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Strategy for Innovative Business
At Glenmark, we believe that great companies take a bit of the future and make it their present. This belief underpins our strategy for transforming ourselves into an innovation-led organisation.
To the world, we are a global branded/ generics company. But we have chosen to see ourselves as an innovator-in-progress. Each day, in our thoughts, plans and actions, we have painstakingly learnt from - and built on - the achievements or reversals of the day before. Over the decade, we have created an internal storehouse of skills, expertise and learnings, which together form the foundation of our innovation programme. We have accepted that wins and losses are part of the high-risk venture of drug research and development (R&D) and stayed the course in the face of challenges.
The results are now becoming apparent.
Today, we have a rich pipeline of specialty and novel molecules in various stages of development in the three focus areas - oncology, respiratory and dermatology. Their development is taking place in our laboratories across India and Switzerland, and in clinical trial sites in multiple global locations. Our focus on these therapy areas is based on their significant size, rapid rates of growth, and our cumulative experience and track record in brand-building and patient-focussed innovation in these areas in emerging markets. We also see a vast unmet need across these therapy areas for better, more economical and/or more convenient therapies.
For cancer patients, especially those who need more efficacious treatment options, we are developing a new range of targeted therapies that have shown promise owing to their novel modes of action. This has been made possible by a breakthrough technological platform that our scientists have developed for producing drugs that use a new approach in targeted therapy - using a drug to lock on to more than one target at a time. Their achievement assumes more importance when viewed against the fact that this approach could not be perfected even by some large pharmaceutical companies who worked on it, in the past.
For those afflicted with respiratory disease, we are working on drug delivery and device formats that can make self-administration of medicines much easier for patient groups such as the elderly who are a large cohort among respiratory disease sufferers. For those having near-debilitating allergies, our scientists have innovated medicines to alleviate symptoms and boost the treatment options available. From an affordability perspective, we are also working on a biosimilar of a blockbuster anti-asthma and Chronic Idiopathic Urticaria (CIU) that could potentially be the first such products in the global market.
By 2025, we anticipate that specialty and innovative products will contribute 30% of revenues.
NME & Speciality Pipeline
Glenmark has a robust pipeline of 10 compounds in various stages of clinical development, primarily focussed in the areas of oncology, respiratory disease, and dermatology.
Notes: Non core assets such as GRC 17536, GBR 900 and GBR 500 deprioritised for any further investment. These 3 and GRC 27864 are candidates for outlicensing as on May 2017
The specialty business marks an important milestone in our journey to emerge as an innovation-led company over the next decade. The barriers to entry for such products are greater as they enjoy regulatory exclusivity for a defined period, have complexity associated with development and are protected through multiple patents.
This will help us withstand competition and pricing pressures in the generics business while making available novel solutions to patients suffering intractable medical problems.
Glenmark is working on an exciting pipeline of specialty products primarily in the respiratory and dermatology therapies. We believe that our efforts will lead to a launch in the US for multiple such assets in the next three to four years.
Chronic respiratory disease, an umbrella term for long-lasting ailments involving the respiratory system, claims millions of lives each year. In recent decades, it is on the upswing compounded by risk factors such as smoking, pollution, and allergens. While the drug industry has made a phalanx of treatments available, more options are needed.
Glenmark’s respiratory pipeline covers key disease areas with products on various device platforms such as multi-dose inhalers, dry-powder inhalers, nebulisers, and nasal sprays. We have introduced multiple unique combinations in emerging markets like India and Russia. For some years now, our R&D teams in India, Switzerland and the US have devoted themselves to finding innovative solutions to fill treatment gaps. Over the last few years we have made significant progress in this endeavour.
1 - World Health Organisation (WHO), 2 - National Health Interview Survey statistics 2015, 3 - IMS Health data
Seasonal Allergic Rhinitis (AR), also called hay fever, is a chronic inflammatory disease. Long-duration AR has a significant bearing on quality of life.
The global pharma industry has developed therapies such as antihistamines, decongestants, and inhaled steroids among others to combat AR. While this has helped bring relief to millions of patients, there is still a need for more choice in the form of innovative drug combinations and delivery formats as all therapies don’t work equally well in all patients.
GSP 301 is a novel fixed-dose combination of two known drugs - the corticosteroid mometasone furoate and the antihistamine olapatadine hydrochloride - in a nasal spray that is being studied for the treatment of seasonal AR.
In March 2017, we announced positive results from a Phase III study in the US that enrolled 1,176 adults and adolescents 12 years of age and older for 14 days of twice-daily treatment with GSP 301 or placebo. The trial was conducted across 43 sites in the US. In the trial, treatment with GSP 301 demonstrated statistically significant and clinically meaningful improvement from baseline in average morning and evening patient-reported reflective Total Nasal Symptom Score (rTNSS), compared with placebo (p <0.001), olopatadine (p=0.028), and mometasone (p=0.019). The treatment was well-tolerated and showed no meaningful differences in reported adverse events across study arms. A long term safety study is being conducted at 34 sites in the US and 600 patients have been enrolled.
Currently, there is only one product available in the US that combines a steroid and antihistamine in a single spray. This limits treatment options for people with hay fever and can increase the cost and complexity of treatment. GSP 301 fills a clear gap in treatment options. From a patient experience and compliance viewpoint, it addresses the bitter taste associated with some existing medications.
GSP 301 is our first branded specialty product to clear a Phase III trial. FDA confirmed that the data from Phase III trial is sufficient and no further studies are needed to support a New Drug Application (NDA) filing for GSP 301. We expect to file for USFDA approval in early CY 18. We are also looking to file for marketing approval for GSP 301 in other markets across the globe.
COPD is a progressive lung disease characterised by damaged air sacs and inflamed airways. The opportunity in this disease area lies not just in new treatments but also in reducing inconvenience, achieving greater patient compliance to therapy and improving quality of life.
GSP 304 is a nebulised, once-daily formulation of tiotropium bromide, a Long-Acting Muscarinic Antagonist (LAMA) for the maintenance treatment of COPD. It targets specific receptors on bronchial muscle cells implicated in airway constriction and interferes with their action. The novelty of GSP 304 lies in its being the first nebulised form of Tiotropium Bromide.
Most COPD medicines are delivered via inhalers. Nebulisers score over inhalers by facilitating more efficient absorption and dispersion of medication and allowing for better dose calibration. They are easier to handle when compared with inhalers - which require greater hand-mouth coordination - and hence, more suitable for the aged population. As geriatric patients form a large group among COPD patients, the use of nebulisers is expected to increase in future.
GSP 304 is currently in a Phase II trial in the US in which 156 subjects with mild to moderate COPD as defined under the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria will be recruited across 25 sites in the US. In this study, GSP 304 will be compared with marketed formulations of the drug over three weeks to inform dose selection for Phase III. We expect to file an NDA with the US FDA by the fourth quarter of CY 19.
1. The Global Asthma Report, 2014, 2. World Health Organisation (WHO)
Asthma is a chronic lung disease that causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. Even a decade ago, the direct and indirect cost of asthma was estimated at USD 56 bn in the US alone, according to the Centres for Disease Control and Prevention. Since then, the number of asthma sufferers has grown. Affordability of care has an important role to play in reducing this burden.
Chronic Idiopathic Urticaria (CIU) is a common skin disease that presents as spontaneously recurring hives or welts. It is often caused by food or drugs. It occurs across all age groups. According to published research, high medication costs put a large burden on patients with CIU.
GBR 310 is a recombinant DNA-derived humanised immunoglobulin G1 kappa monoclonal antibody for allergic asthma and CIU. It is a biosimilar of the monoclonal antibody XOLAIR® (omalizumab). In April 2017, the USFDA cleared our application to start a first-in-human study of GBR 310. The study will assess pharmacokinetics of GBR 310 in comparison to XOLAIR® in healthy adult volunteers between 18-65 years of age.
GBR 310 has the potential to be among the first biosimilars of XOLAIR® in the US. We expect to file for marketing approval in CY 20.
GBR 310 is Glenmark’s only biosimilar programme as it fits well with two of our core therapy areas i.e respiratory and dermatology and also allows us to leverage our biologics expertise in Switzerland.
Novel Molecular Entity (NME) assets
NMEs FOCUSSED ON ONCOLOGY
Cancer is a complex disease that results from dysfunction of multiple systems including how cells repair themselves, how the immune system fights disease, and how human body cells shrink and die. Advances in biology have allowed scientists to understand cancer much better and devise new strategies to combat the disease.
Scientists and drug companies have developed a range of ‘targeted’ treatments that zero in on molecular targets that play a key role in these systems, a departure from the carpet-bombing chemotherapy of the past which did not discriminate between healthy and cancerous cells.
However, the current range of targeted therapy has its limitations. A continuing challenge is the management of toxicity. As cancer is often detected among the elderly, the question is whether they will be able to tolerate the side-effects of therapy. Another challenge is to develop drugs that work in large number of patients instead of smaller sub-sets. Additionally, in some cancers, tumor cells turn resistant to treatment.
Indeed, if this were a war, cancer would be a particularly ingenious opponent, constantly devising new ways to evade being defeated. There is a constant need for new approaches to outsmart the enemy.
Glenmark is proud to have made strides in finessing one such approach. BEAT® or Bispecific Engagement by Antibodies based on the T-cell receptor is a technology platform that allows us to efficiently develop and manufacture drugs that can bind with two key targets instead of one, leading to potentially better speed and efficacy.
Glenmark’s scientists have developed a promising pipelineof biologics known as bi-specific monoclonal antibodies (bsAbs) on the BEAT® platform in the category of immunotherapy i.e. drugs that recruit the immune system to fight disease. Given their dual specificity, they simultaneously bind to targets in the immune system and on tumor cells. This allows T cells - essentially, soldiers of the immune system - to destroy tumor cells more completely and faster than conventional mAbs.
BEAT® is the culmination of many years of intensive R&D by our biologics laboratory in Neuchatel, Switzerland. While the concept of bi-specificity has been known for two decades, the development and efficient scale-up of such drugs poses a Herculean challenge. Bispecific formats have had stability and/or manufacturing issues discouraging many larger companies from pursuing this avenue.
BEAT® scores on multiple fronts. One, molecules based on BEAT® are robust and stable enough to withstand the rigours of scale-up and purification; this translates to relatively swift production of clinical trial batches. Two, bi-specificity allows novel modes of action that can potentially lead to more potent and efficacious therapy. Three, the BEAT® platform lends itself to a variety of clinically relevant targets including those that we may want to pursue in future.
In the last few years, our focus on bispecific antibodies has been validated by the successful launch of the first bsAbs in the US and Europe and by considerable deal-making activity by large pharma companies.
Here’s a look at the key assets emerging out of BEAT®.
1 and 2 – Datamonitor
HER2+ cancer is characterised by a gene mutation that makes an excess of a protein called Human Epidermal Growth Factor receptor 2 (HER2) which promotes the growth of cancer cells. HER2 is overexpressed in a range of cancers.
Trastuzumab, the first targeted mAb therapy for HER2+ cancer, revolutionised its treatment. Despite impressive advances in survival rates with this and other treatments, leading oncologists believe that there is a need to develop more effective therapies and with different methods of action, in order to prevent patient relapse.
Various published studies on resistant metastatic breast cancer suggest that roughly 70% of patients acquired resistance to trastuzumab within a year of treatment. Besides, the drug is most effective in patients with the highest level of HER2 expression - seen in only a portion of all patients with this mutation. Moreover, the few targeted therapy drugs for HER2 overexpression don’t work equally well in all patients.
For instance, currently only two mAbs - trastuzumab and ramucirumab - are available to treat gastric cancer. In such cases, doctors need more options beyond conventional chemotherapy.
GBR 1302 is a potential first-in-class treatment, a HER2 X CD3 bsAb, being studied in breast and gastric cancers. It uses a novel mechanism to attack tumour cells; it has two targets - HER2 and CD3, a receptor that activates T cells. Importantly, it can potentially work even in cases of low-to-moderate HER2 expression.
In preclinical studies, GBR 1302 showed faster and more complete killing of tumour cells compared with first-and-second line treatments namely trastuzumab and pertuzumab. Results of an in-vitro study suggest a potentially large therapeutic window in destroying HER2+ cancer cells compared with normal cells. The compound kills tumor cells at concentrations one thousand-fold lower than was found to kill cells expressing normal levels of HER2.
A Phase I study to determine maximum tolerated dose (MTD) is underway. We have enrolled 12 patients in four sites across Germany for Phase I dose escalation study. In January 2017, the USFDA approved the inclusion of the US sites in the ongoing Phase I clinical study in Germany of GBR 1302. If it clears trials, GBR 1302 stands to emerge as a promising new therapy for previously treated and eventually, newly diagnosed HER2+ tumors.
1,4 – Datamonitor; 2 - Ann Oncol (2010) 21 (suppl_7): vii143-vii150; 3 - National Cancer Institute. Cancer Stat Facts: Myeloma
Multiple Myeloma (MM) is a type of blood cancer caused by plasma cells turning malignant. Even though a number of therapies have been introduced to manage MM, it is still not curable. Patients eventually become refractory to all treatments and succumb to this disease.
Independent assessments of leading doctors in the field estimate that 30% of the frontline patient population with MM does not derive the same benefit from treatment as the rest. Also, there is an acute need for less toxic therapy since most patients are elderly and cannot withstand the side-effects.
GBR 1342 is a humanised bsAb being studied for the treatment of MM in patients who have received prior therapies.
This is our second BEAT®-based molecule. It binds to CD3 receptors and redirects cytotoxic T cells to CD38, a glycoprotein that is one of the few known markers for plasma cells and a well-established target for MM. In pre-clinical studies GBR 1342 shows higher potency and ability to kill tumor cells against leading only CD38 targeting molecules. Going forward, GBR 1342 could also prove effective in other B-cell malignancies.
In May 2017, the USFDA cleared our Investigational New Drug (IND) application to initiate a Phase I study of GBR 1342.
1 – World Health Organisation (WHO); 2- World J Gastroenterol. 2012 Oct 7; 18(37): 5171–5180; 3- Datamonitor
Colorectal cancer or cancer that starts in the colon or rectum, affects more than 1 million individuals. The role of a protein called Epidermal Growth Factor Receptor (EGFR) is well established in the progression of colon cancer. Targeted therapy takes the form of EGFR antibodies that block the mechanism by which tumour cells grow. However, they are known to cause considerable side effects.
EGFR antibodies don’t work in cancer cells with a certain mutation or genetic change. Mutations in the KRAS and BRAF genes are notorious for allowing the cancer to bypass anti-EGFR treatment. KRAS mutations alone occur in 35-45% of colorectal cancer cases. Drugs that target EGFR are not currently indicated for patients with such mutations.
Independent assessments suggest a significant unmet need for more efficacious and safe targeted treatments that prevent disease progression. Almost 60% of patients on first-line treatment progress to second-line therapy.
GBR 1372 is an EGFR-targeting bsAb that is being developed for the treatment of colorectal cancer refractory to existing therapies such as Erbitux/Vectibix.
This BEAT® molecule directs T cells to EGFR-expressing cancer cells to facilitate their destruction. Its novel mechanism of action has shown promise in overcoming the mutation problem - in preclinical trials, GBR 1372 showed good activity in tumours independent of their KRAS and BRAF mutation status.
GBR 1372 is currently in preclinical studies and is also being developed for non-small cell lung cancer and head and neck cancers. Glenmark is likely to file an IND for GBR 1372 with the USFDA in CY 18. Its incidence in the seven major markets is expected to grow to ~656,000 in 2035, largely due to the aging populations across all markets.
A549_7 – KRAS mutated lung carcinoma
Cancer cells are good at evading an attack from the body’s immune system. One way they do this is by using ‘checkpoints’ (proteins such as PD-1 and CTLA-4) to signal the immune system to call off the attack of T cells on the tumour. These checkpoints have emerged as key ‘targets’ and a class of drugs known as ‘checkpoint inhibitors’ has been developed to block them.
Checkpoint inhibitors are most efficacious when combined with drugs that work in tandem to accelerate the immune system response. Indeed, combination therapy is increasingly being seen as the way ahead to overcome resistance.
GBR 8383 is a highly potent OX40 agonist with a novel mechanism of action that can potentially treat multiple cancers. OX40 agonists stimulate the OX40 receptor, a protein found on immune cells. They can be tweaked to enhance a tumour-specific immune response. Preclinical data confirm that GBR 8383 has a strong agonistic effect upon the checkpoint regulator OX40 in comparison to other OX40 agonists, currently in clinic. It has the potential to be a first in a new set of agonists with application in multiple cancers.
* GBR 1342 used in sub-optimal doses; BEAT 1 to 4 are Nivolumab combinations (in BEAT format) with CD27, LAG3, VISTA and 4-1BB
NMEs focussed on dermatology
Skin disease though seldom life-threatening, has a disproportionate effect on quality of life and emotional health.
Skin diseases impact life choices such as the clothes we wear, the jobs we pursue, our relationships and social interactions. It also has a huge impact on self-esteem. Unfortunately, it is also one of the more intractable health conditions to challenge modern medicine. It involves the complex interplay of genes and environmental factors such as stress. Many skin diseases stubbornly resist cure.
Dermatology has been a focus area for Glenmark since its inception. For decades, we have brought existing treatments within reach of patients globally through a range of formulations.
Atopic Dermatitis (AD) is a chronic, immune-mediated, inflammation of the skin with involvement of activated T cells. It is characterised by chronic or relapsing, itchy lesions. Moderateto-severe AD can negatively impact patients’ lives and is associated with a high burden to society both in terms of the direct costs of medical care and prescription drugs, as well as loss of productivity. Topical medicines such as creams and ointments are not effective to control the disease in many cases. Such patients need systemic treatment. These are currently limited to steroids and immunosuppressants, but there is a need for more efficacious solutions.
GBR 830 is an OX40 antagonist being studied for the treatment of moderateto-severe AD. OX40 is a protein foundon immune cells. It is an established, druggable target which means its role in stimulating the immune system is accepted and it can be blocked or activated using drugs. However, it has been a challenge for the industry to discover antibodies that inhibit OX40 and do not have agonistic properties that would lead to unwanted side effects.
GBR 830 has the potential to be the best-in-class OX40 antagonist antibody. It is also the first OX40 antagonist globally to successfully complete Phase I studies. In these studies conducted in the Netherlands, GBR 830 was well tolerated and its safety and pharmacokinetics profile in healthy volunteers fully supported the transition into the next phase of trials.
In August 2017, Glenmark announced positive data from a Phase IIa study of GBR 830. The study evaluated the safety, biological and clinical activity, and pharmacokinetics of GBR 830, relative to placebo, in adults with moderate-to-severe AD with a history of inadequate response to topical therapies. The double-blind, placebocontrolled study was conducted over 12 weeks, and randomised 62 patients (3:1) with moderate-to-severe AD.
A total of 31 patients were evaluated following the last study visit. Patients were assessed on multiple endpoints after receiving two doses with two viable biopsies. In the GBR 830 cohort, 17 out of 23 patients experienced at least a 50% reduction in their Eczema Area and Severity Index (EASI) scores at day 57 compared to baseline, a key secondary endpoint of the study. Although not powered for statistical differences between GBR 830 versus placebo, data from this analysis suggest clinically meaningful improvement of symptoms that is continuous and sustained, with consistency observed between biological and clinical response. Based on the results of this Phase IIa study, Glenmark is firmly committed to advancing GBR 830 for patients with AD and plans to initiate a Phase IIb trial in the first half of CY 18. Glenmark is targeting a Biologics License Application filing for GBR 830 in 2022. We are also looking to expand GBR 830’s application to other autoimmune diseases such as lupus, graft versus host and rheumatoid arthritis.
NMEs focussed on respiratory
GRC 39815 is a New Chemical Entity currently in IND-enabling toxicology studies. We expect to push this programme into clinical studies in the next 12 months. It is being developed as an inhaled compound for the treatment of Chronic Obstructive Pulmonary Disorder (COPD) and Idiopathic Pulmonary Fibrosis (IPF). It is an inhibitor of the Retinoid-related Orphan Receptor gamma t (ROR y t), inhibiting the release of inflammatory cytokines reported to be involved in the pathogenesis of COPD. GRC 39815 has demonstrated effective lung retention following drug delivery.
NMEs focussed on pain
While effective painkillers have been in the market for decades, they have safety issues. The long-term use of popular painkillers namely non-steroidal anti-inflammatory drugs (NSAIDS) and Cox-2 inhibitors is known to cause severe gastrointestinal (GI) and cardiovascular (CV) side-effects respectively.
This is because these drugs are not selective in their inhibition of specific prostaglandins, a type of hormone, that modulate inflammation and end up also affecting others. In response to this, scientists have isolated a novel target known as microsomal prostaglandin E synthase-1 (mPGES-1) which is up-regulated under inflammatory conditions. Selective mPGES-1 inhibitors are expected to inhibit increased prostaglandin E2 (PGE2) production in the disease state without affecting other prostanoid metabolites and, consequently, may be devoid of the GI and CV side effects seen with NSAIDs and COX-2 inhibitors. PGE2 is a potent proinflammatory prostanoid and mediator of inflammatory response. It has been implicated in many pathological conditions including inflammation, pain, atherosclerosis and fever.
GRC 27864, a product of Glenmark’s India-based research centre, is a potent, selective and orally bioavailable inhibitor of mPGES-1. A Phase I first-in-human single ascending dose study and a multiple ascending dose study have been completed in the UK with no safety concerns. It is currently in Phase II of development.
GRC 27864 is currently being developed as a drug for the potential treatment of pain associated with osteoarthritis.
Glenmark is looking to outlicense this molecule for further development since it falls outside our therapeutic focus areas. Other non-core assets available for outlicensing include GRC 17536, GBR 900 and GBR 500. Therapy