Genzyme Will Act Fast To Design Post-Market Myozyme Study By Review Date

The on-time approval of a larger production scale of Genzyme's Pompe Disease biologic Myozyme could hinge on development of a post-market study protocol prior to the Nov. 29 PDUFA date.

On Oct. 21, FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended accelerated approval of Myozyme (alglucosidase alfa) produced at the 2000 L bioreactor scale with the requirement that Genzyme conduct a post-market study to verify clinical benefit. FDA is likely to require submission of a design of that study before it would grant approval.

"We will be working very hard to get it done by the November date," Genzyme CEO Henri Termeer told investors during an Oct. 22 third quarter earnings call. "We will be meeting as soon as we can, probably early next week with the FDA, and we have a number of proposals in mind. It is a discussion that needs to take place. I think everybody who came through this meeting is extremely aware of the urgency to get on with it. So we will work very hard to meet the requirements to get it all done by the PDUFA date."

Continued growth for the product depends on bringing additional capacity on line. Genzyme also awaits a decision by the EMEA in the first half of 2009 for a 4000 L product it has been developing for the last five years in Belgium. The firm said it has seen no biochemical differences between the 2000 L and 4000 L production scales, and that approval appears to be progressing without the need for a clinical trial.

Compare Product Lots To Resolve LOTS' Issues?

For the 2000 L application in the U.S., despite the lack of robust evidence of clinical benefit, the FDA panel voted 16-1 that the sponsor's single clinical trial, "LOTS," established effectiveness of the product. Their support was in large part based on the fact the Genzyme has not been able to meet demand with the 160 L product, which is the only production scale and Pompe disease treatment approved in the U.S.; the 2000 L product is approved in over 40 countries.

Pompe disease is an ultra-rare, autosomal recessive glycogen storage disease that affects approximately 2,000 patients in the U.S. Death in all forms is usually a result of cardio-respiratory failure.

The accelerated approval the committee recommended would be based on forced vital capacity as a surrogate endpoint reasonably likely to predict clinical benefit. The panel voted 15-2 that post-market efficacy studies should be conducted, and unanimously in support of post-market safety studies.

"I'm impressed with what appears to be a substantial opportunity and need and effects," temporary voting member Thomas Fleming, University of Washington, said. "Then I look at the data and it's much more modest. ... Why should I not be disappointed that we haven't seen more clear, clinical efficacy benefit - even as a signal, if not statistically significantly established - based on what we're hearing from the open public hearing?"

Butting Heads On Head-To-Head Trial

FDA posed to the committee the option of a head-to-head trial comparing the 160 L and 2000 L products; the agency is calling alglucosidase produced at the two scales different products due to the inability to establish comparability based on chemistry, manufacturing and controls, pharmacokinetic, or clinical data.

Though many members supported this design, Genzyme told the committee that production limitations would make a head-to-head comparison trial impossible.

"Comparing the 2000 and 160 head-to-head, the size of the trial we believe would be in excess of 500 patients to show with a non-inferiority design there was no difference - that is something that we absolutely could not supply with 160 [L product]," the representative told the panel.

Temporary voting member David Schade, University of New Mexico, said such a trial would "interfere with a good post-marketing study and be a waste of resources."

"I'd like to see the resources of the sponsor be devoted to a very good post-market study and registry," he added. "In this case where you only have one treatment in town, so to speak, where the sponsor knows everybody who is getting therapy and they won't be on any other therapy for this disease ... a good post-market study is feasible."

Temporary voting member John Teerlink, University of California San Francisco, noted study population gaps that would make such a trial difficult. "In terms of 160 versus 2000, I would point out that 160 hasn't been studied in late-onset patients, so we don't know what its baseline value is or whether it works or not, so I think an active controlled study is very difficult to do," he said.

Disease Continuum Points To Broader Indication

FDA approved the 160 L product in 2006 for all Pompe disease patients, despite lack of data in adult populations, because there was no other treatment available (¹ (Also see "Myozyme Is First FDA-Approved Inherited Muscle Disorder Therapy" - Pink Sheet, 1 May, 2006.)). Due to a shortage of the 160 L product, the 2000 L product is available to Pompe disease patients in the U.S. over the age of 18 through a temporary access program.

Genzyme has proposed that the 2000 L product be indicated for late-onset Pompe disease patients, which the sponsor defines as any patient over 12 months of age with onset of disease and without cardiomyopathy.

"We want the 160 L material reserved for infantile onset patients with cardiomyopathy aged younger than 24 months because ... if we were asked to supply the totality of patients aged 18 or younger today with the 160 L material we would not have a sustainable way to provide for that population going forward," a Genzyme representative told the panel.

Because the LOTS trial enrolled an inadequate number of patients with juvenile-onset Pompe disease, FDA asked the committee whether the 2000 L product should be indicated only for patients diagnosed and with symptom onset over 18 years of age. The committee voted overwhelmingly that no age restrictions should be given, however, because the classification of juvenile and adult-onset forms is a continuum, and a specific age cut-off is hard to clinically define.

"If you say all the 18 and under can have 160 L, they are not going to have enough product for that - they have explained that. This is the problem," committee member Eric Felner, Emory University, said. "So, simply put, if we think that the two-year-old or three-year-old has the same disease as the 30- or 40-year-old - which it sounds like they do - they should all be lumped into the same group."

FDA representatives noted that they understood the issues regarding drug shortage and disease pathophysiology, but still stressed the lack of data.

"I want to make sure that the committee understands that we just don't have the data on 2000 L product in younger patients, and so if we choose to approve in younger patients, then we are taking it on faith," FDA Division of Gastroenterology Medical Officer Lynne Yao said. "The second thing is that ... the 160 L product is approved in this country - we are not talking about a situation in which it is either approved or there is no treatment available. There are manufacturing issues in terms of supply, but it has been approved in this country."

In a press conference following the meeting, FDA declined to comment further on the manufacturing issues or why more of the 160 L product could not be produced. That topic was discussed by FDA and the sponsor in an earlier session of the meeting closed to the public.

Fleming was assured information in juvenile-onset patients could be gathered post-market. "I don't have a good sense about whether there is some important interaction by age between benefit and risk, but have been reassured that by voting for accelerated approval, we will be getting post-marketing evidence that will provide very important, necessary insight about benefit and risk, and I think that insight will allow us to have a better sense about whether there is interaction by age," he said.

A Way Forward

Fleming went on to suggest a design for such a trial. He said it could have two parts, one evaluating infantile onset and one evaluating late-onset populations (which would include both juveniles and adults).

"This needs to be on clinical endpoints, it needs to be done in a proper and timely way - it can't be 'Well, we'll take them as they come and if we finish it in nine years then that's fine' - that's inconsistent with the intention of Subpart H that validation needs to be a prospective, aggressively conducted trial that could involve a wide collection if not all the patients that would subsequently be treated."

The expectation, he added, would be a trial designed to "establish major benefits on these very important clinical efficacy measures."

All members agreed about the need for a rigorous trial. "I think it would be very disappointing to have you come back again and say 'oh, now we can't make the 2000 L anymore - we have this new genetically engineered one so we stopped making the 2000 L so now we just have to approve this new agent.' I think there is a line in the sand here today in terms of need to show clinical efficacy," Teerlink said.

- Jamie Hammon ([email protected])