Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Firms copying innovator therapeutic mAbs face manufacturing and regulatory challenges.

Drug manufacturers have pressed on with advancing complex biosimilars including therapeutic mAbs into the clinic despite regulatory uncertainty and the potentially stiff costs attached to their manufacture. Biosimilar antibodies represent a multibillion-dollar opportunity for generic manufacturers both in the U.S. and Europe. Innovators, on the other hand, have a lot to lose if their blockbusters face market competition once they come off patent.

While the U.S. is setting up its regulatory framework, the EU has an approval process in place and is working on guidelines for antibodies and other more complex biologics. Over 10 biosimilars have been approved in the EU, including Omnitrope, a growth hormone developed by Novartis’ Sandoz and approved as a biosimilars to Pfizer’s Genotropin (somatropin), and Zarzio, Sandoz’ granulocyte colony-stimulating factor developed as a biosimilar to Amgen’s Neupogen (filgrastim).

None of the currently sanctioned biosimilars come close to antibodies in terms of manufacturing challenges, current therapeutic antibody producers are quick to point out. Roche/Genentech, maker of Rituxan, says on its website that due to the complexity of biologics as well as the distinctions introduced by differing manufacturing processes, it believes that each biosimilar “must be shown to be safe and effective on the basis of its own adequate and well-controlled clinical studies.”

The company also says it believes that biosimilar products “should only be approved initially for the indication that is directly supported by the nonclinical and clinical safety and efficacy data package submitted by the sponsor.”

MedImmune believes “That biosimilars, once approved, should have FDA-approved risk management plans to ensure the products are rigorously monitored for post-market safety and immunogenicity. If biosimilars are approved with less clinical data than innovator biologics, the FDA should ensure that longer-term post-marketing outcomes for biosimilars remain similar to those with the innovator product.”

Manufacturing Hurdles

For potential manufacturers of biosimilar therapeutics like antibodies, the financial incentives may be worth the effort. Johnson & Johnson’s Remicade generated 2009 sales of $4.3 billion, while Roche’s Rituxan made $5.5 billion and Herceptin made $14.4 billion in 2009. Patents for Remicade expire in 2018 in the U.S. and 2014 in Europe. Herceptin and Rituxan patents expire in Europe in 2014 and 2015, respectively, and both expire in 2018 in the U.S.

Nonetheless copycats will have to bear a lot of manufacturing process pain as well as associated high costs. They will also need a high tolerance for uncertainty to get into the antibody biosimilar business. Production of biosimilar antibodies is significantly more difficult than conventional small molecule drugs and also relatively smaller approved biosimilars like growth hormones and erythropoietin look-alikes.

Minor changes in manufacturing for the biosimilar product compared to the reference product can contribute to differences in glycosylation, aggregation, and protein folding. All of these can result in altered immunogenicity, antibody targeting, and, potentially, diminished therapeutic activity.

“Production technology is pretty standard for recombinant monoclonal antibodies,” Medimmune’s Gail Wasserman, Ph.D., svp of biopharmaceutical development, told GEN. “What makes the challenge different is that the innovator originally develops the manufacturing in parallel with carrying out nonclinical and clinical studies to establish safety and efficacy. During that time the innovator has the opportunity to identify the quality attributes of the product that are important for safety and efficacy.

“The makers of biosimilars, however, are confronted with the challenge of making a heterogeneous biological molecule similar to the innovator’s without the benefit of having development experience to understand the range of heterogeneity important for the safety and efficacy of the molecule,” Dr. Wasserman points out. “The innovator has insights, therefore, that the biosimilar developer may not.”

Regulatory Uncertainty

Thus far, the EMA has received requests for scientific advice on six biosimilar antibodies, including one from Teva for a biosimilar version of Rituximab.

Regulatory guidelines will not be the same as those for licensing of less complex recombinants like somatotropins and erythropoietins. In November 2010, EMA released new guidelines on biosimilar antibodies for a five-month public consultation period.

It is expected that the EMA guidelines will contain requirements for clinical trials of biosimilar mAbs. As yet the regulations don’t spell out the extent of the clinical testing needed to establish biosimilarity. The agency has not said whether the biosimilar antibody would also be interchangeable with the original.

“We do not support interchangeability between an innovator biologic and a biosimilar product,” states current antibody producer MedImmune. At this time regulations allow generic versions of small molecule drugs to be dispensed interchangeably with the original product at the pharmacy, without the approval of a physician.

Early commentary on EMA guidelines acknowledges that coming up with a “general framework is a near-impossible task in this subject area due to the many differences from one mAb to the next.”

One common thread does exist in EMA’s guidelines—comprehensive risk planning at the early stages. The guidelines particularly focus on the problems manufacturers may experience with current assays used to assess mAb immunogenicity, stating that detection of antibodies against mAbs using ELISAs or radio-immunoprecipitation may not be adequate because of nonspecific binding. It notes that a new generation of assays with the requisite sensitivity for use in clinical settings needs to be developed.

In November 2010, FDA held hearings to obtain input on the implementation of the Biologics Price Competition and Innovation (BPCI) Act of 2009. The act established an abbreviated approval pathway for biological products that are demonstrated to be highly similar to or interchangeable with an FDA-licensed biological product.

The BPCI act currently provides for up to 12.5 years of nonpatent market exclusivity for a biological product approved under a BLA consisting of an initial 12-year exclusivity period that may be extended by 6 months of pediatric exclusivity.

Some other standards will likely pose challenges for antibodies, in particular the standard for interchangeability. To meet this criterion “A sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.” Since use of a biosimilar antibody could potentially preclude the use of the reference product in the same patient due to development of antiantibody antibodies, this regulation sets a high bar.

The guidelines are now open to public comment until May 31. Predictably, current manufacturers with products to protect took a fairly hard line on regulations for biosimilars in general. The Pharmaceutical Research and Manufacturers of America (PhRMA) along with some of brand-name drug makers told the FDA over the course of the two-day hearing that the science is “too lacking” at this point for the FDA to decide that some biosimilars are interchangeable with the original biologic.

Rituxan in the Crosshairs

Nonetheless, as the market for biosimilars in the U.S., Europe, and Japan is projected to exceed $2 billion by 2015, biosimilar antibody manufacturers remain undeterred. Market expansion is inevitable as patents expire, demand for cost-effective therapeutics increases, and the need for biologic drugs to treat chronic and complicated conditions of an aging population grows.

As analysts predicted, Rituxan is an early target for biosimilar developers. Rituxan, marketed in the EU as MabThera, is used to treat rheumatoid arthritis and relapsed or refractory low-grade or follicular CD20+ non-Hodgkin lymphoma.

Sandoz announced on January 10 that it has begun a Phase II trial in rheumatoid arthritis with a Rituxan biosimilar. Sandoz also reported that it has developed a high-yield and large-scale process for producing the biosimilar at its facilities in Schaftenau, Austria.

Teva, the largest generic drugmaker, formed a biosimilar partnership with Swiss contract manufacturer Lonza in January 2009. Teva’s TL011 is being developed as a biosimilar to Rituximab. The company has clinical trials under way in rheumatoid arthritis and non-Hodgkin lymphoma.

In addition, on January 6, Spectrum Pharmaceuticals said it plans to develop its own biosimilar version of Rituxan with its Canadian partner Viropro.

Costs Involved and ROI

The potential cost of making biosimilar antibodies will restrict it to a few companies with deep pockets. Developing a biosimilar mAb for one indication will be about $100 million, estimates the research group Collins Stewart. Starting from scratch, novel therapeutic antibody development takes between 8 and 16 years to complete and costs between $500 million to $1 billion.

Additionally, biosimilar drugs, particularly antibodies, may not produce the cost savings associated with small molecules or less complicated biologics. Generic medicines have saved the EU an estimated €20 billion annually, according to the European generic association, but biosimilars are not generics. Analysts expect price discounts of only 20 to 30% in markets affected by biosimilar competition. Compare that to the average 90% markdown for generic versions of small molecule drugs.

Biosimilar developers will have to find a way to gain a sufficient return on large investments made in development and manufacturing. At the same time biosimilars will have to be marketed at a price that incentivizes payers. Before all that, companies will have to prove, be it through the full slew of preclinical and clinical trials or an abbreviated process, that biosimilar antibodies can achieve the same clinical results as the reference products.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

Previous articleBioTime Buys Assets from Cell Targeting to Boost Its Regenerative Medicine Focus
Next articleOxford BioMedica Buys Manufacturing Facility from RecipharmCobra for £1.9M