ViiV goes for gold: US premium pricing may threaten dolutegravir use in Europe

On 12 August 2013, the FDA approved dolutegravir in the US. i-Base reported the news with an article linked to previous clinical trial results that noted not only the potential advantages but also some of the cautions.  One of the concerns was how the price, which didn’t accompany the original company press statement, would be critical for whether dolutegravir finds a significant market. While pricing is complex, the first indications of where ViiV have set their new drug are not encouraging. Unfortunately, dolutegravir has been priced as a second- rather than first-line option, with a US Wholesale Acquisition Cost (WAC) price of $1175 per month for 30 tablets ($39 per day, $14,105 per year).  When used by someone with integrase resistance the dose increases to 50 mg twice a day, presumably doubling the cost.

Read more here

GSK - ViiV Abandons Lersivirine - An Investigational NNRTI HIV Medication

Dear HIV Community Writer,

ViiV Healthcare has taken the decision to stop the development program investigating the non-nucleoside reverse transcriptase inhibitor (NNRTI), lersivirine.  This is not due to any safety concerns regarding the compound. ViiV Healthcare’s goal is to support the best possible outcomes for people living with HIV, and to deliver new therapies that offer improvement over current options. 

After much deliberation about how to proceed with lersivirine, it was determined that the compound would not provide an improvement over existing medicines in the NNRTI class, and that R&D resources for ViiV Healthcare should prioritize efforts to identify compounds that further HIV treatment.

We remain committed to exploring candidates that will advance HIV treatment and contribute to improving outcomes for people living with HIV.

Please don’t hesitate to reach out to me directly if you have any questions regarding this announcement.

Kind regards,

Marc Meachem | Director, External Affairs

Shionogi-ViiV Healthcare announces initial data from pivotal phase III study of dolutegravir in HIV

This drug will compete against raltegravir (Merck) and elvitegravir (Gilead). 

It will be dosed once a day for treatment naive patients and twice a day for treatment experienced.

Issued: Monday 02 April 2012, London, UK

Press release issued by Shionogi-ViiV Healthcare LLC, a joint venture between ViiV Healthcare Ltd (a global specialist HIV company established by GlaxoSmithKline and Pfizer, Inc.) and Shionogi & Co., Ltd.

SPRING-2 study meets primary endpoint of non-inferiority of dolutegravir compared to raltegravir over 48 weeks in treatment-naïve HIV patients

ViiV Healthcare and Shionogi & Co., Ltd. today announced that initial results have been received from the SPRING-2 (ING113086) Phase III study of the investigational integrase inhibitor dolutegravir in treatment-naïve adults with HIV-1. The study met its primary objective, demonstrating non-inferiority of dolutegravir to raltegravir. Through 48 weeks, 88% of study participants on dolutegravir were virologically suppressed (<50 copies/mL) vs. 85% of participants on raltegravir [with a 95% confidence interval (CI) for the difference, -2.2% to + 7.1%; the lower end of the CI (-2.2%) was above the prespecified -10% non-inferiority limit]. 

SPRING-2 is an ongoing non-inferiority study designed to compare the efficacy and safety of dolutegravir 50mg administered once-daily versus raltegravir 400mg administered twice daily, both with two nucleoside reverse transcriptase inhibitors(NRTIs); 411 treatment-naïve study participants were randomised in each arm. The primary endpoint of the study was the proportion of study participants with undetectable HIV-1 RNA (<50c/mL) through 48 weeks.  The tolerability of dolutegravir was similar to that of raltegravir, with rates of adverse events leading to withdrawal at 2% in both arms. Drug-related nausea was reported by 10% of patients in each arm; no other adverse events related to study medication were reported by more than 5% of participants in either arm. 

“The SPRING-2 findings indicate that once daily unboosted dolutegravir may offer people living with HIV an additional treatment option in the future. These are the first large-scale safety and efficacy data in naïve patients, and we look forward to seeing further data in 2012 to build a more comprehensive picture of the role of dolutegravir” said Dr John Pottage, Chief Medical Officer, ViiV Healthcare. 

“At ViiV Healthcare we have a total focus on the needs of people living with HIV, and as a result we see the continued need for new, effective and convenient therapies.  We are committed to building connections and collaborations, like the Shionogi-ViiV Healthcare dolutegravir programme, to meet these needs.” said Dr. Dominique Limet, Chief Executive Officer, ViiV Healthcare. 

“The SPRING-2 study has met its primary endpoint for dolutegravir in treatment-naïve patients.  This marks an important milestone for the development of dolutegravir and the Shionogi-ViiV Healthcare joint venture. We look forward to completing further Phase III studies in a variety of clinical settings in order to fully understand the potential clinical benefit for a range of HIV patient populations” said Dr. Tsutae "Den" Nagata, Chief Medical Officer, Shionogi & Co., Ltd.

Full results of this study, including the full results of the secondary endpoints, will be presented at an upcoming scientific meeting.  SPRING-2 is the first of four Phase III studies that are due to be reported in 2012. Data from the clinical trials SINGLE (ING114467), VIKING-3 (ING112574) and SAILING (ING111762), will be received throughout the year and will allow further determination of the profile of dolutegravir.  These studies are designed to support a future regulatory file for dolutegravir. 

About SPRING-2

SPRING-2 (ING113086) is a Phase III, randomized, double-blind, multicentre, parallel group, non-inferiority study. The study included 822 HIV-1 infected treatment-naïve participants. The study compares the efficacy and safety of dolutegravir and raltegravir as part of an overall treatment regimen; both treatment arms are administered with investigator-selected dual nucleoside reverse transcriptase inhibitor therapy (either abacavir + lamivudine or tenofovir + emtricitabine).

The primary objective for SPRING-2 is to demonstrate the antiviral activity of dolutegravir 50mg administered once-daily compared to raltegravir 400mg administered twice daily over 48-weeks. Secondary objectives include the assessment of antiviral activity of dolutegravir compared to raltegravir at 96-weeks, to compare the tolerability, long-term safety and antiviral and immunologic activity of dolutegravir to raltegravir and to evaluate viral resistance in study participants experiencing virological failure.

About Dolutegravir

S/GSK1349572 (dolutegravir) is an investigational integrase inhibitor (INI) currently in development by Shionogi-ViiV Healthcare LLC for the treatment of HIV. It is currently the only once-daily, unboosted INI in Phase III clinical development.Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Given the stage of development of this investigational HIV therapy, the full picture of the efficacy and safety of dolutegravir has not been conclusively determined.

Activists Caution HIV+ Patients and their Physicians About Monotherapy in Upcoming Access Program

FOR IMMEDIATE RELEASE: February 9, 2012

Contact: Nelson Vergel (NelsonVergel@yahoo.com)

Activists Caution HIV+ Patients and their Physicians About

Monotherapy in Upcoming Access Program

New York, February 9, 2012—AIDS activists and physician advocates welcome the news that ViiV Healthcare will be providing  expanded access of dolutegravir (DTG), a new investigational integrase inhibitor for HIV patients with few remaining HIV treatment options.  However, they warn patients and physicians to avoid functional monotherapy, or the introduction of dolutegravir as an "add-on" to a failing treatment regimen if the patient’s virus is resistant to all other currently available antiretroviral drugs (ARVs).  Functional monotherapy has been shown to permit rapid HIV resistance to new medications, which can result in more rapid disease progression, health deterioration, and death.

Currently, the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines recommend three ARVs be given in combination to suppress HIV.  But many patients have HIV that has mutated rendering their virus multi-drug resistant (MDR-HIV).  Those with MDR-HIV cannot construct a viable HIV suppressive regimen with current FDA-approved and commercially available ARVs.  "The DHHS guidelines specify that patients that have developed HIV drug resistance to all commercially available antiretrovirals require access to at least two new active drugs to maximize their chances for treatment response.  However, “another new drug to combine with dolutegravir will not be commercially available for at least two years, and some patients cannot wait that long,” said Nelson Vergel, an activist founder of SalvageTherapies.org.  "For them, access to another research drug in combination with DTG is the only hope for survival," added Vergel.

In studies to date, dolutegravir (DTG) appears to be the most potent integrase inhibitor soon to enter the ARV market.  Unlike Gilead's upcoming elvitegravir, DTG has been shown to be effective against HIV that has developed resistance to Merck's Isentress (raltegravir), the only FDA-approved integrase inhibitor currently on the market.

Fortunately, another new ARV that can help patients with MDR-HIV is in active development and clinical trials.  Ibalizumab, a monoclonal antibody from a small biotech firm, Taimed Biologics, may soon be available via patient participation in research studies.  While ibalizumab has yet to enter phase three studies, it can also be provided to patients at risk of death via a named (or single) patient access application permitted by the FDA via a physician’s direct request to Taimed.  However, it is for the company to approve such requests for compassionate access.

There are no documented estimates of how many people have MDR-HIV in the United States.  A report in the Journal of Clinical Infectious Diseases estimates that about 260,000 patients are being treated with HIV in the United States.  However, it is virtually impossible to know how many are now without sufficient treatment options since no registry for such patients exists.  But most experts agree that this population is probably small – possibly up to 10% of the total in treatment.

"With little immune function left and resistance to all approved HIV medications, I have tried desperately to get access to two new drugs to help save my life,” said Christopher Cacioppo, a patient with MDR-HIV in  San Diego who believes he is running out of time. “My doctor tells me that I have little choice but to wait for the dolutegravir expanded access program and some as yet unknown and unavailable second new drug."

A coalition of activists and physicians have been in discussions with Taimed and ViiV for nearly two years to obtain compassionate-use access to their new ARVs in combination for those with MDR-HIV in greatest need of new treatment options.  The AIDS Community Research Initiative of America (ACRIA), a New York City-based community research and education organization, and physicians in San Francisco have proposed solutions to overcome this “two-drug access barrier” in an effort to secure urgent access to patients across the country.

Physicians and providers with patients with MDR-HIV in need of two new ARVs are urged to complete this form.

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Dolutegravir, Trii and new abacavir data- How it all ties together

By Nelson Vergel

Powerusa.org

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.

This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii.  This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).

The development of Trii for approval as a first line treatment seemed risky to me due  to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV.  These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients.  So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?

Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation,  the US Food and Drug Administration (FDA)  presented  a surprising poster on  March 2 that reported  no evidence of an association between abacavir  and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug.  The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.

It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines.  Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to  pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills.   Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.

As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.

Sources:

DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB

Ding X et al. No association of myocardial infarction with ABC use: an FDA meta-analysis.  Poster abstract 808.


More on:
http://www.retroconference.org/2011/Abstracts/42541.htm

http://www.thebodypro.com/content/art60708.html

More on CROI:
http://www.thebody.com/content/art60501.html

Pipeline Problems

by David Evans

In the past month, two companies shelved their once-promising experimental HIV drugs, citing the challenging nature of bringing a profitable product to market. Has the overwhelming success of modern-day HIV drugs jeopardized the future of new HIV treatment options?

Since Matt Sharp first learned that he was HIV positive in 1988, life has been about trying to stay one step ahead of the virus. Like many, he started each new HIV drug only to have it eventually fail, followed by a wait for the next one to be available through a clinical trial, expanded access program or U.S. Food and Drug Administration (FDA) approval. That’s just the way it was—trying to outrun HIV and to hold on until science and the pharmaceutical industry developed the next best thing. There were no other options.

The last three years, however, have been kinder to Sharp. In the space of about a year and a half, from June 2006 through January 2008, four new antiretroviral (ARV) treatments were approved, all of them with the potential to work against even the most drug-resistant HIV. After Sharp started a regimen with one of these new treatments, his virus became undetectable for the first time ever. His CD4 cells, which had been depressed for years, started to inch back up, and he continues to do well today.

Sharp is not alone in his Lazarus effect. Thousands of people with multidrug resistant virus, many of whom were once quite sick, have been able to push their viral loads to undetectable levels and restore their health with the newest antiretrovirals, often in combination with each other. But what happens if their HIV accumulates additional mutations and breaks through? Unfortunately, the number of promising agents waiting in the wings for people with drug resistant virus is dwindling.

Two companies, Avexa and Myriad Genetics, suspended development of their experimental ARV treatments over the past month. From press statements, it appears that both companies determined that their drugs—apricitabine (a nucleoside reverse transcriptase inhibitor) and bevirimat (a maturation inhibitor)—could not be brought profitably to market. While neither drug was perfect, or had a certain shot at FDA approval, some activists and researchers see their failure as evidence of a paradox—that today’s highly effective drugs are hurting the development of tomorrow’s promising agents.

“The very incentives that got industry involved to develop HIV drugs are now working against us,” says Jay Lalezari, MD, the director of clinical research at Quest Clinical Research in San Francisco, who specializes in the study of drugs for people with multiple drug resistance. “But, you know, money is a driver, and you don’t expect these companies to do it for nothing,” he laments.

“It’s getting harder and harder to hit a homerun with a new HIV drug,” says Bob Huff, a longtime HIV treatment activist from San Diego. “The current drugs are very good, and most doctors and patients are fairly satisfied…. The incentive for companies to invest in developing new HIV drugs is not strong right now.”

“It’s disconcerting,” Sharp agrees. “In terms of practical issues around drug development, we do need to put our heads together and strategize about fixing the things that are broken.”

Sharp is working with Huff and Nelson Vergel, an activist from Houston, to help identify novel ways for people who’ve run out of treatment options to get their hands on multiple experimental agents at one time. The three are also looking at creative ways for companies to get drugs approved that might only benefit treatment-experienced people, a market that is increasingly small and potentially less profitable than ever before.

Sharp, Huff and Vergel express concern about options for people who have already become resistant to current meds. With apricitabine and bevirimat now out of the picture, it only leaves a couple of drugs in an advanced state of development for people with multi-drug-resistant virus. Given the uncertain nature of drug development, however, those drugs could also tank or be delayed, and it could be quite a while before something new is approved.

Sharp is not hopeless, however, and cautions that, “There’s no reason to panic. I definitely don’t think this is the end of the world.”

Lalezari agrees that things are not so bleak, at least not yet. He points out that a number of his patients are still doing well clinically, despite going for many years with very low CD4 counts and detectable virus. He stresses that it is possible to pick a regimen and stick with it for a long time, even if your viral load remains detectable. He encourages people to sit tight on such a regimen and to “try to keep this détente with the virus, and we’ll see if gene therapies or other immune therapies can be brought to bear in the future.”

Vergel is another veteran of the treatment wars and knows what it’s like to face uncertainty. He says that if his current drug regimen fails, he’s not sure what he’ll turn to. He’s not despairing, however, because he feels that he and other activists are making progress with the FDA in figuring out how to make new treatment options available, even when the traditional avenues of approval are a challenge.

In the meantime, he distills his own positive outlook for the many hundreds of people with HIV he interacts with each year through his Internet and public speaking activities. As he sums it up: “You have to give them hope.”
A Good News, Bad News Story

“The bigger picture with HIV therapeutics is a good news, bad news story,” says Paul Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital in Boston. “The good news is that HIV treatment success is so high now. The bad news,” he adds, is that “the motivation to develop new drugs, especially drugs to treat resistant virus, has ironically never been lower. There’s this small group of people who have no options even with those newer drugs, and for them, the situation is very discouraging.”

Treatment success has made developing a new drug targeted toward drug-resistant virus problematic in several ways. First, we can no longer simply pit a new drug against a placebo, with no other active drugs to back it up. A number of studies have found that when people take only one active drug at a time, they quickly develop resistance to that drug. For this reason, federal treatment guidelines recommend waiting to start a new treatment, if possible, until two or three active drugs can be combined into a new regimen.

While combining two or three active agents is good for study participants, it's a headache for trial designers. This is because the difference between an experimental drug and a placebo are much smaller and more difficult to measure if their impact is masked by the potency of other powerful drugs.

Sax points to the failure of the drug vicriviroc to demonstrate efficacy over a placebo in treatment experienced participants as a perfect example of this dynamic at work. “The vicriviroc study had the old study design,” Sax explains, “which was [a background regimen chosen by drug resistance tests] plus or minus the [vicriviroc], and they didn’t see any benefit, unless you [only looked at people taking] one other active drug.”

To detect such slight differences you have to either recruit only people with one or fewer active treatments available or design trials with twice as many people. The first option goes against the grain of treatment guidelines, and Sax thinks that the challenging and slow recruitment for a number of recent studies targeting treatment-experienced patients makes it quite unattractive to the companies. Even more unattractive, however, is the second option which almost doubles the cost of the trial.

Vergel has been working with Lalezari and Steve Deeks, MD, professor of medicine at the University of California at San Francisco, to estimate the number of people in the United States with resistance to all of the existing drugs—the kind of people that Sax says would be a challenge to recruit.

Vergel estimates that there are at least 1,500 such individuals, but that number is not growing rapidly. While this may be good news from a public health perspective, it is bad news for people with highly drug-resistant HIV who are depending on the pharmaceutical industry to develop new treatment options. Corporate board members and shareholders demand the highest profit possible with the least expense. With clinical trials potentially getting more expensive and harder to recruit, and the market size staying small, it’s getting very difficult to meet those demands.

“We’re up against the fact that drug development is about making a profit,” Sharp says, “and unfortunately that’s what we have to deal with.”
What the Future Holds

Sharp, who works frequently with Vergel on treatment advocacy projects, says that there are promising treatments further back in the pipeline, and that still other more innovative types of treatment are finally reaching the point where they can move in to clinical trials designed to prove efficacy and safety. What’s more, Sharp remains devoted to advocacy related to eradication: the elimination of HIV from the body.

Lynda Dee, a veteran treatment activist and the president of AIDS Action Baltimore, confirms Sharp’s experience: “Activists have met with companies over the last year, and some have said that they have internal programs looking at new drugs and eradication,” she says. “I’m hopeful that this discontinuation of the development of [apricitabine and bevirimat] doesn’t mean that all of the industry has turned tail and left the HIV field.”

Lalezari thinks that an entry inhibitor from TaiMed Biologics, an integrase inhibitor from ViiV Healthcare, and an attachment inhibitor from Bristol-Myers Squibb might have a shot further down the road. He’s less sanguine than Sharp or Dee about the prospects for antiretroviral drug development in general, given the challenges involved. “I think we could enter a period where there’s an abrupt end to HIV drug development,” he asserts. “That’s not to say that there aren’t new modalities of interest…but in terms of new direct-acting antivirals, it’s going to be very difficult,” he predicts.
Protecting Your Options

Are we on the verge of returning to the days when the best that a long-term survivor could do was guard against opportunistic infections and pray to survive long enough to benefit from the next drugs to come out of the pipeline?

Perhaps not, according to Lalezari. “The thing about the treatment-experienced population, which is astonishing, is that I have a whole bunch of people that I have been following for a number of years now, who are doing just fine. They have detectable virus, and their [CD4] cells are less than 20, but their health is just great, which is not explained in my understanding of the universe.”

Sax stresses that going off treatment would be a lot worse than staying on a failing regimen. “You know, all attempts of treatment interruptions of people with drug resistant virus met with bad outcomes,” he says, “So one thing for sure, is that people should stay on something. The question of what is more difficult. It’s never been well studied.”

In the end, what’s at stake is whether new drug development can stay ahead of HIV-positive people’s needs for new treatment options. Vergel points out that those who’ve yet to develop drug resistance can preserve their future options by finding a tolerable effective treatment and adhering to it religiously. In this regard, the possibility of a dry spell in new drug approvals could encourage people not to take for granted that new options will inevitably keep coming down the pike. “Fear,” Vergel says, “can be a good motivator” by way of emphasizing the importance of treatment adherence.

For people who’ve run out of new options, there is still reason for hope. It is possible to stay clinically healthy despite a failing ARV regimen, as Sax and Lalezari point out, and there are ways to minimize the risk of developing resistance to the experimental agents that might come later. Vergel tries to remind people of that and tells them “to not come from a place of despair.”

Sax thinks it will be helpful for researchers and health care providers to pool together their knowledge and resources to figure out the best care models for people who’ve run out of treatment options, arguing that since few providers have large numbers of such individuals it is difficult to become an “expert” in treating them. He thinks that activists and groups such as the Forum for Collaborative HIV Research in Washington, DC, can aid in that process.

Despite the challenges involved in developing the next generation of HIV therapies, Sax believes in remaining optimistic, especially with his patients who’ve run out of options. He tells them: “Press on. Drug development has helped us in the past. We hope it does again in the future.”