Cambridge, Massachusetts-based Avrobio has closed an oversubscribed $60 million Series B financing round to further its ex vivo lentiviral platform for the treatment of lysosomal storage disorders.

It’s one more sign that after decades of ups and downs, gene therapies have finally arrived.

Announced Thursday, the raise was co-led by Cormorant Asset Management and Surveyor Capital, with support from Aisling, Brace Pharma Capital, Eventide, Morningside and Leerink Partners. Early backers Atlas Venture, SV Health Investors, and Clarus Ventures also chipped in.

It follows a successful Phase 1 trial for Avrobio’s lead program in Fabry disease in 2017. While it was an N of 1 trial (involving just one person), the therapy delivered a complete response, restoring normal enzyme activity for the duration of the six-month study.

With its new Series B, Avrobio plans to launch a follow-up Phase 2 trial for that candidate, AVR-RD-01, while also moving its gene therapies for cystinosis and Gaucher disease into the clinic by mid-2019. A fourth program for Pompe disease is also in the works.

Defined diseases and defined markets
CEO Geoff Mackay founded Avrobio in 2015 with Head of Operations Kim Warren and Chief Science Officer Chris Mason. Rather than focus on one key patent or technology, Mackay said the team “went looking around the world” for the best techniques and tools in the field. This led to the development of Avrobio’s Fabry disease program. A seed round followed in late 2015 from Atlas Ventures.

Since then, the company has raised a $25 million Series A round and expanded its scope to tackle multiple lysosomal storage disorders (LSDs). In a phone interview, Mackay explained that LSDs are particularly well suited to the startup’s lentiviral platform as well as its business model.

On a scientific front, LSDs are monogenic disorders; they’re caused by a single defective gene. This leads to a shortage of just one key enzyme. In the case of Fabry disease, it’s ?-galactosidase A, caused by a faulty GLA gene.

Replacing the missing enzyme is the obvious solution and, to a certain extent, that mechanism of action is already proven. Fabry disease is currently treated with Fabrazyme, an enzyme replacement therapy (ERT) developed by Genzyme and approved in 2003. Administered as a biweekly infusion, the drug helps to slow the disease, but there is still a lot of room for improvement.

The market opportunity for many LSDs is well defined. Fabry disease affects an estimated 1 in 40,000 to 60,000 males (women are less affected because it’s an X-linked disorder). Fabrazyme generated sales of €674 million ($840 million) in 2016, after more than a decade on the market.

“Each of these indications are billion-plus revenue streams for the original company, so we do think if we can improve upon today’s standard of care, it’s a very viable business proposition,” Mackay said.

That basically means no company is essentially stepping on a competitor’s toes.

“At this point in time, there’s only a handful of truly clinical stage ex vivo lentiviral gene therapy companies and we’re not really encroaching on each others’ territory,” Mackay stated. “I mean, there’s 7,000 plus monogenic rare diseases and I think it really doesn’t make sense to be a slow follower with a similar type of technology, especially when the goal is to cure the patient.”

Which brings us to an important question: How does the therapy actually work? Spark Therapeutics’ Luxturna, the first true gene therapy to gain FDA approval, treats an ocular condition. As such, it’s directly administered directly into the eye. By comparison, patients with Fabry disease and other LSDs have an enzyme deficiency throughout the body. How do you treat every cell?

Avrobio’s work takes place outside the body (ex vivo), starting with a blood draw. The blood is transferred to the laboratory, where scientists extract and isolate a key stem cell, known as CD34.

“Then we give them an upgrade,” Mackay said, referring to the targeted changes the company makes to the cell’s DNA.

The goal is to transfer a functional copy of the defective GLA gene into the CD34 stem cells, allowing the patient to produce their own ?-galactosidase A enzymes.

Avrobio does this with its proprietary ‘lentiviral’ platform, drawing on the natural ability of certain viruses, such as HIV, to integrate their genetic material into the nucleus of our cells. Lentiviruses used for gene therapy are heavily modified to instead safely ‘infect’ the target cell with a healthy copy of a defective gene.

Once the healthy gene has been integrated into the DNA, the engineered cells are reinfused into the patient. From there, they are meant to migrate to the bone marrow, where a subset will engraft long-term or even permanently. It is the progeny — aka the daughter cells — of these engrafted hematopoietic stem cells that provide the therapeutic benefit.

“The entire CD34 hematopoietic lineage then circulates through the body, distributing what would be the missing enzyme locally to the cells, tissues, and affected organs,” he stated.

While the goal for gene therapies is to eventually treat many diseases caused by a lack of specific proteins, replacing the activity of an enzyme is a slightly easier target to begin with. Enzymes are catalytic, which means they fuel a chemical reaction without being used up in the process (they’re a renewable resource for the cells). As a result, restoring less than five percent of the intracellular enzyme activity can be enough to drive a sustained therapeutic effect.

It almost sounds easy, but it was a long and trying road to get to where gene therapy is today. The founders of Avrobio were part of that journey; each has decades of experience in senior cell and gene therapy roles.

Which must make recent progress in the field particularly exciting.

“I think that’s an understatement. It’s just thrilling,” Mackay declared. “For those of us that have been in the field for two decades and have really had to endure some times when the investment community, the strategic community had really vacated, to see such a growing body of clinical validation across a number of monogenic diseases, in rare disease and immuno-oncology, is just incredibly exciting.”