Antibiotics Pipeline Is Lively, But Sponsors Are Fragile
Executive Summary
Regulatory uncertainty could imperil the crop of emerging companies making a go of it in the incentive-laden US anti-infective space.
The global response to the antimicrobial resistance crisis has seen success using incentives to attract new specialty companies into the scientifically difficult and commercially unattractive infectious disease space, but now the young crop of sponsors with late-stage candidates must overcome a challenging regulatory environment in the US – and not all can be expected to succeed.
FDA has issued more than 100 designations to more than 60 product candidates under the Qualified Infectious Disease Product (QIDP) designation, an expedited review program akin to the breakthrough therapy designation. QIDP products qualify for priority review and fast-track status, which brings more engagement with FDA, as well as extended exclusivity.
With the June 19, 2017 approval of Melinta Therapeutics Inc. fluoroquinolone Baxdela (delafloxacin), FDA has approved seven novel agents with QIDP status since the designation came into existence under the 2012 Generating Antibiotic Incentives Now (GAIN) provisions in PDUFA V. Six of the seven novel agents are antibiotics; one is an antifungal.
Two more antibiotic new molecular entities (NMEs) are under FDA review, according to the Pink Sheet's FDA Performance Tracker, and at least three are aiming for a 2017 new drug application filing (NDA). More than 15 QIDP products are at the pivotal trial stage, including at least 10 new molecular entities. [Editor's note: The FDA Performance Tracker's QIDP Designations chart keeps track of new designations and pipeline progress.]
Standing in the way of optimism about the promise of this healthy, if not necessarily vigorous, late-stage pipeline is the cautionary example of Cempra Inc.'s first product, Solithera (solithromycin) for community-acquired bacterial pneumonia (CABP). The novel macrolide antibiotic received a complete response letter in December calling for a new 9,000-patient safety study. (Also see "Cempra's Solithera Draws FDA Complete Response Letter On Liver Risks" - Pink Sheet, 29 Dec, 2016.) The company is now striving to find a path forward, which could include trying out the still-untested limited population pathway (LPAD) under the recently passed 21st Century Cures Act. (Also see "The First LPAD? Cempra May Try New Pathway For MRSA Antibiotic, Could Retrofit Solithromycin" - Pink Sheet, 6 Mar, 2017.)
Regulatory And Commercial Inexperience
Baxdela developer Melinta was, like Cempra, a first-time sponsor. So is Symbiomix Therapeutics LLC, the sponsor of Solosec (secnidazole), an oral single-dose antibiotic therapy for bacterial vaginosis that is under FDA review with a Sept. 17, 2017 user fee goal.
With no existing sales and marketing infrastructure, first-time sponsors must build commercial operations from the ground up or find a partner. The concentrated US market for hospital antibiotics for serious infections offers a compelling argument for keeping the approved product in-house; the public health imperative to limit use of new antibiotics to forestall development of antimicrobial resistance also limits the sales potential of the products, and partnering dilutes already slim monetary returns. On the other side, the same market dynamics discourage experienced firms from seeking partnering arrangements with novice antibiotic sponsors.
Melinta is establishing a "compact" sales team to market Baxdela for acute bacterial skin and skin structure infections (ABSSSI) to targeted hospitals with favorable demographics. The company is positioning the drug for the sickest patients; the company touts Baxdela's lower rate of drug-drug interactions than other fluoroquinolones, making Baxdela suitable for patients with other underlying conditions, and activity against both gram-positive and gram-negative pathogens. (Also see "Melinta To Launch First Commercial Drug Baxdela Independently" - Scrip, 22 Jun, 2017.) The company will nonetheless face hurdles from hospital formulary committees, which have proven stringent gatekeepers. (Also see "If You Think Approval Is Hard, Try Selling A New Antibiotic" - Pink Sheet, 16 Nov, 2015.)
The other NME antimicrobial under review at FDA is The Medicines Co.'s I.V. combination of the novel beta lactamase inhibitor (BLI) vaborbactam with an older beta lactam antibiotic, meropenem, to preserve antibiotic effectiveness. The product, formerly known as Carbavance, has an August user fee goal for complicated urinary tract infection (cUTI).
TMC is one of the few sponsors with a track record of bringing a novel antibiotic to approval under the QIDP program: the I.V. lipoglycopeptide Orbactiv (oritavancin) was approved for acute bacterial skin and skin structure infections (ABSSSI) in 2014.
TMC, however, is now exploring divesting its infectious disease business. The hospital-focused specialty company has been divesting product lines since 2015 to generate cash and reduce outlays, and the recent removal of its pain therapy Ionsys from the market further stressed the company. TMC's most recent quarterly filing with the Securities and Exchange Commission (SEC) warns of "substantial doubt about our ability to continue as a going concern."
Commercially experienced companies are also rare in the late-stage clinical antibiotic pipeline. Merck & Co. Inc., essentially the only big pharma still active in antibiotic R&D, has another novel BLI, relebactam, in Phase III for a range of Gram-negative infections as part of the MK-7655A fixed-dose combination with imipenem and cilastin. Two novel Merck antibiotics have already been approved with QIDP status, Zerbaxa (ceftolozane/tazobactam) and Sivextro (tedizolid). Shionogi & Co. Ltd. introduced Doribax (doripenem) in 2007, a different era in US antibiotics regulation, before FDA's 2010 final guidance on non-inferiority standards and the GAIN Act incentives. The Japanese pharma is now preparing an NDA for its cephalosporin cefiderocol in cUTI.
The Phase III pipeline is full of sponsors even less able to recover from a setback than Cempra, which has downsized but was cushioned by past successful fundraising and a second candidate, Taksta (fusidic acid), in pivotal trials. Emerging companies like Zavante Therapeutics Inc., Paratek Pharmaceuticals Inc., Nabriva Therapeutics AG, Motif Bio PLC, and Achaogen Inc. have made it to Phase III, while others like MerLion Pharmaceuticals Pte. Ltd. and AstraZeneca PLC spin-out Entasis Therapeutics are hunting for partners to help bring Phase III-ready candidates forward. (See stories to come for more information on product candidates.)
While many emerging firms are staffed by people who worked in big pharma in the bygone era of big pharma antibiotic R&D, institutional inexperience compounds other challenges.
As the Pew Charitable Trusts observed in "A Scientific Roadmap For Antibiotic Discovery," a 2016 report about encouraging innovation, "faced with poor discovery prospects and diminishing returns on investment, major drug companies have cut back or pulled out of antibiotic research altogether. This has left much of the remaining discovery work to small, 'pre-revenue' companies with no products on the market and limited budgets and R&D capacity."
The company with the most QIDP designations, for example, is not a big pharma but Wockhardt Ltd., an Indian firm known for generics. (Also see "Data Integrity Lapses Continue To Erode Wockhardt" - Pink Sheet, 4 Jan, 2017.) Wockhardt has five antibiotic candidates with QIDP designations.
Clinical Trial Costs
Mounting Phase III trial expenses are frequent hurdles for emerging companies. Cempra, for example, said it would need to seek additional funding if FDA agreed to the company's plan for a new Phase III study of Solithera. More funding is also needed for Motif Bio to complete a second Phase III trial of its dihydrofolate reductase (DHFR) inhibitor antibiotic iclaprim in ABSSSI, and the company now hopes to raise the money by issuing new ordinary shares. (Also see "Motif Bio Seeks Cash For Novel Antibiotic" - Scrip, 2 Jun, 2017.)
Similarly, Summit Therapeutics PLC needs additional funding to complete the Phase III program for ridinilazole, a narrow spectrum antibiotic targeting Clostridium difficile, according to company statements. Summit continues "to explore various funding options," the company noted June 14, including third-party collaborations and government, non-government organizations or philanthropic investment.
Cellceutix Corp. cited clinical trial costs in its decision to change course with its defensin mimetic compound, brilacidin, away from infectious disease. Despite Phase IIb data showing non-inferiority to daptomycin for ABSSSI and a Phase III proposal under consideration at FDA, Cellceutix announced in April that it would instead focus on prevention of radiation-induced oral mucositis and eventually inflammatory bowel disease.
FDA made suggestions for Cellceutix' Phase III ABSSSI trial design under a special protocol assessment (SPA) request submitted in February 2016, but the company decided to "delay its response" because the share price of its stock was too low to support the cost of the study, estimated at $30m. "Our strategy now is to achieve success with other trials and attract partnering opportunities with significant down payments and milestone payments which can fund these trials."
Unlike ABSSSI, a popular target for new antibiotics, the oral mucositis market is wide open. "We believe with Brilacidin-OM that there is the potential to a quick path to market because of the lack of effective options for people suffering from head and neck cancer that must undergo chemoradiation," Cellceutix said. "We strongly believe Brilacidin-OM treatment can gain support from FDA for rapid development and full support from insurance companies, hospitals, and doctors."
High Regulatory Affairs Burden
Companies wanting to access funding and incentives for antibiotic R&D must contend with a bewildering array of entities want to contribute to the fight against microbial resistance, placing a large burden on small companies. Support of various kinds, including financial, is available from US government entities like NIH and the Biomedical Advanced R&D Authority (BARDA), the Obama administration's 2015 National Action Plan for Combatting Antibiotic-Resistant Bacteria (CARB), philanthropic foundations like the Pew Trust, international organizations, and public-private collaborations like CARB-X, which aims to de-risk early-stage antibiotic development.
Still more incentive programs are being advocated, like the transferable exclusivity voucher concept being pushed by the Antimicrobial Innovation Alliance (AIA), an industry coalition that includes many of the companies now using the QIDP program as well as some big players that still have a commercial interest in anti-infectives (even if they have reduced activity in novel R&D), including Allergan PLC, AstraZeneca PLC, Pfizer Inc. (which bought AstraZeneca's small molecule anti-infectives business in December 2016), and Johnson & Johnson. (Also see "Antibiotic Incentives: Pfizer’s Read Touts Exclusivity Voucher" - Pink Sheet, 28 Mar, 2017.) and (Also see "‘Wildcard’ Patents: Why A REVAMP-ed Proposal Might Work In 2017" - Pink Sheet, 17 Nov, 2016.)
Another new incentive model floated by industry is an R&D tax credit. Members of the Antimicrobial Working Group, an association of 13 emerging companies, told the recent Biotechnology Industry Organization (BIO) annual meeting that the additional exclusivity granted by the QIDP designation is not a strong enough incentive given the low sales of resistance-aimed antibiotics. A tax credit that allowed companies to write off R&D costs, especially if it were transferrable, could lower fundraising hurdles. (Also see "Better Incentives Needed For Worsening Fungal Infection Threat" - Scrip, 28 Jun, 2017.)
However, the experience of the QIDP program suggests that accessing resources under incentive programs is not always clear or simple. A recent General Accounting Office (GAO) report on the QIDP program found widespread uncertainty among sponsors about the designation. "Half of the sponsors that we spoke with said they were unclear about how to apply for fast track designation if QIDP designation has been granted and about how FDA is interpreting and applying the market exclusivity incentive," GAO said. (Also see "Antibiotic Development: US FDA Needs Draft Guidance On QIDP Designation, GAO Says" - Pink Sheet, 5 Mar, 2017.)
Still More Need For Guidance
GAO concluded that FDA should issue specific guidance on the QIDP designation, which FDA agreed to develop.
Antibiotic Guidance Checklist
Final
- ABSSSI
- Uncomplicated gonorrhea
- cIAI
- cUTI
- Acute otitis media
- Acute exacerbations of chronic bronchitis
- Acute bacterial sinusitis
- Microbiological data for systemic antibacterials
- Non-inferiority trials
Draft
- HABP/VABP and CAP
- Bacterial vaginosis
- Vulvovaginal candidiasis
- Pulmonary tuberculosis
- Anthrax
GAO also urged FDA to clarify how sponsors use and rely on draft guidance documents for antibiotic development. Major changes in FDA's standards for non-inferiority in antibiotic approvals in 2010 set off a large (and still incomplete) project of guidance development in specific indications, a project that was spurred further by GAIN.
Since GAIN was signed into law in July 2012, FDA has issued final guidances on drug development for seven antibacterial indications, including the high-need areas of acute bacterial skin and skin structure infections (ABSSSI), complicated intra-abdominal infections (cIAI), complicated urinary tract infection (cUTI), and uncomplicated gonorrhea.
In November 2016, FDA published the final version of its 2010 draft guidance on non-inferiority trials, the approach used by most anti-infective compounds tested with active comparators. (Also see "Final Guidance On Non-Inferiority Studies Lacks Industry-Sought Changes" - Pink Sheet, 28 Nov, 2016.)
Still in draft form are indication-specific guidance documents on hospital-associated and ventilator-associated bacterial pneumonia (HABP/VABP), community-acquired pneumonia (CAP) and bacterial vaginosis.
Mapping New Pathways For Limited Populations And Narrow Spectrums
Even as FDA sees an end to the overhaul of its antibiotic clinical development guidances, new pathways are forming (and generating new types of regulatory uncertainty) around products that do not follow the conventional broad-spectrum antibiotic template. Developing products for smaller, more specific populations should slow the development of resistance, but demonstrating safety and efficacy for rare cases presents many hurdles for drug developers and regulators.
The recently enacted 21st Century Cures Act provides a limited population antibiotic development (LPAD) pathway for products that would be restricted to small, specific groups of patients with life-threatening infections. (Also see "Antibiotic Development: Limited Population Pathway In US Removes Barrier" - Pink Sheet, 29 Mar, 2017.)
The real-world value of the LPAD pathway has been a matter of debate, but it will certainly add to regulatory workloads. Older legislation like the ADAPT and PATH Acts, as well as the agency's own 2013 draft guidance on abridged pathways in unmet medical need, already afford FDA considerable flexibility. The 2015 approval of Actavis' (now Allergan's) Avycaz, for example, followed the essential outlines of the LPAD approach. (Also see "Flexibility Or Formal Pathway? Avycaz Suggests FDA Doesn't Need Congress To Expedite Limited Use Antibiotics" - Pink Sheet, 18 May, 2015.)
With the addition of LPAD, the AIA industry coalition calls for a unitary voice from FDA. "A clear statement of a flexible, accelerated pathway for certain novel antimicrobial products would be beneficial in bringing limited population products to patients in need," the coalition said.
At the same time, FDA is starting to set a framework for an active area of antibacterial development with little regulatory precedent: drugs targeting single pathogens. An April 13 meeting of the Antimicrobial Drugs Advisory Committee highlighted some of the issues that will need to be worked out in the narrow-spectrum context, including the role of superiority trials, non-inferiority margins, animal models, surrogate endpoints, and postmarketing studies. (Also see "Flexible 'Menu' Of Antibacterial Development Options Suggested By US FDA Panel" - Pink Sheet, 18 Apr, 2017.)
The regulatory uncertainty created by draft guidances, new legislation, and new initiatives makes for an especially challenging environment for emerging companies without deep resources. Science is only the first hurdle for the companies trying to generate the novel antibiotics that public health requires.