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Global Clinical Trial Investigates Novel Heart Failure Treatment

CEO Adam Berman presents Alleviant Medical's novel, no-implant shunt therapy

Alleviant CEO Adam Berman demonstrated the company’s novel, no-implant approach during RiverVest’s 2023 annual meeting

Venture capital provides the financial wherewithal that early-stage medical device companies like Alleviant Medical need to translate promising science into patient impact. A startup’s pre-clinical work can be financed through a mix of research grants, angel investors, and individuals. Pivotal trials, however — like Alleviant’s global, pivotal trial now enrolling patients — almost always require venture capital. 

 

In this Expert Insight, we discuss the significant unmet need for effective heart failure therapies, Alleviant’s novel solution, and the pivotal study being funded by a Series A equity financing co-led by RiverVest in January 2023.

More Than 26 Million People Worldwide Suffer From Heart Failure

with an additional 3.6 million diagnoses made each year. (1,2)

 

But these millions are far from homogenous – while they share similar symptoms and quality of life challenges, their treatment options vary widely.  Few effective options exist for several large subsets of heart failure (HF) patients, including those with diastolic dysfunction, leaving significant pockets of unmet clinical need.

 

Alleviant Medical is aiming to help close this gap with a novel, no-implant shunt therapy designed to reduce excess pressure buildup within the heart without leaving a device behind. The goal is to reduce symptoms and improve quality of life for patients with HF—especially those for whom other treatment options are ineffective.

“It became clear early on that the approach held a lot of promise,” said James Udelson, M.D., chief of cardiology at Tufts Medical Center in Boston, who observed Alleviant’s early feasibility studies and published the findings in the JACC-HF Journals.[3] Today, Dr. Udelson serves as the global principal investigator of ALLAY-HF, a sham-controlled, double-blind study, which is now enrolling patients globally.

 

“In our initial studies we evaluated a range of factors, including whether pressure in the left atrium had dropped—a key indicator of efficacy and potential driver of symptom relief—as well as different biomarkers and patients’ own self-reported symptoms and feelings,” he continued. “The ALLAY-HF trial builds on those positive results and more than a decade of interatrial shunt study more broadly, incorporating the latest clinical learnings from other pivotal trials to help identify the best candidates for the therapy.”

 

Of the two most common types of HF – reduced left ventricular ejection fraction (HFrEF) and preserved left ventricular ejection fraction (HFpEF) – HFpEF accounts for more than half of all HF cases[4], disproportionately affects women, and is notoriously difficult to manage.[5] With this condition, the heart’s ability to fill or eject blood (rather than its ability to contract) is impaired. There are few therapeutic options and no device treatments available today.

 

“We believe that Alleviant’s novel therapeutic approach has the potential to improve health outcomes for patients with heart failure and reduce the burden of this difficult disease,” said Matthew Price, M.D., clinical professor of medicine and director, cardiac catheterization laboratory, Scripps Clinic. Dr. Price is co-principal investigator of ALLAY-HF.

“It became clear early on that the approach held a lot of promise.”

James Udelson, M.D.

Chief of Cardiology

Tufts Medical Center in Boston

Global Principal Investigator of ALLAY-HF Study

Reduce Pressure, Reduce Symptoms

“Our technology is designed to enable the creation of a therapeutic interatrial shunt, intended to offload elevated left atrial pressure in properly indicated heart failure patients, without the need for a permanent cardiac implant,” said Alleviant chief medical officer and co-founder Jacob Kriegel, M.D. While not a cure, interatrial shunting has been shown to reduce pressure and provide symptom relief in pilot trials, warranting further study.[6][7][8]

Here’s how the Alleviant System works:

The interventionalist inserts the device into the patient’s blood vessel via the groin and advances it over a guidewire, up into the heart, and through the thin interatrial septum. Using image guidance, the physician then opens and slowly retracts the device until the electrode resides on the right side of the septum while the tip remains on the left side. As the device is closed, it grabs a precise segment of the interatrial septum and secures it. A short pulse of radiofrequency energy is then applied to cut the segment, resulting in an interatrial shunt. The device and guidewire, as well as the segment of tissue, are then removed together, leaving nothing behind.

Pathway to Pivotal Trial

“Pilot feasibility studies, such as Alleviant’s ALLEVIATE-HF-1 and ALLEVIATE-HF-2 studies, play an early role in evaluating the safety and efficacy of an investigational device before making a go/no-go decision about proceeding with a pivotal trial,” explained Udelson. “In the case of Alleviant, the data demonstrated that the concept works, and it appears to be safe.”

James Udelson, MD (Tufts Medical Center) presented ALLEVIATE-HF-1 and ALLEVIATE-HF-2 no-implant interatrial shunt outcomes at Cardiovascular Research Foundation in Boston.

Udelson’s findings are available for review in the August 2023 edition of JACC-HF Journals. To summarize:

 

Between August 2020 and March 2022, a total of 28 patients (with a mean age of 68 +/- 9 years, 19 of whom were women) were enrolled in the ALLEVIATE-HF-1 and ALLEVIATE-HF-2 pilot feasibility studies, evaluating safety and efficacy of Alleviant’s no-implant approach to creating an interatrial shunt. At the six-month follow-up visit, all 28 patients had patent shunts that remained stable in size. In addition, there was a significant reduction in pulmonary capillary wedge pressure (PCWP) from baseline to one month, with promising clinical efficacy signals and no serious adverse events through 6 months [9].

The next step was clear: move forward with the pivotal trial.

Taking that step, however, was not so straightforward.

Financing pivotal trials is challenging, with high costs and no guarantee of success. While pre-clinical work can be financed through a mix of research grants, angel investors, and individuals, pivotal trials almost always require venture capital (VC).

 

“Venture capital provides the financial wherewithal that medical device startups like Alleviant need to translate promising science into patient impact,” said Jay Schmelter, co-founder and managing director of RiverVest Venture Partners. “VCs take significant but careful risks in funding novel efforts to address significant medical needs. Without this funding, many important medical innovations would stagnate.”

 

RiverVest, along with S3 Ventures, co-led the $75 million financing needed to proceed with the ALLAY-HF trial. “We invested in Alleviant because we believe in the concept, we believe in the team, and we believe we can help Alleviant drive forward this truly innovative technology,” said Schmelter, who is now also a board member of Alleviant.

Addressing Significant Unmet Needs

Following the success of its earlier trials, the Alleviant System was granted Investigational Device Exemption (IDE) by the U.S. Food and Drug Administration (FDA) in November 2022. The company launched ALLAY-HF in 2023.

The ALLAY-HF trial is focused on patients with HfpEF because they represent one of the largest groups without meaningful treatment options.

 

  • Pharmacological agents, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and digoxin, which have been helpful in treating patients with HfrEF, have not demonstrated significant benefit in treating HFpEF.[10]
 
  • Device-based therapies, including mechanical circulatory support and cardiac resynchronization therapy, are only indicated for HFrEF. There are currently no approved device therapies to improve symptoms or reduce hospital admissions for patients with HFpEF.[1]
 
  • Therapeutic options have therefore been mostly limited to the use of diuretics to relieve volume overload symptoms and lifestyle changes to manage hypertension and other comorbidities.

In situations when treatment options are as severely limited as they are with HFpEF, physicians may find that clinical trials offer the most promising advancements.

 

“With limited therapeutic options, this condition has a significant impact on health outcomes and the burden of cardiovascular disease, especially in older women who often suffer at higher rates,” said Roxana Mehran, M.D., director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute at Mount Sinai School of Medicine. As an executive member of the ALLAY-HF steering committee, Dr. Mehran and her team are supporting both clinical safety and statistical analysis throughout the clinical trial.

 

While the reasons for the disparity are unknown, women with HFpEF tend to experience more significant symptoms, more congestion, lower quality of life, and are more likely to be depressed than men with HFpEF.[12]

 

“Proper hemodynamic testing, including exercise, is another critical component of ALLAY-HF that can help

 identify patients whose HF may essentially be hiding in plain sight,” said Marat Fudim, M.D., associate professor of medicine at Duke University Medical Center. “There is a substantial gap today in both diagnosing and treating these patients suffering from dyspnea and exercise intolerance.”

 

Candidates for ALLAY-HF are chronic heart failure patients with HfpEF or mildly reduced ejection fraction (HfmrEF) with EF ≥ 40% who remain symptomatic despite stable guideline-directed medical therapy.

More than 400 patients will be enrolled at select study sites across the United States, Canada, Europe, Israel, Australia, and New Zealand, the first of which took place at Hendrick Health in Texas in 2023. The primary composite endpoint for the ALLAY-HF Study includes a 12-month follow-up period.

 

Drs. Mark Lawrence and Joji Varghese, Danielle Goss, Bailey Estes and Hendrick Health research team, the first US ALLAY-HF site.

“Alleviant’s mission is to develop a safe, effective no-implant treatment option to potentially help millions of patients suffering from heart failure, and this highly informed study is a critical step forward,” said Berman. “We are making significant progress in our efforts to study this technology for patients who need it all over the world.”

For more information on ALLAY-HF clinical trial eligibility, visit allayhf.com.

REFERENCES

[1] Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017 Apr 3;(1):7-11. Available from: https://pubmed.ncbi.nlm.nih.gov/28785469/ PMID: 28785469; PMCID: PMC5494150.


[2] Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding. Cells. 2020 Jan 18;9(1):242. Available from: https://doi.org/10.3390/cells9010242 PMID: 31963679; PMCID: PMC7016826.


[3] Udelson, J, Barker, C, Wilkins, G., Gooley, R., Lockwood, S., Potter, B., Meduri, C., Fail, P., Darrell, S., Feldt, K., Krigel, J., Shaburishvili, T. No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies. J Am Coll Cardiol HF. 2023 Aug 11;8(2): 1121–1130. Available from: https://www.jacc.org/doi/abs/10.1016/j.jchf.2023.01.024.


[4] Dunlay, S., Roger, V., Redfield, M. Epidemiology of heart failure with preserved ejection fraction. Nature Review Cardiology [Internet]. 2017;14:591-602. Available from: https://www.nature.com/articles/nrcardio.2017.65.


[5] Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014 Jun 20;115(1):79-96. Available from: https://pubmed.ncbi.nlm.nih.gov/24951759/ PMID: 24951759; PMCID: PMC4146618.


[6] Feldman T, Mauri L, Kahwash R, Litwin S, Ricciardi MJ, van der Harst P, Penicka M, Fail PS, Kaye DM, Petrie MC, Basuray A, Hummel SL, Forde-McLean R, Nielsen CD, Lilly S, Massaro JM, Burkhoff D, Shah SJ; REDUCE LAP-HF I Investigators and Study Coordinators. Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial. Circulation. 2018 Jan 23;137(4):364-375. Available from: https://pubmed.ncbi.nlm.nih.gov/29142012/ PMID: 29142012.


[7] Shah SJ, Feldman T, Ricciardi MJ, Kahwash R, Lilly S, Litwin S, Nielsen CD, van der Harst P, Hoendermis E, Penicka M, Bartunek J, Fail PS, Kaye DM, Walton A, Petrie MC, Walker N, Basuray A, Yakubov S, Hummel SL, Chetcuti S, Forde-McLean R, Herrmann HC, Burkhoff D, Massaro JM, Cleland JGF, Mauri L. One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial. JAMA Cardiol. 2018 Oct 1;3(10):968-977. Available from: https://pubmed.ncbi.nlm.nih.gov/30167646/ PMID: 30167646; PMCID: PMC6233816.


[8] Udelson, J, Barker, C, Wilkins, G., Gooley, R., Lockwood, S., Potter, B., Meduri, C., Fail, P., Darrell, S., Feldt, K., Krigel, J., Shaburishvili, T. No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies. J Am Coll Cardiol HF. 2023 Aug 11;8(2): 1121–1130. Available from: https://www.jacc.org/doi/abs/10.1016/j.jchf.2023.01.024.


[9] Udelson, J, Barker, C, Wilkins, G., Gooley, R., Lockwood, S., Potter, B., Meduri, C., Fail, P., Darrell, S., Feldt, K., Krigel, J., Shaburishvili, T. No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies. J Am Coll Cardiol HF. 2023 Aug 11;8(2): 1121–1130. Available from: https://www.jacc.org/doi/abs/10.1016/j.jchf.2023.01.024.


[10] Oktay AA, Shah SJ. Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Curr Cardiol Rev. 2015;11(1):42-52. Available from: https://library.une.edu/research-help/help-with-citations/nlm-style/ PMID: 24251461; PMCID: PMC4347209.


[11] Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JG, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O’Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail. 2014 Apr;2(2):97-112. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028447/ PMID: 24720916; PMCID: PMC4028447.


[12] Regitz-Zagrosek V. Sex and Gender Differences in Heart Failure. Int J Heart Fail. 2020 Apr 13;2(3):157-181. Available from: https://doi.org/10.36628/ijhf.2020.0004

About Alleviant Medical, Inc.

Alleviant Medical, Inc. is a medical device company developing a minimally invasive, implant-free device under clinical investigation for the treatment of chronic heart failure. The Alleviant System was granted U.S. FDA Breakthrough Device Designation in 2021. Headquartered in Austin, Texas, Alleviant is a privately held company backed by S3 Ventures, RiverVest Venture Partners, Vensana Capital, Broadview and Longview Ventures, Gilmartin Capital, ShangBay Capital, TMC Venture Fund, and undisclosed strategic investors.

 

Note: The Alleviant System is an Investigational Device and is limited by federal (or U.S.) law to investigational use. Exclusively for clinical investigation.

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About RiverVest

RiverVest Venture Partners is a leading venture capital firm building life science companies to address significant unmet needs of patients and deliver consistently strong results to investors.