2016 numbers: CNS orphan drugs growing

With 2016 numbers now available, the number of orphan drugs in development for neurological indications is looking quite positive. I have reviewed the numbers of orphan drug designations and approvals by FDA in 2016 to see how popular are neurological orphan drugs today and what the trend is for the near future.

The FDA approved only 22 new drugs last year, a big fall from the 45 approvals it granted in 2015. But not all approvals are for new molecules, there are also many approvals that are new indications of previously approved drugs, also known as “drug repurposing”, so the total number of approvals is actually higher than what news outlets otherwise suggest (see here and here).

We see many cases of drug repurposing in rare diseases, so I have looked at the total number of orphan drug approvals and the total number of orphan drug designations in 2016, including new molecules as well as new indications (or designations) for already approved drugs.

THE NUMBERS

In 2016 the FDA approved 37 orphan drugs, out of which only two were for neurological indications: Spinraza (nusinersen) from Biogen for spinal muscular atrophy, and Carnexiv (carbamazepine injection) from Lundbeck for epilepsy as an alternative to oral carbamazepine. The rest of the approvals, as usual, were dominated by oncology.

This means that only 5% of all orphan drug approvals during 2016 were for neurological indications.

However when we look at the drugs that received an orphan drug designation last year the picture is much better for neurology.

The FDA granted 333 orphan drug designations last year. This number includes some diagnostic reagents so I have only included in my analysis 325 orphan drug designations for the treatment of rare indications. Out of these, 48 orphan drug designations were for neurological indications  (see full list at the end of the article) and again oncology dominated in the remaining cases.

With 48 designations in 2016, neurology accounted for 15% of the cases, indicating that the percentage of orphan drugs approvals for neurological indications could triple in the near future.

THE BREAKDOWN

Among the 48 designations, the largest area was neurodegeneration, followed by epilepsy. This reflects two important trends in CNS drug development.

One trend is to target orphan indications when the large indications become too crowded. This is the case of epilepsy, where many of the orphan designations are for drugs that could have efficacy in broader epilepsies -and in many cases are already approved for broader forms of epilepsy- but choose to seek approval for a specific syndrome or type of seizures (such as acute repetitive seizures) to reduce competition.

The other trend is to use rare diseases to obtain the initial clinical proof-of-concept for a compound that is eventually aimed at targeting the large indications. This has became very common in the neurodegeneration field where a Phase 3 failure can cost many hundreds of millions, so de-risking the program in a smaller and more uniform patient population is an excellent development strategy. Amyotrophic lateral sclerosis (ALS) was traditionally the rare disease model for neurodegenerative compounds and had 6 orphan drug designations in 2016, and frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) have emerged more recently as attractive rare diseases to re-risk molecules in development for Parkinson’s disease or Alzheimer’s disease.

What I classified as neurodevelopmental diseases includes the syndromes of Rett, Angelman, Fragile X and tuberous sclerosis complex. I could have classified some of these as epilepsy based on the trial endpoint, like is the case of the orphan drug designation for treating tuberous sclerosis complex with cannabidiol. Likewise, I could classify some of the epilepsy syndromes as neurodevelopmental diseases given the clinical presentation but kept them under epilepsies for this analysis purposes because of the seizure-focused trial endpoints. Collectively, all of these neurological syndromes characterized by seizures, cognitive, behavioral and motor problems are very popular within the orphan drug space.

Among the remaining designations I found interesting 4 treatments for ataxias (Friedreich's ataxia and spinocerebellar ataxia), and two for narcolepsy.

THE FUTURE

Looking at the 2016 orphan drug designations in neurology (see the full list at the end of the article) I can see how rare diseases are facilitating a revival of a field that has suffered from some areas being overcrowded and others being extremely difficult to pursue (think of Alzheimer’s disease). By providing smaller and more homogenous populations rare diseases offer the possibility of shorter and cheaper development programs, opening the field to smaller companies that could now have developed a clinical asset without partnering with a large company. And the genetic nature of many of the rare diseases has also offered us targets that increase the likelihood of succeeding in those trials versus symptomatic approaches in heterogeneous populations.

But not all is opportunistic strategies to reduce competition or de-risk programs. We are also seeing a growing number of gene therapy or antisense approaches in development that target the cause of these rare diseases, including 2016 designations for Sanfilippo syndrome, Friedreich's ataxia and Batten disease and antisense oligonucleotides for ALS and Huntington's disease.

Based on these numbers the future looks promising for neurological orphan drugs, with numbers that could triple and the development of disease-modifying treatments.

Ana Mingorance PhD

FULL LIST ORPHAN DRUG DESIGNATIONS FOR NEUROLOGY - FDA 2016

What marihuana teaches us about drug discovery

There was one clear star at the American Epilepsy Society Annual meeting last week, and that was Epidiolex. Epidiolex is the brand name of cannabidiol, a drug isolated from medicinal cannabis that GW Pharmaceuticals (Greenwich Biosciences in the US) is developing for the treatment of a number of orphan refractory epilepsies.

Epidiolex was featured in multiple talks and posters, the scientific exhibit hosted by GW Pharma was hands down the most popular one during the meeting, and it was also the main conversation topic in the corridors. It was impossible not to hear about it.

Yet four years ago no one would have thought that the cannabis-derived drug would take over the field of epilepsy in such a big way.

The rise of Epidiolex has been spectacular: during 2016 GW Pharma has announced positive results from three different Phase 3 trials with Epidiolex, with ongoing Phase 2 and 3 trials for other rare epilepsies. Analysts predict peak sales of over a billion dollars. Clearly a very useful drug and a successful commercial product.

The reason why I find the success of this drug such an excellent lesson for drug discovery is that it goes against many of the basic requirements to finance a drug development program:

• Cannabidiol is not a new chemical entity, so GW Pharma doesn’t have a patent on the molecule.

• As a major medicinal ingredient in marihuana, it is relatively easy for patients to access the plant or extracts without needing to purchase the branded product.

• Cannabidiol is only expected to have partial efficacy against the main symptom of these orphan refractory epilepsy syndromes, which is seizures. It does not target the disease and is not expected to provide complete symptomatic relief.

• And on top of all that, the mechanism by which cannabidiol is active in epilepsy is still unclear.

If you had tried to approach venture capital firms with a compound that (1) is derived from a medicinal plant, (2) is relatively easy to source as a plant or extract, (3) is likely to provide moderate symptomatic efficacy, and (4) does not have a defined mechanism of action, you would have come out empty-handed.

I know it because I’ve tried this with another molecule having these characteristics.

Investors (and big pharma) want drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action.

What amazes me is that the same investors that would find all those flaws in the investment proposal that I was supporting would turn around and ask me about Epidiolex and its latest results. When confronted with the observation that the very promising Epidiolex happens to have the same profile as our compound the answer was always the same: true, but they have clinical data.

And that’s what this really all boils down to. We create a number of requirements for drugs candidates as a checklist to minimize risks, but once positive clinical data is available that checklist is no longer necessary. We are not short of drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action, that go on to fail in the clinic. We are short of drugs that actually work in the clinic.

Kudos to the GW Pharma team for understanding this and going straight to generating the early clinical evidence that has taken them to where they are today. 

Clearly not every drug can be fast-forwarded with multiple parallel trials and very aggressive timelines as GW Pharma has done with Epidiolex. But drugs isolated from medicinal plants offer the unique opportunity to be fast-forwarded to generate clinical evidence as GW Pharma did.

In the case of cannabidiol the breakthrough was the extensive availability of safety data that enabled the company to sponsor multiple investigator initiated INDs and obtain early clinical data. In other cases, depending on the nature of the medicinal plant, it might even be possible to run food safety clinical studies to obtain that early clinical data prior to an IND.

For drugs isolated from medicinal plants, where the primary screening was pretty much done in human patients, trying to enforce the IP and mechanistic standards that we apply to hypothesis-driven drug candidates might make us throw away the baby with the water bath. The success of Epidiolex has only been possible because GW Pharma was well-funded and had the vision to ask the right questions.

If clinical data is the main deciding factor, then maybe investors should first ask if a compound has a quick path to be tested in patients. For those compounds where the answer is yes, such as in medicinal plant-derived compounds or repurposed drugs, the priority should be in designing a quick clinical study able to generate that early clinical evidence. For those compounds where the answer is no, then we might continue to use checklists to try and minimize risks prior to any clinical study.

When we ask about the possibility to generate quick clinical data, drugs coming from medicinal plants or repurposed assets, where safety has been established, suddenly become exceptional opportunities. 

I don’t know if investors will be able to look at Epidiolex and reconsider what they ask to early candidate drugs. I, for one, will make sure to tell them the story of what marihuana has taught us about drug discovery and about asking one key question: does this compound offer a possibility to generate quick clinical data.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on December 16 2016

How close are we to creating transgenic people?

The journal Nature just released one of the most anticipated breaking news of the last few years: CRISPR gene editing has been tested in a person for the first time.

In my day-to-day work I interact with families that have a child with a genetic disease. These are diseases where the mutation is produced “de novo”, which means that it happened during the production of the baby. The family didn’t carry any mutation and most likely that child is the only one with that exact mutation, or one of a handful world-wide. 

As you can imagine, ever since scientists announced they had found a way to do copy-and-paste in DNA to introduce or to correct mutations I get one question a lot: how close are we to turn that discovery into a therapy for people with genetic diseases?

And despite the breaking news from Nature the answer is still “not that close”.

Let me elaborate on that.

Before being available as a treatment for people born with genetic mutations the CRISPR technology needs to go through roughly four steps:

1. Show that CRISPR can correct mutations in human cells in a test tube. This was the groundbreaking discovery that got us started in an amazing medical development explosion.

2. Show that these genetically-modified cells can be delivered to patients. This is more cell therapy than gene therapy and it is very useful on its own. Likely to be the first path forward for the CRISPR approach.

3. Show that we can actually correct mutation in patients using CRISP. Now we are talking about gene therapy, and for years this will have to be done in clinical trials under controlled conditions.

4. Finally, get approval for gene therapy using CRISPR technology so that we can fix patient’s mutations, effectively creating transgenic people.

What Nature announces is that scientists at Sichuan University have treated a patient with lung cancer with cells that had been reprogrammed using CRISPR before being delivered into the patient. This is step 2.

It had also been done before using other technologies that enable gene-editing, also in diseases where scientists first modify those cells outside the body and then deliver them to the patient, such as in cases of leukaemia or HIV. CRISPR is predicted to be the most powerful (and easy!) of these methods and is likely to be the one that will become a real treatment so reaching step 2 is great news.

At this second stage, these are all “ex vivo” approaches where the gene editing technology is applied to the cells that will be used to treat the patient, instead of using the technology directly in the patient.

The move towards step 3, editing the patient DNA, opens serious safety concerns:could the gene-editing enzymes cut and paste more letters in the DNA that they were intended to? Could they cause unwanted mutations? Because of that, it is likely to happen first in very localized indications such as tumours or retinal disease.

Moving from those localized diseases to more widespread ones will have the same challenges to reach the target organs that “traditional gene therapy” currently has. For the non-initiated, “traditional gene therapy” doesn’t change the patient DNA, instead it uses virus that have been stripped of the virus DNA to infect the patient and deliver a healthy version of the gene that the patients have mutated. At the end the patient has his own genes plus this new therapeutic gene. And that is not easy to do in hard-to-reach organs such as the brain!

Because delivering the CRISPR enzymes will also rely on viral vectors, even if CRISPR was proven today to be totally safe we wouldn’t know how to apply it to the brain tomorrow, since we still haven’t mastered that delivery aspect yet.

For any patient with a neurological condition caused by de novo mutations (so mutations unique to him/her) this is how the things to do list looks like before we can treat him:

1. CRISPR needs to be proven safe in small regions (step 3)

2. We need to find good viral vectors to deliver genes to the brain, which is larger than the eye or blood cells and happens to come inside of a hard box.

3. Those viral vectors also need to be safe.

4. CRISPR will be first used for genetic neurological diseases that are inherited, which means where the same mutation is found in many people.

5. And only after all that has happened we can think of using CRISPR therapy when the target mutation is unique for each patient, which introduces additional questions: can we get approval for the disease and just change the target sequence that the CRISPR uses? Will companies ever manufacture separate ones for individual patients?  etc

So for the patients I work with, who carry de novo mutations that cause neurological diseases, the answer to how close we are to use CRISPR as a therapy for people like them can only be “not that close”. These are probably the last diseases to benefit from the gene editing technology.

In the mean time we celebrate that we have reached step 2 with CRISPR, delivering edited cells to a patient, and keep our eyes on that next frontier: the in vivo experiment, the first patient that has his own DNA corrected using CRISPR in a clinical trial, the first transgenic people.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on November 16, 2016

You are unique, and medicine knows it

When a doctor prescribes you a medication you will be in one out of four groups of patients: 1) you might have experience and no side effects, 2) you might experience efficacy with side effects, 3) you might not have efficacy nor side effects, or 4) lucky you! you might have no efficacy yet suffer from side effects.

And your doctor cannot know in which of the four groups you will be before prescribing the medication. That’s life! And that’s medicine today for most people.

But healthcare is changing very fast, and one of the biggest transformations is a change in focus from treating populations to treating individuals.

These are the three big trends you should know that are transforming medicine from treating many to treating you:

Trend #1: rare diseases are “in”

I’ve been working with rare disease patient organizations for the last 5 years and in this short time I have witnessed how collectively rare diseases have gone from being the awkward cousin that few people wants to talk to at a party to being the focus of most presentations at pharmaceutical conferences.

The FDA first released the Orphan Drug act to incentivize the development of drugs for rare diseases (orphan drugs) back in 1983, so it is not new to grant them designations and special treatment in the drug development process. What is much more recent is the increased focus by the pharmaceutical industry due to a combination of financial, research and technological factors.

Financially, it has become unsustainable for most companies to run clinical trials for common diseases. As we have been successful at developing medicines for some of the common diseases, the low hanging fruit is taken and we are left with some extremely complicated areas such as neurology and psychiatry where clinical trials are not just enormous but also likely to fail in most cases. Only a few big companies have the luxury to face the monster.

And on the research and technological front, the industry has now gained much understanding of the genetic and molecular basis of many diseases, guiding the development of new drugs (target-based) and making feasible the optimization of such drugs (high-throughput screening).

Because most rare diseases are also genetic, they now represent the ideal initial indication in which to test an experimental medicine before jumping into larger, riskier and more expensive diseases.

Rare diseases are the stepping stone, the gateway to larger indication, and in the case of smaller drug discovery companies, rare diseases are also a legitimate area of focus where they can develop medicines without needing to partner with large pharma. Win-win territory.  

All these trends means good news if you have a rare disease, because there has never been a time better than now for rare diseases to attract the interest and the funding from the pharmaceutical industry.

Trend #2: Personalized medicine

We already knew that not everybody responds well to the same medications. What we didn’t know was how to predict if you would be a good responder or not to a new medication before trying it on you.

But technology, and in particular genetics and bioinformatics, have made it now possible in some cases to match the best drug with the best patient.

The oncology field was one of the first ones to step into this territory that is known as personalized or precision medicine. Initially patients where treated based on where the cancer has started, such as the lungs or the ovaries. By after noticing that cancer can result from a number of genetic mutations and developing medicines for the most common mutations we can now match those patients with those drugs regardless of where the tumor first started in their bodies, saving many more lives.

In his 2015 State of the Union address, President Obama announced the Precision Medicine Initiative to revolutionize how we treat diseases with the goal to being able to tailor specific treatments to the unique characteristics of the patient, moving away from a one-drug-fits-all approach. This was not the first step in that direction but it certainly was a landmark that made the personalized medicine official and will hopefully also provide the funding necessary for such a groundbreaking challenge.  Next step is not treating diseases but treating patients.

We are definitely entering into an amazing period in healthcare that will transform how we understand and treat diseases.

Trend #3: Pay only if it works

Value and cost are not synonyms. The pricing of drugs is based not on how expensive they are to produce (cost), but on the savings that they bring to society by making the patient healthier and therefore less expensive (value). As we make the mental transition from treating patients on a one-drug-fits-all to looking into individualized treatments, payers are also considering if we should pay those drugs based on the value they bring to each given patient, that is, if we should not adopt a pay-for-performance pricing system, also called value-based payment.

There are multiple challenges for a pay-for-performance model to be adopted, and probably the most basic one is how to actually measure that performance or value and if pharmaceutical companies, regulators and payers will agree on those measurements and what they mean. Paradoxically, tracking those parameters might turn out to have a cost in direct tests and added healthcare complexity that it could offset the potential savings on medications.

So as science runs forward at full speed to help us find the uniqueness of each individual patient and develop the best drugs to treat them, policymakers and stakeholders need to sort out how we will be able to afford those medicines.

Take-home message:

1. You are unique, and medicine knows it.

2. Orphan drugs and personalized medicine are paving the way for the future of healthcare.

3. We still need to figure out the best way to pay for individualized treatments.

Of course not all is happy news and we are also seeing some questionable trends such as “orphanisation”, which is the division of common diseases into subsets in order to claim orphan drug benefits and higher pricing for drugs that could have treated the common disease. On the flip side, orphanisation might be also the perfect strategy to enable drug development by smaller VC-backed firms. These are all open questions as medicine is transformed from treating many to treating you.

I would like to hear your thoughts in the comments.

Ana Mingorance PhD

Originally published in LInkedIn on October 31, 2016

Impatient patients

One day I sent an e-mail that changed my life. During my training as a scientist, I had learned how to study what goes wrong with the brain and to research how we could fix it. Then one day I sent an e-mail to a patient.

There are about 7,000 diseases that are considered rare because less than 1 in 2,000 people have it. It is not like diabetes, cancer, or Alzheimer’s disease, that we have all heard about. Most people have never heard about these rare diseases, and often not even physicians have heard about them.

Because they are not that common, it often takes many years to find the right diagnosis for these patients, with many left undiagnosed for the rest of their lives. And for the lucky ones that get the right diagnosis, the likelihood of having an approved medication for their disease is 1 in 20. Imagine a 1 in 20 chance of getting a medication for your cancer or your diabetes. A horrible thought, isn’t it? That is the scary world where 350 million people with rare diseases live every day.

But a revolution is changing the way we learn about and treat rare diseases, and it is driven not by progresses in medicine but in technology. Technology, powered by next generation sequencing and bioinformatics, is making the diagnosis of rare diseases much easier and faster. And technology, through the explosion of social media, is helping people with rare diseases and their families connect with other families. And that’s when magic happens.

Five years ago I read an article about a small group of parents that had created a patient organization to find a cure for their children, all diagnosed with a rare neurological condition. They didn’t know how, but they certainly knew what. Andthat is some times all you need to start.

Before finishing the article I sent them an e-mail. I knew about the brain, I knew about drug development, I knew languages and people, and I knew I wanted to help them. That e-mail changed my life. Working with patients changed my life, and not just in the way I now approach drug development and my career. It also changed the way I understand life. Because the only thing harder that being confronted with the reality that there is just a 1 in 20 chance of getting a medication for your disease is when the one with the disease is your child. And many have chosen to get together and do something about it.

That’s why I like to call them impatient patients.

The impatient revolution is already changing the way we do medicine. Patient organizations are becoming central members of the research community and key partners in the development of new treatments. The momentum the impatient patient movement has gained in some fields like rare diseases is unstoppable. And they are not doing it alone. Just like the social media that helped them get started, it is people connecting to people that fuels this movement. Impatient people willing to reach out to patients and their advocates and help create the connections and bridges that they need to succeed. Just like a LinkedIn network, every time we connect with a patient organization we expand their reach, and what starts as a rare disease of few individuals soon becomes a large network of 3rd degree connections that spans across industries and society.

And that’s when magic happens, and why I like to call them impatient patients.

Ana Mingorance PhD

Originally published in LinedIn, October 28 2016