Unmet needs in arthritis

pharmafile | June 3, 2004 | Feature | |   

Although there is no cure for rheumatoid arthritis (RA), a wide range of drugs are involved in its treatment. Similar painkilling drugs are used to treat RA as osteoarthritis (OA), such as anti-inflammatory drugs like the new COX-II inhibitors and more traditional, non-steroidal anti-inflammatory drugs (NSAIDs) and steroids.

However, RA disease progression can be slowed by the use of disease modifying anti-rheumatic drugs (DMARDs), which target the immune system to slow the immunological attack on the affected joint. New biologic drugs within this class, such as Enbrel and Remicade, are offering the most promising route to slowing or even halting this disease. However, these drugs do not fully address all the requirements of an RA patient, leaving areas for pipeline drugs to improve upon.

Unmet needs

Approximately 180 physicians treating RA across the seven major markets were asked about their top unmet needs in the pharmacological treatment of the disease, and they gave the following priorities:

• Fewer side effects
• Cost-effectiveness
• Efficacy
• Ease of administration
• Safety
• More aggressive therapy from disease onset
• Slowing down of disease progression
• Improved data, evidence, or research
• Compliance
• Tolerability

The responses generated suggest that physicians treating RA are more concerned about side effects and costs of RA therapies than about efficacy. Although RA therapy R&D as a whole is still some way from reaching an efficacy ceiling, such a ceiling does appear to have been reached with traditional NSAIDs and COX-II inhibitors (the development of COX-II inhibitors, which have similar efficacy to but better GI safety profiles than traditional NSAIDs, is in itself a reflection of this).

However, biologic DMARDs are still novel enough to ensure that physicians are still experimenting with these agents to find ways to maximise their efficacy, in particular in combination with traditional DMARDs (the recently reported Enbrel TEMPO study is an example of this).

Thus, while relatively content from an efficacy point of view to experiment with treatment regimes containing existing therapies, physicians are not satisfied with their high costs and side effects.

It remains the case that many of the therapies used by rheumatologists are rejected by other specialists as offering poor risk/benefit profiles; dermatologist perceptions of the dangers of methotrexate is a case in point here. High demand clearly exists for therapies that are both safer than those currently available, and more cost-effective.

Launch factors

Within the pipeline, products like Celltech CDP870 are likely to fare well as a cheaper alternative to the biologics currently marketed, but are unlikely to offer significantly greater safety. With products such as Arava pharma companies have demonstrated the difficulty of developing RA drugs that are both efficacious enough to meet physician demands and safe enough to replace existing therapies.

The factors necessary for a successful launch of a new product in the RA market are:

• Comparative or better efficacy than current products
• Good strategic partnering in terms of both marketing and manufacturing skills, and geographical reach
• More indications such as psoriasis, Crohn's disease and lupus
• Competitive pricing, ie, cheaper manufacturing methods
• Better administration methods than current therapies

It is clear from the list above that simply assessing a drug on its clinical benefits is no longer a predictor of high uptake and sales. External factors and company statistics also play a large role in drug development.

Bristol-Myers Squibb's CTLA4-Ig

Patient potential: BMS is developing CTLA4-Ig (abatacept), a co-stimulation blocker. The patient potential for CTLA4-Ig is slightly larger than competing biologics due to its relatively low manufacturing cost, as it is produced in the milk of transgenic goats.

If approved, this drug will be priced extremely competitively and can treat a large proportion of moderate to severe RA patients. However, the development of this transgenic product is behind the cell culture method and according to GTC Biotherapeutics, is still at a pre-clinical stage as of early 2004.

BMS is undergoing trials of CTLA4-Ig in conjunction with other RA therapies, such as Enbrel. This will position the drug to be used in collaboration, and not as a direct competitor, with current biologic DMARDs, greatly improving patient potential.

Marketing factors: BMS had originally been developing CTLA4-Ig with Novartis; however there has been no discussion of this collaboration since 2000 and it is assumed that BMS is now developing the drug independently (however the transgenic goats used in the manufacture of the drug will continue to be developed by GTC Biotherapeutics).

Repligen claim to be the sole licensee of certain patents owned by the University of Michigan, which relate to the composition and uses of CTLA4-Ig. An inventorship trial ended in September 2003 with the ruling against Repligen and the University. An appeal has been filed, but the initial ruling is likely to hold. However, Repligen does own the exclusive rights to a patent covering a method of treating RA, and four other indications, which may cause marketing disputes with BMS in the future.

BMS's extensive experience in the pharma industry will prove an invaluable asset in the promotion of this drug and this product is well placed for marketing success. BMS's promotional spend over the US and EU was US$192 million in 2003 (MIDAS promotional data, IMS Health, March 2004), below the promotional spend of Wyeth/Amgen but it shows the potential available for this product.

Satisfaction of unmet needs: CTLA4-Ig is unique compared to other biologics being developed in the treatment of RA. As opposed to the majority of new biologics, which will be very expensive, this drug can be made relatively cheaply on a commercial scale because it is produced in the milk of transgenic goats. Although it is anticipated to sell at a higher price than CDP870, CTLA4-Ig will still be much less expensive than the majority of biologics.

In addition to its cost advantage, this drug also represents innovation in terms of its mechanism of action. It is the first in a class of drugs known as co-stimulation blockers and is thought to have a great deal of promise in the treatment of RA. If clinical trial data can prove that blocking T-cell co-stimulation pathways is a superior method of treating RA, this drug will experience a high level of success, as it is likely to be first to market.

However, a drawback with this treatment is the 30-minute IV infusion required for each dose, which may mean this product will lose share to oral or even subcutaneously administered therapies that are currently in development.

Celltech's CDP870

Patient potential: The Anti-TNF antibody fragment is being tested for the treatment of RA, Crohn's disease and congestive heart failure and is expected to be the fourth TNF inhibitor to market – as a result the patient potential for CDP870 is large.

At present, the cost of biologics is a major barrier to their uptake and CDP870 offers great advantages in terms of cost. The advantage of producing a PEGylated Fab is that the antibody fragment is less complex, and can be produced using E. coli bacteria fermentation systems, resulting in lower cost production technology. This contrasts with the expensive and complex mammalian cell culture systems required for production of full-length antibodies.

CDP870 stands to gain substantial uptake, not only as a result of its potential price advantage when compared to the current marketed anti-TNF drugs but also because of the trend of using DMARDs earlier in the treatment of RA.

Marketing factors: At present, CDP870 has a strong commercial profile. The main threat that may hinder its uptake is its late market entry compared to Enbrel and Remicade, both already well established in the market. However, given their high price, CDP870 is expected to surpass these molecules due to its low manufacturing cost and subsequent price advantage.

Celltech is responsible for the development of the Crohn's disease indication, while Pfizer was responsible for two Phase III trials in RA. However, due to a disagreement in renegotiation of financial terms, Pfizer has given Celltech notice of termination of its rights to CDP870. At the end of February 2004 all product development and commercialisation rights and all programme information reverted to Celltech.

Phase III trials were originally initiated in October 2002, but complications including the Pharmacia/Pfizer merger pushed results back from mid-2003. Pfizer planned to complete the first two of these trials before beginning registration for the remaining trials. The results were expected in the first and second quarters of 2004; however, the transfer of responsibility and materials from Pfizer to Celltech is likely to delay the completion of these trials, while they review whether to out-license rights to RA to a new partner or to develop this indication in-house. Due to this delay in RA trials, Celltech plans to launch CDP870 for the Crohn's disease indication first.

Additionally, Celltech entered into a long-term agreement with Biochemie, an affiliate of Novartis AG, under which Biochemie will manufacture for and supply to Celltech PEGylated antibody fragment-based drugs.

Satisfaction of unmet needs: CDP870 represents advancement in terms of treatment regime, cost and proprietary technology in comparison to the current marketed biologics. CDP870's monthly subcutaneous injection regimen is more practical than Enbrel's bi-weekly injections and Remicade's infusion regime.

Similarly, a once-monthly injection is unlikely to produce injection-site reaction. In the context of proprietary technology, CDP870 represents improvement on two levels: its low production cost and its extended half-life as a result of chemical modification by PEGylation, which slows down the drug breakdown.

Roche's Rituxan

Patient potential: The results show potential for a long-term therapy, as efficacy was good 22 weeks after the treatment. Although dosing appears to be required less often than Enbrel, it is intravenous, and therefore requires administration by a physician. Another drawback is the expense of this treatment. However, if clinical trial results continue to be as positive as they have been for the drug when compared with other forms of treatment, the increase in drug strengths will push this into a leading position. Key opinion leaders have highlighted this drug as a very promising candidate, with more than enough potential to compete with the market leaders.

Marketing factors: Rituxan (Rituximab) is already approved in the US and EU for the treatment of non-Hodgkin's lymphoma. It is co-marketed by Genentech and Biogen Idec in the US and marketed by Roche in the rest of the world, except Japan, where it is co-marketed with Zantacs Cody. Because it is being backed by the marketing power of three major players in the biotechnology sector, Rituxan is well-positioned for a strong marketing campaign when approved for the RA indication. However, as none of these companies have experience in the arthritis biologics sector, this marketing strength may not be as potent as it could potentially be.

A long-term manufacturing agreement has recently been signed with Lonza Group to produce commercial quantities of Rituxan. This agreement will allow greater flexibility to deal with product demand, and takes advantage of the experience in dealing in biologics, and a US factory site, supplied by Lonza.

Satisfaction of unmet needs: Rituxan's novel mechanism of action, in terms of targeting the immune system B-cells as opposed to T-cells, represents an innovation in RA therapy.

Strong efficacy has been demonstrated when used as a monotherapy, not in combination with other DMARDs, in early clinical trial data. This, and the three-monthly dosing frequencies, represents significant advantages over most DMARDs. With the relative safety of this product already established in the lymphoma indication, Rituxan has the potential to be an arthritis blockbuster.

Comparing Enbrel and Remicade launches

Johnson & Johnson's Remicade and Amgen and Wyeth's Enbrel were launched in 1999 and to begin with Enbrel led its rival. The first two years of the Enbrel lifecycle show a healthy increasing sales curve, with the only drawback being an extra warning required on the label. It was approved as a first line therapy in moderate to severe RA early in its lifecycle, a big step for this relatively new biologic. However, even though Amgen had facilities to manufacture twice the amount of Enbrel that analysts predicted would be required, demand began to outweigh their production capability.

This supply shortage allowed Remicade to fill the void, and although it was launched second on the market it overtook Enbrel's US sales. The timely release of psoriasis trial results in mid-2001, and the FDA approval for improvement of physical function in moderate to severe RA in mid-2002 ensured Remicade's exponential growth throughout this time.

The US healthcare system does not discriminate against the IV infusion method  required with Remicade, as much as somewhere like the UK. Rheumatologists have opened infusion facilities, many of which are institutionally-based.

Rheumatologists who did not prescribe sufficient quantities of Remicade to make opening an infusion centre profitable could then refer their patients. With a comparable efficacy this meant that Enbrel was substituted for with surprising ease. Research has shown that monthly visits to a clinic ensures compliance and is even now preferred by some patients.

Looking to 2004 and beyond Enbrel appears to be recovering its sales with the approval of a large manufacturing plant on Rhode Island in late 2002. Enbrel's US sales in the last quarter of 2003 were only US$50 million behind Remicade (MIDAS Sales Data, IMS Health, March 2004).

But the expense of these biologics and the detailed justification required by the US insurance companies means that off-label prescribing is difficult. As shown in Remicade's past sales events, indication approvals allow increased revenues. Enbrel follows a similar pattern, but the new indications were not as well-positioned in the lifecycle and appear to create less of an impact.

Leaders of the pack

More than 20 biologic DMARDs are expected to enter the market between 2004 and 2008. Many of these compounds will be similar to Enbrel and Remicade in their price and mechanism of action and are therefore not expected to alter the landscape of the market to a high degree.

Success for these compounds is therefore heavily reliant on strategic marketing such as price advantages, strong DTC marketing campaigns or differentiation in terms of the specific indication for which the compound is approved.

However, the three drugs outlined above stand out from the rest as having high potential: Rituxan's efficacy values are its main advantage, whereas CDP870 will be able to compete in terms of price. CTLA4-Ig offers a novel mechanism, which may be marketed as a therapy to be used in conjunction with other biologics, creating a profitable niche.

These three candidates indicate the movement of RA therapy towards a more effective overall drug. However, as yet there still remains to be found a treatment that can address the majority of scientific and clinical needs while also addressing the high cost issues reducing biologic uptake.