Hi, my name is Glybera...

In a previous post I expressed my confidence that we would see a Gene Therapy product approved by either the EMA or the FDA by 2020...it turns out I was right (although, in hindsight, 2015 would have been a more appropriate cut-off) as the EMA just made a huge step forward with Gene Therapy.

UniQure finally received the nod from the EU regulators for its AAV-based treatment for lipoprotein lipase deficiency (LPLD), Glybera. Hailed by the Gene Therapy and the rest of the scientific community as a "victory" and one of the most significant advancements in the field, everyone is now looking forward to the next important milestone: Glybera entering the market. Judging by the buzz around this, the next few months promise to be very exciting. 

Breaking down the elements in the Glybera story, we see (a) something resembling a "triumph" for the AAV technology, (b) first evidence that it is worth pursuing utra-rare diseases treatment with Gene Therapy, (c) proof that a small biotech (Amsterdam Molecular Therapeutics initially and then uniQure) can get a Gene Therapy product approved and (d) that the EU regulators have finally begun to recognize Gene Therapy approaches as viable options for some patient groups. What we are yet to see though is how this product will actually fare in the market versus existing competition and primarily what its price tag will be (rumored to be more than EUR 1,000,000 / single "lifetime" shot).

Glybera is essentially an AAV-1 vector coding for a functional LPL gene. Inject it into the muscle and you get the muscle cells to produce "healthy" LPL protein. Glybera's other name is alipogene tiparvovec and you can go here for the latest publications on the topic. Safety comes first for regulators, and the AAV-1 vector in Glybera is indeed safe, with no real worrying signals or pathogenicity observed to-date. The promise of long-term supply of the therapeutic protein is also fairly robust, as the virus persists without genomic integration following administration and is not "cleared" by the immune system (low immunogenicity). It is no surprise then that AAV-based vectors have recently become quite popular and the vehicle of choice for gene delivery in many Gene Therapy approaches under development. 

UniQure might still have to face its biggest test though: achieving success in the marketplace with Glybera. This becomes even more important as, apart from demonstrating that the first EU-approved Gene Therapy can compete in the marketplace, uniQure has the chance to open up opportunities for its remaining portfolio of Gene Therapy assets. So far, the majority of market access discussions revolve around pricing and reimbursement for the treatment, with discussions also coming up around how and where the patients will be treated and monitored.

And here is where things get a bit more complicated...The promise of a single-shot cure seems to be the best card that uniQure currently has at its disposal, and that is why it is rumoured to be pricing Glybera above EUR 1,000,000, as previously mentioned. That is probably not so unrealistic a price if you consider that Genzyme's Cerezyme was around USD 200,000/year in 2009 (check out a relevant table here) and the option for paying for Glybera in annual installments could indeed be very appealing to some governments/payors. I believe positioning Glybera as enzyme replacing therapy could justify this high premium and this is what uniQure is probably planning on doing.

However, the "single-shot" and "lifetime" terms are a bit vague in my opinion. Data submitted for registration included a four-year follow up of patients post-administration of Glybera for one of the studies (n=6); patients from the other two registrational studies (n=13 and n=1) were only followed up for two years and one year respectively...I can hear the P&R folks asking questions around what happens at five or 10 years after the patient has received Glybera. Getting a bit more technical, the LPL gene in Glybera is under the control of a human cytomegalovirus promoter (CMV), which is know to "shut down" in several cases in vivo after a certain period of time. So, it would not be unthinkable that in some patients, LPL gene expression could be reduced (and worst case scenario, could cease) after a period of time. 

In terms of administration, the number of 0.5 ml injections containing Glybera is determined based on the patient's weight; expect an one time series of up to 60 injections for a 90 kg patient with immunosuppressive treatment for the next 3 months following treatment. UniQure has already set up a registry for monitoring patients who will be receiving Glybera and the company has also set up a network of centres where trained personnel will be able to offer its Gene Therapy treatment.


If, indeed "lifetime" does not turn out to be what the current hype is all about, what next for Glybera? The approval documents indicate that Glybera is for single administration only as data for repeated administrations over time have not been submitted. So, a scenario where treatment effect lasts for five years and there is no option for receiving the therapy again to sustain the effect for another 5-year period, or something similar, will be very challenging to justify to payors. Additionally, a repeat administration of the same product is probably not feasible due to anti-AAV1 antibodies that patients will develop following the first encounter with Glybera; subsequent administrations will have to overcome pre-existing immunity to the vector.


Nevertheless, uniQure is now approaching the FDA seeking an approval of Glybera in the US with a new US company president (Phillip Astley-Spark, ex-BioVex) and this will be a story to follow closely. A new manufacturing facility for Glybera is also in the cards. Profits from Glybera sales cannot come soon enough though as uniQure faces a EUR 20 million funding gap and funds seem to also be depleted, following a milestone payment to Xenon Pharma (developers of the LPLS447X gene variant included in Glybera and responsible for expression of LPL).

So, here are some of my thoughts on Glybera; although I am very excited with this development and plan to follow it very closely, I believe the real opportunities for uniQure lie in its upcoming pipeline products.

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The Gene Therapy that came in from the cold...

Despite not making any big headlines, a very important development took place in early December 2011: the very first Gene Therapy treatment was approved outside China (Gendicine, an adenovirus-based p53 gene transfer product, and Oncorine, an E1B-deleted adenovector for the treatment of head and neck cancer have both been in the Chinese market since 2004 and 2006 respectively)! The Human Stem Cell Institute's (HSCI) product, Neovasculgen, a plasmid-based vector encoding VEGF (165 aa), driven by a minimal CMV promoter, received the nod from the Russian authorities following positive results in its Phase IIB/III trial.

Neovasculgen's target population are patients suffering from Peripheral Arterial Disease (PAD) and Critical Limb Ischemia (CLI). For more information you can find an interview with the company's CEO here. Sale of Neovasculgen is scheduled for Q2 2012 in Russia followed by launch in Ukraine.

This piece of news comes right after Amsterdam Therapeutics was denied approval of its Gene Therapy candidate, Glybera, for the treatment of lipoprotein lipase deficiency (LPLD). But does the approval of Neovasculgen indicate that in the next few years more and more Gene Therapy products are to be approved??

In a previous post, I highlighted the companies most active in developing Gene Therapy products: Oxford Biomedica, Sibiono, Genzyme, Introgen, Diamyd to name a few. In the meantime, Sanofi added two more products in Phase I development: RetinoStat for the treatment of age-related macular degeneration and StarGen for the treatment of Stargardt disease; both assets originally from Oxford Biomedica. So the interest is there from big (and not so big...) pharma...but what is happening with the regulators? 

Well,decent efforts by both the EMA and FDA in the past few years indicate that the two agencies are trying their best to educate themselves and the public on these new approaches. As everyone is aware by now, safety is the prime concern for both agencies. Companies with Gene Therapy products in their pipelines should be prepared to invest significant amounts of time and energy in establishing informative interactions with the regulatory authorities, in order to understand each other's needs and priorities. 


I am relatively confident that we will see a Gene Therapy product approved either by the EMA or the FDA by 2020; not so sure what HSCI's plans are with Neovasculgen either and whether the company aims for approval outside Russia. Costs associated with developing and testing Gene Therapy products have increased and budgets have shrunk in the past few years but I am optimistic for the future...

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AAV making a splash (?)

Looking at Sanofi's early stage pipeline I noticed a couple of Gene Therapy products (coming through from Genzyme's pipeline) in Phase I development:

• AAV2-sFLT01 for Age-related Macular Degeneration (AMD, more about this disease here) 
• AAV2-hAADC2 (human Aromatic L-Amino Acid Decarboxylase-2) for Parkinson's disease

As can be seen by the names of the candidates, they both make use of adeno-associated virus serotype 2 (AAV2) gene delivery technology. Doing some research around how Genzyme got hold of this tech, I stumbled across Avigen Inc.; Genzyme appears to have licensed the AAV technology from Avigen in 2005 and has been developing products based on it since then. 

A quick search for "AAV" or "adeno-associated virus" on clinicaltrials.gov returns 9 ongoing Phase I and Phase II studies (with about another 50 or so studies that have previously been completed/terminated). It is interesting to note at this point, that it is mainly AAV2 or AAV1 serotypes that are being used in these studies, despite development of other AAV serotypes (from serotype 3 all the way up to serotype 11 as well as some of their hybrid versions such as AAV-2/5). This is not entirely surprising, given the experience that researchers have working with these vectors. A nice recent review on AAV-based gene therapy can be found here.

The main problems with this gene delivery approach revolve mainly around safety (avoiding unwanted effects due to virus integration in the host genome), identifying the vector serotype with the appropriate tropism for the target tissue/organ and quite importantly, being able to achieve production of large high grade GMP amounts of viral vector.

So, I would be interested to see how Sanofi's trials develop and how the FDA will look upon this approach. Looking at some other interesting news around AAV-based therapeutics, AMT's Glybera failed to get approval by the EMA earlier this year, although it had shown some promising results (more info about Glybera, the AAV1-based delivery of lipoprotein lipase can be found here). Glybera would have been the first gene therapy product to be marketed in Europe, however now the program is suspended and AMT is facing tough financial problems. 

In conclusion, it is pretty early days for an AAV-based therapeutic to hit the market although a few companies are working in the field. I would keep an eye out for news coming from Ceregene though as they have a strong advisory board (including R.J. Samulski) and that could translate into some interesting tech and positive clinical outcomes.

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