Anteris Technologies Ltd

Invention:	Biomimetic aortic valve
Trademark:	DurAVR™
Patents:	10+
ASX:	AVR

EXECUTIVE SUMMARY

DurAVR is a transcatheter aortic valve replacement (TAVR) used to treat aortic stenosis (a narrowing of the aortic valve). Unlike competitor valves, the anti-calcification material (called Adapt) from which it is made produces zero calcification (a primary cause of stenosis), making the valve more durable. Furthermore, unlike other anti-calcification materials, Adapt can be molded. This allows the company to produce a mold of Adapt material in the shape of a native aortic valve, whereas existing valves comprise three pieces of tissue sutured to a frame. This "biomimetic" shape produces normal hemodynamics and flow, whereas three-piece valves leave the patient in mild stenosis.  

​Multiple patents protect Adapt, the biomimetic design of the DurAVR valve, and the ComASUR catheter system that delivers the valve. 
 
The incumbent valve (Sapien) from which DurAVR will take market share currently has over 100 times the market value of Anteris.

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AVR

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INTRODUCTION

Aortic stenosis is a narrowing of the aortic valve, causing an increase in blood pressure above the normal level. Picture the effect that the narrowing of a water nozzle has on water pressure.
 
It is mostly caused by calcification – the buildup of calcium – around the valve, but is also caused by wear-and-tear on the valve. There is no pharmacological therapy for calcification. The only solution is to replace the valve with an aortic valve replacement (AVR) by open-heart surgery (SAVR) or transcatheter (TAVR). TAVR procedures have outnumbered SAVR procedures in the US since 2019:

DurAVR has been designed for delivery with the company's proprietary catheter system, called ComASUR, which uses a balloon-expandable approach. The valve is placed on the catheter, which is then inserted through the femoral artery and fed over the aorta. Once the valve is manoeuvred into position, a balloon on the catheter expands the valve, and the catheter is removed leaving the valve in place. 

As at June 2024, DurAVR is yet to achieve TGA, CE or FDA approval. The valve has been successfully implanted in over 60 human patients, 15 of which were conducted in the United States as part of the company's FDA Phase II Early Feasibility Study (EFS). Design and recruitment for a Phase III pivotal trial is set to commence in 2024. The pivotal trial is a randomized trial that will compare DurAVR to the standard of care (Sapien and Evolut); and its primary endpoint is non-inferiority (all-cause mortality, stroke, or hospitalization) at 12 months. 


A PRIMER ON HAEMODYNAMICS

The aortic valve opens and closes with the passage of blood flow. The clearance provided for blood flow when the valve is maximally open is called the effective orifice area (EOA). A normal (healthy) valve has an EOA of ~2cm^2. When a valve’s EOA is reduced below normal levels by calcification or wear-and-tear, the valve is said to be in stenosis. The result is an increase in blood pressure (mean gradient) above the normal (healthy) level of 5-10mmHg (millimetres of mercury). The lower the EOA, the higher the mean gradient. 
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In the context of AVR, haemodynamics refers to the effects that the EOA has on mean gradient. In summary, an aortic valve with ‘healthy’ haemodynamics would have an EOA of ~2cm^2 and a mean gradient of 5-10mmHg.

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COMPETITION FACTORS

Direct competitors

Edwards Lifesciences Corp have 65% of the TAVR market with their Sapien valve. MedTronic PLC has the other 35% with its Evolut valve. DurAVR and Sapien are balloon-expandable transcatheter approaches, whereas Evolut is a self-expanding approach. DurAVR is expected to take market share directly from Sapien, its closest incumbent substitute. 

Substitutes
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There is currently no pharmacological therapy for calcification. 


THE INVENTION

Existing TAVR valve leaflets are made from animal tissue that is treated with a proprietary anti-calcification process. For example, Sapien 3 Ultra RESILIA (the standard of care by Edwards Lifesciences) uses a proprietary material, called RESILIA, which is bovine pericardium. The valves are made by suturing three pieces of such material to a frame.

1. Tissue science (biochemistry): Adapt
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The material from which the DurAVR leaflet is made is bovine pericardium tissue that has been treated with the company's patented anti-calcification process, called Adapt. Adapt-treated tissue is the only TAVR leaflet material on the market to show zero calcification at 10 years (NWR Healthcare Conference, March 2023). This is due to the fact that Adapt has undetectable levels of free aldehydes, a main driver of calcification-mediated valve deterioration.

2. Valve design: Biomimetics
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The Adapt process has a unique property of allowing the processed bovine pericardium to be molded. This allows Anteris to produce a mold of Adapt-treated tissue in the shape of a native aortic valve.​​

Adapt tissue molded to the shape of a native aortic valve

The ​DurAVR valve is essentially such a mold sutured to a cobalt chromium stent. 

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PERFORMANCE ADVANTAGES

Durability
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As a result of Adapt's superior anti-calcification profile, DurAVR is more durable than existing valves. Its single-piece leaflet construction also requires far fewer sutures to be secured to the stent frame (roughly 100 compared to 800 for existing 3-piece valves). This provides greater structural integrity, further increasing the valve's durability. ​The increased durability makes the valve accessible to younger patients, and thus increases the size of TAVR's addressable market (USD$10b by 2028). 

Hemodynamics

The leaflets of 3-piece valves are secured to a stent frame with hinges that restrict the opening area of the valves. DurAVR’s single-piece tissue mold can be secured to a frame without the use of this infrastructure. As such, its leaflets open to the full extent of the frame and thus provide additional clearance for blood to flow through the aorta.
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DurAVR

Sapien 3UR

​The restoration of an essentially normal (pre-disease) hemodynamics means that DurAVR is curative. ​

​Here is how DurAVR compares to Sapien 3 in head-to-head hydrodynamic bench tests (Janar Sathananthan, MD - presented at TCT 2022):
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Clinicians have classified DurAVR as the first "biomimetic" valve (i.e. one whose geometry mimics the anatomy of a native valve), thus giving DurAVR a first-in-class designation. Below we can see that, due to the molded construction, DurAVR's leaflets are shaped to be closed like a native valve:

DurAVR

Sapien 3

​​Leaflet kinematics and coaptation

Leaflet kinematics refers to the motion of the valve leaflets. DurAVR's biomimetic design results in a more native-life leaflet kinematics, whereby the leaflets tend to bulge as they begin to open and then finally "snap" or "pop" open into a fully expanded position that they maintain during systole. This contrasts with the leaflets of existing valves, which tend to swing like doors on a hinge and produce a flapping motion while open.

​Due to a longer coaptation zone (>8mm), which measures the portion of the leaflet tips that are in contact when in the closed position, the leaflets also exhibit less pinwheeling (twisting). These properties result in a lower level of turbulence on the valve, which further benefits durability. 

Aortic flow

The most important consequence of native-like leaflet kinematics and coaptation is a normalization of aortic flow, which concerns the directionality of the blood's flow through the aorta. Whereas existing TAVR valves result in a turbulent flow, DurAVR's biomimetic design produces a laminar (and therefore normal or pre-disease) aortic flow. 
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The more turbulent the flow of blood, the more energy the heart is expending to distribute blood through the body. As such, by normalizing aortic flow, the valve's biomimetic design is increasing the heart's energy efficiency. 

Aortic flow is measured by Flow Displacement (FD) and Flow Reversal Rate (FRR). For reference, a healthy aortic valve might have Flow Displacement of ~12% and a Flow Reversal Rate of ~0%. Here is how DurAVR compares to other valves on these dimensions in bench tests (presented at AVR AGM 2022):
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Commissural alignment

The ComASUR system includes a patented feature that enables the valve to be uncoupled from the delivery system and rotated for commissural alignment. The native design of the leaflets also enables the valve to be better aligned with the native commissures, which relieves backward pressure on the ventricle and permits greater "washout" of the sinuses, both of which improve the valve's aortic flow.

Coronary access

The native design also enables a shorter valve frame height without sacrificing haemodynamics. This is beneficial for coronary access in the event of future valve-in-valve interventions. 

COST ADVANTAGES 

The lower quantity of sutures in the DurAVR valve may confer an advantage in production costs. 

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​PRICING

Several factors enable TAVR to sustain a price (~USD$35,000) far in excess of the SAVR substitutes (~USD$8,000), and far in excess of unit costs:

• TAVR duopoly (Edwards and Medtronic)*
• Low concentration (bargaining power) of hospitals as a buyer group
• Lower length of hospital stay compared to SAVR
• Low price sensitivity and high performance sensitivity of physicians

* TAVR can also be modelled as two monopolies: Edwards in balloon-expandable systems, and Medtronic in self-expanding systems. 

​Physicians are expected to transition to DurAVR when priced at parity with incumbent TAVR products. 


INTELLECTUAL PROPERTY
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Anteris has 60 patents covering Adapt, the single-piece mold of the leaflets and the structural design of the DurAVR valve, and the ComASUR catheter system. See reference number US11648107 for the patent covering the biomimetic design.

​It is largely the unique properties of the Adapt material that enables the company to manufacture a single-piece leaflet that is molded to the shape of a native valve. The anti-calcification materials used by competitor valves (such as the RESILIA material used in the most recent iterations of Sapien) are difficult to mold into single-piece 3D configurations. Being a biochemical substance, the Adapt material and its associated production processes are difficult to reverse engineer. And even if competitors succeed in molding their respective anti-calcification materials into a single-piece configuration, Anteris's patents on the biomimetic design will inhibit their commercialisation. 

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​KEY OPINION LEADERS

Remarks by TAVR specialists on the DurAVR valve:

• "Think about how our patients are benefiting from this...The ability now to think that we could treat younger people with bioprosthetic valves with the hope that it might be the only valve they ever need, with haemodynamics that simulate a normal valve. It's pretty mind-boggling." - Marty Leon, MD (TCT discussion, 2022)
• "It's pretty much a slam dunk for older patients." - Rebecca Hahn, MD (AGM interview, 2022)
• "For other clinicians who have never seen the data, you've just got to be there to look at the valve, look at the leaflet and the numbers. It's quite astounding." - Carl Poon, MD (AGM interview, 2022)
• "I think there is always a trend in research, people try to follow each other. You need sometimes for someone to come and say that we need to look at things differently. This is why DurAVR is a new concept, which I am sure will have major implications for the future of this therapy." - Thomas Modine, MD (TCT discussion, 2022)
• "The haemodynamics of this valve are absolutely stunning." - Mike Reardon, MD (TCT discussion, 2022)
• "What we are seeing is single digit mean gradients and EOAs above 2 for intra-annual technology in small annuli. And I have not seen that with any technology thus far." - Azeem Latib, MD (PCR discussion, 2023)
• [Re. valve-in-valve] "I was searching for a valve that would be a short frame valve, but I wanted to give the patient a good hemodynamic result. And I had concerns in a smaller surgical valve that I wasn't going to get that with the commercially available balloon-expandable short-frame...One of the attractive features of the DurAVR is the short frame, the windows are large, the coronary access is preserved...but it's really the superior hemodynamics - the single-leaflet construction, no suture lines, and really being able to put an intra-annular prosthesis in place in a short frame but then giving a good hemodynamic result and being able to get back in the coronaries...Initially on the table post valve deployment we had a mean gradient of 7. The following day on trans-thoracic echo we had a mean gradient of 13. So in a small Trifecta with a balloon expandable intra-annular valve, that's spectacular...It's certainly as good as the results we've seen with the supra-annular valves that we've used. Actually even better I would say." - Anita Asgar, MD (PCR interview with Vinayak Bapat, MD, 2023)

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VALUE FACTORS

Notwithstanding the risks inherent in the clinical trials of a pre-commercial medical device, Anteris appears dramatically undervalued when we consider the following. 

Anteris has a market cap of AUD$350m (USD$235m) as at 29th June 2024.

​Sapien revenues (65% of the market) are USD$3.5b per annum, and comprise 65% of Edwards revenue. Edwards has a market cap of USD$50b.

If we assume Sapien comprises $35b (65%) of Edwards market cap, then the Sapien product - the valve most likely to lose share to DurAVR - is currently priced at over 100 times the market value of Anteris. 


Image credits: Anteris Technologies, Edwards Lifesciences