Cipla Chief Calls For Invigorating Focus On Repurposed Drugs
Executive Summary
Cipla chairman underscores the potential and value of repurposing drugs for Indian researchers and pharma firms looking to build their R&D activities, amid signs of growing attention to the promising area globally.
Cipla Ltd.’s chairman Dr Yusuf Hamied recently doled out some important advice to researchers at India’s Tata Institute of Fundamental Research (TIFR) – don’t ignore the potential of repurposing or repositioning of drugs.
Hamied, in an address at the institute, said that repurposing was emerging as a promising approach to overcome the hurdles of fundamental R&D. Several pharma start-ups, he noted, were essentially based on finding new uses for existing drugs, largely with an eye on better prospects for regulatory approval. TIFR, a national center of the Government of India, is engaged in basic research in physics, chemistry, biology, mathematics, computer science and science education.
Hamied noted that between 2012 and 2017, approximately 170 repurposed drugs entered the drug development pipeline globally, and of these 70% were sponsored by academia and the balance by industry.
Drug repurposing can entail a broad scope of activities including developing new therapeutic uses for existing drugs or novel combination therapies, repositioning on-market therapies to new disease indications, and also targeting drugs discontinued for a specific indication during trials to new disease indications.
Cipla’s Repurposing Focus
Backing his position on repurposing, Hamied referred to how Cipla had introduced, almost two decades ago in the area of HIV/AIDS and for the first time in the world, a fixed-dose combination of three drugs, “each individually being the monopoly of a different drug company.”
The Indian company “combined the three drugs into one tablet called Triomune [lamivudine + nevirapine + stavudine] way back in the year 2000 and offered this to Africa, when no other company could combine the three individual drugs due to intellectual property rights. This Cipla initiative which involved a repurposed drug resulted in saving millions of lives in Africa,” Hamied, seen as an antimonopoly champion in this part of the world, said in his address at the TIFR earlier this month.
Cipla’s "crusade" in the HIV/AIDS segment - as Hamied has often referred to the firm’s efforts in the past - is well documented. In 2001, the firm introduced the first once-daily triple cocktail for HIV/AIDS at a cost of less than a dollar a day, thereby increasing access to HIV medicines manifold in Africa and elsewhere.
Hamied, who retired as Cipla’s managing director in 2013 but continues to be the firm’s chairman in a non-executive role, also noted that Cipla’s R&D division had “virtually discontinued” fundamental research and is now concentrating its resources and efforts into repurposing.
This includes many interesting areas of work such as pro-drugs, metabolites, liposomal drugs, nanoparticles, enhancers, boosters, co-crystals, chiral drugs, polymorphs, fixed-dose combinations, newer indications, newer delivery systems and newer routes of administration, he explained.
“Again, the ultimate objective is to get regulatory approval as this is easier for repurposed drugs than for a new chemical entity,” Hamied stressed.
Last year, the executive had shared that Cipla was in the early stages of developing a prodrug of the HIV antiviral tenofovir. At the time, Cipla’s chief maintained that the prodrug, tenofovir pivafenamide fumarate, was “equipotent” to TAF (tenofovir alafenamide) but without the “negative aspects” of this molecule. The latest situation with the prodrug could not immediately be ascertained. (Also see "Amid Pharma ‘Landmarks’ Cipla Develops Tenofovir Prodrug" - Scrip, 31 Aug, 2018.)
Strong Precedent
Hamied told Scrip that several specialty medicines of today are essentially repurposed therapies, pointing to thalidomide as perhaps a “very good example” of a repurposed drug.
The controversial therapy once linked with birth defects was approved way back in the 1950s as a sedative and then later to treat leprosy, but has since gone on to be approved for the treatment of multiple myeloma, as Celgene Corp.’s Thalomid.
In 2006, lenalidomide (Celgene's Revlimid), an orally administered thalidomide analog, received US FDA approval for use with dexamethasone in patients with multiple myeloma who have received at least one prior therapy. In 2017, it was also approved as a maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
Quick Return On Investment
Other experts too endorsed how repurposing could possibly be of interest for Indian firms that are trying to straddle the bridge between their generics business and more fundamental R&D.
Salil Kallianpur, a former executive vice president at GlaxoSmithKline India, now running a digital health consultancy, told Scrip that a highly attractive aspect in drug repurposing is that the “barrier to entry” is low, at least in comparison to a full drug discovery operation.
However, he added, the availability of high-performance computing and databases of various forms are a must to enhance the ability to pose “reasonable and testable hypotheses” for drug repurposing, rescue, and repositioning.
“That said, there are some Indian majors who have invested in strong R&D capabilities. These companies should definitely be interested in this relatively low cost and quick return on investment scenario to build differentiated products for the Indian market,” Kallianpur said.
Global Repurposing Efforts
Globally, there is significant activity already underway in the area of repurposing.
In the EU, for instance, pharmaceutical industry bodies and the regulatory authorities have been working on a draft “repurposing framework” that would help to identify and evaluate new uses for current off-patent medicines.
Under the plan a “champion” - a person/academic unit/learned society/research fund - with a particular interest in repurposing a compound/product for a new indication can put forth a repurposing proposal for regulatory evaluation. (Also see "‘Champions’ To Lead European Drug Repurposing Project" - Pink Sheet, 30 Oct, 2018.)
Ex-GSK executive Kallianpur believes similar formalized repurposing efforts in India too would be "very welcome," with domestic firms likely to be interested. He cited the example of the government of the Indian state of Kerala working with the World Health Organization and leading researchers to find repurposable drug candidates to treat an outbreak of Nipah virus in May 2018.
“Such instances may not interest the industry. However if the government states its position through a policy framework, the industry might be tempted to consider this [repurposing] venue,” he said, but added that the “confounding factor” would be patentability of the repurposed drug. This, he believes, might be the reason the Indian government isn’t considering a framework (at least so far), given its "paranoia" that multinationals would consider this as a concession to evergreen their patents in India by undermining Section 3(d) of the country's Patent Act.
The controversial section, essentially intended as a deterrent against evergreening of patents, broadly deals with incremental inventions that are not patentable unless they show improved efficacy or unless a known process results in a new product or employs at least one new reactant.
Around the world, both established and young firms have supported or are engaged in drug repurposing. AstraZeneca PLC for instance has established linkages with the US National Institutes of Health’s National Center for Advancing Translational Sciences, aimed at encouraging the discovery and exploitation of new therapeutic indications for existing drug candidates. (Also see "AstraZeneca Has Stake In Three Of Nine NCATS Research Projects" - Pink Sheet, 18 Jun, 2013.)
Others like UK company Nuformix are identifying known therapies with potential to treat unmet medical needs, in this case using proprietary cocrystal technology to protect and enable new therapeutics.
More recently, Unilever PLC spin out Arecor Ltd., which has been helping big pharma reformulate drugs, filed a clinical trial application with the Austrian regulatory authorities for a Phase I study in type 1 diabetes patients of its ultra-rapid acting insulin product, AT247. (Also see "Standing On The Shoulders Of Giants: Could Arecor Enter The Race To Revolutionize Diabetes? " - Scrip, 7 Jan, 2019.)
Newer Technologies
Meanwhile, Cipla's Hamied, who completed his PhD in organic chemistry under the late Nobel Laureate Lord Todd at the University of Cambridge in the UK in 1960, noted that medical science is shifting from chemistry to biology, and that while it is imperative to adopt newer technologies that are revolutionizing health practices in India, it was also important to use “adaptable technologies and existing capabilities.” (Also see " Profile: Cipla's Hamied On Cambridge, O-Levels And Sticking It Out " - Scrip, 6 Oct, 2015.)
He referred to newer technologies such as 3D, artificial intelligence (AI), digitalization and continuous manufacture that are already being closely researched and implemented, but underscored that India needs appropriate technology.
“This should be scientifically sound, relevant, adaptable to local needs and using available resources. It follows Mahatma Gandhi’s [the leader of India’s independence movement] slogan of self-reliance and self-sufficiency,” the outspoken Cipla chief added.
Interestingly, TIFR is collaborating with the premier Indian government think tank NITI Aayog and global IT giant Intel to set up a Model International Center for Transformative Artificial Intelligence (ICTAI), aimed at developing and deploying AI-led, application-based research projects. (Also see "India’s Big AI 'Garage' Ambition – Can It Get The Mechanics Running ?" - Scrip, 25 Jun, 2018.)
The Model ICTAI aims to conduct advanced research to incubate AI-led solutions in three key areas – healthcare, agriculture and smart mobility – by bringing together the expertise of Intel and TIFR, the partners said last September.