While the efficacy of three central nervous system (CNS) drugs awaiting regulatory approvals is not vastly different from currently marketed products, their formulations and methods of delivery, combined with what payers will support, make them formidable players in the multiple sclerosis (MS) and migraine markets.
Two of these drugs on the Cortellis Drugs to Watch list are for relapsing MS and include ozanimod (RPC-1063) from Bristol-Myers Squibb and Co., of Princeton, N.J., and ofatumumab (OMB-157) from Novartis AG, of Basel, Switzerland. It may be easier to prescribe ozanimod if the FDA does not require a series of tests needed for other drugs in its class such as Gilenya (fingolimod, Novartis AG) and Mayzent (siponimod, Novartis AG). Ofatumumab offers an at-home subcutaneous delivery compared with its biggest potential competitor, Ocrevus (ocrelizumab, Roche Holding AG), which requires expensive infusions at a facility or hospital.
For migraine, rimegepant from New Haven, Conn.-based Biohaven Pharmaceutical Holding Co. Ltd. could become a new oral option for patients with acute, or episodic, attacks. It would be the second oral small-molecule calcitonin gene-related peptide (CGRP) antagonist, just behind Ubrelvy (ubrogepant, Allergan plc), which was approved by the FDA in December. The two orals follow three injectables in the CGRP class that entered the market in 2018.
If approved, all three drugs – ozanimod, ofatumumab and rimegepant – are expected to reach annual sales of more than $1 billion within five years.
Tackling MS with ozanimod and ofatumumab
Neurologists diagnose MS patients as having one of three types. About 85% fall into the relapsing-remitting form of MS, while 15% have primary progressive disease. More than half of those with relapsing MS later become secondary progressive MS (SPMS) patients. With MS, a patient’s immune system attacks the myelin sheath that surrounds neuronal axons, disturbing motor and sensory functions, with damage that can lead to paralysis and cognitive dysfunction. It affects about 2.5 million people worldwide, according to the U.K.-based Multiple Sclerosis Trust.
In March 2017, the MS community in the U.S. gained access to Ocrevus not only for relapsing forms of the disease, but it became the first therapy to treat the primary progressive forms of MS.
“There were no disease-modifying therapies before 1993,” said neurologist Barry Hendin, who has a private practice in Phoenix and serves as the director of the MS clinic at Banner University Medical Center. “The first one was in 1993 and over the next few years we got a total of four agents during the 90s. Now we have close to 20, and that means that there’s an explosion of choice. For me, that’s been extraordinary.”
Before Betaseron (interferon beta-1b, Bayer AG), neurologists only treated MS symptoms with available drugs for things like spasticity, depression and bladder issues. Today, patient treatments vary, Hendin said, from older injectable agents with less power but less immunosuppression to higher efficacy agents with more power and risk.
With the March 2019 filing of an NDA in the U.S. and an MAA in Europe, ozanimod may be the next approved oral MS therapeutic. It stumbled with a refuse to-file-letter from the FDA in February 2018, but the resubmission addressed preclinical and clinical pharmacology questions. Summit, N.J.-based Celgene Corp., which Bristol-Myers Squibb acquired for $74 billion in November 2019, announced that the agency accepted the NDA, setting the PDUFA date as March 25, 2020. The EMA also validated the MAA for the drug and a decision is expected in the first half of 2020. If approved, sales could reach $1.621 billion by 2024, according to a Cortellis analysis.
Ozanimod is an oral agonist of the sphingosine 1-phosphatase (S1P) 1 and 5 receptors. The filings were based on phase III data from the Sunbeam and Radiance trials, both of which met the primary endpoints, showing the annualized relapse rate (ARR) at 12 months was 0.18 with ozanimod vs. 0.35 with Avonex (interferon beta 1a, Biogen Inc.) and the ARR at 24 months was 0.17 vs. 0.28, respectively.
Safety data show similar cardiac events to placebo, which may differentiate ozanimod from the first S1P therapy and oral disease-modifying agent approved in 2010, Gilenya. The second approved in March 2019, also from Novartis, was Mayzent. Cardiovascular risk observed in some patients became a hurdle for Gilenya. Mayzent gained approval for relapsing MS, but it also became the first therapy approved for the SPMS population. It was soon followed in April 2019 with another relapsing MS and SPMS treatment, Mavenclad (cladribine, Merck KGaA), a synthetic chlorinated deoxyadenosine analogue.
Hendin said ozanimod will show similar efficacy to Gilenya, but that both Mayzent and ozanimod “are cleaner in that they have more receptor specificity” as agonists of S1P1 and S1P5, he said. Gilenya is an agonist of S1P1, S1P3, S1P4 and S1P5.
Both Mayzent and Gilenya require additional testing before a patient can take either drug, which may open the door for ozanimod. Gilenya requires electrocardiogram tests prior to and for six hours following the first dose to monitor for signs of arrhythmia. Both Mayzent and Gilenya require ophthalmology evaluations and blood work.
Without the same requirements, ozanimod “will be easier to prescribe,” Hendin said.
It will, however, face intense competition from other oral MS drugs, such as Tecfidera (dimethyl fumarate, Biogen Inc.) and Aubagio (teriflunomide, Sanofi SA), and possibly the not-yet-approved oral therapy, Johnson & Johnson’s ponesimod, which works similarly to Gilenya but appears to have a better safety and efficacy profile. Other oral competitors with different mechanisms are Vumerity (diroximel fumarate, Biogen Inc. and Alkermes plc), approved by the FDA in October 2019, which has shown improved gastrointestinal tolerability compared to Tecfidera, and Mavenclad, which is superior to Gilenya in terms of progressive multifocal leukoencephalopathy risk.
Anti-CD20 monoclonal antibodies also could be strong competitors and include ofatumumab. The drug binds to CD20 to eradicate the B cells that would otherwise attack the myelin. Novartis gained full rights to the drug from Copenhagen, Denmark-based Genmab A/S in December 2015, and submitted filings to the FDA in the fourth quarter of 2019 and to the EMA in January 2020. If approved, a Cortellis analysis projects sales of subcutaneous ofatumumab to be $1.261 billion in 2024.
In comparing ofatumumab with Ocrevus, Hendin said that “there is no head-to-head comparison that would suggest to me that one is more efficacious than the other. They are both in the same orbit of high efficacy. There may be some subtle differences once they get out into the community in terms of safety.”
The main difference of the two products is their mode of delivery. Ocrevus requires a visit to an infusion center, whereas ofatumumab is a self-injection at home.
In the Asclepios phase III trials, ofatumumab, compared with Aubagio, showed a reduction of more than 50% in annualized relapse rates, and it met key secondary endpoints, such as delayed time to confirmed disability progression and by reducing the number of lesions. While Aubagio is a relatively low bar, Rebif (interferon beta-1a, Merck Serono) was used as the comparator for the Ocrevus trials.
Neither Aubagio or Rebif “are considered high efficacy agents,” Hendin said. “They’re both vaguely comparable in their power and they fulfill the FDA requirement that there be an active comparator.”
Analyst Cory Kasimov of J.P. Morgan wrote in October that neurologists he spoke with thought the Asclepios phase III trials exceeded expectations and ofatumumab was comparable to Ocrevus with the “main differentiator commercially” being the subcutaneous dosing each month vs. Ocrevus’ intravenous dosing every six months.
Intravenous costs are anywhere from $800 to $1,000 at a community site or $3,000 to $4,000 at a hospital, Kasimov said. Ocrevus, however, is negotiated between the site providing the infusions and the wholesaler, meaning the lack of payer pressure offers incentive for some physicians to keep their patients on Ocrevus. Nevertheless, half of the patients taking Ocrevus could be shifted to ofatumumab within its first year on the market.
“I think the payers will have a very significant role,” Hendin said.
In its agreement with Novartis, Genmab is entitled to royalties of 20% of worldwide net sales of ofatumumab to treat cancer and 10% for noncancer treatments. Ofatumumab was approved as Arzerra for certain chronic lymphocytic leukemia indications in the U.S., the EU and several other countries, but due to competitive pressures, it has exited markets or reduced its availability outside of the U.S. and Japan.
For relapsing MS, however, both ofatumumab and ozanimod potentially offer new options for the patient community this year as research continues for a disease that had no modifying treatments 30 years ago.
“I think we’ve reduced progression, disability, mortality,” said Hendin, who also serves as chief medical officer of the Multiple Sclerosis Association of America. “This isn’t the last step. We’re right now improving our ability to reduce inflammation, relapses, and thereby reduce progressive disability. We’re hoping the next threshold is being able to do things that are reparative for MS.”
Rimegepant to treat acute migraine
A third CNS drug, rimegepant, is up for FDA review in the first quarter of 2020. The NDA, using a priority review voucher, was filed in the U.S. in the second quarter of 2019 seeking approval to treat acute migraine. Worldwide rights were acquired by Biohaven in 2016 from Bristol-Myers. If approved, sales are expected to rise to $1.03 billion in 2024, according to Cortellis analysis, although rimegepant would compete with Ubrelvy and orals from other classes, such as the 5-HT 1f agonist Reyvow (lasmiditan, Eli Lilly and Co.), approved by the FDA in October 2019. Other potential competitors include Trokendi XR (topiramate, Supernus Pharmaceuticals Inc.) and Botox (botulinum toxin type A, Allergan plc).
Frederick Godley is the president and founder of the Association of Migraine Disorders (AMD) based in North Kingstown, R.I., an organization borne out of an interesting finding among a group of otolaryngologists. They discovered that approximately 18% of patients coming through their doors screen positively for migraine, a debilitating headache condition often accompanied by nausea and vomiting and sensitivities to light, sound and smells.
Migraine is suspected to be caused by changes in ion channel conductivity, leading to a wave of cortical-spreading depression, trigeminal nerve activation and CGRP release from the trigeminovascular system. More than 25 million people in the U.S. get migraines. The World Health Organization calls it one of the top four neurological causes of disabling conditions.
One of Godley’s patients, Alicia Torborg, who now serves as executive director of the association, began getting migraines once a week as a child. While they disappeared during her teen years, they returned during pregnancy and then again in her mid-40s when “they were different,” she said. “They were not as severe, so I didn’t have this fork-in-the-eye kind of pain, but they would last for months at a time.”
Torborg tried everything from heart to seizure medications, backed off her athletic pursuits, and saw a number of different doctors, including chiropractors, acupuncturists, herbalists, homeopaths, neurologists and eventually an otolaryngologist to check for allergies.
The first set of drugs designed to treat migraines were triptans, with Imitrex (sumatriptan, Glaxosmithkline plc) entering the market in 1995, later followed by Zomig (zolmitriptan, Amneal Pharmaceuticals Inc.) and Maxalt (rizatriptan, Merck and Co. Inc.). Triptans bind to serotonin receptors and block the CGRP neurotransmitter. Generics are widely available. Newer formulations include Onzetra Xsail (sumatriptan, Currax Pharmaceuticals), Rizaport (rizatriptan oral film, Intelgenx Corp.) and Zosano Pharma Corp.’s zolmitriptan patch.
“Triptans really have been an innovation and workhorse, but they don’t work for everybody. They’re effective in about 60% of patients and there are contraindications, so if they have any cardiovascular disease, angina or stroke or uncontrolled hypertension, you can’t use a triptan,” Godley said.
The first monoclonal antibody injectable molecules that block CGRP, Emgality, Aimovig and Ajovy, received FDA approval in 2018. Aimovig (erenumab-aooe, Amgen Inc.) works by binding to the CGRP receptor to block its activation, while Emgality (galcanezumab-gnlm, Eli Lilly and Co.) and Ajovy (fremanezumab-vfrm, Teva Pharmaceutical Industries Ltd.) block the CGRP ligand’s binding to the receptor. A key strength of the drugs is their prophylactic use in chronic migraine patients.
“They’ve been terrific because there’s no drug interaction and they are quite highly effective,” Godley said, explaining that CGRP is the relay between nerves, “so if you can block the messenger, keep him from arriving at the next station” the pain signals will decrease.
Torborg has tried two of the CGRP injectable therapies, one of which stopped working. On her second one for nine months now, she continues to get migraines but “they don’t last as long as they used to,” she said.
Anecdotal evidence within Godley’s own practice suggest the drugs could be expanded to treat facial and sinus pressure pain. They are not without side effects, however, including constipation and hair loss in some patients.
That is where rimegepant and other small oral CGRP receptor antagonists come in. CGRP is a peptide expressed in both the peripheral and the central nervous system, although it is unknown as to whether the oral therapies, known as gepants, will cross the blood-brain barrier.
Analyst Marc Goodman, of SVB Leerink, said in a research note that the injectable therapies have “caused a paradigm shift in the migraine space” and multiple key opinion leaders “have indicated that they are also eager to try the oral CGRPs for their convenient dosing and good safety to date, and we believe both Ubrelvy and rimegepant could be substantial products as a result.”
Aside from treating acute migraine patients, rimegepant could fill the gaps for chronic patients with breakthrough migraines and provide a new option for those unable to take triptans, as well as serve as a preventive therapy based on phase III data expected in the first quarter of 2020.
A huge advantage to gepants do appear to be that side effects – such as dry mouth, nausea, fatigue, dizziness and somnolence – were not any worse than placebo, Godley said, suggesting they could be used in diagnosing patients with migraine variance. If they respond to the drug, “you might strengthen your conviction that they have migraine without putting them at any great risk,” Godley said.
Rimegepant’s NDA was based on two phase III trials in which the proportion of patients achieving pain freedom at two hours were 19.2% and 19.6% vs. 14.2% and 12% for placebo. Those achieving freedom from the most bothersome symptom were 36.6% and 37.6% compared with 27.7% and 25.2% for placebo. An orally disintegrating formulation, rimegepant Zydis ODT, also showed pain freedom at two hours of 21.2% vs. 10.9% for placebo, and freedom from most bothersome symptom of 35.1% vs. 26.8% for placebo.
Although there are concerns of liver toxicity that led to the failure of Merck & Co. Inc.’s CGRP antagonist, telcagepant, Biohaven provided phase II/III data showing no liver safety signals after up to one year of dosing even in those receiving rimegepant daily.
Ubrelvy’s labeling allows patients with severe hepatic or severe renal impairment to take the 50-mg dose and a second dose after two hours. “We think this language could foreshadow favorable labeling for rimegepant’s potential approval given that, on a numerical case-by-case basis, we would argue that rimegepant has more ‘placebo-like’ numbers vs. that of Ubrelvy from clinical trials,” Goodman said.
Nevertheless, triptans work better, Godley said. The therapeutic gain of gepants, specifically rimegepant, is 5% to 7.56% over placebo, “which is kind of sobering.” Sumatriptan 100 mg has shown pain freedom at two hours of 35%, he said.
Still, gepants have an important gap to fill among patients who cannot take triptans and who might prefer an oral therapy over an injectable one.
“I cannot even tell you,” Torborg said, “how excited I am for these to help. Hopefully, insurance will cover them. Hopefully, pharma will offer some support for payment.”
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