Chapter 1
New Trends in Drug Discovery

Gerd Schnorrenberg

Boehringer Ingelheim GmbH, 55216 Ingelheim, Germany

1.1 Introduction

Productivity in drug discovery has been a prominent topic over the past years. The decline of number of new drug approvals and the parallel increase in research and development (R&D) costs have been a matter of concern [1]. It has raised questions on the overall strategy, the effectiveness of R&D, and the sustainability of the business model of pharma. The consequences of the productivity gap have been discussed extensively in many publications, and a plethora of proposals on how to overcome the issue have been made [2-5].

In 2014 and 2015, the number of new drug applications rose substantially, leading to a new 66-year high of Food and Drug Administration (FDA) drug approvals in 2015 [6].

1.1.1 Analysis of New Molecular Entities Approved in 2015

In 2015, 51 new molecular entities (NMEs) were approved by the FDA (see www.fda.gov/novel drug approvals CDER & CBER [7]), a number that has only been achieved in 1950. From these 51 approvals, 31 (61%) have been on new chemical entities (NCEs), while 20 were for new biological entities (NBEs). Over the past years, a considerable increase in the NBE share took place, rising to now 39% in 2015. Out of the 20 NBEs, 12 were "classical" antibodies and therapeutic proteins, and other approvals were on hematological supplement therapies, one on a vaccine and one on an oncolytic virus.

Linking the approvals to indications, it becomes apparent that the last decade's research focus on oncological projects translated into 16 new cancer drug approvals (31% of all approvals). Rare diseases were the target of many approved drugs, with some examples given below, followed by hematological diseases and infectious diseases with five approvals each (10% each), cardiovascular and mental disorders with four approvals each (8% each), metabolic diseases (3 NMEs, 6%), and respiratory diseases (2 NMEs, 4%).

From these 51 new drug approvals, a remarkable number of 27 NMEs (53%) went through an accelerated FDA (CDER) approval process. These accelerated approvals are indicators for an estimated therapeutic advance and are categorized into "fast track," "therapeutic breakthrough," and "accelerated approval." 10 NMEs (20%) obtained the "therapeutic breakthrough" designation: five NCEs and five NBEs, as summarized in Table 1.1.

Table 1.1 FDA 2015 approvals with therapeutic breakthrough designation

Thirty-five percent (18 NMEs) were "first-in-class" drugs: sugammadex (Bridion®) to reverse postsurgical neuromuscular blockade caused by certain kinds of anesthesia, palbociclib (Ibrance®) to treat advanced metastatic breast cancer, and idarucizumab (Praxbind®) to reverse adverse anticoagulant effects caused by the blood-thinner drug, dabigatran. Twenty-five NMEs were targeting rare diseases: Sebelipase a (Kanuma®) to treat lysosomal acid lipase deficiency, a rare disease that can lead to liver disease, cardiovascular disease, and life-threatening organ damage; asfotase a (Strensiq®), a long-term replacement therapy in patients with hypophosphatasia, a serious and sometimes fatal bone disease; dinutuximab (Unituxin®), a ganglioside GD2 inhibitor to treat pediatric patients with neuroblastoma; and uridine triacetate (Xuriden®), a new therapy to treat patients with hereditary orotic aciduria, which can lead to blood abnormalities, urinary tract obstruction, and developmental delays.

Noteworthy cancer treatments include daratumumab (Darzalex®), elotuzumab (Empliciti®), panobinostat (Farydak®), and ixazomib (Ninlaro®) (to treat patients with multiple myeloma), alectinib (Alecensa®) and osimertinib (Tagrisso®) (to treat certain patients with non-small cell lung cancer), cobimetinib (Cotellic®) (to treat certain patients with metastatic melanoma (skin cancer)), tipiracil (Lonsurf®) (to treat patients with metastatic colorectal cancer), and trabectedin (Yondelis®) (to treat soft tissue carcinoma). It is a reflection of the intense research and the success in the field of oncology that 5 out of the 10 FDA NMEs with "therapeutic breakthrough" designation are new cancer drugs (see Figure 1.1).

Figure 1.1 Structures of osimertinib, lumacaftor, ivacaftor and palbociclib.

To summarize reflections on the year 2015 FDA approvals,

1. 1. A new high of 51 approvals reflects the reemerging success in drug discovery.
2. 2. NBEs have a share of nearly 40% of all approvals. These are mainly therapeutic antibodies and proteins, but vaccines and new modalities like oncolytic virus have also been approved. The share of NBEs increased considerably over the past years.
3. 3. The majority of the approvals target oncology and rare diseases. It is interesting to note that the commercial viability of NMEs for rare diseases has been questioned in the past. With the new approvals, there will be a good opportunity to track reimbursement policies by healthcare systems.
4. 4. Fourteen approvals were given to start-up companies and 37 to larger pharma companies (please note that the definition of "start-up" and "larger pharma" company is variable).

Despite the large number of new drug approvals in the past years, we need to acknowledge that the currently available therapeutic armamentarium is still insufficient in many aspects. In general, many diseases are still without satisfying therapy, and many widespread diseases lack therapies leading to significant improvements with respect to outcome. This leads to the conclusion that drug discovery needs to strongly align with medicine to clearly define target product profiles (TPPs) to precisely direct the search for new approaches targeting the therapeutic gaps. For illustration, a few examples of therapeutic gaps are given here. Many rare diseases are still without therapy though the consequences are fatal in many cases. Despite the large number of new cancer drug approvals, there are still cancer types and outcome aspects open for new drugs. The need for an effective pancreatic cancer therapy is still high, and with cancer types like non-small cell lung cancer to which new therapies have recently been introduced, we urgently need complementation by therapies targeting specific subtypes and mutations and targeting long-term survival. Also other broad diseases like cardiovascular diseases require new drugs to improve outcome and survival rates. In diabetes we need to better target diabetic complications like diabetic retinopathy and diabetic nephropathy. Moreover new diabetes drugs slowing or even stopping disease progression would address long-term outcome. In CNS drug discovery, we are still facing a significant therapeutic gap with respect to psychiatric diseases. Existing therapies either have a high rate of side effects or are only effective in part of the patient population. The newly introduced taxonomy of psychiatric diseases specifying symptom complexes may offer ways to more specifically target CNS diseases. Neurodegenerative diseases like Alzheimer's disease or Parkinson's disease lack disease-modifying therapies. Another therapeutic gap comes from the increased number of multidrug-resistant infections. Here we need more effective and MDR-overcoming anti-infectives to save lives.

In all these cases, we will have to identify new targets with a strong link to human disease. To establish this link to human disease will need considerable pre-investments into target characterization before proceeding to drug discovery. Many of these new targets will likely belong to precedented target classes like G-protein-coupled receptors (GPCR) with diverse functional impact like agonists (partial, inverse, full), antagonists, nuclear hormone receptors, enzymes with inhibitors or function/expression stimulation, kinases as enzyme subclass...