By Ethan Guillen and Zion Maffeo

I’ve written previously about the pricing of PrEP. To recap, currently, only Gilead’s Truvada is approved for use as PrEP, and in the US Truvada can be $14,000 while in developing countries Truvada can be as low as $70. While for many potential PrEP users in the US the cost would be largely shouldered by private or public health insurance or Gilead through access programs, there are still those that are uninsured. And some insurance companies are making PrEP more difficult to obtain due to the high cost. And no matter who pays, public or private, someone pays and it places an additional burden on an underfunded health system.

The short answer: Our best guess is that generic Truvada could be available in December 2017, initially produced by Teva, a major generic producer. Two other generic companies, Lupin Pharmaceuticals and Cipla may follow soon after creating competition that can really bring prices down.

The long answer: The intricacies of the US patent and drug registration system mean that it is hard to know when a generic of a medicine might become available. The patents a company lists as being relevant to a given brand drug may not actually be from the perspective of a generic producer or the patents may be weak and open to challenge by a generic company. Generic companies have an incentive to challenge patents because they can also get a small period of exclusivity when they are the only generic on the market. This all means that the date of expiration of the last patent on a medicine may be relevant but often isn’t.

In this case, Teva has not challenged Truvada directly. In separate litigation they have challenged components of Truvada – tenofovir disoproxil fumarate (also known as TDF) and emtricitibine (also known as FTC). For TDF, they challenged the patents on the drug and reached a settlement which allows Teva to start selling TDF generic in December 2017. In the same case Teva challenged the patents on the combination of TDF/FTC together – which is Truvada. We don’t know the details of the settlement – only the December 2017 date for generic TDF that was noted in the press release. In a separate case, Teva challenged a combination used for HIV treatment TDF/FTC/EFV (EFV is efavirenz; this combination is Truvada plus EFV, a three-in-one combination used to treat HIV). The settlement of that case has not been disclosed.

However, we do know that most companies have stopped pursuing cases against FTC. While we can’t say definitively why, we suspect this is for several reasons: 1) In the non-PrEP, HIV treatment market, there may be a belief that suitable off-patent drugs already exist – i.e. another drug, lamivudine, is considered by many to be interchangeable with FTC for HIV treatment; 2) since the first key FTC patent expires in September 2015, companies may have felt they could use that expiration to bring FTC to market; 3) publicly traded companies must answer to their shareholders. TDF is the key money maker so primary resources were directed toward challenging the TDF patents; and 4) at the time the Teva litigation started, Truvada had not yet been approved for PrEP and so it may have been a lower priority.

Does this mean that Teva will start producing Truvada in December 2017? We do not know Teva’s plans. Given that PrEP represents a significant new market for Truvada beyond its traditional use for treatment of HIV, it would seem to make sense that they would.

Also of note: due to the uncertainty of the settlements, we do not know what the settlement was on the combination patent for TDF/FTC together as one pill. It is possible that initially they would have to be sold as two pills packaged together in a blister pack, but we can’t know for sure due to the secret settlements. (A side note: the secret settlements are likely what is called pay-for-delay deals in which a pharmaceutical company pays cash to get a generic to drop its challenge of a drug. This allows the pharmaceutical company to keep the price high for longer, reaping extra profits. The practice has recently been a point of well-deserved controversy.)

Will the cost drop immediately to developing country-level prices in December 2017? No. There may be a period when only Gilead and Teva are selling Truvada and usually this means a price drop of only 20%. But as more generics enter the market, the price may drop by more than 80%. We don’t know exactly when that will happen but given that both Lupin Pharmaceuticals and Cipla, additional generic firms, followed Teva in reaching settlements with Gilead, it may not be long. We don’t know the details, however, as both settlements were confidential. Mylan, another major generic company, only recently launched a challenge to key Truvada patents meaning it may have an eye on the Truvada market as well.

An additional point: 7 generic companies have already filed abbreviated new drug applications with the FDA indicating that once patent barriers are removed, they are in theory prepared to manufacture Truvada. This is another indication that generic competition for Truvada may be strong, bringing the price down dramatically if many of them do indeed come to market.

What to do? As advocates, now would be a good time to start talking to Teva and other generic companies to find out their plans for generic Truvada. Having more information on what the timelines are for rollout of generic PrEP can help us better understand how to afford to get it to everyone who needs and wants it.

Below you can see charts showing the patents relevant to Truvada and its components, TDF and FTC. A second chart shows recent litigation related to TDF and FTC.

As always, thoughts, questions, and critiques are appreciated.

Special thanks to guest star, Zion, for all the help he provided getting much deeper into certain legal questions than I ever like to do.

Litigation campaigns to invalidate Gilead patents on TDF, FTC, and TDF/FTC.

Campaign Company Length of Campaign ANDAs and coverage Outcome 1 Teva Dec. 12, 2008 – Feb. 13, 2014 90894 – FTC91612 – TDF90894 – TDF Settled under mostly confidential terms. Teva may produce at least TDF in Dec. 2017. 2 Lupin Aug. 16, 2012 – Sep 23, 2014 204131 – TDF204402 – TDF205590 – TFC + Truvada Settled under confidential terms at pleading stage 3 Cipla Aug. 20, 2012 – Jul. 28, 2014 078800 – TDF Settled under confidential terms at pretrial stage 4 Mylan Jun 02, 2014 – current 206436 – FTC + Truvada Ongoing

TDF, FTC and TDF/FTC (Truvada) patents that have been challenged.

Patent Number** Relevant Medicine/Molecule What is patented Expiry of patent Who challenged? 5814639 FTC FTC molecule and its use to treat HIV Sep 9, 2015 Teva, Lupin, Cipla, Mylan – Mylan litigation still active 5914331 FTC FTC esters and their use to treat HIV Jul 2, 2017 Teva 5922695 TDF Synthesis of TDF and the TDF molecule Jul 25, 2015 Teva, Lupin, Cipla 5935946 TDF Synthesis of TDF , the TDF molecule, and oral antiviral use. Jul 25, 2015 Teva, Lupin, Cipla 5977089 TDF TDF molecule and oral use to treat HIV Jul 25, 2015 Teva, Lupin, Cipla 6043230 TDF TDF compounds Jul 25, 2015 Teva, Lupin, Cipla 6642245 FTC Selection of most effective FTC enantiomer* and its use to treat HIV Nov 4, 2020 Teva, Lupin, Cipla, Mylan – Mylan litigation still active 6703396 FTC Selection of most effective FTC enantiomer* and its use to treat HIV Mar 9, 2021 Teva, Lupin, Cipla, Mylan – Mylan litigation still active 8592397 Truvada Combination of FTC/TDF used to treat HIV Jan 13, 2024 Teva, Lupin, Cipla, Mylan – Mylan litigation still active 8716264 Truvada Combination of FTC/TDF with enhanced shelf life used to treat HIV Jan 13, 2024 Lupin

* This appears to be a classic example of pharmaceutical patent “ever-greening.” . Here one enantiomer was identified as particularly effective so methods to isolating that enantiomer were both patented and subsequently listed in the Orange Book. Ever-greening is a general term for a strategy pharmaceutical companies use to keep their medicines patented for as long as possible.

** see Orange Book http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021752&Product_No=001&table1=OB_Rx

Companies Ready to Produce Generic Truvada and Its Individual Components

There are a number of generic companies waiting who have filed ANDAs (the application filed by a company wanting to produce a generic of an existing drug) covering either Truvada or its components but most have not litigated the issue. The complete list of all ANDAs follows. Note: these are companies who are prepared to bring a generic to market once the patent barrier is removed.

For FTC

Name ANDA

Aurobindo Pharm 079188

Matrix Labs 090049

Matrix Labs 090488

Aurobindo Pharm 090513

Teva Pharm 090894

Cipla 090958

Strides Arcolab 091055

Cipla 091168

Hetero Labs Unit 3 201806

Mylan Labs 206042

For TDF

Name ANDA

Cipla 078800

Matrix Labs 079071

Invagen Pharm 090636

Aurobindo Pharm 090647

Strides Arcolab 090742

Teva Pharm 091612

Macleods Pharm 203232

Lupin 204402

For Truvada

Name ANDA

Matrix Labs 090049

Aurobindo Pharm 090513

Teva Pharm 090894

Cipla Ltd 090958

Strides Arcolab 091055

Hetero Labs Unit 3 201806

Mylan Labs 206436

Source: http://fdazilla.com/maude/application