uniQure Gets Its Groove On: An Interview With CEO Jörn Aldag

UniQure made history in 2012 for winning approval in the EU for the first gene therapy accepted by regulators in a major market. CEO Jörn Aldag shares his views on uniQure's ambitious expansion plans.

It’s been a long road for scrappy Dutch biotech uniQure NV. The company achieved a triumph in November 2012 when its Glybera (alipogene tiparvovec) received EU approval for ultra-orphan disease lipoprotein lipase deficiency, giving it the first gene therapy accepted by regulators in North America, Europe or Japan. But success didn’t come easily: predecessor company Amsterdam Molecular Therapeutics BV survived several near-death experiences, drug rejections and layoffs along the way, before the company and its backers created a new start-up that now houses a groundbreaking drug.

CEO Jörn Aldag joined uniQure in October 2009, then an 11-year-old company, after a 12-year stint at Evotec AG, then steered it through a difficult time. AMT halted work on Glybera and halved its staff after European regulators rejected it twice in 2011 (Also see "Gene Therapy Firm AMT Forced To Go Private, Backed By Forbion" - Pink Sheet, 21 Feb, 2012.). The following January, the European Commission’s Standing Committee asked CHMP for more detail on the therapy. With little cash and few options, AMT soon announced a corporate restructuring and financing transaction in which newly created uniQure acquired all assets and liabilities of AMT. On completion of the transfer and delisting, uniQure received an equity boost from backer Forbion Capital Partners, a former investor in AMT.

Aldag spoke with “The Pink Sheet” about the prospects for gene therapy in the major pharmaceutical markets, the company’s unique gene therapy platform, its expansion of manufacturing capacity in the U.S. in preparation for Glybera’s approval and launch, pricing considerations, and uniQure’s near- and mid-term plans in the wake of the Chiesi Farmaceutici SPA partnership [See Deal].

With committed investors and a determined management team, Aldag has led uniQure through the first approval of a gene therapy product in the Western world, the first commercial partnership for an approved gene therapy, and the first significant expansion of gene therapy infrastructure and operations to another major market.

The deal with Chiesi puts Glybera in the hands of a well-capitalized partner that can maximize its sales in Europe and selected emerging markets (Also see "uniQure Grants Chiesi Select Commercial Rights For The EU’s First Approved Gene Therapy Glybera And Hemo B Gene Therapy" - Pink Sheet, 10 Jul, 2013.). That frees up uniQure – which plans to file Glybera in the U.S. in the first half of 2014 and, if all goes well, launch in the second half – to expand its end-to-end gene therapy platform into the U.S. uniQure now leads the field in adeno-associated virus (AAV) production for both its own clinical and commercial needs and its prospective partners’.

In the coming years, uniQure will seek approval in the U.S., Japan, and other global markets for Glybera and AMT-060 gene therapy for hemophilia B, currently in Phase I/II; and globally for its other pipeline candidates, including the Phase I/II programs AMT-021 (acute intermittent porphyria), AMT-90 (Parkinson’s disease), and AMT-110 (Sanfilippo B). Farther back are preclinical programs in hemophilia A, Huntington’s disease, and hyperoxaluria.

Up-front and equity funding from the Chiesi deal, royalties, and near-term revenue from Glybera in uniQure’s territories will help it advance its wholly owned pipeline.

“The PINK SHEET”: Do you think the investment and regulatory climate is changing for the better for gene therapy in the EU and U.S.?

Jörn Aldag: Gene therapy has followed the path of many technologies that initially garner interest based on the potential and promise and then fall out of favor when the path forward becomes complicated. After all, antibodies were also at one time seen as not feasible as therapeutics. The approval of Glybera has made all the difference. It shows that gene therapy can be safe and effective, potentially curative and approvable. This substantial regulatory hurdle has been overcome in the EU; now the next step is the U.S. No one can read the future, but Glybera is the first gene therapy to be approved and there are exciting compounds in the pipeline that will expand further the potential application of gene therapy.

Read more about gene therapy investment and start-ups in this week’s issue: (Also see "VC Enthusiasm For Gene Therapy Is Going Viral" - Pink Sheet, 22 Jul, 2013.)

“The PINK SHEET”: Are you planning to take uniQure public? Do you think bluebird, with its successful IPO, derisked the path for other gene therapy companies?

Aldag: We admire bluebird bio Inc. and are happy with the success of their IPO. We think it has demonstrated an appetite in the capital markets, and we’re also seeing increased interest on the part of pharma. But any IPO needs to be properly planned rather than momentum driven. We have ample funding from the Chiesi deal and the promise of product-driven revenue in the future. So, at the moment, we feel no urgent need to go public.

“The PINK SHEET”: You are currently building two manufacturing lines in Lexington. Describe your manufacturing technology.

Aldag: uniQure’s novel manufacturing approach is based on the use of a combination of baculoviruses and insect cells. It is a highly flexible process that can be easily and quickly adapted to produce a wide variety of products to commercial scale based on our vector technology, thereby significantly reducing the time needed for development. In the past, the production of gene therapy products, especially AAV-based vectors, has been hampered by the challenges of scaling up to commercial production – traditionally carried out in adherent mammalian cells – in an economic way.

We already have an EMA-approved plant in Amsterdam. The Massachusetts facility will come online in 2015, greatly increasing our capacity. In fact, we will have capacity to manufacture our pipeline products as well as products for other companies and institutions developing gene therapy products using AAV vectors. However, it is not our strategy to be a service provider.

“The PINK SHEET”: Does the AAV vector lend itself to large-scale manufacturing?

Aldag: Yes, the baculovirus-based AAV manufacturing platform of uniQure is well suited for large-scale manufacturing. This is a distinct advantage over the production of lentiviral and other viral vector systems, which are more intractable. Another added advantage of AAV vectors is that they score high both on the level of expression and the duration of expression.

Using unique manufacturing technology, uniQure is able to package a wide range of therapeutic genes into the relevant vector in a modular way. Therefore, we expect to be able to address a large number of disease indications.

“The PINK SHEET”: Why do you need the extra capacity?

Aldag: Our proprietary manufacturing is very central to the value proposition of our company and our product pipeline. We also want to make sure that we have back-up production capabilities in two locations to minimize interruptions in supply.

We are recognized today as the leader in the manufacture of AAV-based products. We have cGMP compliant manufacturing facilities that can produce commercial quantities. This is important for all those who wish to not only show proof-of concept but also provide medications to patients in the market. In that regard it is very important for our current and future partners – both academic as well as from the pharmaceutical industry.

“The PINK SHEET”: Glybera has been approved in the EU for lipoprotein lipase-deficient patients who have experienced either severe or multiple pancreatitis attacks. Is this a subset of the 4,400 addressable patient population (all LPLD) you cite for the U.S. and EU?

Aldag: We tested a group of 320 severe hypertriglyceridemiacs in Germany for changes in the LPL gene, and found that 3% to 5% of those patients have at least two variations of the LPL gene, making them potentially eligible for LPL deficiency treatment. If you apply that 3% to 5% to the prevalence of severe hypertriglyceridemia, you get 4,400 patients in Europe and the U.S.

“The PINK SHEET”: How will you zero in on that population, the ones with LPLD and in addition who have pancreatitis, in real world medical practice?

Aldag: We have done a diagnostic trial, using a companion diagnostic and next-generation sequencing in patients with severe hypertriglyceridemia, to determine the 3% to 5% with LPLD. Once we’ve determined that they have severe hypertriglyceridemia and they have two mutations in the LPL gene, we next need to determine that they have pancreatitis. So, some patients who present with acute pancreatitis are put into an ICU. Usually, no one will do next generation sequencing on them to see if they have LPLD. They just treat the pancreatitis. When it resolves, they send the patient home.

But now there is a treatment for LPLD. We will gradually raise awareness. Often times, people will present to a general practitioner with mild pain but without overt pancreatitis. Now GPs send a blood sample to the lab for a lipid profile. If the lipid profile shows elevated triglycerides, the GP should go back to the diagnostic lab and ask for sequencing to determine if the patient has LPLD. Some of the larger labs are starting to report back to the GP and say, your patient has high triglycerides, you should check to see if it has a genetic origin.

“The PINK SHEET”: Pancreatitis is also present in alcoholics, so it will be necessary to rule that out. All of this – awareness of outward symptoms, lab testing, proper referrals – will require educating general practitioners, patients, cardiologists and lipidologists, and diagnostic laboratories. That’s a tall order.

Aldag: Yes. The good news is that patients with pancreatitis are easy to find. Now that there is a therapy, the education has begun. But getting back to the patient population, as we sometimes see when an orphan drug comes out, the number of patients increases.

“The PINK SHEET”: Are you in talks with EU regulatory authorities to expand the label to include all patients with LPLD?

Aldag: We do have plans to eventually request expanding the indication but we believe that we first need to get more patients on the treatment under the current indication. We have not discussed particulars with the EU regulators regarding additional trials.

“The PINK SHEET”: And do you plan to file in the U.S. for the same pancreatitis-specific indication that you have in the EU, or for the wider LPLD indication?

Aldag: We are working hard to obtain in 2013 regulatory clarity on a U.S. FDA submission. Until we have that clarity we cannot speculate about specific indications.

“The PINK SHEET”: So, for the territories that you’ve retained in your agreement with Chiesi – the U.S., Japan, etc. – the plan is to go it alone?

Aldag: We’ve not made that decision regarding all the markets, but North America certainly is one of the markets that we’d like to develop ourselves. Japan is not decided. There are some other important regions, like Korea, Israel, and others where we also have not made a decision yet, but we could potentially go it alone. The market we’re particularly focused on is North America.

“The PINK SHEET”: Describe your U.S. organization.

Aldag: In January of this year we named Philip Astley-Sparke, former President and CEO of BioVex Inc., as president U.S. to provide strategic leadership and help build our clinical, regulatory, and commercial infrastructure for our Boston-based U.S. organization. We currently have four full-time people. The organization will grow as we get closer to launch.

“The PINK SHEET”: And are you getting regulatory support and commercial support specific to the U.S?

Aldag: The core of what needs to be done regarding the regulatory process has to do with getting a common understanding with regulators about what’s really important and unique in the context of gene therapy. We went through this process in Europe with the EMA, so we know better than anyone what we need to focus on and how to present certain things so that the differences between gene therapy and other therapeutic modalities are made clear.

We have some regulatory people on staff in the U.S. In addition, we use consultants who have worked with us in Europe and who also have experience working with FDA. We also use a local consultant who helps with day-to-day business interactions with FDA.

As for commercial preparations, we’re in the initial stage of launch plans – KOL and patient identification, pricing discussions, and so forth.

“The PINK SHEET”: Regarding pricing, this is unchartered territory. What are your thoughts about pricing your hemophilia B gene therapy?

Aldag: The important thing is that we’re truly delivering very high value to patients. Rather than going to a clinic three times a week, or every other week with the extended formulations now coming to market from Biogen Inc., we’re offering a one-shot treatment. The patient would not have to come back to the hospital for many, many years. That value, obviously, should be reimbursed.

We’re pioneering this now with Glybera, and the big question is, are you asking for a big down payment, or are you asking for annuity payments? That is, are you asking for a large upfront payment, or, in view of the unknown duration of effect, for payment in stages over time?

And this is very much dependent on the kind of therapy you’re considering. We’re looking at monogenic diseases now for orphan indications. But gene therapy can go beyond monogenic diseases. Obviously, Parkinson’s would not command as high a price as you’d see for a monogenic orphan disease. The pricing paradigm will change dramatically when you get into chronic diseases of neurodegenerative origin, or some of the other larger disease categories.

“The PINK SHEET”: Do you plan to retain full rights over the programs not included in the Chiesi deal?

Aldag: Our plans are to maintain ownership of our programs with the exception of the Parkinson’s disease program, which will require the resources of a larger organization to bring it to market.

“The PINK SHEET”: Can you disclose your current cash position?

Aldag: We’re a private company, and we don’t give financial guidance of that sort. But it’s larger than the $58 million we took in with the Chiesi deal and the convertible debt triggered by Chiesi’s equity investment. [See Deal].