Reinvigorating R&D

By Suzanne Elvidge

Improving productivity and reinvigorating innovation in biopharma R&D

The biopharmaceutical industry is struggling. It is facing a raft of issues — R&D productivity is falling, the rates of rejections from regulatory bodies are increasing, and the overall costs of drug development are skyrocketing. So, what can a biopharma company do?

According to Mohammed Azab, M.D., MBA, chief medical officer, SuperGen, biopharmaceutical companies can reinvigorate their innovation and improve productivity by following the four “rights” of drug development — the right targets, the right drugs, the right patients, and the right clinical trials. SuperGen, based in Dublin, CA, is developing small-molecule therapeutics for cancer using its drug discovery platform technology CLIMB.

R&D Productivity Is Falling
Biopharmaceutical companies are pouring ever-increasing amounts of money into drug development. According to the Tufts Center for the Study of Drug Development (CSDD), it costs over $1 billion and takes more than seven years to get a drug through clinical development, meaning that only around 3 in 10 drugs will make enough money to sustain R&D. However, this isn’t increasing the rate of drugs that make it through the process and onto the market. “The average number of 20 to 25 drugs approved each year in the United States hasn’t changed in 60 years,” says Azab.

Why, when companies are putting so much money into R&D, are the numbers of new drugs not climbing equally as fast? According to Azab, in the early days of modern drug development, companies aimed at the easy targets and developed effective therapeutics. This has created two obstacles to recent drug development. First, for many of these targets, it’s now harder for new entrants to the market to improve on the efficacy and safety of existing drugs. Second, this first wave of development has left the diseases where the targets or drugs are harder to identify.

As well as these technical and scientific difficulties, there are also regulatory difficulties for companies to face. Regulatory requirements have become stricter, particularly in the last decade, and this seems to tie in with Merck’s voluntary worldwide withdrawal of the painkiller VIOXX (rofecoxib) in 2004 and the subsequent legal and media exposure.
“Because the FDA’s mandate is for the safety of the public, and the public’s trust of the biopharma industry has been dented by the high profile safety issues and withdrawals such as VIOXX and more recently Avandia [a drug for diabetes], there has been a lot of pressure on the FDA to put an emphasis on larger and longer trials with more safety data,” explains Azab.

Emphasizing Safety: Conservatism In The FDA
Because the safety and efficacy requirements have become more stringent for approval, there seems to be an increase in the rate of rejection of new drugs, particularly in certain therapeutic areas. “In just the past six months, the FDA has declined the approval of three different drugs for obesity,” says Azab. “All three drugs were declined for safety reasons, although they had reached the efficacy standards provided in the FDA’s guidance for developing drugs in this therapeutic area.”

In a complete response letter in October 2010, the FDA turned down approval of Arena Pharmaceuticals’ selective serotonin 2C receptor agonist lorcaserin (Lorqess), requiring further nonclinical studies to look at the abuse potential of the drug and to establish any links between the cancer findings in rats and risk of cancer in humans. In another complete response letter in October 2010, the FDA declined the approval of Vivus’s Qnexa, an oral, controlled-release formulation of low dose phentermine and topiramate, based on issues relating to birth defects and risk of cardiovascular disease. This is despite the fact that phentermine is already approved for use in weight loss, and topiramate is available as an anticonvulsant. The FDA has asked for analysis of existing healthcare databases for further data. In a complete response letter in February 2011, the FDA turned down a third obesity drug — Orexigen’s Contrave, a sustained release combination of naltrexone and bupropion, both approved individually for other indications. The regulatory authority has asked for a large placebo-controlled trial to assess the risk of major adverse cardiovascular events in overweight and obese subjects.

These types of responses are driving companies to conduct more and more complex and larger clinical trials. According to the Tufts CSDD, the median number of procedures per clinical trial increased by 49% between 2000 to 2003 and 2004 to 2007, and the total effort required to complete those procedures grew by 54%. “More complex and burdensome protocols are extending study cycle times, increasing costs, and challenging patient recruitment and retention,” said Tufts CSDD Senior Research Fellow Ken Getz.

The Impact On The Industry
All of these obstacles are increasing the cost and length of time required to develop a drug through to the market, making it harder for a company to get a return on its investment. The median period of exclusivity for marketed drugs is dropping, from 10.2 years in the 1970s to 2.5 years in 2000 to 2003, according to Tufts CSDD.

“The attrition rate in drug development is very high; even once they have entered late stage Phase 3, around half of the drugs will not reach the market,” says Azab. “Late stage Phase 3 trials contribute more than 2/3 of R&D expenses, so if we can improve the attrition rate by just 10% to 20%, it will have a huge impact on improving productivity.” This is supported by data from Tufts CSDD — of every six compounds developed by the top 50 pharma companies and entering clinical trials, only one will make it to the market.

“The biopharma industry is the main source for new drug discovery and development, accounting for 2/3 of the current total R&D spend in the United States, and if companies can’t improve productivity, there will be no new drugs for the high-mortality diseases such as cancer, diabetes, and heart disease.”

What’s The Solution?
One of the first approaches is to try to improve the public’s trust in the biopharma industry, and this could reduce the public and political pressure on the FDA. “This trust issue can partly be tackled through improved engagement and communication and also through following reasonable drug pricing policies, which should be easier to do if we improve productivity,” says Azab.

The trust issue can be described as a macroenvironmental issue. SuperGen is tackling the issue by focusing on four “rights”:

The Right Targets
In general, drug development starts with targets, but according to Azab, these need to be the right targets. At SuperGen, the researchers start by selecting the target and exploring its biology and its impact on cancer. “Understanding the biology of the disease and the target right at the beginning is extremely important. If it is wrong at the beginning, everything subsequent is irrelevant,” says Azab.

The Right Drugs
The next step is to develop the right drug — something that is potent and selective and carries no pharmaceutical liability. “It must have a good toxicity profile, it must be able to be formulated, and it should have as few ‘off-target’ effects as possible,” explains Azab. Using its CLIMB in silico drug discovery platform, the teams predict, evaluate, identify, and select lead candidates. “By using computational chemistry, we can simulate and assess the drug candidates before synthesizing them, reducing time and resources, and therefore costs, says Azab.

The Right Patients
The drug should target the right patients. “The term personalized medicine is new, but this approach has been around for many years, we just called it ‘good patient selection.’ Physicians and drug developers have always tried to identify the patients who will benefit the most from a particular drug; we now just have better tools, such as new biomarkers,” says Azab.

The benefit of biomarkers in patient selection can be dramatic. It has been seen early in some drug development pathways. For example, significant improvements were seen with Genentech’s Herceptin (trastuzumab) in breast cancer patients who overexpress the HER2 protein.

In patients with lung cancer who have an EGFR (epidermal growth factor receptor) mutation, as assessed by Genzyme’s companion diagnostic, the response rate for Roche’s Tarceva (erlotinib) is around 60%, which is better than standard-of-care first-line chemotherapy.

“We must try to identify the right patient groups as early as possible in drug development. Early on in Phase 1 trials and moving into Phase 2, it’s possible to start to identify the biomarkers and stratify the responses and efficacy according to these,” says Azab. “This can make the drug development process faster and more efficient.”

The Right Trials
In order to get the best possible data for a drug, the clinical trials must have the right design. They need to show, as clearly as possible, that the drug works on the target and the selected patients, and the patient numbers and randomization should be optimized.

“A good place to start is with an early, clear development plan to try to prove — or disprove — the biological hypothesis. Ask questions, such as, ‘Does this inhibit the target? Does this result in the desired patient outcomes?’ If the answers aren’t right, be prepared to kill the drug early, at the proof-of-concept stage. While perseverance is important (and it is worth trying again and seeing why a drug failed), if all the studies come up with the same negative results, the project should be terminated. There are always drug champions who will fight for their pet project, but there is a very fine line between perseverance and insanity in drug development,” says Azab. “Borrowing a concept from a famous quote, a good mantra for drug developers is: God, give me perseverance to solve the drug problems that I can solve, the sanity to abandon drugs whose problems I cannot solve, and the wisdom to know the difference.”

The Future Of Trial Design
The science of trial design is very important and has evolved significantly in recent years. The lines between the phases of trials are becoming increasingly blurred. SuperGen sometimes uses adaptive trial design elements using PK (pharmacokinetics) and biomarkers early in Phase 1 cancer trials to guide dose escalation and dose selection. In later stages of development, there are trial designs that adapt the patient numbers based on emerging data. This should also make clinical development more efficient, and Azab expects this type of trial design to play an increasingly large role.

“We now see the development process as a paradigm, with drugs at either ‘before clinical proof of concept (b-cPOC)’ or ‘after clinical proof of concept (a-cPOC),’ with cPOC as the go/no-go decision point for registration trials. We get as much data as possible as early as we can — we try to get biomarker and efficacy data as early as Phase 1, and we do more of the c-POC type Phase 2 studies as randomized trials, becoming more like a small Phase 3 trial,” says Azab. “Getting the right cPOC decision before entering the expensive time-consuming late-stage registration trials could make all the difference.”