BioPharmaceutical Industry Reduces CNS Drug Development

By Larry Gorkin, Ph.D., Contributing Writer

Pfizer announced in 2018 the intent to discontinue development of neuroscience R&D programs. More specifically, programs for Alzheimer’s disease (AD) and epilepsy were eliminated. Although not a dominant player in the CNS domain, Pfizer’s Lyrica, to treat fibromyalgia and diabetic neuropathic pain, generated worldwide sales of $4.51 billion in 2017. In years past, Pfizer had blockbuster drugs to treat AD, major depressive disorder (MDD), and schizophrenia.

Pfizer is not alone. According to an analysis of FDA data, only 12 therapeutics were approved for CNS indications between 2012 and 2016, as compared with 19 during the prior five-year period. In contrast, during 2012 to 2016, the FDA approved 50 new oncology therapies, as compared with 24 from 2007 to 2011. Part of disparity is due to marked pricing differences favoring oncology versus other diseases. Experts note that what is known about pathophysiology is more advanced in cancer than in CNS indications. The explanation for these developments differs across CNS indications. Here, we will focus on four CNS indications: AD, MDD, migraine, and schizophrenia .

Alzheimer’s Disease

Alzheimer's affects more than 5 million Americans, a number that's expected to increase markedly over the next decade. AD drugs are marked by a lack of efficacy: (1) no novel drug to treat AD has been approved by the FDA since 2003 (/Lundbeck/Forest’s Namenda/memantine); and (2) all approved AD drugs only slow the progression of AD minimally. Yet, like Odysseus to the sirens, biopharmas are drawn to the $10 billion opportunity in global annual sales that awaits the first disease-modifying drug approved to reverse AD symptoms. The Odyssey simile is appropriate given a 99 percent failure rate of AD clinical trials in the past 15 years, including all Phase 3 studies. For instance, in 2018, Merck halted a large trial of beta-secretase 1 (BACE1) inhibitor, verubecestat, in prodromal AD due to lack of efficacy. BACE1 inhibition reduced beta-amyloid levels in the brain, but this effect didn’t mediate significantly improved cognitive functioning.

New FDA guidelines recognize the potential role of cognitive screening algorithms, imaging studies, and biomarkers. In terms of AD outcomes, only improvements in memory have to be demonstrated to gain regulatory approval. This follows from a paradigm shift to recruiting patients in an earlier stage of AD, in which functional status may not be a relevant concern. Potentially, Phase 3 programs may include individuals with no symptomatic signs of dementia, or functional impairment.

There is growing consensus that the current beta-amyloid hypothesis is “dead,” although some keep trying. Abbvie has a different paradigm, utilizing a one-time, gene-therapy approach via biotech Voyager. Therapeutic antibodies target AD-linked protein tau, and genetic engineering allows more of the medication to pass the blood/brain barrier than conventional approaches. Facebook’s Chan/Zuckerberg Initiative is awarding multiple $2.5 million contracts for researchers with innovative pathway approaches toward the ultimate treatment of AD.

Major Depressive Disorder

No novel breakthrough in the treatment of MDD has occurred in nearly three decades, notwithstanding approximately 16 million Americans who suffer from MDD each year. Treatment is dominated currently by first-line, generic treatments, such as the SSRIs/SNRIs (selective serotonin reuptake inhibitor/serotonin–norepinephrine reuptake inhibitor). Approved second-line drugs are available, such as the generic atypical antipsychotic agents. It is surprising, therefore, that a 2018 Forbes article claimed that 2/3 of newly diagnosed MDD patients globally do not receive treatment, particularly the elderly. About 80 percent who seek therapy prefer medication to psychotherapy; approximately 2/3 of these will respond to treatment.

Sage Pharmaceuticals seeks to change the status quo and has received the FDA’s Breakthrough Therapy Designation for two developmental drugs to treat MDD in the past two years. That the potential breakthrough of “game-changing” treatments are in CNS categories makes these findings even more impressive. Sage’s lead developmental drug, brexanolone, is being tested for the treatment of moderate-to-severe postpartum depression (PPD), and an experimental drug, SAGE-217, is being tested for MDD. Both drugs are related to GABA (gamma-aminobutyric acid) receptors.

Brexanolone treats PPD, a form of MDD afflicting an estimated 10 to 20 percent of women following childbirth. In studies, it was found to be safe and well tolerated. The expected price is to be about $15,000 to $20,000 annually.

When SAGE-217 was tested in a Phase 2, placebo-controlled study of 89 adult patients with moderate-to-severe MDD, it differentiated significantly in terms of reducing rates of MDD. Traditional treatments for MDD usually take at least one month for efficacy to emerge.

Allergan, which has emerged successful with injected Botox in the CNS arena for the treatment of migraine headaches, tested the agent in moderate-to-severe MDD. On the basis of Phase 2 results, Allergan found evidence of efficacy for Botox in one of two doses, and is planning a Phase 3 program extension.

Migraine Prevention

Current treatments for migraine prevention include  oral generic agents, including Topamax, Inderal, Depakote, and Blocadren. While cost is not an issue, adverse events do make them unsafe or unpleasant for certain patients. Injected Botox is also approved for chronic migraine prevention. Allergan reported that about 20 percent of Botox global revenue, $864 million in 4Q17, was from the migraine indication.

The potential market for migraine prevention involves millions of patients, which makes the opportunity inviting. Developmental agents target a novel pathway, calcitonin gene–related peptide (CGRP), via monoclonal antibody biologics. One of these developmental agents, Amgen’s Aimovig , was evaluated among 955 patients over six months. The company says 50 percent of patients randomized to a high dose of the drug reduced their migraine days by 50 percent or greater, as compared to a corresponding 26.6 percent with placebo. It offers no systematic adverse events, besides soreness at the site of injection. CGRP biologics offer fewer injections than Botox.

The FDA has accepted Amgen’s application for a new biologic, with an expected decision date in May 2018. Lilly’s galcanezumab should receive an FDA decision date a few months later. Three other companies have products in late-stage development, including the generic powerhouse, Teva, and biotech Alder. Allergan is working on an oral CGRP therapy the company licensed-in from Merck in 2015. The results from Aimovig seem representative of the class as a whole.

Treatments are expected to start at $8,500, which could be cost-prohibitive, given co-pays of 20 percent or higher. If accurate, though, this price would be markedly lower than the price set for the two monoclonal antibodies (Repatha and Praluent) approved to treat high cholesterol in 2015. Amgen, as well as Regeneron/Sanofi, set the price of Repatha and Praluent, respectively, at greater than $14,000 annually. Competing with high-intensity, generic oral statins, the biologics have generated marginal revenue. Sanofi reported the equivalent of $193 million in global sales for Praluent in 2017. Amgen recorded corresponding global sales of $319 million for Repatha.

Payers perceive multiple, nononcology drugs launched within a short period of time of one another as an opportunity as well. This creates a déjà vu for payers, reenacting a successful strategy applied to the expensive, curative agents for hepatitis C. Payers were able to extract major discounts/rebates that lowered the price of these highly efficacious agents by about 50 percent. A major difference, though, is that the hepatitis C market was much more indigent than the migraine prevention market, with the former relying heavily upon involvement of governmental programs (e.g., Medicaid, Veterans Administration).

Schizophrenia

Although the U.S. share of total prescription biopharma sales, as a percentage of global sales, is generally only about 40 percent in 2018, this is not the case in schizophrenia. In 2008, the year that the first branded oral atypical antipsychotic agent lost patent protection, JNJ’s Risperdal , U.S. sales represented greater than 60 percent of global revenue for these agents. Combined sales were about $16 billion. U.S. sales reflected the anomalous role that Medicaid played in such sales. Medicaid would pay for branded drugs that cost 80-fold more than the generic typical antipsychotic agents, such as Haldol . For example, Medicaid paid $5.5 billion in 2005 for antipsychotic agents, and this total was reduced markedly in 2011, to $3.76 billion, as generic drugs became increasingly available. 

In 2018, all oral atypical agents are generic, and no novel class of antipsychotic drugs has emerged. Do generic drugs dominate the U.S. market? Not exactly. Branded long-acting injectable (LAI) antipsychotic agents, derived from the atypical oral meds, are being prescribed increasingly with the rationale to improve medication adherence and prevent relapse. The LAI drugs cost several hundred dollars per monthly treatment. Poor adherence is a major concern in treating schizophrenia, involving at least 1/3 of patients. Accordingly, patients are shifting to LAI versions earlier in the treatment cycle. However, randomly assigned studies have failed to reliably demonstrate an increased level of patient compliance to LAI medication than to oral meds.

Outcome-based studies, conducted with naturalistic designs have been more supportive of the LAI drugs. Indeed, in 2018 the FDA approved JNJ’s Invega Sustenna, a monthly injection, with labeling that the LAI led to a six-month longer delay until treatment failure (arrest/incarceration, psychiatric hospitalization or increase in services, treatment discontinuation, or suicide) versus seven traditional oral treatments for schizophrenia. Overall, 39.8 percent of the LAI group and 53.7 percent of the oral antipsychotic group experienced a treatment failure event during the 15-month study, with arrest/incarceration being the most common reason for failure in both groups. The approval was based on an open-label, randomized study of 444 U.S. adults who had been imprisoned at least once in the past two years. 

JNJ is foremost on the list of pharma companies with LAI agents, as they have several such agents: Invega Sustenna /Invega Trinza, with $2.57 billion in global sales in 2017, and Risperdal Consta , with $805 million in worldwide sales in 2017. An LAI of the former blockbuster, Abilify, is sold by the manufacturer, Otsuka, in partnership with Lundbeck. Sales are reportedly approaching $1 billion U.S. annually. Lilly’s LAI formulation of Zyprexa, Relprevv, was approved with a REMS (risk avaluation and mitigation) program regarding post-injection delirium/sedation syndrome. Not surprisingly, Relprevv sales have been modest.

Fellner (2017), in Pharmacy & Therapeutics, nicely summarized what is needed in novel treatments of schizophrenia: drugs that enhance cognition, treat negative symptoms (e.g., social withdrawal, agitation), and increase compliance (particularly oral options) to reduce rates of treatment-resistant patients. Unfortunately, Fellner listed more developmental LAI drugs than novel drugs that addressed the issues listed.

One issue, enhanced safety, is being addressed by Neurocrine with its 2017 FDA approval of Ingrezza, (40-mg dose). Ingressa significantly reduced abnormal involuntary movements among schizophrenic patients (50 percent reduction in symptoms was achieved by 40 percent with Ingrezza versus 8.7 percent with placebo). Costing greater than $60,000 annually, Ingrezza generated $64 million in the last quarter of 2017. Neurocrine more recently announced that the FDA approved an 80-mg dose, which will be sold at the same price. Thus, this essentially cuts the price of Ingrezza in half for potential patients.

Summary

Although the CNS field is marked by relative few drug candidates in development, there is progress;  there are several candidates likely to impact migraine prevention and MDD, and schizophrenia is flush with branded products. AD, however, is in need of a reset.

Larry Gorkin, Ph.D., is a clinical psychologist who was a grant writer affiliated with Brown University, Providence, and then joined Pfizer/Health Economics at Manhattan world headquarters. Larry started the one-person shop, Gorkin & Cheddar Consulting in 2009, after 13 years at Pfizer.