Multiplying options for MS

The future is looking brighter for patients affected by multiple sclerosis (MS), an inflammatory, autoimmune disease which causes progressive disability. MS is characterised by the patient's own immune system attacking the myelin sheaths around axons of the brain and spinal cord. This pathology impairs interneuronal electrical communication and may result in a myriad of neurological signs and symptoms.

The condition often progresses to physical and cognitive disability. The relapsing-remitting form is most common and the one towards which most drug therapy is directed. Although much is known about the mechanisms involved in the disease process, the underlying cause remains unknown, which poses difficulty in creating an effective treatment paradigm. Once-daily oral therapies are providing wider opportunities for prescribing clinicians.

Current treatments
Prior to 2010, only a handful of therapies was available to patients with MS. Recommended pharmacological treatments included one of three interferons (Biogen Idec's Avonex or EMD Serono/Pfizer's Rebif, which are both formulations of interferon ß-1a, or Bayer's Betaseron, an interferon ß-1b), glatiramer acetate (Teva's Copaxone), mitoxantrone (EMD Serono's Novantrone) or natalizumab (Biogen Idec/Elan's Tysabri). However, while these therapies have efficacy in decreasing disease relapses and accumulated disability, tolerability profiles are poor.

Novantrone has only been approved in the US, and its use must be monitored as it can cause cardiomyopathy and infertility, and patients have an increased risk of developing leukaemia. Tysabri carries a small but perturbing risk of progressive multifocal leukoencephalopathy. Interferons must be injected once a week or more frequently, with the attendant discomfort of flu-like symptoms. Copaxone appears the most tolerable; however, it requires injection three times per week which can cause a post-injection reaction manifested by flushing, tightness in the chest, heart palpitations, breathlessness and anxiety. For these reasons, research into more effective disease-modifying MS drugs is a burgeoning area, with oral formulations a strong trend.

As it stands, three oral therapies have been launched for the treatment of MS. Novartis' Gilenya (fingolimod), a sphingosine-1-phosphate receptor modulator, is the current market leader. Gilenya was the first oral treatment to be approved in the US for patients with relapsing forms of MS. It was launched there in October 2010. Approval was based on data from the TRANSFORMS and FREEDOMS trials in patients with relapsing-remitting MS. Gilenya has also been approved in Switzerland, Russia, Australia and the United Arab Emirates for the treatment of MS. In January 2011, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for Gilenya (0.5mg daily) as a disease modifying therapy in patients with highly active relapsing-remitting MS despite treatment with beta-interferon and in patients with rapidly evolving severe relapsing-remitting MS.

According to inThought analysts, Gilenya sales are expected to exceed $1.5bn worldwide in 2018. However, although anticipation for Gilenya is significant, the majority of neurologists appear to remain sceptical about substituting the agent for interferons or Copaxone as first-line therapy. Gilenya's known adversity profile is not sufficiently alarming to limit use, though fears stem from the unknown adversities. Opportunistic infections and cutaneous malignancies, including malignant melanomas, may be magnified outside the clinical trial setting. Besides safety, high cost, uncertainty surrounding third party payer reimbursement and tedious monitoring have been cited as the most significant impediments to optimal use of Gilenya.

Acorda and Biogen Idec's Ampyra (fampridine sustained-release), a potassium channel antagonist that has been shown to restore conduction in demyelinated axons in patients with MS, was approved in the US and Puerto Rico in March 2010 as a treatment to improve symptoms of impaired walking. In phase III trials, walking speed was increased by 25 per cent with Ampyra compared with placebo.

Ampyra was the first symptom management therapy specifically for MS that had been approved by the US Food and Drug Administration (FDA) since 2004. Regulatory approval has also been filed in the European Union (EU), Canada and Australia. However, in January 2011, the CHMP issued a negative opinion against its approval. Biogen Idec intends to appeal this opinion and request a re-examination. InThought analysts predict that the appeal will be unsuccessful. However, projected worldwide sales remain at $310m in 2018 in the revenue model.

Also suffering major setbacks to approval is Merck Serono's cladribine, an adenosine deaminase-resistant analogue of deoxyadenosine. While cladribine has been marketed in Australia and Russia, regulatory reviews for MS in the EU and the US are ongoing. In January 2011, the CHMP issued a final negative opinion against approval of cladribine for MS. Merck cannot re-appeal the decision without further clinical data.

The committee first issued a negative opinion in September 2010, following the submission of a marketing authorisation application (MAA) filing to the EMA for cladribine tablets as an oral, short-course, disease-modifying treatment for patients with relapsing-remitting MS, in July 2009. This submission was supported by results from the CLARITY trial. However, the committee stated that, based on available data, the benefits did not outweigh the risks. Regulators took particular issue with cases of lymphopenia, prolonged immunosuppression and increased risk of cancer. Most recently, in the US, Merck received a complete response letter from the FDA in March 2011.

Although the FDA found substantial evidence of cladribine's efficacy in the data from the CLARITY trial, it requested an improved understanding of the overall benefit-risk profile. Merck should be able to address the FDA's concerns with data from the CLARITY extension, ORACLE MS and ONWARD trials. InThought analysts maintain an approximate likelihood of cladribine gaining regulatory approval in the US as 71 per cent, with July 2012 as an estimated approval date.

InThought analysts have also removed EU revenues from the cladribine model, with peak worldwide sales now reaching $208m in 2015. Nevertheless, cladribine will still have three years of market exclusivity regardless of when it launches or its patent status. While the delay gives more lead time for Gilenya, the MS market has room for more than one oral agent. Probably, the use of both cladribine and Gilenya will be driven less by competition between the two and more by acceptance in specific MS populations where interferons and Copaxone are ineffective or inappropriate.

Potential competitors
Teva's laquinimod, a once-daily, orally administered immunomodulatory compound, was granted fast-track status by the FDA in February 2009 and is likely to compete directly with Novartis' Gilenya. In December 2010, top-line results from the pivotal phase III ALLEGRO trial were announced, indicating that the drug met its primary endpoint of reducing annualised relapse rates in patients (n=1106) with relapsing-remitting MS. The primary and secondary endpoints were met with acceptable safety.

Teva is also running a second pivotal phase III trial of laquinimod: the two-year, three-armed BRAVO trial comparing relapse rates across patients treated with laquinimod, interferon ß-1a or placebo. Completion of this trial is expected later in 2011. In light of the top-line results from ALLEGRO, inThought analysts have increased the approvability index for laquinimod to 55 per cent probability and predict US approval by October 2012. Revenue estimates for laquinimod are projected as $986m in worldwide sales by 2018. While neurologists favour Gilenya over laquinimod, phase III data will be critical to evaluate the future for oral MS drugs.

Also chasing Gilenya is sanofi-aventis' (S-A) teriflunomide, a dihydroorotate dehydrogenase inhibitor. This immunomodulatory agent has a similar efficacy profile compared with injectable interferons, but its potential is limited by its tolerability profile, primary tolerability concerns being pregnancy issues and liver toxicity. Teriflunomide is being investigated as a monotherapy in a thorough phase III clinical programme, including the TEMSO, TENERE and TOWER trials.

According to inThought analysts, the likelihood of it gaining regulatory approval for MS is 67 per cent, with approval forecast for March 2013, with worldwide revenue reaching $400m in 2018. Their model assumes that teriflunomide becomes a rescue drug for select patients who experience treatment failure with Gilenya as well as interferons or Copaxone. It will potentially compete with other oral agents including cladribine, laquinimod and Biogen Idec's BG-12 (dimethyl fumarate). S-A is also investigating teriflunomide as an adjunctive therapy. The phase III TERACLES study is ongoing in this indication, with regulatory submission predicted for 2014.

Biogen Idec is also a major player with BG-12 (dimethyl fumarate), a second generation derivative of fumaric acid, for the treatment of relapsing-remitting MS. BG-12 appears to have a dual mechanism of action as both an immunosuppressive/anti-inflammatory compound and a cytoprotectant. Although its efficacy appears to be on a par with interferons and Copaxone, it may struggle to compete with teriflunomide in dosing convenience (twice or thrice daily versus once daily).

The long-term safety of BG-12 may be acceptable, but persistent gastrointestinal issues and issues related to the liver still require close scrutiny. However, the fact that its analogue has been used in the EU for the last decade may increase confidence in its long-term safety profile. Results from the DEFINE trial are expected in the next few months. InThought analysts estimate that BG-12 will be approved in July 2012 in the US and in early 2013 in the EU, with worldwide revenue sales reaching $526m by 2018.

Further, a number of oral therapies are currently in, or have completed, phase II trials. Novel interferons, immunomodulators, monoclonal antibodies and even an estriol pill are all possible candidates.

The Author
R&D Prospect was written by Ashley Hallsmith of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or Email: Kuljeet.Sohanpal@wolterskluwer.com

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