or could give off chemicals that might be toxic.

In July the FDA designated the recall class 1, the most serious kind. 

Foam party

Following the initial recall, Philips devised a plan to replace the faulty foam with a different, silicone-based foam. The FDA approved this plan on the back of results of tests on the new foam Philips provided to the agency in June.

During an inspection of one of Philips’ manufacturing sites, however, the FDA found that the new silicone-based foam used in a device sold outside the US had failed a safety test for the release of volatile organic compounds. 

Devices authorised for marketing in the US had passed similar tests, the agency said.

The FDA has requested that Philips retain an independent laboratory to determine what risks may be posed to patients by the silicone-based foam. Philips said yesterday that it was already working with independent labs. 

In the mean time, devices with this silicone foam are already in use by patients in the US. The FDA said that it does not yet have enough data to be able to say how risky these products might be; for now it has stopped short of recommending that patients stop using them. 

Timeline of Philips' ventilator troubles
Date	Event
Jun 14, 2021	Philips voluntarily withdraws certain ventilators, bi-level positive airway pressure and continuous positive airway pressure machines after the sound abatement foam they use is found to be potentially toxic
Jun 30, 2021	The FDA issues a safety alert about the devices
Jul 22, 2021	The FDA designates the recall class 1, the most serious kind
Nov 12, 2021	The FDA releases the findings of an inspection of one of Philips' manufacturing sites, stating that the new foam used to replace the foam previously identified as faulty has also failed a safety test
Nov 14, 2021	Philips responds to the FDA's findings, saying it will will work closely with the agency to resolve the situation, and pointing out that it is working with independent labs to conduct further testing of its products.
Source: FDA and company communications.

While Philips might have avoided another recall for now, its stock has taken a battering. Berenberg analysts wrote that the FDA’s request for further study of the foam could have “wider connotations” for all sleep apnoea device players, including Resmed, which they say is the major adopter of silicone-based foam components today. 

So far any connotations appear to be positive. Investors in Resmed and Fisher & Paykel clearly believe that these groups can step in to the gap left by Philips, as today’s stock jumps show. 

Even before the latest development, sales of Resmed’s respiratory technologies had been forecast to grow at an annual rate of 10% out to 2026, according to Evaluate Medtech’s sellside consensus data, and F&P’s at 5%. Philips’s respiratory business, meanwhile, is forecast to grow at 3% per year. 

AHA 2021 – Amarin not prepared in Covid battle

 Amarin is officially two for two in its failure to prove that its only product, Vascepa, has any impact on reducing infections, hospitalisation rates or death from Covid-19. Today it was the turn of the Prepare It-2 trial to disappoint. Results presented at the AHA conference showed that, among non-hospitalised Covid patients, there was no significant difference with Vascepa versus placebo on the primary endpoint, Covid hospitalisations or death. However, there was a numerical improvement with Vascepa. A generous interpretation might be that Prepare It-2 was underpowered. But confirmation of any signal would require Amarin to conduct a much larger trial, a difficult endeavour given rising vaccination rates and improved treatment options. Today’s data follow a flop in the Prepare It-1 trial, which showed that Vascepa did not prevent healthcare and public workers at high risk of Covid from catching the virus. Success in any of the trials would have been helpful for Amarin, which this year lost a battle to protect patents on Vascepa. With no seeming Covid boost on the horizon, and US competitors already on the market, Amarin will have to rely on increasing Europe sales, but a recent launch in Germany has disappointed.

Prepare-IT slide

https://www.evaluate.com/vantage/articles/news/snippets/aha-2021-amarin-not-prepared-covid-battle