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Optimization is the name of the game in lentiviral gene therapy

Former President & CEO

Geoff MacKay | Former President & CEO

In the field of lentiviral gene therapy, there is considerable focus on the most technical and novel steps of the process: transducing the patient’s stem cells and building a manufacturing system that can deliver optimized drug product at scale. AVROBIO is no exception; we’ve spent quite a lot of time driving improvements in these areas.

But we can’t stop there.

We take technology leadership seriously; it’s essential to advance not just our programs but the field as a whole. Towards that goal, we must continually examine the lentiviral gene therapy process and push innovation at every step. I take inspiration from the history of aeronautics: The first breakthroughs in the early 20th century astounded, and key advances over the decades that followed captured the popular imagination. (In fact, AVROBIO is named for one of those advances, an avant-garde Canadian fighter jet called the AVRO Arrow.) Between the flashy moments, however, it took decades of steady, incremental improvements to bring air travel to the mainstream.

In recent months, we have been focusing intently on how to bring innovation to one of the less visible, but still crucial, steps in delivering successful lentiviral gene therapies — the personalized conditioning process. I’m pleased to share news of two collaborations that reflect our philosophy of continuously investing in innovation to move both our programs and the field of gene therapy forward.

Conditioning is the process of clearing space in a patient’s bone marrow in order to make room for transplanted therapeutic stem cells to permanently engraft. The gold standard for lentiviral gene therapy conditioning is busulfan, an extensively validated conditioning agent. The challenge with busulfan is that the rate of its breakdown can vary significantly from patient to patient and from one day to the next within the same patient. At AVROBIO, we use a process called Therapeutic Drug Monitoring (TDM) to enable the bone marrow to potentially receive a targeted drug exposure of 90mg/hr/L, often abbreviated to “Bu90.” We do this by dosing the patient every day for four days, but adjusting the dose each day to reflect changes in the patient’s metabolism of busulfan over this period. It is therefore critically important to be able to quickly and simply measure the patient’s blood busulfan level, in order to calculate the next day’s dose. The goal is to personalize the therapeutic regimen in order to precisely hit an optimum target exposure — Bu90 — with the aim of maximizing engraftment while minimizing side effects. Optimization really is the name of the game, for every patient, and for every part of our process.

We believe TDM provides an important benefit for patients and we see an opportunity to use technology to enhance that benefit. The current assays that inform the next day’s dose can take hours to return results. They must be processed by trained staff at specialized laboratories, which means that for some sites, patient blood samples must be rushed elsewhere for analysis. We have developed robust procedures to address these logistical challenges, but in our ongoing effort to create a lentiviral platform that automates and streamlines, we want to be smarter about how this step is managed.

That’s why we have entered into a collaboration with Saladax Biomedical that we hope will make TDM more convenient and practical for every patient and clinician using personalized conditioning with busulfan.

A new vision for therapeutic drug monitoring near the patient

Saladax, a leading diagnostics provider, specializes in developing blood tests for personalized dosing. Under the collaboration, AVROBIO will fund Saladax’s work developing, validating and seeking regulatory approval of a fully automated immunoassay kit designed to greatly accelerate the monitoring of busulfan. The new assay kit under development by Saladax is designed to analyze busulfan levels in blood from a small blood sample, using any of the common automated analytical devices found in hospitals and clinics. We expect this will greatly expand access to personalized conditioning with busulfan. Best of all, the results can be returned in minutes, not hours.

Saladax expects to submit its validated immunoassay kit for regulatory clearance in the U.S., EU, Canada, Australia and other countries next year.

While we are funding development of the high-speed assay, we will not hold it as a proprietary technology. As I’ve already noted, we strongly believe that innovation at every step is essential to advance the field of lentiviral gene therapy into the mainstream. TDM is an important piece of that puzzle; making it easier to use will help both current patients and future research. So, under the terms of our agreement, Saladax has agreed to make the assay kit commercially available to its customers around the world, such as hospitals, clinics, medical offices and labs, following applicable regulatory clearance. Our hope is that the assay will improve patient care by enabling precision dosing for all patients undergoing busulfan conditioning.

Exploring innovation in conditioning for gene therapy

The second collaboration we announced recently, with Magenta Therapeutics, also has the potential to further advance innovation in lentiviral gene therapy.

Under terms of the collaboration, we will work together to evaluate the potential utility of Magenta’s novel antibody-drug conjugate conditioning agent MGTA-117, which currently is in preclinical development for patients receiving AVROBIO’s investigational lentiviral gene therapies.

MGTA-117 is designed to precisely deplete hematopoietic stem and progenitor cells. Magenta has reported that MGTA-117 has shown high selectivity, potent efficacy, wide safety margins and broad tolerability in non-human primate models, suggesting that it may be capable of clearing space in bone marrow to support long-term engraftment in humans. Magenta is advancing MGTA-117 in GMP manufacturing and GLP toxicology studies. They have announced that they plan to complete IND-enabling studies this year and that they are on track to present initial clinical data in patients with blood cancers in 2021.

We are proud of our personalized conditioning approach using busulfan with TDM. As the Saladax agreement shows, we’re committed to continually refining and improving that approach. Nonetheless, we believe it’s in the interest of AVROBIO and the entire sector to continue to optimize our approach to lentiviral gene therapy by exploring early-stage technologies such as Magenta’s and we look forward to learning more.

At AVROBIO, we like to say that we are powered by plato®, our state-of-the-art gene therapy platform. But we also need to power plato. The two collaborations announced recently reflect our philosophy of continuously investing in innovation to push both our programs and the field of gene therapy forward, not just with breakthrough discoveries but also with relentless optimization. That’s the only way we’ll achieve our vision of freeing patients around the world from a lifetime of genetic disease.

This blog contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding AVROBIO’s business strategy, prospective products and goals, the therapeutic potential of our preclinical and clinical product candidates, the anticipated benefits of our gene therapy platform, and the potential benefits of our collaborations with Saladax Biomedical and Magenta Therapeutics. Any such statements in this blog that are not statements of historical fact may be deemed to be forward-looking statements based on current expectations, estimates and projections and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. For a discussion of these and other risks and uncertainties, see the section entitled “Risk Factors” in AVROBIO’s most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission. AVROBIO is not affiliated with Saladax Biomedical or Magenta Therapeutics, except that a member of AVROBIO’s board of directors serves on the board of directors of Magenta Therapeutics. AVROBIO expressly disclaims responsibility for any forward-looking statements in this blog attributed to Saladax Biomedical or Magenta Therapeutics.