Millipede’s Play In Percutaneous Mitral Valve Repair

Executive Summary

As medtech strategics race to develop a percutaneously deliverable replacement mitral valve for patients with mitral regurgitation, start-ups tackle an array of mitral repair strategies. Building on a tried-and-true surgical approach, Millipede is developing a catheter-delivered adjustable annuloplasty ring that reduces annular dilation of the mitral valve in order to reduce or eliminate mitral regurgitation.

Market Developments

In 2015, there was rapid progress on multiple fronts in non-invasive cardiac valve replacement and repair. Transcatheter aortic valve replacement (TAVR) is now highly successful, as is Abbott Laboratories Inc.’s mitral-repair procedure MitraClip. Although global experience to date numbers in only dozens of patients, analysts predict a multibillion-dollar market in transcatheter mitral valve replacement (TMVR) that could dwarf even the large TAVR market. Heeding those projections, strategics last summer and fall snapped up companies developing TMVR technologies, including Edwards Lifesciences Corp.’s acquisition of CardiAQ Valve Technologies Inc in July. Medtronic PLC’s of Twelve Inc. in August, HeartWare International Inc.’s of Valtech Cardio Ltd. in September, Abbott’s of Tendyne Holdings Inc. and its optioning of Cephea Valve Technologies Inc.in September and Boston Scientific Corp.’s additional investment in MValve Technologies Ltd. in October. Approaches to the tricuspid valve are in the hopper at several companies as well.

In the meantime, numerous start-ups are betting on percutaneous mitral valve repair, among them Millipede Inc. Based in Santa Rosa, CA, the company was started in August 2012 by renowned University of Michigan mitral-valve surgeon Steven F. Bolling, MD, with the goal of reproducing the surgical repair gold standard – a complete, rigid annuloplasty ring – but delivering it with a catheter. The company has developed an adjustable annuloplasty ring, one that is seated in an abnormally dilated mitral-valve annulus, then cinches closed to resize the annulus closer to normal.

Patients with mitral valve regurgitation fall into two main categories: those whose mitral valve itself is damaged, a condition called degenerative mitral regurgitation (DMR), and those whose otherwise unremarkable mitral valve has been stretched open due to the diseased ventricle in which it is embedded, called functional mitral regurgitation (FMR). For DMR patients, the current standard of care consists of complex, multi-step surgical repair.

The ideal treatment for FMR patients, on the other hand, remains unclear, but few are considered good surgical candidates, and many companies are developing minimally invasive repair options for this group.

These FMR-treatment companies often adapt their approach from an array of surgical techniques used in DMR patients. One such approach is called ring annuloplasty. This procedure consists of altering the mitral annulus, the valve’s fibrous ring that becomes abnormally dilated, dragging the valve leaflets apart, as the ventricle dilates after injury (such as a heart attack). Surgeons can correct this abnormal dilation by inserting an annuloplasty ring that reduces the diameter of the annulus, bringing the leaflets back together, increasing what is called the coaptation zone, and reducing or eliminating MR. This procedure, altered for delivery via catheter, is Millipede’s approach.

Designed in-house by CEO and co-founder Randall Lashinski and a team of engineers, the Millipede device consists of a collapsible nitinol ring whose zigzag frame suggests a circular version of a collapsible security gate. At each zigzag’s peak there is a collar that is individually controlled. When the collar is screwed down the ring contracts, when it is unscrewed the ring enlarges, allowing the clinician to customize the sizing of the ring. During deployment the ring is enlarged to the size of the dilated annulus. Corkscrew-shaped anchors attach the ring to the fibrous annulus without disturbing the leaflets. The implant is then contracted, reducing the dilated annulus to a normal physiological size, restoring leaflet coaptation and eliminating regurgitation.

The ring is fully repositionable and adjustable allowing the clinician to titrate the ring size while watching on echo to maximize outcome. The implant remains completely in the left atrium, eliminating the risk for left ventricular outflow obstruction. The device is designed to be delivered by a transfemoral route.

“Our technology allows you to land the implant on the annulus with a high degree of precision, then allows you to adjust the implant after it’s been attached, to be able to resize it and to be able to reduce the annulus up to or more than 50% if need be,” says James Eadie, MD, a board member and a partner with Millipede investor Santé Ventures. “There is nothing else out there that can come close on that degree of closure.”

Unlike replacement valves, which are subject to high systolic blood pressure from ventricular contraction, the Millipede device’s position in the left atrium means it is not subject to the kinds of heavy forces a replacement valve’s anchoring would need to withstand, according to Lashinski. “The forward flow [of blood toward the ventricle] is really the only force acting on it, other than the [force of the] annular reduction,” Lashinski says.

“Our technology allows you to land the implant on the annulus with a high degree of precision, then allows you to adjust the implant after it’s been attached, to be able to resize it and to be able to reduce the annulus up to or more than 50% if need be.” James Eadie, MD, Santé Ventures.

As with other repair technologies, because Millipede’s approach preserves the mitral anatomy, it should allow for future valve repair or replacement if needed. That means such repair could be undertaken in younger patients, thus warding off secondary damage to the ventricle that can occur with longstanding MR.

Lashinski is an engineer and entrepreneur who also founded Claret Medical, which is testing a cerebral embolic protection device; he also helmed Alure Medical and Direct Flow Medical and was a VP at Medtronic/AVE. Founder Bolling is a professor in the Department of Cardiac Surgery at the University of Michigan, a widely published valve expert and a member of the Mitral Valve Academic Research Consortium, which sets standards for research in the field.

Millipede filed for a Track 1 (accelerated) US patent in December 2014; it was granted in November 2015, and the company continues to file patents.

The device has been evaluated in animals with a transatrial approach – that is, through the top of the heart or atrium, as the animal heart is too small, as compared with the human heart, for a transseptal approach. Though some minimally invasive mitral repair and replacement devices access the heart through the tip of the ventricle – the so-called transapical approach – many industry insiders agree that transseptal delivery, as TAVR systems and MitraClip offer, is where the mitral field is headed. To this end, Millipede is now perfecting its own transfemoral delivery system, which will allow for classic transseptal access in humans.

Early first-in-human procedures took place in the spring of 2015, when three patients with DMR received the device temporarily in the course of valve surgery; it was removed prior to further surgical intervention. The team verified no interference with electrical conduction or trouble with anchoring, and the ring achieved nearly a 50% reduction in annular diameter, according to Eadie and Lashinski. Procedures in human cases utilizing transcatheter delivery are planned for 2016. Lashinski says the company’s priority at present is to generate solid clinical data; it has not yet disclosed when it will approach the FDA.

Austin, TX-based Santé Ventures has so far been Millipede’s sole backer with a $6 million round at the company’s founding; a Series B round is planned for early 2016. At present, the company has no strategic partnerships.

There is considerable competition in the minimally invasive mitral-valve repair space. Eadie names as examples MitraClip, which is FDA-approved for DMR but used often in FMR patients as well; HeartWare’s Valtech, whose Cardioband annuloplasty system is one of several mitral technologies in its portfolio; Cardiac Dimensions Inc.’s CARILLON device, which received a CE mark in 2009 and began enrolling for its fourth clinical trial last June; and Israeli start-up ValCare Medical Inc., which is also developing a catheter-delivered annuloplasty ring.

More generally, mitral repair faces competition from TMVR, as last year’s strategic acquisitions suggest. However, many experts in the field say TMVR will be more difficult than TAVR was. Compared with its aortic counterpart, the mitral valve apparatus is larger, more complex and subject to much stronger mechanical forces, creating real technical challenges related to miniaturizing, anchoring and strengthening replacement valves. Moreover, it remains unclear whether replacing the valves of FMR patients – those who, with their currently poor set of options, are so attractive to innovators – is a good idea. Bolling, for his part, says that a replacement valve large enough to seat tightly into a dilated valvular apparatus could compromise a diseased ventricle’s ability to undergo beneficial remodeling, even after the stressor of MR is resolved.

“I don’t believe there’s going to be a complete swing from repair, which is standard of care now in mitral, to complete replacement,” Lashinski says. “We’ve seen a lot of valve replacements struggle after first-in-man experiences.”

“We’ll have to see how it plays out, but there’s going to be very meaningful market slices for replacement and repair,” Eadie adds. In the meantime, he says, development is continuing apace at Millipede, and the coming months should see a release of data: “2016 should be a pretty big year for the company.”

Source

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Millipede’s Play In Percutaneous Mitral Valve Repair :: START-UP :: Pharma & Medtech Business Intelligence

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Author: Jenny Blair

Published January 28 2016