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“Over the past year, we have made tremendous progress in advancing our lead program toward a clinical trial, and I continue to be inspired by the plight of the patients whom we are aiming to help, and by the potential transformative benefit that our gene therapy can bring.” Rick Modi
You can read our first interview with Rick Modi from Nov 2024 here.
Could you recap what Affinia is working on?
Our lead indication is BAG3 dilated cardiomyopathy (BAG3 DCM). Over the past year, we have made tremendous progress in advancing our lead program toward a clinical trial, and I continue to be inspired by the plight of the patients whom we are aiming to help, and by the potential transformative benefit that our gene therapy can bring. I often recall the story of Mateo from my time at AveXis.
In spinal muscular atrophy, if neurons are not resuscitated fast enough, the cells die and you cannot recover that function. One dose of gene therapy literally saves them! They can return to a normal life - to walk, run, and have a career.
We recently invited Becky, a young woman in her prime who is affected by this genetic heart failure condition, BAG3 DCM, to speak to our company. Heart cells are different from neurons - you can rescue them over time. The only other possible treatment for these patients might be a heart transplant.
With one dose of gene therapy, using our novel capsid, we believe we can bring back the heart function that people like Becky have lost.
How is that pipeline progressing?
About a year ago, we had a classic pre-IND meeting with the FDA for our lead program, AFTX-201 in BAG3 DCM. We aligned on the studies needed to demonstrate effect, and safety, in animals, and on what the clinical trial would look like after the IND is accepted.
We designed the studies completely in line with FDA guidance, and the results are very promising. The team is now furiously writing up the IND and plans to submit this quarter (Q4 2024).
Once approved, we want to begin dosing patients, see what this medicine can do to help them, move on to pivotal studies and, ultimately, commercialization.
What could we expect to see from the UPBEAT trial, early next year?
Patients with BAG3-DCM have a mutation in the BAG3 gene; it’s a protein that works in muscle cells, and especially in heart muscle cells.
In these patients, there is insufficient BAG3, and it’s not secreted outside the cell, so you need a capsid that gets to as many cardiac cells as possible, and produces the necessary protein, at as low a dose as is possible.
In gene therapy, the higher the dose, the more side effects you can have.
Over the last year, we invented a muscle capsid, for this therapy, that does exactly what you would want: in animal experiments, it reaches many heart cells at a very low dose, produces BAG3, gets these heart cells to function normally, and to regain heart function.
Conventional AAV capsids, used by everyone else, run into dose-limiting toxicity constraints, meaning the higher you dose, the more safety events you see. Lowering the dose reduces risk, but also reduces benefit. Our capsid, ATC-0187, fixes those issues. We can give it at five to ten times, or lower, doses. We can reach many more heart cells and produce more protein. In animal experiments, we were able to normalize heart function.
We also did a head-to-head animal study versus a conventional capsid. Using our capsid we saw normalized heart function; the conventional capsid showed no difference compared with placebo.
In the UPBEAT clinical trial, planned for early next year, we will look at heart function (by echocardiogram), and at daily function - things like climbing stairs or lifting a child - using validated measures that clinicians and the FDA use, such as NYHA class (New York Heart Association) and exercise capacity, three-to-twelve months after dosing.
Over the past year, two important partnerships have been with Vertex and Forge Biologics. Could you share with us the progress?
From the start of the company, we promised that we could make new capsids for many tissues - heart, skeletal muscle, CNS - and Vertex was very keen on gene therapy.
We worked together for about four years: two years of early assessment that they loved, then they double-dipped for another two years, with more funding and more work. Near the end, they had a strategic reprioritization.
Despite us earning the maximum performance milestones, their priorities shifted. We had candid dialogue; they went their way, and we got the rights back, notably for Duchenne and myotonic dystrophy 1.
I would do that deal again in a heartbeat. The caliber of the science at Vertex helped to set a high bar; one of those capsids now powers our in-house heart program (BAG3 DCM), and we are discussing relicensing for other diseases (Duchenne, myotonic dystrophy 1, and others).
Forge Biologics is a contract drug manufacturer with deep gene therapy expertise, now owned by Ajinomoto. We do process development, internally, at our Waltham site, then transfer to Forge for GMP supply.
Our internal innovations at Affinia deliver about ten times higher yield, roughly four times higher purity, with the percentage of full capsids in the final product north of 90 percent – while some companies move products that are around 50 percent full capsids. I can brag openly here, because the data support it.
Even more striking is that Forge reproduced our data and did even better at GMP. Where many companies run 500-liter batches, Forge ran a 50-liter for us, and that’s enough to supply more than a hundred patients for our first-in-human Phase 1b/2 UPBEAT trial thanks to the Affinia innovations. It’s unheard of, and it puts us in a very strong position!
What role does your tech-stack play?
We were using machine learning before people were AI-washing their companies! For three to four years, we have used algorithms and predictive modeling to design capsids - small peptides on AAV9 - because the permutations are too large for simple regression.
That work generated all the capsids we actually need, across cardiovascular, skeletal muscle, and neurological diseases. We’re now winding down the platform and evolving into a medicines company.
We have characterized these capsids much more deeply than others with regards to safety, the mechanism of action, and animal data, and we are eager to advance them into clinical trials, with all the risk mitigation put in place.
Now, we are exploring AI in more mundane, back-office functions - finance, HR, business operations - so people can focus on more creative and strategic work, and let operations hum in the background.
Affinia recently closed a Series C in a tough gene therapy funding climate. How will you allocate the funds, and how do you see the broader market shaping up?
This is my third downturn. It’s not an industry for the faint of heart. Early this year - roughly from January to April - macro uncertainty was high; indices, like the XBI, tested multi-year lows; rates were not coming down; inflation was a question mark; and generalists had other avenues to invest in - AI, or even U.S. Treasuries.
The least-favored investments then were biotech, preclinical, platform companies, and gene therapy. You might laugh, we checked all four of those boxes.
During our fundraise, sadly there were serious adverse events reported by other companies in gene therapy - all with conventional capsids at high doses. Preventing this is exactly why we founded Affinia.
The fact that we got the Series C done - raising 40 million dollars and bringing in Eli Lilly as a new strategic investor - speaks to our perseverance, the quality of the science, the caliber of the team, and the scientific potential of treating BAG3-DCM patients.
Investors liked our new capsids at much lower doses, with higher yields, purer products, and the potential to completely restore lost function in tens of thousands of patients across developed markets.
The path to approval can be quite rapid here: you can biopsy the heart, to show transgene expression, and track functional measures, to see if they return higher than baseline or almost normalize. The Series C proceeds are primarily for the BAG3-DCM lead program, with secondary support for the programs behind it.
Could you share one leadership insight that helped you navigate the past year’s volatility?
Some things were planned and worked; others were unplanned and we figured them out.
Markets took a down-turn; the pandemic happened; science meanders…The constant throughout is recruiting around a vision.
Craft a vision, be committed, share it, and recruit the right people - scientists; the investor syndicate; the board; partners and patients; clinical sites; and investigators. It’s about good judgment, and the ongoing ability to recruit people to the cause.
We could have rushed to go public, but we pulled back. Do the right thing by the patients, first, and the rewards always follow. The funding is closed, Lilly’s in, IND to be submitted imminently, and for a very high-need indication with tens of thousands of patients.
There is immense commercial value in our lead program, because there is no other treatment besides a heart transplant - and many never get one. So my advice is don’t rush. It would have been easy to rush into the clinic, years ago, with a conventional capsid, we did not. Keep your purpose – the patient – foremost!
